Immunoglobulin allotypes and IgG subclass antibody response to Pseudomonas aeruginosa antigens in chronically infected cystic fibrosis patients.

Chronic Pseudomonas aeruginosa lung infection is the leading cause of death in patients with cystic fibrosis (CF). Poor prognosis correlates with a high number of anti-pseudomonas precipitins and with high levels of IgG2 and IgG3 anti-pseudomonas antibodies. Reports of several highly significant associations between certain Gm (genetic markers of IgG on human chromosome 14) and Km (k-type light chain determinants on chromosome 2) phenotypes and immune responsiveness to various antigens suggest that allotype-linked immune response genes do exist in man. Furthermore correlation between Gm types and IgG subclass levels has been reported. A group of 143 CF patients were investigated (31 non-infected and 112 chronic infected). The IgG subclass antibodies to three different P. aeruginosa antigens (P. aeruginosa standard antigen (St-Ag), alginate and LPS) were determined. Immunoglobulin allotypes were determined by haemagglutination inhibition. Samples were typed for G1m(1,2,3, and 17), G2m(23), G3m(5,21), and Km(1,3). Statistical analysis of our data demonstrate that IgG3 anti-pseudomonas antibody levels and Gm markers are related. IgG3 antibody levels to all investigated P. aeruginosa antigens are significantly higher in sera homozygous for Gm(3;5), somewhat lower in heterozygous sera, and significantly lower in sera homozygous for Gm(1,2,17;21). We suggest that genetic differences between the patients may explain the present differences in subclass patterns.


Cellular immunity in tuberculous pleural effusions: evidence of spontaneous lymphocyte proliferation and antigen-specific accelerated responses to purified protein derivative (PPD).

The kinetics of in vitro cellular proliferation against a PPD of Mycobacterium tuberculosis or streptococcal antigen (streptokinase-streptodornase) was evaluated in pleural fluid and peripheral blood mononuclear cells (PBMC) from patients with tuberculous and non-tuberculous pleuritis. The peak proliferative response to PPD by mononuclear cells from pleural fluid occurred earlier (day 3) in 65% of patients with tuberculosis, a finding not seen in non-tuberculous effusions. Spontaneous lymphocyte proliferation of both peripheral blood lymphocytes and pleural effusion lymphocytes was frequently observed, irrespective of etiology. However, 20 of 21 tuberculous patients manifesting spontaneous lymphocyte proliferation had accelerated kinetics of proliferation to PPD, which was antigen-specific. These results suggest that spontaneous lymphocyte proliferation occurs as a response to antigen stimulation at the site of disease, and is not a non-specific response to inflammation. Furthermore, enhanced reactivity against mycobacterial antigen, manifested by accelerated kinetics of proliferation, has diagnostic potential in patients with pleural effusions.


The significance of serum soluble IL-2 receptor as a marker for active visceral leishmaniasis in Sicilian patients.

Sera from nine Sicilian patients with confirmed visceral leishmaniasis (Leishmania donovani infantum; VL), at the moment of the diagnosis, during the course of the disease and after clinical recovery, were analysed for the concentration of soluble IL-2 receptor (sIL-2R). The results show that sIL-2R is a marker of disease activity, since it is in high concentration at the beginning of infection and returns to the normal range following successful chemotherapy. At the same time of serum analysis for sIL-2R, peripheral blood mononuclear cells (PBMC) of VL patients were stimulated with phytohaemagglutinin (PHA) or antigen and supernatant tested for IL-2 and interferon-gamma (IFN-gamma) production. Data demonstrate that there is an inverse relation between concentration of IL-2 and IFN-gamma in the supernatants and sIL-2R secretion in the sera.


Cellular changes in the bronchoalveolar lavage (BAL) of pigs, following immunization by the enteral or respiratory route.

Normal young pigs were immunized by the oral or aerogenic route with the viable or inactivated lung-pathogenic bacterium Actinobacillus (Haemophilus) pleuropneumoniae. Three weeks later the cellular composition as well as the lymphocyte subset composition of the bronchoalveolar space were examined by BAL. Lymphocytes in the lavage increased significantly, including CD4+ and CD8+ T cells. After oral immunization a dramatic increase of plasma cells and lymphoid blasts was found. Among immunoglobulin-positive lymphocytes IgG+ cells showed the most pronounced increase. For most lymphocyte subsets there was no difference between viable and inactivated bacteria. Oral immunization with a lung-pathogenic bacterium results in increased numbers of lymphocytes in the bronchoalveolar space and might play a critical role in protection against lower respiratory tract infections.


Activation of normal neutrophils by anti-neutrophil cytoplasm antibodies.

Anti-neutrophil cytoplasm antibodies (ANCA) are markers of systemic vasculitis for which a pathogenetic role has been postulated. We have examined the effect of these autoantibodies on the function of normal human neutrophils in vitro. In the presence of ANCA positive sera luminol-amplified chemiluminescence was significantly increased compared to the values seen in the presence of normal or anti-double stranded DNA positive sera (P < 0.01). Five of six ANCA positive F(ab)2 preparations also produced significant neutrophil activation as demonstrated by the chemiluminescence response. This response was totally abrogated by the addition of neutrophil cytoplasm extract, containing the ANCA antigen. Addition of inhibitors to the chemiluminescence system demonstrated that the chemiluminescence response was inhibited by azide and salicylhydroxamic acid and reduced by histidine, suggesting that the chemiluminescence response was due to activation of myeloperoxidase, with generation of singlet oxygen. The chemotactic response to f-Met-Leu-Phe, a bacterial chemotactic peptide, was significantly augmented in the presence of ANCA. Chemotaxis to zymosan-activated serum and chemokinesis was not affected. Phagocytosis was also unaffected. We propose that neutrophil activation and modulation of neutrophil migration by ANCA may be of pathogenetic significance in systemic vasculitis.


T lymphocyte expression of complement receptor 2 (CR2/CD21): a role in adhesive cell-cell interactions and dysregulation in a patient with systemic lupus erythematosus (SLE).

Complement receptor 2 (CR2, CD21), the receptor for both the C3d,g portion of human complement component C3 and the Epstein-Barr virus, has been recently described on peripheral T cells. By using dual stain flow cytometric analysis, we have also observed that a peripheral T lymphocyte subpopulation of normal healthy donors bears CR2 in a range varying from 1.1 to 23.2% (mean 12.6%) of total CD3+ cells. T lymphocytes from nine patients with inactive SLE expressed CR2 in a similar range. Three patients with active SLE were also studied. One of them, having neuropathy and glomerulonephritis, displayed an expansion of the CR2 T cell subpopulation which reached as much as 89% of total CD3+ cells. To examine potential functional roles of T cell CR2, cells from a Jurkat-derived CR2 expressing T cell line were found to bind in vitro to human CR2-, complement-coated K562 cell targets in a CR2- and complement-dependent fashion. Based on these studies, we hypothesize that CR2 might act to increase adherence of T cells to nucleated target cells bearing C3d,g, a function which may be relevant to cytotoxicity or other T cell activities requiring cell-cell interaction.


In vitro induction of IgG anti-DNA antibody from high density B cells of systemic lupus erythematosus patients by an HLA DR-restricted T cell clone.

An HLA-DR restricted T cell clone (26G11) which recognized a lymphoid cell-derived autoantigen associated with DR4 molecule was shown to induce not only autologous but also allogenic DR4+ B cells to produce large amounts of antibodies of the IgG and IgM classes. Using the helper activity of this clone, we investigated the mechanism of anti-DNA antibody production in DR-matched patients with systemic lupus erythematosus (SLE). When cultured with 26G11 cells, B cells from DR-matched normal control subjects produced large amounts of IgM anti-DNA antibody, but did not produce IgG anti-DNA antibody which is thought to have a pathological role in SLE. In contrast, B cells from DR-matched patients with active SLE spontaneously produced a fairly large amount of IgG anti-DNA antibody, and the production was augmented by the T cell clone. Little IgG anti-DNA antibody was produced by the B cells of patients with inactive SLE in either the presence or absence of T cell clone. We next fractionated B cells into low density B (LD-B) and high density B (HD-B) cells by centrifugation on discontinuous Percoll density gradients. IgG anti-DNA antibody was spontaneously produced by LD-B cells of active SLE patients but not by those either of inactive SLE patients or normal controls. On the other hand, although IgG anti-DNA antibody was not spontaneously produced by the HD-B cells of both active and inactive SLE patients, it could easily be induced by their culture with the T cell clone. Our results clearly show the existence of IgG anti-DNA antibody-producing B cells in the peripheral blood of SLE patients irrespective of their disease activity and suggest that autoreactive T cells may play a pathogenic role in SLE through the induction of autoantibody production.


Detection and characterization of immunoconglutinins in patients with systemic lupus erythematosus (SLE): serial analysis in relation to disease course.

The levels of IgA, IgG and IgM immunoconglutinins (IK) were assessed in sera from 20 patients with SLE which were followed for 8-month periods. At the time of the exacerbation, IgG IKs were significantly increased to 226 +/- 90 arbitrary units (mean +/- s.e.m.) compared with both the minimum value of 75 +/- 28 in the SLE patients and with 31 +/- 2 in healthy controls (P < 0.05). There was no difference between SLE patients and controls in the levels of IgM and IgA IKs. Most of the SLE patients in this material showed maximal IgG IK levels before exacerbation, but there was no correlation between the clinical disease index and the levels of IgG IK. The specificity of IgG IKs showed a broad diversity for microtitre-fixed C3b, iC3b, C3c and C3dg. The antibodies were of IgG1, IgG3 and in two patients, IgG4 subclass. IgG IKs were correlated to the C3d/C3 ratio which suggested that the IK responses were secondary to C3 activation. In summary, unlike other conditions associated with complement activation where elevated IgM IKs are common, an increase in IgG IK levels was observed. It is possible that this diverging IK response contributes to the pathophysiology of the disease.


IgA rheumatoid factor in mucosal fluids and serum of patients with rheumatoid arthritis: immunological aspects and clinical significance.

In order to gain insight into the production and clinical significance of IgA rheumatoid factor (IgA-RF) in mucosal fluids of patients with rheumatoid arthritis (RA), we examined tear fluid, saliva and serum from 80 patients with RA. Significant correlations were found between IgA-RF levels in tear fluid and saliva (P = 0.002, r = 0.57), saliva and serum (P < 0.001, r = 0.79), and serum and tear fluid (P < 0.001, r = 0.31). No significant correlations were found between total IgA levels in these fluids. Comparison between circulating and mucosal IgA-RF levels after correction for total IgA, revealed that mucosal IgA-RF levels are on average 2.5 times higher than circulating IgA-RF levels. Analysis of IgA-RF specificity showed that lacrimal and salivary IgA-RF reactivity with various IgG subclasses is similar and differs from serum IgA-RF specificity. These results indicate local production of IgA-RF in salivary and lacrimal glands and support the view of a common origin of IgA-RF producing B cells present in mucosal tissues. Mucosal and circulating levels of IgA and IgA-RF were not associated with tests that quantify tear fluid production. This indicates that mucosal and circulating levels of IgA and IgA-RF in patients with RA cannot be regarded as markers for the development of secondary Sjögren's syndrome.


Suppression of spontaneous murine lupus by inducing graft-versus-host reaction with CD8+ cells.

Splenic CD8+ (Lyt-2+) cells of C57BL/6 mice were injected into semiallogeneic (NZB x BXSB)F1 mice, which spontaneously develop lupus nephritis, in order to examine whether the disease was somehow modified by the occurrence of graft-versus-host reaction. The development of lupus nephritis in the F1 recipients was strongly inhibited and immunopathological parameters such as anti-DNA antibodies, circulating immune complexes (CIC) and splenic immunoglobulin-producing cells (IgPC) were markedly reduced. The injection of CD4+ (L3T4+) T cells into F1 recipients did not result in similar effects. These findings suggest that the development of autoimmune disease could be ameliorated by CD8+ cells responding to MHC class I antigens. The significance of the data is discussed in terms of the treatment of autoimmune diseases.


The putative role of cytokines in the induction of primary anti-phospholipid syndrome in mice.

Antiphospholipid syndrome (APLS) is characterized by thrombocytopenia, thromboembolic phenomena and recurrent fetal loss, associated with anti-cardiolipin antibodies (ACA) and/or lupus anticoagulant. The syndrome may be primary or may be associated with other conditions such as systemic lupus erythematosus (SLE). In this study we induced primary APLS following immunization of BALB/c mice with a human monoclonal ACA (H-3). Analysis of the cytokine profile of the mice with experimental APLS indicated low production of IL-2, IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) by concanavalin A (Con A)-stimulated splenocytes of H-3 immunized mice. It seems that the low levels of IL-3 and GM-CSF have a potential role in the fetal loss of the APLS. Whatever the mechanism of IL-3 and GM-CSF in preventing fetal loss, these results may have therapeutic bearing on the reproductive outcome in women and other species with APLS.


Circulating antibodies to heat-shock protein 60 in Crohn's disease and ulcerative colitis.

Heat-shock proteins (HSPs) are highly conserved immunogenic intracellular molecules that are induced by inflammatory mediators and may induce autoimmune phenomena in vivo. We have recently demonstrated the increased expression of HSP-60 in the colonocytes of patients with ulcerative colitis. To study further the role of HSP-60 in inflammatory bowel disease, we have now measured antibodies to recombinant mycobacterial HSP-65 (a member of the HSP-60 family) in patients with Crohn's disease, ulcerative colitis, healthy volunteers and, as disease controls, patients with confirmed bacterial diarrhoea. In comparison with healthy controls (n = 20; median level of 89 ELISA units; range 24-292), serum IgA HSP-60 antibodies were elevated in Crohn's disease (n = 21; 157; 57-364; P < 0.05) and active ulcerative colitis (n = 16; 188; 58-373; P < 0.01) but not bacterial diarrhoea (n = 10; 106; 51-285). Increased IgA HSP-60 antibody levels in patients with inflammatory bowel disease may occur as the result of HSP release from injured gut epithelium; alternatively, increased intestinal permeability could facilitate mucosal access of luminal antigens and the generation of cross-reactive anti-bacterial HSP antibodies.


Expression of T cell receptors alpha beta and gamma delta in the ileal mucosa of patients with Crohn's disease and with spondylarthropathy.

The expression of the alpha beta and gamma delta heterodimer of the T cell receptor (TCR) was studied in normal human ileal mucosa or in ileal biopsies featuring Crohn's disease or acute and chronic spondylarthropathy-related gut inflammation. With an immunohistochemical technique we demonstrated that the increase of mucosal lymphocytes per mm mucosa in Crohn's disease and spondylarthropathy-related ileitis is exclusively due to expansion of the alpha beta + T cell compartment. In Crohn's disease and chronic ileitis observed in some spondylarthropathy patients the alpha beta + T cells were increased amongst intraepithelial lymphocytes (IEL). The lamina propria lymphocytes (LPL) were augmented in all studied inflammatory conditions. The gamma delta + T cells showed no changes in IEL or LPL and their proportions were not altered. They were evenly dispersed throughout the ileal mucosa and did not seem to participate in the inflammatory process. This study confirms that gamma delta T cells are a distinct subset in the intestinal mucosa. The increase in alpha beta + T cells suggests augmented mucosal antigen handling and involvement of the major histocompatibility complex in the pathogenesis of spondylarthropathy-related gut inflammation and Crohn's disease.


The role of T cells and the effect of hydrocortisone on interleukin-4-induced IgE synthesis by non-T cells.

The role of T cells for IL-4-induced IgE synthesis by peripheral blood mononuclear cells (PBMC) was investigated. The removal of monocytes from PBMC abolished IL-4-induced IgE synthesis. When PBMC were separated into T and non-T cells, non-T cells alone were not able to secrete significant amounts of IgE in the presence of IL-4. Depending on the separation procedure, the reconstitution of non-T cells with T cells prepared by rosetting did not restore IgE secretion, whereas T cells obtained by the use of anti-CD3 antibodies could co-induce IgE formation. However, when the T cells were first irradiated, large amounts of IgE were produced, which strongly exceeded those found in unseparated PBMC cultures. IL-4-induced IgE synthesis was also obtained in co-cultures of formaldehyde-fixed T cells with non-T cells. Furthermore, not only autologous but also allogeneic T cells, which have been irradiated or fixed, could provide the costimulatory effect on IgE formation by non-T cells in the presence of IL-4. Mitogenically pre-activated T cells, however, were not able to support IgE synthesis. Hydrocortisone (HC) potentiated the IL-4-induced IgE synthesis by PBMC and enabled non-T cells to secrete IgE in the presence of IL-4. Adding both HC and T cells led to a marked synergistic effect on IL-4-induced IgE production. We conclude that monocytes are required for the induction of IgE synthesis in PBMC in addition to T cells and IL-4. Our results support the view that the T cell signal is delivered via cognate and non-cognate T/B cell membrane interaction. Furthermore, active and proliferating T cells rather suppress IgE synthesis. Finally, HC appears to be a potent alternative stimulus, which bypasses the necessity for T cells in IL-4-induced IgE formation.


Production of serum amyloid A and C-reactive protein by HepG2 cells stimulated with combinations of cytokines or monocyte conditioned media: the effects of prednisolone.

The hepatic production of the acute phase proteins in response to inflammatory cytokines, and the interaction of corticosteroids within this response, has been the subject of considerable recent research. In this study we have examined the effects of the corticosteroid prednisolone on the production of IL-1 alpha and IL-1 beta by lipopolysaccharide (LPS)-stimulated monocytes, and the ability of the monocyte conditioned media (MOCM) obtained under these conditions to induce human hepatoma HepG2 cells to produce serum amyloid A (SAA) and C-reactive protein (CRP). We also examined the production of SAA and CRP by HepG2 cells exposed to different combinations and concentrations of recombinant human (rh) IL-1 alpha, rhIL-1 beta, rhIL-6, recombinant human tumour necrosis factor-alpha (rhTNF-alpha) and prednisolone. The findings indicate: (i) prednisolone substantially inhibits the production of both IL-1 alpha and IL-1 beta by LPS-stimulated monocytes. The MOCM from prednisolone-treated monocytes induced less SAA and CRP production by HepG2 cells; (ii) IL-1 alpha and IL-1 beta both induced CRP and SAA synthesis by HepG2 cells, but only in the presence of IL-6. IL-1 beta was the more potent inducer for SAA production, but for CRP production IL-1 alpha and IL-1 beta were equivalent; (iii) prednisolone enhances the production of SAA by HepG2 cells, but does not enhance the production of CRP; (iv) TNF-alpha in the presence or absence of IL-6 and/or prednisolone did not induce the production of SAA or CRP by HepG2 cells. These findings offer a tenable solution to a disparate production of SAA compared with CRP in corticosteroid-treated cystic fibrosis (CF) patients.


Secretory IgA are elevated in both saliva and serum of patients with various types of primary glomerulonephritis.

Secretory immunoglobulin A (IgA) was determined by means of an enzyme-linked immunosorbent assay (using as capture antibody an MoAb specific for secretory component) in saliva and serum from 46 patients with IgA mesangial nephritis (IgAGN), 36 with an idiopathic nephrotic syndrome (INS), 30 with an idiopathic membranous nephropathy (MGN) and 40 healthy controls. Secretory IgA levels were elevated in both saliva and serum of patients with primary glomerulonephritis (P < 0.05; Mann-Whitney test) regardless of the histological type of the primary glomerulonephritis. Salivary IgA1 and IgA2 levels were increased in the saliva of patients with IgAGN, INS and MGN (P < 0.05; Mann-Whitney test). The monomeric/total IgA ratio, and interferon-gamma and soluble IL-2 receptor levels, in saliva did not differ between the patients and controls (P > 0.05; Mann-Whitney test). We conclude that the mucosal immune system is activated in forms of glomerulonephritis other than IgAGN.


Isolation and characterization of the tubular basement membrane antigen associated with human tubulo-interstitial nephritis.

The target antigen, a 54-kD glycoprotein (gp54), reactive with sera from patients with anti-tubular basement membrane (anti-TBM) nephritis, was isolated from collagenase-digested (CD) bovine TBM. The purified gp54 was shown to be non-collagenous by amino acid analysis, and to be a unique basement membrane component by amino-terminal sequencing. The nephritogenicity of gp54 was demonstrated by immunizing strain XIII guineapigs with purified gp54, and producing anti-gp54 antibody and tubulo-interstitial nephritis. Anti-gp54 antibody, affinity-purified from sera of patients with anti-TBM nephritis, bound by immunoblotting to 54-kD and, to a lesser extent, 48-kD components of partially purified human CD-TBM. Indirect immunofluorescence showed that gp54 was present in the basement membrane of proximal tubules of the kidneys of normal human, cow, rabbit, guineapig and Brown-Norway rat but not in Lewis rat. Immunoelectron microscopy revealed localization of gp54 along the interstitial side of the TBM and its association with interstitial collagen fibres. These results indicate that gp54 is the nephritogenic antigen involved in tubulo-interstitial nephritis, and is unique in chemical characteristics and localization in the kidney.


Urinary excretion of nitrite and nitrate in experimental glomerulonephritis reflects systemic immune activation and not glomerular synthesis.

In immune-induced glomerulonephritis (gn), glomeruli (gl) synthesize nitric oxide (NO), and urinary nitrite (NO2-) excretion is increased. In mammals on a low nitrate (NO3-) diet, urinary NO3- is a measure of endogenous NO3- synthesis. Excretion is increased after administration of macrophage activators, reflecting induction of NO production. To determine whether increased urinary NO2- gn is due to glomerular synthesis we studied urinary NO2-/NO3- in accelerated nephrotoxic nephritis induced by preimmunization with rabbit immunoglobulin G (IgG), followed by rabbit anti-rat nephrotoxic globulin, and in control rats similarly preimmunized with rabbit IgG, but followed by normal rabbit serum. Both urinary NO2- and NO3- were increased by i.p. preimmunization with rabbit IgG (peak 463 +/- 171 nmol NO2-/60.3 +/- 9.4 nmol NO3-/24 h, P < 0.001 for both NO2- and NO3- compared with preimmunization levels). Repeat immunization with i.v. rabbit anti-rat nephrotoxic globulin (nephritic rats) or normal rabbit globulin (control rats) again increased urinary NO2- and NO3-. There was no statistically significant difference in urinary NO2- and NO3- levels between nephritic rats where globulin had nephrotoxic activity and the control rats injected with normal rabbit globulin, despite increased NO2- synthesis in ex vivo nephritic glomeruli after nephrotoxic globulin (7.9 +/- 1.9 nmol/2000 gl/48 h; controls 3.2 +/- 1.0 nmol/2000 gl/48 h). Thus neither urinary NO2- nor NO3- levels reflect local activation of the NO pathway in glomeruli. As reported for other stimulants, we show here that systemic stimulation with foreign antigen increased NO synthesis.


Immunohistochemical characterization of infiltrating mononuclear cells in the rat heart with experimental autoimmune giant cell myocarditis.

The pathogenesis of giant cell myocarditis remains unclear. Subsets of inflammatory infiltrating cells may reflect the pathogenesis and etiology of the disease. Therefore, we examined subsets of infiltrating mononuclear cells in the heart of the rat with experimental giant cell myocarditis. Lewis rats were immunized with cardiac myosin in Freund's complete adjuvant (FCA). Severe myocarditis characterized by congestive heart failure and multinucleated giant cells were elicited. The lesions were composed of predominant mononuclear cells, polymorphonuclear neutrophils and fragments of degenerated myocardial fibres. The subsets of infiltrating mononuclear cells were investigated using MoAbs against rat CD4+ T cell (W3/25), CD8+ T cell (CX8), B cell (OX33) and macrophage (OX42). By serial examination, bound immunoglobulin could only be found on degenerated myocardial fibres. In this model, most infiltrating mononuclear cells were composed of macrophages and CD4+ T cells. The frequencies of macrophages and CD4+ T cells were 73.7% and 13.8%, respectively. CD8+ T cells were scarce and B cells were rare in the lesions. The frequencies of CD8+ T cells and B cells were 4.5% and 0.4%, respectively. The dominance of macrophages and CD4+ T cells was the constant finding among the sites of the lesions and throughout the course of the disease. These characteristic subsets of infiltrating cells were in contrast to those of murine viral myocarditis which were mainly composed of natural killer (NK) cells and CD8+ T cells. Clarifying the subsets of infiltrating cells in myocarditis may contribute to differential diagnosis of myocarditis between viral and autoimmune types. From this study, the pathogenesis of experimental autoimmune giant cell myocarditis seemed to be closely related to CD4+ T cells and macrophages.


Changes in circulating B cells and immunoglobulin classes and subclasses in a healthy aged population.

The study of 87 adults of different ages, including 15 centenarians, selected for their healthy status, showed that profound changes of humoral immunity occur throughout life. In particular, a statistically significant age-related increase of the serum level of immunoglobulin classes (IgG and IgA but not IgM) and IgG subclasses (IgG1, 2 and 3, but not IgG4) was detected. A parallel age-related decrease of circulating B cells was also observed. The hypothesis of a complex derangement of B cell function and/or compartmentalization with age is put forward, together with the proposal that healthy centenarians (as representative of successful ageing) may be helpful in identifying the physiological age-related modifications of the immune system.


Origin of urinary epidermal growth factor in humans: excretion of endogenous EGF and infused [131I]-human EGF and kidney histochemistry.

1. This study examined (i) whether blood-infused epidermal growth factor (EGF) can pass into urine; (ii) whether infused labelled EGF behaves like endogenous plasma immunoreactive EGF; and (iii) which parts of the human nephron show morphological evidence of EGF synthesis? 2. We infused human [131I]-EGF into a volunteer. After 6 min, only 66% of the plasma counts represented intact EGF. At the end of infusion, the T1/2 of EGF was calculated to be 1.6 min. The tail of the curve lasted for at least another 2 h. The total excretion of the labelled EGF was 2.45% of the infused dose and was proportional to the urine volume. 3. After a water load, the excretion of endogenous EGF was, on the contrary, inversely related to urine volume. 4. Immunohistochemically, human kidneys were not stained by monoclonal anti-EGF antibodies but showed positive in situ hybridization for EGF mRNA in the nuclei of glomerular mesangial cells, distal convoluted tubules and collecting tubules. 5. We conclude that human kidneys synthesize EGF and release it into urine. Plasma-derived EGF constitutes under normal conditions only a small part of the urinary EGF. Contrasting volume-dependency of the excretion of endogenous and [131I]-EGF requires further study and cautions against extrapolating results obtained with labelled EGF to physiological conditions.


Endothelin-3-induced microvascular incompetence and mitochondrial damage in rat myocardium.

1. To determine the possible role of an endothelin in the development of postischaemic microvascular incompetence, isolated buffer-perfused rat hearts were perfused with endothelin-3 (ET-3) in phosphate buffer. 2. ET-3 produced a reduction in coronary flow rate, heart rate and arrhythmia. There was a marked reduction in the density of competent capillaries, and the myocytes showed vacuolation and mitochondrial damage in regions where microvascular incompetence was most severe. 3. These results indicate that ET-3 can substantially reduce microvascular perfusion in the heart and can also cause damage to the myocyte.


Arachidonic acid metabolism in nicotine-treated rats and nicotine-incubated rabbit aortic smooth muscle cells.

1. The changes in plasma levels of thromboxane-B2 (TXB2) and 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha) were examined in rats given 5, 25, 50 or 100 micrograms/mL nicotine in drinking water for 10 days. 2. The effect of nicotine on prostacyclin (PGI2) synthesis from endogenous arachidonic acid by cultured rabbit aortic smooth muscle cells was also studied. 3. Plasma levels of TXB2 were increased dose-dependently by treatment for 10 day with nicotine. 4. 6-Keto-PGF1 alpha values were lowered dose-dependently, both in the plasma of nicotine-treated rats and in rabbit aortic smooth muscle cells incubated with the alkaloid. 5. The results suggest that endogenous synthesis of thromboxane-A2 and PGI2, as reflected by TXB2 and 6-keto-PGF1 alpha levels, respectively, is influenced by nicotine treatment. These findings may be related to cardiovascular diseases associated with cigarette smoking, but further studies are needed.


Angiotensin-converting enzyme inhibition causes deterioration in renal function in one-kidney Goldblatt hypertensive rats with and without renal arterial stenosis.

1. The renal and hypotensive effects of a new angiotensin-converting enzyme (ACE) inhibitor, cilazapril, were evaluated in 18 one-kidney, one-clip Goldblatt hypertensive rats (1K1C), 10 one-kidney normotensive rats (1K) and eight 1K1C rats with acute unclipping (1KU). Cilazapril was infused intravenously (25 micrograms/kg per min) into anaesthetized rats, and the arterial blood pressure (BP) and renal clearance of rats were measured. 2. In 1K rats, cilazapril reduced BP from 123 +/- 4 to 117 +/- 4 mmHg (P < 0.05), and produced diuresis, natriuresis and kaliuresis without significantly changing glomerular filtration rate (GFR). 3. In 1K1C rats, cilazapril significantly reduced BP (from 157 +/- 5 to 143 +/- 6 mmHg; P < 0.05), GFR (14.4 +/- 6.7%), urine flow (27.1 +/- 8.5%) and sodium excretion (39.4 +/- 7.4%). Mechanically graded reductions of renal arterial pressure alone also produced parallel decreases in GFR and renal excretory function. 4. In 1KU rats, removal of the renal arterial clip significantly decreased BP and increased renal function. Subsequent infusion of cilazapril further reduced BP and urinary excretions of sodium and water but did not significantly change GFR. 5. These results suggest that the renal function of the 1K1C hypertensive model is pressure-dependent, and that ACE inhibitor exerts a mild antihypertensive effect but causes a pressure associated reduction in renal function. Furthermore, the detrimental effect of ACE inhibitor on the residual kidney persists after acute surgical correction of the stenosis.


Response of plasma renin-angiotensin system to a single captopril administration in patients receiving long-term treatment with captopril.

1. The responses of angiotensin II (AII), AIII, aldosterone and plasma renin activity (PRA) to a single dose of captopril were investigated in hypertensive patients receiving long-term (more than 1 year) captopril therapy (CT patients) and compared with those of non-treated hypertensive patients (NT patients). 2. Baseline levels of AII and aldosterone were significantly lower in CT patients than in NT patients. AIII tended to be lower and PRA was slightly higher in CT than in NT patients, but these differences were not significant. 3. A single administration of captopril (50 mg orally) significantly decreased plasma levels of AII, AIII and aldosterone as well as blood pressure in both CT and NT patients. 4. These results demonstrate that chronically repeated administration of captopril to hypertensive patients effectively reduces the daily blood pressure and concomitantly the plasma AII level to acceptable levels in patients with no experience of ACE inhibition.


In vivo and in vitro effects of atrial natriuretic peptide on renin release.

1. This study investigated the effect of atrial natriuretic peptide on renin release from the kidney. The in vitro direct effect was examined in the animal experiment using renal cortical slices of rat, and the in vivo effect was observed in the human infusion study. 2. In the in vitro experiments, alpha-human atrial natriuretic peptide (alpha-hANP) ranging 10(-9) to 10(-6) mol/L did not change the basal renin release rate from the renal cortical slices (-9% at 10(-6) mol/L, NS). Isoproterenol (10(-6) mol/L) increased renin release by 40% (P < 0.001), whereas angiotensin II (10(-6) mol/L) suppressed it by 48% (P < 0.001). However, alpha-hANP did not affect the stimulative effect of isoproterenol or the inhibitory effect of angiotensin II. 3. Also in the human study, infusion of 25 ng/kg per min alpha-hANP failed to change the plasma renin activity in normotensive subjects (-4%) or patients with essential hypertension (+5%), or even in patients with raised renin levels such as renovascular hypertension (+10%) or congestive heart failure (-13%). 4. These results put forth negative views on the direct involvement of atrial natriuretic peptide in renin release from the juxtaglomerular apparatus.


Mechanism and prevention of chronic colonic inflammation with trinitrobenzene sulfonic acid in rats.

1. The role of prostanoids in experimental colitis with trinitrobenzene sulfonic acid (TNBS) in rats was investigated. The effects of cyclosporine A (CsA) on the development of experimental colitis were also examined. 2. Five kinds of prostanoids were detected in rat colonic tissue by high performance liquid chromatography. These were 6-keto-prostaglandin (PG) F1 alpha, PGF2 alpha, PGE2, PGD2 and thromboxane B2. 3. In TNBS-induced experimental colitis, all prostanoid concentrations except PGD2 increased, although the time courses differed from each other. 4. Medication with indomethacin markedly reduced prostanoid concentrations in TNBS-induced colitis. However, indomethacin did not show any effect on damage scores. 5. Cyclosporine A reduced damage scores 14 days after TNBS treatment, and the protective effects were observed, whereas CsA did not affect colonic tissue prostanoid concentrations. 6. Prostanoids might be produced secondarily in the genesis of TNBS-induced colitis, although they may attenuate the inflammatory response. It was also suggested that CsA was likely to have therapeutic effects on experimental colitis by inhibiting the immune reaction with TNBS, which induced the chronic inflammation.


Different biventricular remodelling of myosin and collagen in pulmonary hypertension.

1. To clarify the metabolism of contractile and non-contractile proteins of the ventricles during the development of right ventricular hypertrophy (RVH) and accompanying congestive heart failure (CHF) in response to a pressure overload, monocrotaline was injected subcutaneously into Sprague-Dawley (SD) rats. Myosin isoenzymes (MIE) were analysed by pyrophosphate gel electrophoresis under non-dissociating conditions. Acid-soluble collagens were analysed by an improved, noninterrupted sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE). Tissue collagen content was also measured after the estimation of hydroxyproline concentration in tissues. 2. Monocrotaline induced RVH, but not left ventricular hypertrophy, at 2 weeks after the injection of monocrotaline, with severe RVH with CHF present at 4 weeks. In the right ventricles (RV) treated with monocrotaline, MIE shifted significantly from V1 to V3 at 2 weeks. The shift of MIE was more pronounced at 4 weeks. The proportion of type III collagen increased significantly compared with controls at 2 weeks. At 4 weeks, the proportion of types III and V collagens increased significantly compared with controls. 3. In left ventricles (LV) treated with monocrotaline, a similar but less remarkable shift of MIE was observed without remodelling of collagen types at 2 and 4 weeks. The concentration of collagen in either the RV or LV treated with monocrotaline showed no significant changes at 2 and 4 weeks compared with controls. 4. These results demonstrate a remodelling of the contractile and non-contractile proteins during the development of RVH and accompanying CHF, and provide evidence for changes in protein metabolism of the counterpart of RV (i.e. the LV). These results may provide important insights into the pathophysiology of adaptive or non-adaptive cardiac hypertrophy in response to a pressure overload.


Soluble interleukin-2 receptor levels in lupus nephritis.

Soluble interleukin-2 receptor (IL-2R) levels were measured and correlated prospectively with clinical, histologic and serologic findings over a 9-month period in 62 lupus patients. Initially, 39 patients had clinical nephritis and 23 patients did not have nephritis. The 62 lupus patients has significantly higher IL-2R than 15 normal controls, most of this difference attributable to patients with nephritis. During lupus nephritis flare 9 of 10 patients showed significant elevations of IL-2R while only 6 of the 10 patients showed either elevation of anti-DNA antibody or decrease in CH50. During disease remission or stable clinical activity changes in IL-2R levels paralleled changes in anti-DNA antibody and CH50. Nephritis patients with cellular proliferative histology had significantly higher IL-2R levels than those with membranous or mesangial nephropathy. IL-2R correlated strongly with histologic activity and chronicity indices, IgG and C3 deposition whereas anti-DNA antibody and CH50 levels did not. IL-2R levels did not correlate with serum creatinine suggesting that elevations of IL-2R were not simply due to decreased clearance. These observations suggest that serum IL-2R level is a useful marker of disease activity in lupus nephritis and may serve as a helpful adjunct in management of this disorder.


Detection and clinical usefulness of urinary interleukin-6 in the diseases of the kidney and the urinary tract.

Interleukin-6 (IL-6) plays a key role in inflammatory and immune responses in the host. In the present study, the IL-6 activity in urine from patients with various renal diseases was examined to elucidate the pathological and clinical significance of urinary IL-6. In patients with mesangial proliferative glomerulonephritis (mes-PGN) including, IgA nephropathy, the urinary IL-6 activity tended to increase with the progression of mesangial hypercellularity. In four patients with IgA nephropathy, urinary IL-6 activity increased markedly but transiently during episodes of acute exacerbation associated with upper respiratory tract infection. In addition, it was demonstrated that urine from patients with other types of PGN such as poststreptococcal acute glomerulonephritis and membrano-proliferative glomerulonephritis contained large quantities of IL-6. However, the levels of urinary IL-6 activity were almost within the normal range in non-proliferative glomerular diseases such as membranous nephropathy, minimal change nephrotic syndrome and lupus nephritis (WHO class I and V), non-glomerular bleeding and orthostatic proteinuria. It should be noted that a marked increase in urinary IL-6 was often observed in the patients with urinary tract infection. These results indicated that IL-6 in urine might be derived from various types of cells participating in inflammatory reactions not only in the renal parenchyma but also in the urinary tract.


A prospective study of urine and serum myoglobin levels in patients with acute rhabdomyolysis.

Serum and urine myoglobin levels, measured by radioimmunoassay, were determined prospectively in eight patients with acute rhabdomyolysis, within 24 hours of admission. Five patients had urine myoglobin concentrations greater than 1,000 ng/ml (normal < 5 ng/ml); four of these patients subsequently developed acute renal failure. In three patients whose urinary myoglobin levels ranged from 19 to 275 ng/ml, acute renal failure did not occur. This difference in the occurrence of acute renal failure between the two patient groups was statistically significant (p < 0.05). Mean peak serum creatinine was significantly higher in the patients with high urine myoglobin (6.4 +/- 1.3 mg/dl) compared to those with low urine myoglobin (2.2 +/- 0.3 mg/dl), p < 0.02. There was no statistical correlation between level of serum creatine phosphokinase and serum or urine myoglobin, although the serum and urine myoglobin levels correlated well with each other. These findings suggests that among other factors, urine myoglobin may need to reach a critical level in order for myoglobinuric renal failure to ensue.


Traumatic rupture of the urinary tract in a patient presenting nephrogenic diabetes insipidus associated with hydronephrosis and chronic renal failure: case report and review of the literature.

We report the case of a 34-year-old Japanese man suffering from a nephrogenic diabetes insipidus (NDI) associated with bilateral hydronephrosis, hydroureters and enlarged trabeculated bladder without obstruction. He also presented with chronic renal failure which has rarely occurred in similar cases. The patient was admitted after a traumatic rupture of the left urinary tract which had never been described until now in NDI. He was treated successfully by transient peritoneal and vesical drainages. This paper focuses on the very rare complication of chronic renal failure secondary to hydronephrosis in cases of NDI. The literature of this association is reviewed.


Circulating and excreted forms of atrial natriuretic peptide in healthy subjects and patients with renal diseases.

The immunoreactivity of plasma and urine atrial natriuretic peptide (ANP) was measured in patients with renal disease and in healthy volunteers. The molecular forms of ANP in these subjects were estimated by gel permeation chromatography and reverse phase high performance liquid chromatography. No significant increase in plasma ANP was observed in patients with nephrotic syndrome or non-oliguric chronic renal failure compared to healthy volunteers. However, plasma ANP levels were significantly increased in patients on hemodialysis (normal 18.6 +/- 11.4 fmol/ml; hemodialysis 91.2 +/- 69.9 fmol/ml, p < 0.01). Chromatographic analyses revealed that plasma ANP consisted of only alpha-ANP or combined alpha- and gamma-ANP in healthy volunteers and in nephrotic patients, whereas beta-ANP frequently appeared in the plasma of both dialyzed and non-dialyzed chronic renal failure patients. Excreted forms, except in subjects free from renal disease where gamma-ANP may serve as a potential marker of glomerular injury in humans.


Thyrotropin-releasing hormone: pharmacokinetic and pharmacodynamic properties in chronic renal failure.

The pharmacokinetics of thyrotropin-releasing hormone (TRH) were determined following a single i.v. administration in ten patients with chronic renal failure (CRF) maintained on chronic hemodialysis and in six normal subjects. A TRH-test (200 micrograms) was performed in all subjects on nondialysis days and was followed by sequential venous blood sampling at 0, 2, 5, 10, 20, 30 and 60 min. Plasma TRH and serum concentrations of TSH, T4, FT4 and T3 were measured by specific and sensitive RIA's. Serum thyroid hormone concentrations were lower in the hemodialysis patients than in the normals (p < 0.001). Basal TRH and TSH levels were similar in patients and in controls, however, a blunted response of TSH to TRH in CRF (3.8 +/- 2.4 vs. 11.2 +/- 2.6 mU/l, p < 0.001) was observed. Mean peak TRH concentrations (Cmax) were 34.445 (11.085, SD) fmoles/ml in CRF and only (13,400 (1.020) in the normals 2 min after TRH administration (tmax). The mean elimination half-life (t1/2) of TRH was 16 min in CRF and 6.5 min in normals (p < 0.001). The metabolic clearance rate (MCR) was markedly lowered in CRF, 58.3 (19.1) compared to normals (82.2 [15.3] l/m2/day, p < 0.001). The area under the plasma concentration-time curve (AUC) was 57.529 (28.562) fmoles.ml-1.min in CRF and 37.339 (5.026) (p < 0.005) in normals. These findings indicate that the pharmacokinetic properties of TRH are impaired in CRF. The kidney might be an important catabolic organ for exogenous TRH. Dosing schedules of TRH require possible adaptation to renal function.


Impact of dialysis modality on body composition in patients with end-stage renal disease.

Loss of muscle mass and altered body fat distribution (i.e. increased central fat stores in the presence of normal peripheral fat stores) have been reported in patients on hemodialysis (HD), when compared to normal volunteers. Whether treatment of end-stage renal disease (ESRD) with continuous ambulatory peritoneal dialysis (CAPD) would alter body composition in a different manner than HD is unknown. To answer this question, two groups (n = 11 each) of male patients with ESRD (matched for age, residual renal function, body weight and body height as well as physical activity) were studied. Muscle mass and body fat distribution were assessed using computed tomography. Mid-thigh muscle area, peripheral and central fat stores were similar between the two groups of dialysis patients. In both patient groups muscle mass and fat stores were independent of duration of dialysis, age, daily protein intake and residual renal function. In CAPD-patients mid-thigh muscle area was correlated with plasma albumin (r = 0.56, p < 0.05), while serum cholesterol level was correlated with mediastinal fat area (r = 0.81, p < 0.01). The present results indicate that both treatment modalities of ESRD (HD vs CAPD) result in similar changes of body composition. Despite continuous glucose loading in CAPD-patients, neither central nor peripheral fat stores are increased in these subjects compared with HD treated patients.


Surgical treatment of hemodialysis-related shoulder arthropathy.

Thirteen patients with hemodialysis-related shoulder arthropathy were treated either with arthroscopic synovectomy or with open surgery. Arthroscopic synovectomy was performed in eight patients who had shoulder pain, shoulder immobility or both but did not have cystic bone lesions. The therapy was effective for pain relief and improvement of shoulder function for six months but in 12 months the shoulder pain reappeared in most of the patients. Open surgery was done in 5 patients who, in addition to shoulder pain and immobility, had humeral head bone cysts. Resection of the deposited mass on the biceps tendon sheath, of hypertrophied synovium and bursa as well as curettage of cysts and calcium hydroxyapatite ceramic implantation were performed. The therapy was effective for pain relief throughout the follow-up period (12 months). No adverse effects were noted for either procedure. Resected specimens of the synovia contained amyloid as indicated by a positive Congo-red stain by light microscopy and the presence of amyloid fibrils by electron microscopy. Deposition of amyloid in the biceps tendon sheath, synovium and bursa and invasion of the humeral head by amyloid were observed upon open surgery. The results suggest that the resection of deposited material induces the improvement of the shoulder arthropathy.


Patient selection for assisted reproduction.

Patient selection is a critical factor in influencing results in assisted reproduction. Patients should be assessed individually in terms of all relevant fertility factors including age, duration and aetiology of infertility and psycho-social attitudes so that an approximate prognosis of their management can be made. Restrictive criteria for patient selection will enhance a programme's results but at the expense of depriving some couples of their only chance of conception. The best overall management of each individual infertile couple should always remain the main criteria for selection into a particular assisted reproduction programme.


In vitro fertilization in the natural cycle.

In vitro fertilization in the natural or spontaneous reproductive cycle was first described by Edwards and his colleagues in 1980 following the birth of their first natural cycle IVF baby 2 years earlier. Many groups attempted to follow their lead but it was almost ten years later that the next publication of success appeared (Foulot et al, 1989). The concept of IVF in the natural cycle is particularly attractive and so in 1987 our group also started evaluating the technique. Initial success in the patients with tubal lesions was not translated to patients with other infertility indications. Unfortunately the technique as initially developed was relatively inefficient with significant procedural losses at each stage. Over the succeeding four years a number of changes have been introduced and the efficiency considerably improved. Although these changes have improved take-home baby rates, overall pregnancy rates per embryo have not altered and are still lower than spontaneous in vivo pregnancy rates. It is likely that in the future, with current developments in culture techniques and greater understanding of gamete biology, this situation will change significantly.


The role of treatment with growth hormone in infertile patients.

The reality of the interaction of GH and its mediator, IGF-I, with gonadotrophins is now established. The results of these studies and others have obvious implications, both physiologically and clinically. Co-treatment with GH augments the gonadal response to gonadotrophins, and it seems to be of particular value in patients who are poor responders to gonadotrophin treatment and who have pituitary hypofunction induced surgically, idiopathically (hypogonadotrophic hypogonadism) or medically (treatment with GnRH analogues). There is conflicting evidence as to whether the observed effect of GH is exerted directly on the ovary or mediated through IGF-I. Treatment with GH causes a distinct increase in serum IGF-I concentrations, which correlate with, but are always higher than, follicular fluid levels, suggesting that GH stimulates hepatic production of IGF-I and that the effect on the ovary is endocrine. Further research will, hopefully, clearly define the precise therapeutic role of GH in the induction of ovulation, the selection of the most appropriate group of patients to be treated, and the minimum dose of GH needed to sensitize the ovary. Further studies are also needed to explore the action of GH and to define the role of IGF-I in the process of follicular development.


Non-Alzheimer non-Pick dementia with Fahr's syndrome.

Five patients with non-Alzheimer non-Pick dementia combined with Fahr's syndrome were studied. Atypical clinical pictures emerged from an evaluation of these cases. Their symptoms and signs could be attributed neither to Alzheimer's disease nor to Pick's disease but to a partial mixture of both. The neuropathological changes were characteristic, and the common findings were as follows: 1) the absence of senile (neuritic) plaques, 2) the widespread presence of numerous neurofibrillary tangles throughout the neocortex, 3) a calcareous deposition of Fahr's type, 4) a circumscribed cerebral atrophy in the temporal or/and frontal lobes, 5) a moderate or severe demyelination and fibrous gliosis in the white matter of the atrophied areas and 6) a mild or moderate neuronal loss in the nucleus basalis of Meynert. These neuropathological changes were not due to Alzheimer's disease nor to Pick's disease. Similar cases reported previously were reviewed.


Trimethyltin poisoning: report of a case with postmortem examination.

A 48-year old woman died six days after intake of an unknown amount of trimethyltin (TMT). Early clinical features were tinnitus, lightheadedness, aggression and episodes of unresponsiveness. She gradually developed coma and died of multiorgan failure. The main pathologic findings were confined to the nervous system which revealed generalized chromatolysis of the neurons in the brain, spinal cord and spinal ganglia. Recent neuronal necrosis, which probably was caused by toxic effect of TMT, was present in the fascia dentata of the hippocampus and in the spinal ganglia. Recent necrosis was also present in the pyramidal cell layer of the hippocampus, cerebral cortex, basal ganglia and Purkinje cell layer of the cerebellum, but some of these changes could have been caused by an anoxic episode shortly before death. Electron microscopy revealed marked accumulation of lysosomal dense bodies and disorganization of the granular endoplasmic reticulum in the neurons. The findings were similar to those described in experimental TMT intoxications. Cytoplasmic zebra bodies, which were described in a previous human case of TMT intoxication, were not observed in the present case.


Vaginal ultrasound in assisted reproduction.

Vaginal scanning of the ovaries and the uterus is a diagnostic and monitoring tool of utmost importance in assisted conception. Although the value of ultrasound for monitoring follicular growth has been questioned, few groups working on assisted conception do not use it. Follicle aspiration under the guidance of vaginal sonography is the method of choice. With such a simple and safe technique available, using laparoscopy for retrieving oocytes for assisted conception cannot be justified. The introduction of ultrasound-guided transvaginal retrograde tubal catheterization has meant that laparoscopic GIFT and ZIFT procedures will probably soon be unnecessary. Vaginal sonography is one of the most clinically important diagnostic instruments in assisted conception.


Cryopreservation of human embryos.

This chapter describes general cryobiological principles and the different methods for cryopreservation of supernumerary human embryos obtained after several procedures for medically assisted procreation. Different factors that influence the performance of freezing and thawing of human embryos are reviewed: the data from international and national surveys of results, the cryopreservation procedures, the stages of embryonic development, the morphological appearance of the cryopreserved embryos, the numbers of embryos transferred, the storage times of embryos in liquid nitrogen, the ovarian stimulation protocols in the IVF cycle and the replacement cycles of cryopreserved embryos. Cryopreservation of embryos circumvents the difficult problem of synchrony between the ovarian cycles of donor and acceptor patients in an oocyte donation programme.


Viability of preimplantation embryos.

Only about 10% of embryos obtained after in vitro fertilization (IVF) are able to implant after transfer in utero. Detecting the viable embryos is therefore the prerequisite condition to increase the overall efficiency of the technique. Zygote and embryo morphology is partly related to their viability. Indeed, fertilized oocytes with a timely fertilization and pronuclear growth, leading to embryos with equally sized blastomeres reaching at least the 4-cell stage about 42 h after insemination, have the best chance of implanting. The metabolic approach, although requiring sensitive microassays, seems promising. Indeed, in a small series 100% of the pregnancies were predicted when the level of interleukin 1-alpha was > 60 pg/ml and the suppressive level (antiproliferative activity using tumour cell lines) was > 20% in the supernatant of transferred embryos. Lastly, invasive assessment of the chromosome status of embryos should allow us in future to discard severely abnormal embryos, thus increasing the success rate of IVF.


Gamete intrauterine transfer.

Gamete intrauterine transfer has been performed at a very limited scale until now. The main target group of patients for such a treatment would be women with infertility due to the tubal factor, but other infertile patients could benefit also, as the procedures reduce incubation time in the laboratory and implies fertilization in vivo. Few studies have been reported from 1982 to 1990 on the transfer of oocytes and spermatozoa directly to the uterus, and only five clinical pregnancies have been achieved. Transfer of oocytes and spermatozoa inside a biodegradable capsule has only been performed in one study comprising 26 cycles with no ensuing pregnancies. A critical evaluation and a status is carried out.


The implantation window.

The implantation window is defined as that period when the uterus is receptive for implantation of the free-lying blastocyst. This period of receptivity is short and results from the programmed sequence of the action of oestrogen and progesterone on the endometrium. Implantation itself is a process that commences with apposition, continues through attachment to trophoblast outgrowth and decidualization. For maximal effectiveness of assisted reproductive technologies in women, it is important to know the optimal time for embryo transfer which implies a need to predict the period of uterine receptivity. At present there are no good markers of, or for prediction of, uterine receptivity. In cycles where endogenous hormonal activity is suppressed or absent, the optimal time for embryo transfer can be easily defined and lies between luteal days +3 to +5, where luteal day +1 is the first day of exogenous progesterone treatment. In the human, it is suggested that blastocyst apposition begins about LH day +6 and is complete by LH +10. Human embryos survive in vitro manipulation well, and the stage of development at which they are placed in the uterus seems less critical than in other species, provided they are at an earlier stage of development than that of the endometrium.


Indications and outcomes of assisted reproduction.

Since 1978 many healthy children have been born after in vitro fertilization and embryo transfer, fulfilling the wishes of many previously childless couples. In vitro fertilization and subsequently developed methods (GIFT, intratubal embryo transfer) have contributed to progress in the diagnosis and treatment of unwanted childlessness. Furthermore these techniques have improved knowledge of ovarian function, fertilization and early embryo development.


[Movement-related cortical potential in patients with cerebellar dentate degeneration].

We reported movement-related cortical potentials (MRCPs) in 11 patients with lesion of the dentate nucleus (Machado-Joseph disease (MJD) 7 cases, dentato-rubro-pallido-luysian atrophy (DRPLA)1, myoclonus epilepsy associated with ragged-red fibers (MERRF)1, dyssynergia cerebellaris myoclonica (DCM) 2), and compared with those of 7 cases of multiple system atrophy (MSA) who were postulated to have mild dentate lesions (striato-nigral degeneration 2 cases, Shy-Drager syndrome 2, sporadic olivo-ponto-cerebellar atrophy 3), and 7 control subjects without any neurological findings. Further we classified the diseases into the following two groups based on the lesion of the dentate nucleus. One was MJD group that had normal or slightly abnormal electroencephalogram (EEG), and the other was DN group (DRPLA, MERRF, DCM) that had markedly abnormal EEG. One of the main findings from this study was smaller slope of the Ns' in the MJD and DN group and normal slope of BP. There was no significant difference in the slope of Ns' between MJD patients and DN patients. This result shows EEG abnormalities have no influence on MRCP recordings. These results suggest that Ns' component may reflect the function in the cerebellar dentate nucleus, and that MRCP is a useful diagnostic method in patients with cerebellar ataxia.


[Central nervous system disorders in myotonic dystrophy--with special reference to neuron-specific enolase, S-100b protein and creatine kinase BB isoenzyme levels in CSF].

In order to evaluate central nervous system disorders in myotonic dystrophy (MyD), neuron-specific enolase (NSE), S-100b protein and creatine kinase BB (CK-BB) isoenzyme were measured using enzyme immunoassay in MyD. Intelligence quotient (IQ) test (WAIS, 17 cases), electro-encephalography (17 cases) and brain computed tomography (18 cases) were examined. In patients with MyD, NSE level was significantly elevated in comparison with 25 age-sex matched control subjects. In some cases of MyD levels of S-100b protein and CK-BB in CSF were elevated. IQ test disclosed intellectual impairment in 70.6% of the patients examined and EEG study demonstrated slowing of basic rhythm in the majority of the cases. On brain CT both enlarged ventricles and dilated sulci were commonly found. The results of the present study suggest that in MyD the CNS is involved not only functionally but structurally as well. Since NSE, S-100b and CK-BB are localized in neuronal and glia cells, their elevated levels in CSF indicate existence of organic lesions in the central nervous tissue in patients with MyD.


[The role of interleukin-6 in Crow-Fukase syndrome].

We measured serum interleukin-6 (IL-6) levels in 14 patients with Crow-Fukase syndrome. Five out of 14 patients with Crow-Fukase syndrome showed high serum IL-6 levels above 10 pg/ml, which was statistically significant in comparison with control subjects with other neurological diseases. Serial studies of serum IL-6 levels in two patients revealed the increase before the exacerbation of clinical symptoms of edema, and pleural or cardiac effusion, and the fall after the treatment by high dose pulsed methylprednisolone. We suggest that serum IL-6 level appears to be a useful marker to predict its exacerbation. Also we performed immunohistochemical study on cutaneous angioma from three Crow-Fukase syndrome patients using anti-IL-6 antibody. The cytoplasm of endothelial cells of cutaneous angioma from two patients was positively stained, which might imply the abnormality of endothelial cells in Crow-Fukase syndrome.


[Central nervous system disorders in patients with myotonic dystrophy--in relation to respiratory dysfunction].

Although central nervous system (CNS) involvement, such as intellectual impairment simulating dementia, in myotonic dystrophy (MyD) has been well documented, the cause of this condition remains unclear. In has been reported that the progressive cases of MyD are often accompanied with respiratory disturbance and sleep apnea syndrome (SAS). We studied the relation between CNS involvement and respiratory disorders in 15 MyD patients. They consisted of 10 males and 5 females with ages ranging from 21 to 58 years (average 46 +/- 8.4 years old). Arterial blood gas (ABG) analysis, respiratory function test, and monitoring of arterial oxygen saturation (SaO2) during sleep were carried out. In some cases abnormal respiration during sleep was analyzed with polysomnography. For an assessment of CNS involvement the following examinations were performed; intelligence quotient (WAIS-IQ); electroencephalography (EEG); brain computed tomography (CT); and cerebrospinal fluid (CSF) levels of neuron-specific enolase (NSE), S-100b and creatine kinase BB isoenzyme (CK-BB) which were estimated by using enzyme immunoassay. ABG analysis demonstrated the presence of hypercapnia (PaCO2 > 45 torr) during wakefulness in MyD patients. During sleep 14 of the 15 patients showed frequent desaturation phenomenon (SaO2 < 90%), indicating the episodic hypoxemia. Polysomnographic study revealed the occurrence of SAS of both obstructive and central types in all the cases examined. IQ test disclosed intellectual impairment in 80% of the 15 patients, and EEG showed slowing of basic rhythm in the majority of the cases. On brain CT both enlarged ventricles and dilated sulci were commonly observed.(ABSTRACT TRUNCATED AT 250 WORDS)


[Alteration of atrial natriuretic peptide in progressive muscular dystrophy with congestive heart failure].

We measured plasma levels of atrial natriuretic peptide (ANP) in 9 patients of Duchenne muscular dystrophy (DMD) and 3 patients of Becker muscular dystrophy with congestive heart failure (CHF). Administration of digitalis, catecholamine and angiotensin converting enzyme inhibitor resulted in decrease of ANP levels as well as improvement of clinical symptoms of CHF and cardiomegaly. Four DMD patients whose ANP levels were more than 200 pg/ml after the treatment of CHF showed poor prognosis. These results suggest that ANP is a useful marker for the treatment of CHF in progressive muscular dystrophy.


[Clinical and neuroradiological studies on orbital myositis and Tolosa-Hunt syndrome].

Tolosa-Hunt syndrome and orbital myositis have common features such as ocular pain, ophthalmoplegia and exophthalmos. Both syndromes are thought to be caused by a granulomatous inflammation involving the cavernous sinus area in the former and the orbital cavity in the latter. The question whether these two conditions represent different presentations of a single disease, or they belong to different entities has not been settled. To address this question, we reviewed our cases having clinical diagnosis of either Tolosa-Hunt syndrome or orbital myositis. Six cases were diagnosed as Tolosa-Hunt syndrome, and 7 orbital myositis. In the thin-slice enlarged orbital CT, hypertrophic and high-density changes of at least one of the extraocular muscles were found in all cases with orbital myositis, but in none of the patients with Tolosa-Hunt syndrome. The age of onset was younger and the duration of the disease before admission was shorter in Tolosa-Hunt syndrome. They responded to steroid therapy better than those with orbital myositis. These findings lead us to conclude that Tolosa-Hunt syndrome and orbital myositis belong to different syndromes, although clinical manifestations have many similarities. Then we studied the relationship between the hypertrophic change of the extraocular muscle and the direction of the oculomotor restriction. For this purpose four additional cases with dysthyroid ophthalmopathy were also studied. We found that the presence of hypertrophic change was frequently associated with the restriction of ocular movement to the direction not only of the hypertrophic muscle but also of the opposite muscle.(ABSTRACT TRUNCATED AT 250 WORDS)


[A case of adrenoleukodystrophy having progressed from the frontal lobes].

A 12-year-old boy was admitted to our hospital in May 1990. Since two years previously, he became restless and could not adapt himself to his new school mates and teacher. He came to refuse going to school, and his intellectual performance rapidly deteriorated, thereafter. During the following two years, he gradually became mutic and incontinent with dystonic involuntary movements, and was admitted to our hospital. Examination revealed melanoderma, mutism, dementia and grossly normal visual and auditory system except for bilateral optic atrophy. Volitional movements were severely limited because of marked truncal and extreme dystonia and spastic paresis. Urinary 17-KS and 17-OHCS were decreased. Serum cortisol did not increase normally on rapid ACTH test. Very-long-chain fatty acids in serum were increased. Serial CTs and MRI demonstrated marked ventricular dilatation and diffuse white-matter lesions involving the frontal lobes, corpus callosum, internal capsules, and less markedly parieto-occipital regions with slight calcification in the optic radiations. Those in the frontal lobes had been visualised in CTs taken 18 months after the onset. School refusal, the initial symptoms of the patient, is one of serious socioeducational problems in Japan. While the majority of children with school refusal might be of non-organic affections, those with apparent mental deterioration and behavioral abnormalities should undergo non-invasive CT or MRI evaluation during the early stage of the disorder. And if diffuse white matter lesions is suggested even in the frontal lobe, the possibility of adrenoleuko-dystrophy should be considered.


[A case of progressive supranuclear palsy dramatically improved with L-threo-3,4-dihydroxyphenylserine].

We report a 67-year-old female with progressive supranuclear palsy (PSP) who dramatically improved when given L-threo-3,4-dihydroxyphenylserine (L-DOPS). This patient developed dysarthria, lack of facial expression, and slowness at age 64. She was admitted to a local hospital, diagnosed as having parkinsonism and treated with antiparkinsonian drugs. Despite this treatment, she had difficulty in turning over in bed and standing up from a seat, and began to fall backward at age 65. One year later, she had trouble in walking due to frequent falls and became bedridden. The patient was admitted to our hospital in July 1991 under treatment with 20 mg/200 mg of carbidopa/L-dopa and 4 mg of trihexyphenydyl hydrochloride per day. Neurological examination revealed masked face, pseudobulbar palsy, and dystonic rigidity of the neck and upper trunk. Eye movements were normal except for impaired vertical saccades and convergence inability. Deep tendon reflexes were generally brisk and the plantar responses were flexor bilaterally. Tests of pulsion showed that her postural reflex was markedly disturbed, especially in retropulsion. Her gait showed severe unsteadiness. Neuropsychological tests showed intellectual impairment, frontal lobe dysfunction, and memory disturbance. Computed tomography showed an atrophic midbrain with prominent enlargement of ambient and quadrigeminal plate cisterns. Single photon emission computed tomography (SPECT) using 123-I-isopropyl-iodoamphetamine demonstrated marked frontal hypoperfusion. L-DOPS was administered at a dose of 100 mg per day and gradually increased up to 600 mg per day over a period of five weeks, while carbidopa/L-dopa and trihexyphenidyl hydrochloride were continued as on admission.(ABSTRACT TRUNCATED AT 250 WORDS)


[A case of "syndrome of progressive muscle spasm, alopecia, and diarrhea (Satoyoshi)" treated with steroid pulse therapy].

A 20-year-old man was admitted to our hospital because of generalized muscle cramp with pain. At the age of 12 years, he began to have painful muscle cramps in calf muscles, which gradually extended to all limb and truncal muscles and became more severe and frequent. He also had diarrhea and mild hair loss. On admission he had mild baldness, left shoulder deformity, and hypertrophic muscles. Muscle cramps were observed especially in the extremities. Routine laboratory studies revealed moderately high serum CK and low IgG levels. He had been treated with several muscle relaxants and antiepileptic drugs, but with no favorable effect. During his admission he received high-dose intravenous methylprednisone of 1000 mg/day for three days, followed by oral prednisolone tapered over 4 weeks. Soon after the initiation of the treatment, painful muscle cramps were gradually decreased and his activity of daily life apparently improved. In conclusion steroid pulse therapy is a useful treatment for patients who are not responsive to dantrolene sodium administration, and the effectiveness suggests that a certain autoimmune mechanism plays a role in pathogenetic mechanism.


[Chronic inflammatory demyelinating polyneuropathy--an electrophysiological and histological study of the ulnar nerve from a case with intractable persistent conduction block].

We report a 71-year-old male with CIDP, in whom complete motor conduction block persisted for more than several years. Corticosteroid and plasma therapy showed little effect to his weakness. He died of pneumonia. The ulnar nerve in which complete conduction block had persisted was taken out immediately after death and studied with conventional histological and morphometrical techniques. In the transverse section, many thinly-myelinated fibers and some cluster formations were confirmed. Active axonal degeneration was scarce. Myelinated fiber density was 7,417/sgmm. Fiber diameter histogram showed a two-peaked normal distribution. It is thus concluded that demyelination with little axonal degeneration can be the main pathological process causing intractable weakness and poor prognosis of CIDP. Low CMAPs should not lead to therapeutic nihilism, because it may simply be caused by demyelination without exonal degeneration in CIDP.


[Necrotic plaque formation in a case of frontal lobe multiple sclerosis].

We reported an unusual case of multiple sclerosis (MS), clinical manifestations and neuroimagings of which were restricted to the frontal lobes and Gd-enhancing plaques on MRI later changed to necrotic lesions. A 36-year-old previously healthy man developed behavioral changes without any other neurological manifestations in a few weeks. Findings of magnetic resonance imaging (MRI) together with visual evoked potentials pointed to MS and corticosteroid pulse-dose therapy was initiated. Despite fairly uneventful, but rather delayed clinical recovery, repeated MRI disclosed rows of multiple, periventricular plaques localized to the bilateral frontal white matter and indicated the majority of lesions were not those of demyelination but necrosis. Frontal lobe syndrome is rarely encountered as a sole manifestation and rates only a few percent of MS cases in the literature. We speculated on the pathogenesis of necrotic plaques in this particular case; tumor necrosis factor, interleukin-1 and other cytokines that are known to be accompaniments of inflammatory cell infiltrates and activated glia in MS may ultimately destroy the CNS tissue, if the inflammation is not readily controlled. It is not certain, however, that what are determinants of demyelination and what drives further to the devastating tissue necrosis. Despite the uncertainty, this case indicates a necessity of immediate institution of adequate immunosuppressive therapy when neuroimaging study indicates active inflammation and openings of the blood-brain barrier in demyelinating plaques.


[Unusual pathological ocular movement caused by dysfunction of the saccade generation mechanism].

We describe a patient with abnormal ocular movement, probably due to dysfunction of saccade generation mechanism in the lower pons involving the omnipause neuron and a feed-back circuit. A 26-year-old man had fever, mild headache and sore throat for a few days and also noted unstable gait and diplopia. These symptoms subsided, but he noticed oscillopsia about 2 months later. On admission in our hospital, the neurological examination revealed no abnormalities except for abnormal eye movements, which were induced by voluntary or involuntary ocular movement and lasted for a few minutes. The abnormal ocular movement was irregular in direction, amplitude and rhythmicity, and the voluntary and involuntary ocular movements could not be elicited during the period of this abnormal ocular movement. The abnormal ocular movement completely disappeared for about 1 hour by intravenous injection of TRH. At this time bilateral mild abducens palsy was demonstrated by EOG examination. The abnormal ocular movement in this patient, which has nerve been reported in the literature, was considered to be due to a disinhibition of excitatory burst neuron (EBN) caused by the dysfunction of omnipause neuron, and possibly due to a delay of feed-back information of saccade to the EBN.


[Spinal cord sarcoidosis--diagnostic value of Gd-enhanced MRI].

A 50-year-old man was admitted because of slowly progressive myelopathy for the last ten months without a correct diagnosis. The CSF showed mild pleocytosis (predominantly mononuclear cells) together with elevated protein content. MRI findings after administration of Gd-DTPA were characteristic: diffuse swelling of the lower cervical and upper thoracic cord, multiple patchy enhanced areas in the cord parenchyma adjacent to meninges, and linear meningeal enhancement. Based on these observations, a scalene node biopsy was performed, yielding a pathological diagnosis of sarcoidosis. The clinical neurological signs as well as the abnormal MRI findings of myelopathy were considerably improved after prednisolone therapy. An early diagnosis of spinal cord involvement in sarcoidosis should be established, because it is treatable in the earlier stage. Mild inflammatory evidence in CSF and Gd-enhanced MRI findings may be the cardinal clues to the diagnosis.


[Botulinum toxin trial for spasticity].

We treated three patients with spastic paraparesis with botulinum toxin (BTX). Two of them had scissors gait reflecting the hypertonus of adductors. In both, an injection of BTX to the responsible muscles improved gait, albeit transiently. The effect was shortlived, probably because increased tonus in non-injected portions compensated for the weakness of injected portions. In the third patient with no abnormality in tonus of the adductors, BTX injection in quadriceps caused a weakness with exacerbation of gait disturbance. We concluded that, in selected cases, BTX therapy is useful for spastic paraparesis to alleviate hypertonicity of the adductors.


[Transverse myelopathy in a patient with systemic lupus erythematosus associated with positive anticardiolipin antibody--a case report].

A 52-year-old woman who developed acute transverse myelopathy following systemic lupus erythematosus (SLE) was reported. At the age of 46, she was diagnosed as having atypical psychosis. Neurological examination revealed mild depressive state, paraparesis, diffuse hyperreflexia, hypesthesia below the breasts, and urinary disturbance. Gait was slightly ataxic and Romberg sign was positive. Laboratory study disclosed lymphocytopenia, positive antinuclear antigen, false positive Venereal Disease Research Laboratories flocculation test and prolonged activated partial thromboplastin time. IgG anticardiolipin antibody (aCLA) was positive, whereas IgM aCLA was negative. Cerebrospinal fluid was normal except the elevation of %IgG. Nerve conduction studies were normal and no abnormality was detected in the brain and spinal cord by MRI and CT. We treated her by two series of steroid pulse therapy, which resulted in marked improvement of symptoms and disappearance of aCLA. Before and after the pulse therapy, symptoms were fluctuated in parallel with the levels of aCLA. These findings suggest the relation of aCLA to the transverse myelopathy in SLE. This is the first case report of a good prognosis of myelopathy in a SLE patient who was treated by steroid pulse therapy with the aim of disappearance of aCLA.


[Chlamydia trachomatis infection with symptoms and signs of the central nervous system damage--a case report].

A 32-year-old woman developed myalgia, fever, consciousness disturbance, mental disorder, pyramidal tract signs and meningeal irritation signs at about 2 months after a normal labor. Laboratory examination showed hypopituitarism (decreased ACTH, TSH), renal dysfunction and hypercalcemia. A variety of antibiotics, acyclovir and gamma-globulin failed to improve her symptoms. A diagnosis of Chlamydia trachomatis infection was considered from the elevated antibody titers. In this case, minocycline was very effective. Rarely Chlamydia trachomatis infection involved general organs, including the central nervous system. It was interesting that she had endocrine disorders. We must take a look for Chlamydia trachomatis infection because this infection infrequently involves general organs, including the central nervous system and minocycline is very effective for this infection.


[Strongly succinate dehydrogenase-reactive blood vessels (SSV) in various neuromuscular diseases].

The strongly succinate dehydrogenase-reactive blood vessels (SSV) are shown to have increased numbers of enlarged mitochondria in smooth muscle cells of the vessel wall on electron microscopy. They are seen in biopsied skeletal muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) at high frequency. The present study was done to examine the incidence of SSV in biopsied muscles from various neuromuscular diseases. Among 107 patients with mitochondrial encephalomyopathies (MEM) including 50 with chronic progressive external ophthalmoplegia (CPEO), 7 with myoclonus epilepsy with ragged-red fibers (MERRF), and 50 with MELAS, SSV were seen in nearly a half of the patients, and comprised approximately 24% of small arteries. On the other hand, SSV in 100 patients with various neuromuscular diseases other than MEM were exceptional, and only one of 8 patients with myotonic dystrophy had SSV. These findings suggest that the SSV are induced by functional abnormality of mitochondria in smooth muscle cells, and that an identification of the SSV is an additional crucial evidence to make a pathological diagnosis of MEM.


[Surface anatomy scanning image by MRI in herpes simplex encephalitis].

We present surface anatomy scanning (SAS) image by weighted-summation technique using MRI images in herpes simplex encephalitis. Recently, SAS has been developed as a technique that visualizes brain surface structures. This patient was a 64-year-old male who suffered from aphasia and memory disturbance after herpes simplex encephalitis. He was transferred to our hospital for rehabilitation. Neuropsychological tests showed Wernicke's aphasia and memory impairment. SAS was performed for the purpose of analyzing these neuropsychological deficits, especially the Wernicke's aphasia. In SAS image, sulci were enhanced and gyri were easy to identify clearly. The affected structures disclosed low intensity areas in the entire left temporal lobe, including the superior temporal gyrus. It was clarified that the damage to the left superior temporal gyrus resulted in his Wernicke's aphasia. We think that SAS is very useful for cortical lesion analysis, not only in encephalitis but also in other disorders presenting higher brain dysfunctions.


Laparoscopic versus conventional cholecystectomy. Use of biliary scintigraphy.

Laparoscopic cholecystectomy has become a popular alternative to traditional open cholecystectomy for uncomplicated, acute cholecystitis. At some centers, laparoscopic cholecystectomy is already the more frequently performed procedure. The presence or suspicion of common bile duct (CBD) stones or obstruction may necessitate conventional surgery or additional procedures. This report describes a patient with acute cholecystitis for whom the surgical management changed based on biliary scintigraphy. The demonstration of an unsuspected CBD obstruction by biliary imaging allowed the surgeon to change the initial plan for laparoscopic cholecystectomy to conventional open surgery. Stones in the common bile duct were removed.


Comparison of gallbladder ejection fraction with histopathologic changes in acalculous biliary disease.

This selective retrospective study was undertaken to establish whether the gallbladder contraction (ejection fraction) calculated during cholescintigraphy correlates with the histopathologic changes in the surgical specimen. The medical records of 243 patients who underwent hepatobiliary scintigraphy were reviewed. Of these, 215 patients had cholecystokinin cholescintigraphy and 100 went on to cholecystectomy. The original histologic slides from 67 gallbladders were available and reviewed by a pathologist who graded each specimen based on presence and severity of changes associated with "chronic" cholecystitis. There was no significant correlation between the severity of histopathologic change and cholecystokinin-induced gallbladder emptying.


Tc-99m albumin scintigraphy in the localization of protein loss in the gut.

Scintigraphic localization of gastrointestinal protein loss has been recently reported. A noninvasive method for the localization of protein loss in the gut using Tc-99m labeled albumin seems encouraging and is described here. In six patients studied for protein-losing enteropathy, scintigraphic results of four were positive.


Intraperitoneal bleeding demonstrated by Tc-99m labeled red blood cell scintigraphy.

Tc-99m RBC scintigraphy is known to be useful for the evaluation of gastrointestinal bleeding. The authors describe a patient with a posttraumatic peritoneal tap in whom Tc-99m RBC imaging showed bleeding into the gastrointestinal wall and into the ascitic fluid.


Combined Ga-67 and In-111 leukocyte scintigraphy to characterize a liver mass in a patient with lymphoma.

A 32-year old man with Hodgkin's disease was admitted to the hospital with a liver mass. The primary diagnostic possibilities, infection and lymphoma, require markedly different therapy. The combination of Ga-67 and In-111 white blood cell imaging correctly diagnosed the mass as lymphoma.


Occult aortic arch mycotic aneurysm diagnosed by radiogallium scintigraphy.

Aortic arch mycotic aneurysm, an uncommon cause of sepsis, carries a grave prognosis. Clinical presentations as well as laboratory and radiologic examinations may be noncontributory and often misleading. In a patient with a fever of unknown origin, only the radiogallium study could enable an accurate diagnosis and pinpoint the anatomic localization of the mycotic aneurysm as the cause of fever.


Brain SPECT imaging in progressive aphasia.

Progressive aphasia without dementia is a relatively uncommon neurobehavioral syndrome. The initial presentation of progressive aphasia without cognitive impairment may pose a diagnostic dilemma. The authors report a patient with progressive aphasia. The initial neuro-imaging studies (MRI, CT) were not diagnostically helpful. However, brain SPECT imaging with Tc-99m HMPAO clearly demonstrated a left temporal lobe abnormality. This report discusses the potential clinical usefulness of brain SPECT imaging in the evaluation of neurobehavioral disorders.


Ga-67 citrate accumulation in adenomatous goiter.

An elderly woman with a diffusely enlarged goiter and multiple miliary nodular lesions on chest x-ray showed Ga-67 accumulation in the right thyroid lobe. Histologic findings obtained after total thyroidectomy and open lung biopsy revealed papillary carcinoma in the left lobe with pulmonary metastases and adenomatous nodules in the right lobe. This is the first report of Ga-67 accumulation in adenomatous goiter.


Early and delayed imaging of Tc-99m HMPAO versus Tl-201 in benign and malignant thyroid tumors. Similar uptake but different retention.

The authors performed both Tc-99m HMPAO and Tl-201 scintigraphy in 30 patients with thyroid tumors (21 papillary adenocarcinoma, three solid follicular adenoma, six adenomatous goiter with cystic degeneration). Increased accumulation of both Tc-99m HMPAO and Tl-201 was seen in 14 patients with papillary adenocarcinoma and three with solid follicular adenoma, whereas two patients with papillar adenocarcinoma had low accumulation of both tracers. Of the six patients with adenomatous goiter with cystic degeneration, four had low accumulation of both Tc-99m HMPAO and Tl-201, and one patient had low accumulation of Tc-99m HMPAO only. Iso accumulation (same accumulation as the normal thyroid) of Tc-99m HMPAO was seen in five patients with papillary adenocarcinoma and one with adenomatous goiter. The distribution of Tc-99m HMPAO in the thyroid tumors and normal thyroid tissue was independent of time from 2 to 120 minutes after injection. The results of dynamic studies using Tc-99m HMPAO suggested that the accumulation of Tc-99m HMPAO in thyroid tumors reflected mainly tumor blood flow. The resultant Tc-99m HMPAO images were essentially similar to the Tl-201 images obtained 10 minutes after injection. Tc-99m HMPAO imaging can be a suitable substitute for Tl-201 imaging, and it may possibly be used to estimate tumor blood flow in patients with thyroid tumors.


Localization of Tc-99m DTPA in a chordoma.

The authors report a patient with chordoma that was demonstrated as a photopenic region on Tc-99m MDP bone imaging but that localized Tc-99m DTPA intensely. An explanation for the discrepancy is discussed. Complementary Tc-99m DTPA imaging in the preoperative evaluation of sacral tumors is suggested.


Fracture of the laryngeal cartilage. An incidental finding on bone scintigraphy.

A patient complaining of headaches and bone pain at multiple sites had Tc-99m MDP scintigraphy performed for possible bone trauma after a motor vehicle accident. Bone imaging revealed a small focal increase in tracer uptake in the area of the laryngeal cartilage. There was some reluctance to place a label on this abnormality because the findings were so unusual. The initial diagnosis was a probable fracture of the laryngeal cartilage. Computed tomography of the neck also demonstrated a fracture but correctly localized it to the thyroid cartilage.


Detection of renal artery stenosis by means of captopril renal scintigraphy in patients with multiple renal arteries.

Both captopril renal scintigraphy (CRS) and conventional arteriography were retrospectively evaluated in 64 patients to study CRS efficacy in hypertensive patients with multiple renal arteries (MRA). The presence of MRA was angiographically demonstrated in 9 patients, 7 unilaterally and 2 bilaterally, with a total of 11 kidneys supplied by 2 or more arteries. Overall, 25 MRA were identified and 7 were affected by stenosis of > 50%, causing a reduction of arterial supply in 5 of 11 kidneys. CRS correctly diagnosed all five ischemic kidneys (true positives) and five of six nonischemic kidneys (true negatives); in one case in which perfusion was not reduced, the CRS diagnosis was falsely positive. In the presence of MRA, CRS proved effective in identifying renal artery stenosis of > 50%, involving either one or all the MRA. This study shows that the presence of MRA is not a drawback in the evaluation of renal artery stenosis by means of CRS.


Ga-67 lung uptake in patients with adult respiratory distress syndrome. Association with lung infection and patients' prognosis.

Nine patients with adult respiratory distress syndrome (ARDS) were studied with Ga-67 imaging in search for a site of infection. Different degrees and two patterns of Ga-67 lung uptake scoring in comparison with liver uptake were demonstrated. All patients had diffuse lung uptake, whereas five of them also showed additional focal lung activity. In only one patient was an abdominal focal uptake detected. Chest radiographs of all patients revealed diffuse and focal lung infiltrates that correlated with the Ga-67 uptake patterns. Therefore, Ga-67 imaging was unhelpful in differentiating patients with ARDS with lung infection from patients without lung infection. The intensity of Ga-67 uptake, as expressed by Ga-67 scoring, correlated with the course and outcome of ARDS. Patients exhibiting a high Ga-67 score had long periods of hospitalization and eventually died (four patients), whereas those who had low Ga-67 scores had a short disease course and survived (five patients). It is concluded that Ga-67 imaging in ARDS patients is unable to detect lung infection; however, it may be useful in the assessment of patients' prognosis.


Osteitis pubis, Tc-99m MDP, and professional hockey players.

Three cases of osteitis pubis detected by bone scanning with Tc-99m MDP in professional ice hockey players are presented. This entity is related to mechanical stress and aggravated by forceful contraction of the adductor and rectus abdominis muscles. The signs, symptoms, and laboratory data are relatively nonspecific, as are radiographic findings in the early stage (pubic symphysitis). The use of bone scanning in the appropriate clinical setting aids in diagnosis.


Portal vein aneurysm demonstrated by blood pool SPECT.

Portal vein aneurysms are rare and are occasionally suggested by ultrasound and usually confirmed by invasive angiography. Such a case was diagnosed by scintigraphic studies, most importantly blood pool SPECT, which clearly separates it from hepatic cysts.


Pulmonary scintigraphic findings in children with pectus excavatum by the comparison of chest radiograph indices.

Pulmonary scintigraphy, including Xe-133 ventilation combined with Tc-99m MAA perfusion scans, was performed in 23 children (3 girls, 20 boys, ages: 2-9 years) with pectus excavatum, and the indices from lateral chest radiography were used for comparison. The findings of pulmonary scintigraphy were analyzed as 1) ventilation fractions (VF), and 2) perfusion fractions (PF) between bilateral lungs; and 3) ventilation-perfusion ratios (V/Q ratio) of both lungs. The results showed that 6 of 23 cases had impaired VF, 11 of 23 cases had impaired PF, and 7 of 23 cases had an impaired V/Q ratio in the right and left lung, respectively. The severity of sternal depression in pectus excavatum was shown as certain indices that were obtained on routine lateral chest radiographs. However, no significant correlations existed between the differences in the fractions and the indices. Our results suggest that pulmonary scintigraphy is not necessary for children with pectus excavatum to predict the severity of sternal depression and pulmonary function, because 1) pulmonary scintigraphy is very difficult to perform in children; 2) unnecessary radiation exposure should be avoided; and 3) it is not well correlated with the severity of the depressed sternum.


Regional cerebral blood flow measured with I-123 IMP SPECT in a case of subcortical arteriosclerotic encephalopathy (Binswanger's disease).

N-isopropyl-p-[I-123] iodoamphetamine (I-123 IMP) SPECT studies were performed on a 75-year-old patient who could be clinically classified as subcortical arteriosclerotic encephalopathy (Binswanger's disease). Regional cerebral blood flow (rCBF) was quantitatively measured by a microsphere model, and was diffusely decreased in the whole brain (mean rCBF: 36 ml/100 g/minute). After a ventriculoperitoneal shunt operation, his clinical symptoms were markedly improved, and the improvement was validated by a 32% increase of mean rCBF. However, MRI and CT images showed no significant interval changes before and after the shunt operation. Regional rCBF measurement by I-123 IMP SPECT should be performed and plays an important role in the evaluation of Binswanger's disease.


Portacaval graft patency demonstrated by scintigraphic calculation of portal contribution to hepatic blood flow.

The case presented refers to a cirrhotic patient with portal hypertension in whom a portacaval graft bypass was surgically implanted. The calculation of the portal contribution to hepatic blood flow helped to demonstrate the patency of the graft.


Clinical value of lung scintigraphy with Tc-99m gluconate in distinguishing benign from malignant lung diseases.

One hundred patients were studied with three-phase lung scintigraphy with Tc-99m gluconate. The results showed that there were statistically significant differences between benign and malignant lung lesions in the intensity of accumulation, the blood supply index ratio, and the radioactive uptake ratio. However, no difference was observed between the benign lung lesions and the healthy lungs. Analysis of false negatives and false positives revealed that false negatives had something to do with the cell types of the malignancies, in addition to the relatively small size of the lesions; the false positives were mostly caused by acute inflammation, for which obstructive pneumonitis might be responsible in part. It is concluded that Tc-99m gluconate is tumor-avid and can be used as an agent for positive imaging of lung cancer, because quantitative parameters, blood supply index ratio, and radioactive uptake ratio are more objective in distinguishing malignant lung lesions from benign ones, and are of relatively higher sensitivity and specificity. Thus, lung scintigraphy with Tc-99m gluconate provides an efficient supplementary measure for differentiating between malignant and benign lung lesions.


Explanations and therapies for penicillin failure in streptococcal pharyngitis.

A disturbing trend toward penicillin failure has developed in the treatment of streptococcal pharyngitis in some parts of the United States and abroad. A variety of explanations has been proposed to account for these penicillin-treatment failures. With the resurgence of serious complications from streptococcal infection, successful bacteriologic eradication has regained importance. In communities with a high incidence of penicillin failures, alternative antimicrobials should be considered. Cephalosporins, amoxicillin/clavulanate, and the extended-spectrum macrolides represent logical options under such clinical circumstances.


Cholelithiasis in infants with Down syndrome. Three cases and literature review.

Only four cases of cholelithiasis have been reported in patients with Down syndrome and none in Down syndrome infants. The cases of three Down syndrome infants (all males) with cholelithiasis are reported. Each exhibited different fetal complications, and in each, Down syndrome was diagnosed at birth. Gallstones apparently were congenital (a rarity) in one infant, since they were detected on the first day of life. Cholelithiasis was an incidental finding in another of the infants when, at 12 weeks old, he had renal ultrasonography because of a urinary tract infection. The third infant was 4 months old when sonographic studies revealed a gallstone. Despite the confirmation of cholelithiasis in all three infants, none has since had any signs or symptoms that suggest the need for intervention. Cholelithiasis is probably more common in Down syndrome infants than has been supposed, but whether Down syndrome infants with gastrointestinal (GI) malformations are more likely to have gallstones than are children with similar GI malformations but with normal karyotypes is unknown.