The effect of chlorpromazine on endotoxin-induced uveitis in the Lewis rat. Chlorpromazine (CPZ) has been used extensively in the treatment of psychiatric disorders, and has recently been shown to possess systemic anti-inflammatory properties as well. To investigate the potential effects of CPZ on ocular inflammation, we evaluated its action on endotoxin-induced uveitis (EIU) in Lewis rats. At three different dosage levels, CPZ produced highly significant reductions in the mean aqueous aspirate inflammatory cell counts and histological inflammatory scores as compared to controls treated with vehicle only. Analysis of aqueous fluid demonstrated a similar decrease in protein concentration and phospholipase A2 (PLA-2) activity in the treated animals. The ability of CPZ to inhibit the development of EIU may be related to its properties as a calcium channel blocker and inhibitor of the enzyme phospholipase A2.


Collagenolytic/gelatinolytic metalloproteinases in normal and keratoconus corneas. Cells of keratoconus corneas have been reported to produce higher levels of collagenolytic/gelatinolytic enzymatic activities than do cells of normal corneas. The current study investigates the contribution of 1) specific enzyme gene products, and 2) the degree to which these proteins are present in the activated forms, to the increased enzymatic activities. We demonstrate that two neutral gelatinolytic enzymes, a 66/59 kD form and a 92 kD form, can be directly extracted from both normal and keratoconus corneas. These enzymes are identified as the pro- and activated forms of MMP-2 and as the pro-form of MMP-9, specific members of the matrix metalloproteinase family. Normal and keratoconus corneas show no significant differences in amounts or types of extractable neutral gelatinases, nor in the amounts or types that they synthesize in culture. Furthermore, in both the normal and keratoconus corneas, gelatinases are found primarily in the inactive form. These studies suggest the possible importance of changes in proteinase inhibitor levels to the characteristic biochemical features of keratoconus corneas.


The retinal pigment epithelium induces fenestration of endothelial cells in vivo. Rodent photoreceptor dystrophies are characterized by late stage ingrowth of retinal blood vessels into the retinal pigment epithelium (RPE) where they proliferate. Some of these vessels develop the fenestrated phenotype of the choriocapillaris (CC). To determine if development of fenestrae in these endothelial cells is a function of the duration of time the endothelial cell had been encapsulated by the RPE, we did an ultrastructural morphometric study of these vessels in urethane induced photoreceptor degeneration in Long-Evans rats. Retinas of animals aged 20, 24, 40 and 56 weeks were studied. The fraction of vessel profiles within the RPE that had fenestrated endothelial cells increased from 10% to 90% between 20 to 56 weeks. The average number of fenestrae per vessel increased approximately 25 fold between 20 and 24 weeks but stabilized after that, despite a decrease in the number of vessels present at 56 weeks. A large number of degenerated retinal vessel profiles were seen in the RPE at 40 weeks. These facts support the idea that the presence of the RPE induces endothelial cell fenestrae, and also show that a complex process of remodelling including proliferation and degeneration is occurring in these vessels. Analogies between the basic cell biology of neovascularization occurring in these rodent models and that of proliferative diabetic retinopathy and age-related macular degeneration are discussed.


Retinyl ester hydrolysis in the rabbit lacrimal gland. The lacrimal gland stores retinyl esters which are synthesized by the enzyme acyl CoA:retinyl acyl transferase. Retinol is released from retinyl ester reserves by retinyl ester hydrolase (REH). Since the lacrimal gland secretes retinol, this gland should also contain this enzyme. To identify bile salt-dependent REH activity, rabbit lacrimal glands were homogenized in 0.05 M Trismaleate buffer, and enzyme activity was determined in the tissue homogenate, in the membrane fraction and in the cytosolic fraction by measurement of production of retinol from retinyl palmitate (nmol retinol produced/mg protein/h). In the lacrimal gland, production of retinol was optimal in the presence of 200 mM CHAPS at pH 7. The REH activity in the presence of 1000 microM retinyl palmitate was 2.38 +/- 0.18 nmol/mg/h in the homogenate, 1.13 +/- 0.16/nmol/mg/h in membranes and 3.25 +/- 0.26 nmol/mg/h in cytosol. By comparison, REH activity in rabbit liver was 6.58 +/- 0.75 nmol/mg/h. The REH activity in lacrimal gland was not affected by vitamin A deficiency. These data are consistent with the presence of retinyl ester hydrolase activity in the lacrimal gland and provide further evidence that this gland is adapted for metabolism and secretion of retinol.


The 53kDa polypeptide component of the bovine fibre cell cytoskeleton is derived from the 115kDa beaded filament protein: evidence for a fibre cell specific intermediate filament protein. The 115kDa protein found enriched in the PMCC (plasma membrane-cytoskeleton complex) fraction of the cortex in bovine lens fibre cells is proteolytically processed to a stable 53kDa product. The 115 kDa protein and the 53kDa polypeptide have been purified by a combination of ion exchange and hydroxyapatite chromatography. Tryptic peptide mapping using reverse phase HPLC and subsequent peptide sequencing confirmed that the 53kDa polypeptide is derived from the 115kDa protein. The 53kDa fragment is also a component of the PMCC as well as being a major component of the urea soluble fraction of lens plasma membranes which have been extracted with buffers containing 1M KC1. The 53kDa polypeptide has escaped identification as a breakdown product of the 115kDa protein because it is not recognised by a commonly used monoclonal antibody, R2D2, specific for the bovine 115kDa protein. This result suggests that proteolysis is important in determining the function(s) of the 115kDa protein, and that part of this function is satisfied by the 53kDa protein core. Both the purified 115kDa protein and the 53kDa polypeptide were unable to form either beaded or intermediate filaments on their own but they were able to form short 10nm rods indicative of an intermediate stage in intermediate filament assembly. Comparison ot the assembly properties of the 53 and 115kDa proteins indicate that there are sequences in the 115kDa protein which inhibit in vitro assembly. This is similar to the situation with neurofilament proteins. We suggest that the 115kDa protein is a lens-specific intermediate filament protein.


Cell-specific expression of LBP-32 mRNA in retina and other locations of newborn mouse eye as revealed by in situ hybridization. LBP-32 is a cell surface and cytoplasmic protein which is thought to both mediate cell attachment to laminin and play a role in translation initiation. In the present study, antisense RNA for LBP-32 was used to document its cellular mRNA expression pattern in newborn mouse eye. In situ hybridization revealed that LBP-32 was distributed uniformly through the retina as well as over anterior oblique muscle, in corneal and lens epithelial cells and in capillary endothelial cells of the choroid. This unique cell-specific expression raises interesting questions of the role of LBP-32 in eye development.


Binding of actin to lens alpha crystallins. Actin has been coupled to a cyanogen bromide-activated Sepharose 4B column, then tested for binding to alpha, beta, and gamma crystallin preparations from the bovine lens. Alpha, but not beta or gamma, crystallins bound to the actin affinity column in a time dependent and saturable manner. Subfractionation of the alpha crystallin preparation into the alpha-A and alpha-B species, followed by incubation with the affinity column, demonstrated that both species bound approximately the same. Together, these studies demonstrate a specific and saturable binding of lens alpha-A and alpha-B with actin.


The epidemiology and genetics of endogenous uveitis: a review. Epidemiology is frequently neglected in the study of uveitis. Little is known on the incidence and prevalence of this disease. This review presents data on the subject from the literature and from the uveitis clinic at Rotterdam. The distribution of uveitis varies in different parts of the world and these differences might be attributed to geographic, alimentary or genetic factors. The discovery of associations of certain types of uveitis and HLA antigen subclasses provided at least part of an explanation for racial and genetic factors. These associations are dealt with in more detail.


Adoptive transfer of experimental autoimmune uveoretinitis in HgCl2 injected rats. We previously demonstrated that mercuric chloride (HgCl2) injected-(Lewis x Brown-Norway) F1 rats are protected against experimental autoimmune uveoretinitis (EAU) induced by active immunization with the retinal S-antigen (S-Ag). To better understand the mechanisms of the protection promoted by HgCl2, we studied the effect of HgCl2-induced autoimmune disease on transferred EAU. We demonstrate herein that HgCl2 has no effect on adoptively transferred EAU. Therefore, the HgCl2-induced autoimmune disease does not affect effector S-Ag specific T cells activated in vitro but acts at an earlier stage.


Induction of experimental autoimmune uveitis by the retinal photoreceptor cell protein, phosducin. Experimental autoimmune uveitis (EAU) and experimental autoimmune pinealitis (EAP) are CD4+ T cell mediated inflammatory diseases of the retina and uveal tract of the eye and the pineal gland respectively. They can be induced in experimental animals by immunization with several well characterized retinal autoantigens. We induced a mild to moderate EAU and EAP in Lewis rats by immunization with phosducin, a 33K retinal phosphoprotein which is involved in the phototransduction of vision. In contrast to the severe EAU induced by other retinal antigens like S-antigen (SAg) or interstitial retinoid binding protein (IRBP), the clinical disease was late in onset, low grade in severity and predominantly affected the posterior segment of the eye. Our study demonstrates that another photoreceptor cell protein, phosducin, is capable of eliciting EAU and EAP.


Pathogenicity and immunogenicity of recombinant human retinal S-antigen fusion protein. A full-length cDNA clone to human S-antigen (HS-ag) was isolated from lambda gt 10 human retinal library and expressed as a fusion protein with glutathione S-transferase (GST) in E. Coli. Uveitogenicity and immunogenicity of recombinant GST-HS-ag fusion protein and native HS-ag were compared in EAU-susceptible Lewis rats. Recombinant HS-ag was found less uveitogenic than native HS-ag. Animals inoculated with recombinant HS-ag developed EAU on day 17, three days later than those inoculated with native HS-ag, the incidence of the disease was reduced from 80% to 58% and the score of clinical severity reduced from 2.2 to 1.3 points respectively. In contrast, rGST-HS-ag was more immunogenic than native HS-ag as it elicited four times higher levels of antibodies which reacted specifically with both antigens.


Interphotoreceptor retinoid binding protein induced experimental autoimmune uveitis: an immunophenotypic analysis using alkaline phosphatase anti-alkaline phosphatase staining, dual immunofluorescence and confocal microscopy. Using a Lewis rat model of IRBP induced EAU, we have examined the progress of leucocytes infiltrating the uveitic eye. APAAP and dual immunofluorescence were used to show that ED7 and 8 (CD11b/CD18) positive monocytes, W3/25 and OX8 (CD4 and CD8) lymphocytes were prominent in the initial inflammatory exudate around the retinal vessels and in the choroid. ED1 positive monocytes were also observed in the choroid. As disease progressed, these cells moved into the inner retina, vitreous and ROS. ED8 positive cells were the first to appear in the ROS. This was followed by the later appearance of ED2 tissue macrophages in the vitreous and ED3 inflammatory macrophages in the vitreous and ROS.


Suppression of experimental autoimmune uveoretinitis by prazosin, an alpha 1-adrenergic receptor antagonist. S-antigen (S-Ag)-induced experimental autoimmune uveoretinitis (EAU) was suppressed in Lewis and PVG rats by treatment beginning 4 days post immunization with prazosin, a specific alpha 1-adrenergic receptor antagonist. A significant suppression of EAU was observed at clinical and histological levels in both treated groups compared to a severe EAU which developed in controls. Fluorescein angiography showed no leakage of dye from the optic disc of a treated PVG rat presenting no ocular inflammation by clinical examination. The treatment had no effect on the titer of anti-S-Ag antibodies. Perivascular infiltrates of T-lymphocytes and macrophages together with alterations of blood-retinal barrier permeability are early events in EAU. Prazosin, by acting on the vascular alpha 1-adrenoreceptors, inhibits vasospasm, preserves blood-retinal-barrier integrity and prevents vascular edema and early inflammatory cell infiltration observed in EAU.


Pinealitis coincident with recurrent uveitis: immunohistochemical studies. Although experimental models of autoimmune uveitis predict pinealitis coincident with uveitis, there is no direct evidence of pineal pathology accompanying a human uveitis. Horses with naturally occurring uveitis are a potential source of eye and pineal tissues that are not available from human patients with active uveitis. We have observed pinealitis in a mare with equine recurrent uveitis. By immunohistochemistry we demonstrated immunoglobulin and MHC Class II antigen on infiltrating and resident cells of eye and pineal gland. These results support the relevance of the animal models and suggest that pinealitis may be coincident with some human uveitides.


Adhesion molecules are expressed in the human retina and choroid. Immunoperoxidase staining of samples of normal human retina and choroid was performed to demonstrate selected adhesion molecules in vivo. Intercellular adhesion molecule-1 (ICAM-1), lymphocyte function-associated antigen-3 (LFA-3) and endothelial leucocyte adhesion molecule-1 (ELAM-1) were expressed on retinal vascular endothelium and ICAM-1 and ELAM-1 in the region of the external limiting membrane. The very late antigen-2 (VLA-2) was found around the retinal ganglion cells and in the inner and outer fibre layers. The endothelium on the choriocapillaris showed moderate staining of ICAM-1, and slight staining of LFA-3 and ELAM-1. The presence of these molecules in this distribution strongly suggests they have an important role in the pathogenesis of immunologically mediated ocular conditions.


Production of interleukin-6 by human retinal pigment epithelium in vitro and its regulation by other cytokines. Interleukin-6 (IL-6) is a pleiotropic cytokine which produces uveitis if administered intraocularly. It has been demonstrated in the aqueous of patients with various uveitis entities. We have investigated the ability of human retinal pigment epithelium (RPE) to produce IL-6 in vitro, both unstimulated, and in the presence of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF), interferon (IFN) gamma, and lipopolysaccharide (LPS). Five human RPE cell lines were cultured over a 6-day period, both unstimulated and in the presence of these cyokines. IL-6 in the supernatants was measured using an ELISA assay. Unstimulated RPE produced small amounts of IL-6. IL-1 at 100 or 10 U/ml markedly upregulated IL-6 production, and TNF at 1000, 100 or 10 U/ml did so to a lesser extent. Neither IFN gamma or LPS alone increased IL-6 expression, but together gave significant upregulation. Thus human RPE can produce IL-6 and may be the source of this cytokine in ocular inflammatory states.


Analysis of IL-6 levels in human vitreous fluid obtained from uveitis patients, patients with proliferative intraocular disorders and eye bank eyes. Several studies suggest a role for IL-6 in the pathogenesis of uveitis. Earlier we have shown that aqueous humour obtained from patients with uveitis contained raised levels of IL-6. In the study described here we investigated the IL-6 levels in vitreous fluid samples obtained from 75 uveitis patients with different uveitis entities. Vitreous samples from 14 patients with proliferative intraocular disorders (PID) and 29 eye bank eyes were used as controls. All the samples were tested in the IL-6 B9 bioassay as well as in a sensitive ELISA for IL-6. Raised IL-6 levels were detected in the vitreous fluid of uveitis patients as well as patients with PID, implicating IL-6 as a common inflammatory mediator. The highest mean level of IL-6 was found in the vitreous fluid of patients with acute retinal necrosis. The mean IL-6 levels measured by the ELISA were higher compared to the levels measured by the B9 bioassay. This may be caused by the presence of B9 bioassay inhibitory factors in the vitreous fluid of these patients.


Cytokines in human intraocular inflammation. The presence of interleukin 6 (IL-6), interleukin 1 (IL-1), interleukin 2 (IL-2) and tumour necrosis factor (TNF) was investigated in vitreous and aqueous aspirates from eyes undergoing vitrectomy for the treatment of different inflammatory conditions. Cadaveric vitreous from 10 normal subjects were used as controls. IL-6 was observed in 5 specimens from eyes with idiopathic uveitis (range = 26-264 pg/ml), in 2 specimens from eyes with uveitis complicated with retinal detachment (28 and 279 pg/ml, respectively), in 6 samples from eyes with diabetic retinopathy (range = 5-480 pg/ml), in one sample from an eye with phacolytic glaucoma (1190 pg/ml) and in one specimen from an eye with Behçet's disease (366 pg/ml). Although IL-1 was detected in 80% of all the samples investigated, concentrations of this cytokine greater than 3 pg/ml were only observed in 2 specimens from eyes with uveitis (5 and 20 pg/ml, respectively) and 2 samples from eyes with diabetic retinopathy (3 and 31 pg/ml, respectively). TNF was present in 3 specimens from eyes with uveitis (range = 2-24 pg/ml) and 1 sample from eyes with diabetic retinopathy (4 pg/ml), but was not detected in the eyes with phacolytic glaucoma or Behçet's disease. IL-2 (less than 0.1 U/ml) was detected in one sample from an eye with uveitis, one specimen from an eye with uveitis complicated with retinal detachment and 2 samples from eyes with diabetic retinopathy. None of the cytokines measured were detected in any of the control vitreous. The present observations suggest that cytokines, particularly IL-6 and IL-1, may act as local amplification signals in pathological processes associated with chronic eye inflammation.


Soluble interleukin-2 receptors in retinal vasculitis. Soluble interleukin-2 receptor (sIL-2R) levels were measured in the serum of 27 patients with retinal vasculitis, 16 with vasculitis purely isolated to the eye (RV) and 11 with vasculitis associated with a systemic inflammatory disease (RV+SID). Levels of sIL-2R were statistically significantly increased (mu 986, SD 845 U/ml, p = 0.013) only in the RV+SID group as compared to healthy controls. The highest levels being found in patients with sarcoidosis (mu 1436, SD 1083 U/ml). There was no correlation with disease activity or with systemic corticosteroid therapy. Serum sIL-2R measurements appear to be of limited use in the management of patients with retinal vasculitis, but may be of value in those patients with sarcoidosis. Longitudinal measurements with larger numbers of patients are required to confirm this. Serum sIL-2R levels were also statistically significantly increased (mu 843, SD 171 U/ml, p less than 0.0001) in 21 patients with Fuchs' heterochromic cyclitis. As this is a chronic condition with mild inflammatory activity and no associated systemic disease, the explanation for this finding is unknown.


Anti-endothelial cell antibodies in retinal vasculitis. Auto-antibodies to endothelial cells are found in a variety of vasculitic disorders including two diseases associated with retinal vasculitis: Behcet's disease and multiple sclerosis. In this study we have examined the prevalence of anti-endothelial cell antibodies [AECA] in 15 patients with retinal vasculitis [RV] associated with Behcet's disease, multiple sclerosis or sarcoidosis and 20 patients with idiopathic retinal vasculitis. 47% of patients with RV associated with systemic disease and 35% of patients with idiopathic RV had AECA, compared to 1% of 70 normal controls. The mean levels of AECA were similar in both groups of patients, and comparable to levels found in other systemic vasculitides.


Anticardiolipin antibodies in uveitis.

Anticardiolipin antibodies in uveitis. Anticardiolipin antibodies (ACA) have been described in association with thrombosis and several vascular diseases and may be involved in retinal vasculitis. To investigate this question we tested sera from 86 patients with posterior uveitis and 100 healthy controls for the presence of anticardiolipin antibodies. The antibody was present in 15 patients: in 7 of the patients with acute retinal necrosis (n = 24), in 4 with idiopathic retinal vasculitis (n = 10), 3 with syphilis (n = 6) and in one SLE patient with retinal vasculitis. Ten patients had IgA-type anticardiolipin antibodies, 6 had IgM-type and 4 had IgG-type anticardiolipin antibodies. Anticardiolipin antibodies could not be detected in sera from uveitis patients with Behçet's disease (n = 10), sarcoid (n = 9), toxoplasmosis (n = 7), multiple sclerosis (n = 3) or Birdshot chorioretinopathy (n = 10). Ten of the healthy controls had cardiolipin antibodies of the IgM class. The exact role of these auto-antibodies in the pathogenesis of retinal vasculitis remains to be resolved.


The use of lithium clearance studies in the early detection of cyclosporin A (CsA) nephrotoxicity: a protocol of renal function assessment with CsA therapy. Cyclosporin A nephrotoxicity was studied with the use of lithium and creatinine clearance tests in 18 patients with chronic intraocular inflammation (duration of treatment 3-48 months). In 11 patients lithium clearance and fractional excretion of lithium were significantly reduced (compared with pretreatment levels) within the first six months of treatment. There was no significant change in either serum creatinine or creatinine clearance within this period. In 14/18 patients there was a significant reduction in lithium clearance and fractional excretion of lithium during the treatment period. 7 patients whose therapy was stopped because of continuing nephrotoxicity despite dose reduction, demonstrated some reversibility of renal function on cessation of cyclosporin A. We propose a protocol for the assessment of renal function in these patients so that with dose modulation the changes in these parameters can be minimised, reducing the risk of renal impairment, whilst maximising immunosuppressive treatment.


The blood-retinal barrier in experimental autoimmune uveoretinitis (EAU): a review. The blood-retinal barrier (BRB) is believed to play an important part in the pathogenesis of experimental autoimmune uveoretinitis (EAU). Central to the disease process is the recruitment of inflammatory cells from the circulation, a mechanism that is controlled in part by the BRB. As the disease progresses the BRB becomes disrupted first to small and then to large molecular weight tracers. In these two respects EAU shares many similarities with experimental autoimmune encephalomyelitis (EAE) in which there is dysfunction of the blood-brain barrier (BBB). In EAU, however, the differential roles played by the two barrier sites that comprise the BRB are not clear although some evidence would suggest that it is the retinal endothelium that is initially involved. BRB breakdown in EAU has been found to occur concomitantly with lymphocyte infiltration by mechanisms that remain to be elucidated.


Eye-derived cytokines and the immunosuppressive intraocular microenvironment: a review. The normal aqueous humor contains a variety of soluble immunosuppressive factors, including transforming growth factor-beta, alpha-melanocyte stimulating hormone, and vasoactive intestinal peptide. These factors are largely the secretory products of parenchymal cells of the iris and ciliary body. TGF beta has recently been shown to alter the functional capacity of intraocular antigen presenting cells, such that they are capable of inducing Anterior Chamber Associated Immune Deviation (ACAID). This deviant systemic immune response is characterized by an impaired capacity to mount an effective cell-mediated immune attack directed at antigens that are placed in, or arise within, the eye. A second property of immunosuppressive factors in aqueous humor is to suppress directly the expression of delayed hypersensitivity in the anterior chamber. In fact, even when the intraocular microenvironment is disturbed by local instillation of gamma-interferon, making it possible for limited expression of cell-mediated immunity in the eye, the microenvironment of the anterior chamber remains profoundly immunosuppressive. In this latter instance, prostaglandins replace TGF beta as the major molecular mediators of suppression in the aqueous humor. In the aggregate, factors present in the normal (or perturbed) intraocular microenvironment have the capacity to modify both the afferent and efferent limbs of the systemic immune response, and this accounts for the longstanding observation that the anterior chamber is an immunologically privileged site. Since evidence suggests that the eye can mobilize more than one molecular mechanism in its effort to limit the sight-destroying potential of immunogenic inflammation, we believe that elucidation of intraocular cytokines and factors that create and maintain an immunosuppressive microenvironment will contribute to a better understanding of the pathogenesis of the acute and chronic uveitides, especially those of autoimmune and infectious etiology.


Antigen processing and presentation in the eye: a review. The recognition event between self-antigen, the MHC and the T cell receptor has become the target for potential immunotherapy of T cell mediated autoimmune disease. For this approach to succeed in uveoretinitis, uniformity in T cell receptor usage, restricted MHC usage and limited epitope recognition by individuals would be required. In this study we have shown that despite clonal heterogeneity of response to multideterminate retinal extract antigens, proliferation to the antigens tested was restricted by the IA MHC class II molecule. Different patterns of reactivity to retinal antigens in the presence of various protease inhibitors was observed. Natural processing of IRBP appears to be complex, requiring a number of enzymes to generate immunogenic fragments, in contrast, for S-antigen, plasmin alone may suffice. The RPE cells which are potential processors and presenters of retinal antigens produce PGE2 and may act as suppressors of ocular inflammation.


Epitopes and idiotypes in experimental autoimmune uveitis: a review. Retinal S-antigen (SAg) and interphotoreceptor retinol-binding protein (IRBP) induced experimental autoimmune uveitis (EAU) and experimental autoimmune pinealitis (EAP) are good models for studying the mechanisms involved in autoimmune diseases. Many immunogenetically active epitopes have been identified in these proteins but immunodominance of one or more epitopes in vivo, has not yet been established. In this paper we present and discuss some experiments that led to the discovery of a dominant "tolerogenic" epitope in SAg. We also demonstrate the presence of cross reactive epitopes in the two potent retinal antigens, SAg and IRBP and finally introduce early data on a unique anti S2.4.c5 idiotypic (Id) monoclonal antibody (MAb) which appears to be a site non associated antibody that binds not only to s2.4.c5 but also to SAg.


Macrophages in experimental autoimmune diseases in the rat: a review. In the pathogenesis of most experimental autoimmune diseases T lymphocytes play a crucial role in the initiation, whereas macrophages are essential in the effector phase. This review deals with several methods to elucidate the exact role macrophages play in different stages of autoimmune models in the rat. By using monoclonal antibodies an inventory has been made on the different macrophage subsets that are present in the infiltrates of the affected tissues. That macrophages play a decisive role in provoking the clinical signs has been shown by several macrophage elimination studies. The severe tissue damage caused by macrophages is brought about by the release of inflammatory mediators. Especially interference with the production or action of these products could provide new therapeutical means.


Genetic factors in susceptibility and resistance to experimental autoimmune uveoretinitis. Experimental autoimmune uveoretinitis (EAU) can be induced in susceptible stains of rats and mice by immunization with purified retinal antigens, and serves as a model for human uveitis. Because strong HLA associations have been noted in a number of human uveitic diseases, we investigated the role of major histocompatibility complex (MHC) vs. non-MHC genes in the control of susceptibility to ocular autoimmunity, using the mouse and the rat EAU models. It was shown that EAU expression in mice requires both a susceptible MHC haplotype and a "permissive" genetic background. MHC control of susceptibility was tentatively mapped to the I-A subregion in H-2k. I-Ek expression appeared to have an ameliorating effect on disease. Susceptible H-2 haplotypes exhibited highest disease scores on the B10 background, and disease was reduced, or even absent, on some other (nonpermissive) backgrounds. Factors which may determine "permissiveness" or "nonpermissiveness" of a particular genetic background, as studied in mice and rats, may include diverse genetic mechanisms spanning regulation of cytokines, hormones, vascular effects and the T cell repertoire. Taken together, the data suggest that, in individuals susceptible to uveitis by virtue of their MHC, the final expression of disease will be determined by the genetic background.


Use of ACAID to suppress interphotoreceptor retinoid binding protein-induced experimental autoimmune uveitis. Experimental Autoimmune Uveitis (EAU) was induced by immunization with bovine interphotoreceptor retinoid binding protein (IRBP) in B10.A mice. The experiments were performed to evaluate whether Anterior Chamber Associated Immune Deviation (ACAID) can be induced by IRBP when injected intracamerally. The results indicate that anterior chamber (AC) injection of IRBP impaired the development of IRBP-specific delayed hypersensitivity and prevented the expression of EAU following immunization with IRBP-CFA. Adoptive transfer of spleen cells obtained from mice that received IRBP into AC suppressed EAU, whether administered prior to or after the uveitogenic regimen. Most important, IRBP-specific suppressor cells from AC-IRBP treated mice when injected into IRBP-EAU mice suppressed and eliminated already established intraocular inflammation. IRBP-specific, ACAID-inducing suppressor T cells act on the efferent limb of the immune response, and represent ideal modalities for treating already established EAU.


Retinopathy of prematurity.

Retinopathy of prematurity. ROP is a common disorder among extremely low-birth-weight premature infant survivors and may cause total vision loss in as many as 2% to 4% of those weighing less than 2 lb (1 kg) at birth. Regular examinations begun in the intensive care unit permit early detection and treatment of progressive ROP, reducing visual impairment. Ongoing research into antioxidants, angiogenesis, light exposure, and newer surgical techniques may offer new approaches for preventing and treating established ROP. Infants who have had ROP that regressed should continue regular ophthalmologic follow-up to detect and treat myopia, strabismus, and if they have cicatricial sequelae, late retinal detachments as teens or adults. Infants who develop retinal detachments should be referred for early intervention and special education programs and remain in regular ophthalmologic follow-up for the detection and treatment of further ophthalmic complications.


Lumbosacral spine imaging: physioanatomic method. Noninvasive evaluation of low back and leg pain has progressed rapidly over the past decade. The development of computed tomography, single-photon emission-computed tomographic bone scan, and magnetic resonance imaging has markedly increased diagnostic accuracy in detecting pathologic conditions. With this increased accuracy has come recognition of a 50% prevalence of underlying abnormalities in patients between 20 and 60 years old who have no symptoms. When such patients have a back injury, subsequent imaging will show in half of the population studied abnormalities that are not related to an acute injury. Degeneration of the spine progresses in all patients throughout their lifetime, and nearly all of the population will have back discomfort at some time. Political- and judicial-based compensation for back injuries related to accidents and on-the-job injuries provides an incentive for patients not to improve on therapy and to exaggerate symptoms, further complicating the clinical evaluation of their condition. The goal of physioanatomic noninvasive and invasive imaging evaluation presented in the following chapters is to increase specificity by differentiating pain generators from asymptomatic underlying pathologic conditions. When used with intensive conservative management and psychologic testing, this physioanatomic approach has resulted in much better treatment outcomes in our experience. The physioanatomic approach is quite simple, consisting of rigorous correlation of pathologic changes demonstrated by noninvasive imaging modalities (computed tomography, single-photon emission-computed tomographic bone scan, and magnetic resonance), or invasive modalities (diskography-enhanced computed tomography, nerve root block and facet block) with the patient's symptoms to evaluate whether the symptoms and the pathologic lesion are concordant or discordant. Patient symptoms and history are evaluated by use of a pain drawing and information sheet. The patient's pain pattern is categorized into a nonspecific pattern or into one of four recognizable pathway patterns (radicular, dorsal ramus, polyneuropathy, and sympathetic). Because each spinal lesion is typically manifested primarily via one of the four symptom pathways, the distribution of expected symptoms from each pathologic feature can be compared with the patient's pain drawing, and an assessment of the significance of imaged lesions can be made. The patient's presenting symptoms are also used to determine the most cost-effective and efficacious use of initial diagnostic imaging evaluation. In a minority of patients the findings on noninvasive imaging either will not correlate with the patient's symptoms or will demonstrate multiple abnormalities that could account for the patient's symptoms. In these patients, invasive techniques are extremely helpful in defining a pain generator or pain generators.(ABSTRACT TRUNCATED AT 400 WORDS)


Membrane cofactor protein.

Membrane cofactor protein. MCP serves to down-regulate the activation of complement on host tissue. It performs this function by serving as a cofactor for the factor I-mediated cleavage of C3b and C4b. MCP is most likely an intrinsic regulator, i.e., it primarily protects its home cell. The wide tissue distribution of MCP mirrors this critical function of host cell protection. With the exception of erythrocytes, every cell and tissue examined expresses this protein. MCP is represented as two broad heterogeneous bands on SDS-PAGE with M(r)s of 51,000-58,000 and 59,000-68,000. The quantity of each form expressed is inherited in an autosomal codominant fashion. In most cells and cell lines, four isoforms of MCP predominate and arise by alternative splicing of a single MCP gene. All forms possess four repeating modules of--60 aminoacids, an area enriched in serines, threonines, and prolines [(STP), probable site of O-linked glycosylation], a short area of unknown function, a transmembrane domain, and a cytoplasmic tail. The isoforms differ, however, in the length and composition of the STP region and in the cytoplasmic tail. Alternative splicing of a single exon within the STP region determines the protein phenotype. Alternative splicing at the COOH_terminus gives rise to two distinct cytoplasmic tails. The biological significance of these structural variations in the STP and cytoplasmic tail regions is being investigated.


Mononuclear phagocytes as targets, tissue reservoirs, and immunoregulatory cells in human immunodeficiency virus disease. We have presented evidence in this review for the following: 1. Macrophages are likely the first cell infected by HIV. Studies document recovery of HIV into macrophages in the early stages of infection in which virus isolation in T cells is unsuccessful and detectable levels of antibodies against HIV are absent. 2. Macrophages are major tissue reservoirs for HIV during all stages of infection. Unlike the lytic infection of T cells, many HIV-infected macrophages show little or no virus-induced cytopathic effects. HIV-infected macrophages persist in tissue for extended periods of time (months) with large numbers of infectious particles contained within intracytoplasmic vacuoles. 3. Macrophages are a vector for the spread of infection to different tissues within the patient and between individuals. Several studies suggest a "Trojan horse" role for HIV-infected macrophages in dissemination of infectious particles. The predominant cell in most bodily fluids (alveolar fluid, colostrum, semen, vaginal secretions) is the macrophage. In semen, for example, the numbers of macrophages exceed those of lymphocytes by more than 20-fold (Wolf and Anderson 1988). 4. Macrophages are major regulatory cells that control the pace and intensity of disease progression in HIV infection. Macrophage secretory products are implicated in the pathogenesis of CNS disease and in control of viral latency in HIV-infected T cells. This litany of events in which macrophages participate in HIV infection in man parallels similar observations in such animal lentivirus infections as visna-maedi or caprine arthritis-encephalitis viruses. HIV interacts with monocytes differently than with T cells. Understanding this interaction may more clearly define both the pathogenesis of HIV disease and strategies for therapeutic intervention.


Genital psoriasis.

Genital psoriasis. Psoriasis of the genitalia occurs in all age groups from infancy to the elderly. Approximately one-quarter to one-half of various epidemiologic studies report that genital psoriasis occurs with a higher frequency in males than in females. Therapeutic modalities for management of psoriasis in this site underscore the need for caution in not irritating the sensitive genital skin. Preventive measures include avoiding tight under- and outer-garments that provoke penile or vulvar psoriasis as well as maintaining cleanliness of the genital area.


Persistent painful plaque due to a brown recluse spider bite. The bite of the arthropod Loxosceles is known to cause subdermal hemorrhage, dermal-epidermal separation, inflammatory infiltrates, as well as occlusion and necrosis of small arterioles. We report a case of a brown recluse spider bite that presented as a chronic painful skin plaque, with the unusual histologic findings of a cutaneous and deep subcutaneous hyalinizing panniculitis and myonecrosis.


Tongue and cheek: oral lesions in pityriasis rosea. Fifty-one consecutive patients with clinical findings and history consistent with pityriasis rosea underwent a complete oral examination to search for any concomitant oral lesions. One case was omitted from the statistical analysis because the results of a rapid plasma reagin test were positive. Of the fifty remaining cases, eight patients (16 percent) were noted to have various oral lesions, all of which were asymptomatic. These findings suggest that the actual incidence of oral lesions in pityriasis rosea may be higher than previously reported. A complete oral examination in a patient presenting with a papulosquamous eruption may be helpful in ascertaining the diagnosis of pityriasis rosea.


Fixed drug eruption to Tylenol: report of two cases and review of the literature. Fixed drug eruptions due to Tylenol (paracetamol, acetaminophen) are very rare. The authors report two additional cases and review the literature.


Aquagenic urticaria.

Aquagenic urticaria. Aquagenic urticaria is a rare form of physical urticaria characterized by small follicular wheals with an erythematous flare upon exposure to water. We describe typical lesions in a seven-year-old boy with aquagenic urticaria, cholinergic urticaria, and symptomatic dermatographism, who responded to treatment with ultraviolet B and oral antihistamines.


Multiple pilomatricomas: report of two cases and review of the association with myotonic dystrophy. Two patients are reported who experienced multiple pilomatricomas beginning in childhood. Although one patient had no evidence of associated diseases, the second patient was diagnosed with myotonic dystrophy subsequent to the onset of the pilomatricomas. Previous reports of multiple pilomatricomas and the association with myotonic dystrophy are reviewed.


Cutaneous pleomorphic large cell lymphoma. The case of a primary cutaneous pleomorphic large cell lymphoma occurring in a twenty-one-year-old woman who presented with a blue-reddish nodule on her left cheek of three months' duration is presented. The tumor consisted of pleomorphic blast cells showing high mitotic activity. On immunohistochemical examination, the majority of the tumor cells expressed CD 3 (Leu-4), CD 4 (Leu-3), HLA-DR CD 30 (Ki-1/Ber-H 2), and CD 25 (IL2 receptor). Twenty-two months after excision of the tumor there is no detectable systemic spread of the lymphoma. This case provides further evidence for recent observations that primary cutaneous Ki-1-positive large cell lymphomas without lymph node involvement may have a favorable prognosis after local treatment despite showing histologic pattern of malignancy.


Cutaneous nocardiosis associated with insect bites. We report the first case of cutaneous nocardiosis associated with insect bites. The patient received these insect bites while camping a few days before he presented to the emergency room. The patient was a healthy twenty-six-year-old man, who was asplenic as a result of a motor vehicle accident. He presented to the emergency room with fever, multiple insect bites to his left lower extremity with pustules, lymphangitis, and left inguinal adenopathy. He was hospitalized but his condition failed to improve despite treatment with intravenous nafcillin for three days. Wound and blood cultures subsequently grew Nocardia brasiliensis. Treatment with intravenous amikacin (5 mg/kg every eight hours) was instituted along with oral trimethoprim-sulfamethoxazole double strength twice a day. The patient recovered with minimal scarring of the extremity. The amikacin was stopped after seven days and the patient was discharged to receive oral trimethoprim-sulfamethoxazole. This disease should be kept in mind when cutaneous infections do not respond to standard antibiotics, especially in the southwestern United States.


Salicylate intoxication after use of topical salicylic acid ointment by a patient with psoriasis. The authors describe a therapeutically well managed case of severe salicylate intoxication in a patient with psoriasis who treated himself with 40 percent salicylic ointment applied to approximately 41 percent of his body surface. Nineteen hours after the application of salicylic acid, his blood level of the agent was 6.04 mmol/liter. The patient underwent hemodialysis and was discharged after fourteen days in good general health.


Eyewear, cataracts, and periorbital basal cell carcinoma. Ultraviolet exposure is an important risk factor for basal cell carcinoma. Since eyewear may have a photoprotective effect, this study evaluated the use of prescription eyeglasses and sunglasses in patients with periorbital basal cell carcinoma compared with other facial sites. There was no difference in prescription eyewear use between the groups, and only four patients in each group had regularly worn glasses since childhood. There was an increased occurrence of cataracts and cataract surgery in the group of patients with periorbital tumors, which may indicate a greater cumulative ultraviolet exposure to the orbital and periorbital sites in these patients.


Molecular and cytogenetic characterization of radiation hybrids specific for human chromosome 16. Two hundred and twenty-three radiation hybrids retaining random fragments of human chromosome 16 were isolated during two successive experiments in HAT medium and screened with a total of 38 DNA probes, corresponding to anonymous DNA or gene sequences localized on chromosome 16. The presence of single or multiple human chromosomal fragments in a small subset of these hybrids was determined using in situ hybridization with total human DNA. The results confirm that individual radiation hybrids are often heterogeneous with respect to the retention and distribution of human fragments, as already suggested by their characterization with DNA probes. A number of these 223 radiation hybrids, whose detailed characterization has not been previously reported, represent a resource for the rapid isolation of new DNA markers or coding sequences from specific regions of chromosome 16 where human disease genes are already known to map.


Fluorescence in situ mapping of the human nuclear NAD+ ADP-ribosyltransferase gene (ADPRT) and two secondary sites to human chromosomal bands 1q42, 13q34, and 14q24. A 3.5-kb cDNA probe containing the 23 exons from the coding sequence of human nuclear NAD+ ADP-ribosyltransferase (poly [ADP-ribose] polymerase [ADPRT], E.C.2.4.2.30) was used to map the gene and two additional sites by nonisotopic in situ chromosomal hybridization. The previous localization of the structural gene on 1q42 was confirmed. Two other hybridization peaks on 13q34 and 14q24 suggested the presence of ADPRT pseudogenes.


Localization of the human GM-CSF receptor beta chain gene (CSF2RB) to chromosome 22q12.2-->q13.1. The gene for the beta-chain of the human GM-CSF receptor (CSF2RB) has been mapped to chromosome 22 by PCR analysis of a series of human x rodent somatic cell hybrids. In situ hybridization to normal human chromosomes and two translocations involving chromosome 22 and the chromosome expressing the rare fragile site FRA22A place the gene in the region 22q12.2-->q13.1, proximal to the fragile site.


Regional localization of the gene for clusterin (SP-40,40; gene symbol CLI) to human chromosome 8p12-->p21. The human clusterin (SP-40,40) gene, designated CLI (complement lysis inhibitor) by the Human Gene Nomenclature Committee, has previously been assigned to chromosome 8. In situ hybridization allowed us to map the locus at 8p12-->p21.


Localization of the beta A4-crystallin gene (CRYBA4) on human chromosome 22 in the region q11.2-->q13.1. The chromosomal localization of the human gene (CRYBA4) coding for the eye lens protein beta A4-crystallin has been carried out using a nearly full-length cDNA clone encoding bovine beta A4-crystallin. A panel of 21 human-mouse or human-hamster hybrid cell lines derived from different parental combinations was characterized with respect to the human chromosomal content and the presence of well established human chromosome-specific markers. These panels were screened for the presence of CRYBA4 using the bovine cDNA clone as a probe. A 100 percent concordance was observed between the presence or absence of the CRYBA4 and human chromosome 22 indicating that the gene resides on this chromosome. By using cell hybrids containing translocated chromosome 22 segments, the localization could be refined to the region 22q11.2-->q13.1.


Chromosomal localization of the mouse prealbumin gene (Ttr) by in situ hybridization. Prealbumin is a serum protein which plays an important role in plasma transport of retinol and thyroxine. The accumulation of a variant prealbumin is associated with a hereditary disorder, familial amyloidotic polyneuropathy (FAP). In situ hybridization with a mouse prealbumin gene cDNA probe was carried out in mouse fibroblasts. Analysis of 114 R-banded metaphases showed that 13% of the total grains were located on chromosome 4 and 46% of the grains on this chromosome were in the region C6-D1. Linkage and syntenic group analysis showed that the prealbumin gene (Ttr) is located between two syntenic groups on mouse chromosome 4, which corresponded to two syntenic groups present on human chromosomes 1 and 9.


Mapping of repetitive bovine DNA sequences on cattle Y chromosomes. Three male-specific PCR products of the sequences BC1.2, lambda ES6.0, and BRY.1 were used as probes for Southern blot analyses. Each of these probes generated a complex male-specific band pattern, which showed some quantitative variations among bulls. Hybridization patterns obtained with the BC1.2 and lambda ES6.0 PCR products were interrelated. Chromosomal locations of these repeats were determined by hybridizing the tritiated PCR products in situ to male metaphase spreads. The BC1.2 and lambda ES6.0 PCR products hybridized to Yp13-->p12, whereas the BRY.1 PCR product hybridized over the entire Y chromosome. In addition, the BC1.2 and lambda ES6.0 PCR products hybridized to the distal half of the acrocentric Y chromosome of Bos indicus, indicating that the short arm of the B. taurus Y chromosome is homologous with the telomeric end of the B. indicus Y and supporting the notion that the Y chromosomes of these two species differ by a pericentric inversion.


Synaptonemal complex analysis of a three-breakpoint translocation in a subfertile bull. Somatic chromosome analysis of a subfertile Brown Swiss bull demonstrated a three-breakpoint translocation involving chromosomes 1, 8, and 9 in G- and R-banded karyotypes. Based on standard bovine chromosome nomenclature, the translocation was defined as t(1;8;9)(q43;q13;q26). Synaptonemal complex analysis of the chromosome aberration by electron microscopy revealed a hexavalent configuration in 52 of 53 pachytene cells. Twenty-seven cells (51%) had a completely paired hexavalent configuration showing distinctly nonhomologous pairings between normal and/or translocated chromosomes involved in the exchanges. Thirteen cells showed a hexavalent configuration with centrally unpaired chromosome segments but with completely paired terminal arms. In 13 cells (including one at zygotene) the translocation chromosomes formed an open hexavalent, and in one cell there were two completely paired trivalents. Thirty-two cells at diakinesis-MI demonstrated 28 configurations, including one large hexavalent. Testicular histology, testis size, and seminal characteristics were normal.


Synaptonemal complex analysis of an autosomal trisomy in the horse. Synaptonemal complex analysis by electron microscopy of a trisomy 28 in a male horse demonstrated a trivalent or a bivalent plus a univalent in primary spermatocytes. Two of the chromosomes making up the trivalent were, most often, completely paired with each other and only partially paired or associated with the third one. Half of the spermatocytes analysed demonstrated heterologous pairing or association between the free axis of the trivalent and the sex bivalent. The pairings remained, to a large extent, into diakinesis-metaphase I. In most pachytene cells one autosomal bivalent showed proximal asynapsis and paired often, heterologously, with the trivalent or the sex bivalent. The horse demonstrated azoospermy, which was due, at least in part, to degeneration at both the spermatocyte and spermatid levels.


Assignment of the rabbit genes for alpha (PHKA) and beta (PHKB) phosphorylase kinase subunits. The chromosomal locations of the rabbit genes for the alpha and beta subunits of phosphorylase kinase (PHKA and PHKB) were determined by in situ hybridization using rabbit cDNA probes. Our results localize PHKA to the X chromosome at the proximal end of the long arm, near the centromere, and PHKB to the same location on chromosome 5. These assignments support previously reported homoeologies of rabbit and human chromosomes.


Male meiosis and gametogenesis in wild house mice (Mus musculus domesticus) from a chromosomal hybrid zone; a comparison between "simple" Robertsonian heterozygotes and homozygotes. Wild male house mice Mus musculus domesticus were collected from the hybrid zone between the John o'Groats race (2n = 32) and the standard race (2n = 40) in northern Scotland. Meiosis in both homozygotes (2n = 32, 36, and 40) and single Robertsonian heterozygotes (2n = 33, 35, and 37) was found to be orderly. At prophase/metaphase I in heterozygotes, a trivalent was formed from the metacentric and two homologous acrocentrics. At pachytene, this trivalent usually had a single side arm at the position of the centromeres, as a result of nonhomologous pairing of the acrocentrics. This side arm persisted into diplotene. Generally only a single chiasma was formed between each acrocentric and the metacentric. Anaphase I nondisjunction frequencies were estimated as 1.5% for the homozygotes and 2.7% for the heterozygotes. The extent of germ cell death between the pachytene and round spermatid stages was 18% greater in heterozygotes than in homozygotes. Our results concur with previous studies which indicate that single Robertsonian heterozygotes in wild house mice have near-normal fertility.


Chromosome painting using chromosome-specific probes from flow-sorted pig chromosomes. Biotinylated chromosome-specific probes were prepared from flow-sorted pig chromosomes 1, 13, 18, X, and Y using the degenerate oligonucleotide-primed polymerase chain reaction. Probes prepared in this way can be used to confirm the identity of chromosomes in the bivariate pig flow karyotype and in pig x mouse somatic cell hybrids.


Epidemiology of pain requiring strong analgesics outside hospital in a geographically defined population in Denmark. Based on obligatory notifications from pharmacies to the National Board of Health about prescription of strong analgesics as well as questionnaires to the prescribing doctors, the occurrence and causes of pain requiring strong analgesics outside hospitals were analysed over a period of one month in Denmark in a limited population (480,000), corresponding to nearly 10% of the Danish population. During one month, strong analgesics were prescribed to 0.2 per cent of the population. The commonest acute conditions were back pain (23%) and trauma (17%). The commonest recurrent acute conditions were headache (25%) and angina pectoris (17%). The commonest chronic non-malignant conditions were back pain (29%) and pancreatitis (7%). The commonest malignant conditions were lung cancer (20%) and colorectal cancer (14%). The commonest conditions indicated under the chronic pain syndrome were headache (33%) and back pain (13%). Conditions requiring strong analgesics reflect to some extent the distribution of painful conditions in the general population.


Recording of postoperative wound infections in Denmark. Implementation, surgeons attitude, status and recommendations. To evaluate the state of the surveillance of surgical infections in Denmark. To investigate whether a negative attitude to infection registration on the part of the chief surgeon is correlated to departments with no plans of recording their infections. Questionnaire sent to all surgical and gynaecological departments in Denmark. The National Centre for Hospital Hygiene, Statens Seruminstitut, Copenhagen, Spring 1991. 73 general, 34 orthopaedic, eight thoracic and vascular surgical departments, seven reconstructive, five neurosurgical, and 31 gynaecological departments. Kind of specialty, attitudes to infection registration, do register, plan to register, no plans to register, type of program, year of start of registration, satisfaction, problems and suggestive improvements. Out of 170 possible units, 65 were already recording their infection rates, 59 had plans to start registration, 34 had no plans to start, five did not state whether they had any plans to start, and seven units did not respond. The units which were recording their infections had a more positive attitude towards surveillance systems. We found that the Danish public health service had a high degree of concern about infection surveillance without any legislative or other regulative pressures, and the process of implementing surveillance is still ongoing. The adoption of a common minimal data set is recommended in order to make a national and international comparison of infection surveillance data possible. Enlarging the infection control team may result in a better wound infection surveillance in hospitalised patients. More intensive studies are needed to examine how effectively surveillance prevents postoperative infections.


Scintigraphic quantification of pharyngeal retention following deglutition. A procedure is described for quantifying the amount of bolus material retained in the pharynx after completion of a swallow, using radionuclide swallow techniques. Data are derived from scintigraphic time-activity curves. The procedure takes into consideration the differential attenuation of radioactivity through various regions in the body, and expresses the result as a percentage of the total radioactivity in the ingested bolus. Illustrative examples are provided for swallows by normal individuals and patients with head and neck cancer.


Viscosity measurements of barium sulfate mixtures for use in motility studies of the pharynx and esophagus. Detailed viscosity measurements have been made of barium sulfate mixtures over a wide range of viscosities for use in radiography of the esophagus, stomach, and duodenum. A new methodology was developed for more accurate estimation of viscosity in non-Newtonian fluids in conventional cylinder-type viscometers. As base cases, the variation of viscosity with shear rate was measured for standard commercial mixes of e.z.hd (250% w/v) and a diluted mixture of liquid e.z.paque (40% w/v). These suspensions are strongly shear thinning at low shear rates. Above about 3s-1 the viscosity is nearly constant, but relatively low. To increase the viscosity of the barium sulfate mixture, Knott's strawberry syrup was mixed to different proportions with e.z.hd powder. In this way viscosity was systematically increased to values 130,000 times that of water. For these mixtures the variation of viscosity with temperature, and the change in mixture density with powder-syrup ratio are documented. From least-square fits through the data, simple mathematical formulas are derived for approximate calculation of viscosity as a function of mixture ratio and temperature. These empirical formulas should be useful in the design of "test kits" for systematic study for pharyngeal and esophageal motility, and clinical analysis of motility disorders as they relate to bolus consistency.


Esophageal motor disorders in patients evaluated for dysphagia and/or noncardiac chest pain. During the period January, 1983-October, 1990, 429 subjects were referred for functional evaluation of dysphagia and/or noncardiac chest pain. Of these, 304 (70.8%) were shown to have some kind of esophageal motor abnormality. The most frequent motor abnormality of the esophagus was represented by nonspecific motor disorders (31%), followed by achalasia (13%), whereas the other dysfunctions accounted for a smaller percentage. In particular, diffuse esophageal spasm was shown to be quite rare. It is concluded that esophageal manometry may provide a high diagnostic yield in patients presenting with dysphagia and/or noncardiac chest pain.


Laryngologic aspects of bolus asphyxiation-bolus death. Among 12,982 forensic autopsies, 78 cases of café coronary due to bolus impaction in the larynx (bolus death) were observed from 1947 to 1988. In all cases bolus material occluded the entry to the larynx; only once was a singular occlusion of the glottis observed. The bolus frequently extended into the mouth, trachea, and bronchial tree or esophagus. In all cases small amounts of aspirated material were observed in the deeper parts of the bronchial tree. The most commonly observed bolus was not masticated meat or a meat product. In adults and the elderly the bolus was often too large to pass the physiological narrowings of the hypopharynx. It was commonly lodged above the arytenoid cartilages. Forty-five of the bolus events were observed by bystanders. In 43 of the victims vital reactions were observed by bystanders or at the autopsy. This justifies the hope that many lives could have been saved had the right diagnosis and immediate therapy been initiated. The first step should be manual extraction or use of the Heimlich maneuver; in cases of failure of both attempts, immediate tracheotomy followed by hospitalization and bronchial lavage are indicated.


The Johns Hopkins Swallowing Center database. A special database has been constructed for faculty working in the Swallowing Center of The Johns Hopkins University School of Medicine. The database supports the clinical, research, and publication needs of the Center. This database on swallowing disorders includes over 6000 references to the literature dating from the mid-1960s. The system operates on microcomputer technology and uses relatively inexpensive and intuitive software programs. Monthly updates keep members informed of the latest developments in a multidisciplinary literature.


Swallowing problems after excision of tumors of the skull base: diagnosis and management in 12 patients. Acute-onset dysphagia can be a debilitating complication of operative intervention in skull base surgery. A retrospective study performed at Baptist Hospital investigated the oropharyngeal deficits, compensatory swallow techniques, and diet modifications of 12 patients who had undergone excision of skull base tumors. Oropharyngeal dysfunction, reduced laryngeal elevation, and copious pharyngeal retention were the most prominent swallowing deficits. Aspiration occurred in 75% of the patients studied. The most frequently employed compensatory swallow techniques were head turns to the affected side, supraglottic swallow, double swallows, alternating liquids and solids, carbonated beverage swallows, and small bolus size. Approximately 2 weeks following skull base surgery, 58% of the patients were able to tolerate oral intake with the aid of compensatory swallow techniques and diet modifications. Only 1 patient in this group remained unable to tolerate food by mouth. This paper focuses on identification of the disordered components of the swallow and the therapeutic management techniques characteristic of the patient who has undergone excision of a skull base tumor.


Scintigraphic detection of salivary aspiration: description of a new diagnostic technique and case reports. Pneumonia is the feared consequence of persistent aspiration of saliva. Although some persons with impaired protection of the laryngeal airway are thought to be at risk, it is not known with certainty which factors are important. Some patients receive tracheostomies to enhance airway safety, often without clear evidence of aspiration of oropharyngeal secretions. A simple, readily available technique is described by which oral secretions are scintigraphically labeled with technetium-99m sulfur colloid via slow intraoral infusion. Subsequent sequential chest imaging with a gamma camera allows detection and tracking of the aspirated material. Three persons are described in whom this technique was used. In one, the scintigraphic analysis was instrumental in implicating infected saliva as the likely source of recurrent pulmonary infections. Although the method is useful in detecting aspiration of saliva in high risk persons, more study is needed to equate the degree of aspiration visualized with the risk of pulmonary disease.


Multiple swallows and piecemeal deglutition; observations from normal adults and patients with head and neck cancer. The incidence of multiple swallows for liquid and paste, and the time delay between multiple swallows, was determined from videofluoroscopic records of modified barium swallow tests. In a comparison of liquid and paste, the overall incidence of multiple swallows did not differ, for either patients with head and neck cancer or normal controls. However, for liquid swallows the incidence in patients with cancer was abnormally high, predominantly in patients with pharyngeal cancer.


Impact of the diagnostic procedure on outcome measures of swallowing rehabilitation in head and neck cancer patients. This study was designed to determine whether swallow rehabilitation outcomes were affected by the type of evaluation procedure utilized by the clinician. The two evaluation techniques compared were the bedside examination and videofluoroscopy (the modified barium swallow). Ten institutions participated in this study, enrolling a total of 103 partial laryngectomized patients, 21 in the bedside arm and 82 in the videofluoroscopy arm. Data on recovery of oral intake were collected weekly. All patients received an X-ray study of swallow at 3 months after the operation. Mean time to oral intake of food was significantly lower in patients assessed with bedside examination. Overall swallow measures of transit times and swallow efficiencies after 3 months revealed significantly better function in the videofluoroscopy group. Results are discussed in terms of the visibility of swallow physiology with the two assessment techniques, the accuracy of therapy planning with the bedside examination versus videofluoroscopy and the ability of head and neck cancer patients to tolerate some aspiration without developing aspiration pneumonia.


Perendoscopic pneumatic dilatation in achalasia: assessment of outcome using esophageal scintigraphy. Sixteen patients (nine male) underwent perendoscopic pneumatic dilatation for achalasia. The Witzel dilator was chosen as it allows placement of the balloon under endoscopic vision. Its efficacy was assessed using esophageal scintigraphy. Symptom score and esophageal transit values at 100 s and after a drink of water all improved significantly (P less than or equal to 0.014) after dilatation and there was a significant correlation between the improved symptom score and the change in transit values after 100 s (r = 0.586, P = 0.017). At follow-up at 8 (3-16) months [mean (range)], 15 of 16 patients (94%) are symptom free. The Witzel dilator is effective in the treatment of achalasia. Esophageal scintigraphy offers a quantitative assessment of esophageal function, helping the clinical investigator evaluate new forms of therapy.


Clinical and demographic data in 75 patients with near-fatal choking episodes. The clinical background and circumstances of 75 patients who had survived a near-fatal choking episode, i.e., had undergone a Heimlich maneuver, oropharyngeal suctioning, or intubation, is reported. Sixty had choked on a solid bolus (often of a complex texture like sandwiches and chicken soup). Four patients had choked on mashed banana. In 30 patients neurologic disease (such as cerebrovascular disease, Parkinson disease, or dementia) was present. Choking occurred during breakfast (16 patients), lunch (21), dinner (26), and snacks (12). Twenty-five choked at home, 18 in nursing homes, 14 in hospitals, nine in restaurants, and nine in drinking establishments. Twelve were being fed at the time of choking. Fifty-eight of the individuals had oral, pharyngeal, or esophageal abnormalities on radiographic examination that could explain the choking episode. Fourteen patients who were able to vocalize during the choking episode had probably suffered from esophageal impaction. Our study indicates that elderly individuals and those with neurogenic dysphagia are at risk for choking. Dysphagia diet (semisolids) may actually contribute to the risk in these patients. Young adults may also be at risk during episodes of consumption of alcohol and snacks.


Dysphagia in cerebral palsy: a comparative study of the Exeter Dysphagia Assessment Technique and a multidisciplinary assessment. Eighteen children with cerebral palsy in a special school, most of whom had feeding difficulties, were studied to compare the diagnostic value of the Exeter Dysphagia Assessment Technique (EDAT) with an exhaustive clinical assessment undertaken by a multidisciplinary team experienced in the diagnosis and treatment of dysphagia of neurological origin. Four feeding skills were assessed by each method independently, viz. anticipation, intraoral sensory perception, oral-motor efficiency, and pharyngeal triggering. Comparison of the two sets of results showed agreement in at least 78% of the assessed skills. The possible reasons for the few discrepancies are discussed. The noninvasive EDAT equipment was easy to use with the children, who had a range of type and severity of cerebral palsy. The test was undertaken in their familiar surroundings and took 15 to 20 min per child. Interpretation of the results showed that EDAT provided a rapid, reliable diagnostic aid which assisted in the assessment of the degree of feeding impairment within each of the four feeding skills tested.


Foreign body entrapment in the esophagus of healthy subjects--a manometric and scintigraphic study. Foreign body entrapment and mucosal injury caused by oral medications are increasingly reported to occur in the upper esophagus in apparently normal subjects. We performed esophageal manometry in 40 normal volunteers to determine whether a unique motility pattern in the upper third of the esophagus predisposes to entrapment of foreign bodies at this site; 18 normal volunteers also had transit scintigraphy of a gelatin capsule filled with a radionuclide. The esophageal body was divided into five consecutive segments starting proximally, with each segment corresponding to 20% of the total length. Amplitude, slope, and velocity of the esophageal contraction were markedly decreased in the second segment compared with the other segments. Entrapment and dissolution of a gelatin capsule occurred in 39% of volunteers in the proximal esophagus correlating to the second segment, i.e., the segment with the lowest amplitude, slope, and velocity of esophageal contractions. The observation that wet swallows have greater amplitudes (P less than 0.01) and steeper slopes (P less than 0.05) than dry swallows explains why the occurrence of pill entrapment was reduced when taken with sufficient water. However, even with a water chaser of 120 mL, pill entrapment occurred at the second segment of the esophagus in 1 of 18 volunteers. The observed motility pattern in the proximal esophagus provides a better explanation for the entrapment of foreign bodies at this site than compression of the esophagus by the left main stem bronchus, aortic arch, or left atrium as suggested by other investigators.


Velar activity and timing of eustachian tube function in swallowing. Velar motion for dry and liquid swallows was investigated. as well as velar activity in speech, based on X-ray microbeam pellet tracking data. Electromyographic recordings for tensor and levator veli palatini were obtained simultaneously. Velar pellet trajectories for swallowing were more complex than for speech, since there was a high-velocity anterior component in swallowing. For some swallows this anterior component was integrated with velar elevation (especially in liquid swallows), but in other cases initial velar elevation occurred considerably earlier (chiefly in dry swallows). The burst of tensor and levator veli palatini activity characteristic of swallowing was associated with the anterior component of velar pellet motion, but not consistently with velar elevation per se. The conventional view on timing of tensor veli palatini contraction in a swallow, which governs Eustachian tube opening, is that this is associated with velar closure. The X-ray microbeam data suggest rather that Eustachian tube ventilation is more closely associated in time to the onset of pharyngeal peristalsis, which may or may not coincide with initial velar elevation.


Oral dysfunction following Nissen fundoplication. In this case report we describe a child with mild neurologic impairment who developed debilitating gagging and retching, and severe oral-motor dysfunction following Nissen fundoplication and gastrostomy tube placement. All oral intake ceased after the operation. Evaluation for postoperative dumping syndrome was negative, and the child's symptoms failed to improve despite numerous medical and surgical measures. However, immediately following reversal of the Nissen fundoplication, the child's gagging and retching ceased, and his oral-motor function began to improve. This is a previously undescribed complication of Nissen fundoplication, a surgical procedure commonly employed in children with neurologic impairment.


Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Photodynamic therapy has been used since 1980 at our institution for the management of cancer of the tracheobronchial tree. We identified 13 patients (14 cancers) who were thought to be surgical candidates but who elected to have photodynamic therapy. Thirteen cancers (93 percent) had a complete response to hematoporphyrin-derivative phototherapy. Ten cancers (71 percent) showed a complete response after single treatment, and three (21 percent) required a second course of therapy to achieve a complete response. Ten (77 percent) of 13 cancers have shown no local recurrence. Three patients with persistent cancer underwent surgical resection and were found not to have nodal involvement. We concluded that photodynamic therapy is an alternative to surgical resection in the management of early superficial squamous cell carcinoma.


Bronchoalveolar lavage in trauma patients for diagnosis of fat embolism syndrome. Fat embolism syndrome (FES) is a rare but serious complication occurring after long bone fractures. Presence of fat droplets in cells obtained by bronchoalveolar lavage has been proposed as a specific tool for FES diagnosis in trauma patients. We evaluated this technique over a 15-month period in 85 patients. Twenty-eight patients were excluded. The remaining 57 patients were divided into three groups: group 1, 26 patients without trauma as control; group 2, 22 patients with trauma but without evidence of FES; and group 3, nine patients with trauma and evidence of FES. Six of 26 patients in group 1 and nine of 22 patients in group 2 exhibited fat droplets in alveolar macrophages, whereas three of nine patients of group 3 had not. This study suggests that (1) presence of fat droplets in alveolar macrophages is not a reliable method for diagnosis of FES after long bone trauma, and (2) many conditions are associated with fat droplets in alveolar macrophages.


Sputum cytology-positive, bronchoscopically negative adenocarcinoma of the lung. Among a total of 114 cases of resected lung adenocarcinoma that were examined by sputum cytologic study before bronchoscopy, 17 were sputum cytology-positive, but had no abnormal bronchoscopic findings. In most of these cases, the reason for detection was sputum and bloody sputum (58.8 percent). Pathologically, many cases were classified as stage III A or more (82.4 percent) due to mediastinal lymph node metastases. More than 70 percent of the cases showed vascular invasion. The proportion of well-differentiated cases was also high (52.9 percent). The prognosis of these cases was worse than sputum cytology-negative adenocarcinoma without abnormal bronchoscopic findings and better than sputum cytology-positive adenocarcinoma with abnormal bronchoscopic findings. There was no significant difference between these cases and sputum cytology-negative adenocarcinoma with abnormal bronchoscopic findings. Combined with the bronchoscopic findings, sputum cytologic study is useful for preoperative evaluation of lymph node metastasis and prognosis. This combined approach can provide information necessary to perform sufficient dissection of mediastinal lymph nodes and proper adjuvant therapy in sputum cytology-positive adenocarcinoma cases, even though there are no abnormal bronchoscopic findings.


Relationship between pleural changes after myocardial revascularization and pulmonary mechanics. It is known that coronary artery bypass grafting (CABG) results in impairment of postoperative pulmonary function. There is also a high incidence of pleural changes (pleural effusion or pleural thickening) after CABG. We hypothesized that those patients with pleural changes in the postoperative period would have a greater decrease in pulmonary function test (PFTs) results. The present study reports the results of 110 male patients who underwent CABG. The chest films and the PFT results obtained preoperatively and on the sixth postoperative day were reviewed. The relationship between pleural changes and PFTs was analyzed in patients who received saphenous vein graft alone (SVG group: 50 patients) or in combination with internal mammary artery grafting (IMA group: 60 patients). In the IMA group, the patients who had pleural changes had significantly greater decreases in their pulmonary function than did the patients without pleural changes. The decrease in the FVC, TLC and FEV1 in the patients with pleural effusions (37.6, 27.8 and 36.8 percent) was similar to that in patients with pleural thickening (34.6, 28.3 and 35.0 percent) and both were significantly greater (p < 0.05) than the changes in the patients with a normal radiograph (26.1, 17.6 and 26.9 percent). In the SVG group, the presence of pleural changes was not significantly related to the decrement in pulmonary function. The values of RV, FRC, Cst, and blood gases were not affected in the SVG or IMA group by the presence of pleural changes. We conclude that the presence of pleural changes on the chest radiograph is associated with a larger decrement of pulmonary function after CABG in the IMA group. This larger decrease probably reflects added thoracic trauma and is not due to the presence of pleural changes per se.


Arterial blood gases after coronary artery bypass surgery. Coronary artery bypass graft (CABG) surgery adversely affects arterial blood gas (ABG) determinations. The purposes of this study were to assess serial changes in ABGs following bypass surgery and identify factors that may influence these changes. Room air ABGs were obtained preoperatively and on days 1, 2, 4, 6, and 8 postoperatively on 125 patients undergoing bypass surgery. Fifty-five patients (saphenous vein grafting [SVG] group) had only SVG grafting while 70 (internal mammary artery [IMA] group) received one (60 patients) or two (10 patients) IMA grafts in addition to the SVG grafts and were subjected to pleurotomy. The mean preoperative values (+/- SD) were as follows: PaO2, 75.1 +/- 7.7 mm Hg, P(A-a)O2, 20.9 +/- 7.5 mm Hg; PaCO2, 33.6 +/- 4.1 mm Hg; pH, 7.43 +/- 0.04; hemoglobin, 14.8 +/- 1.4 g/dl; and hematocrit, 44.2 +/- 3.9 percent. There was a large decrease in the PaO2 postoperatively. The nadir for the PaO2 (55.7 +/- 6.6 mm Hg) occurred on the second postoperative day. Eight days postoperatively, there were still significant abnormalities; the PaO2 was 65.7 +/- 7.3 mm Hg, the P(A-a)O2 was 33.2 +/- 8.8 mm Hg; the hemoglobin was 10.5 +/- 1.4 g/dl; and the hematocrit was 31.7 +/- 4.0 percent. The decrease in the PaO2 was particularly noteworthy given the large decrease in the hemoglobin and hematocrit. The changes in the PaO2 were not significantly correlated with the age, number of grafts, pump time, length of anesthesia, or endotracheal intubation or smoking history. Immediately postoperatively, changes were similar in both groups (p > 0.05); on the second postoperative day, the PaO2 had decreased 26.9 percent in the SVG group and 25.5 percent in the IMA group. However, the postoperative abnormalities resolved more slowly in the IMA group (p < 0.05). These observations suggest that the additional trauma to the lungs and chest wall in the IMA group (pleurotomy, the placing of pleural drains, etc) will result in a longer recovery time in the IMA group than in SVG group.


An evaluation of severity-modulated compliance with q.i.d. dosing of inhaled beclomethasone. Although the asthmatic subject's compliance with a regimen of inhaled corticosteroids is often poor, it has been suggested this may improve during periods of increased severity. To test this, we measured daily peak expiratory flow rates (PEFRs), asthma symptoms, and the use of an albuterol inhaler over nine weeks period in ten patients with moderately severe asthma. The effect of changes in these severity indices on compliance with a q.i.d. regimen of inhaled beclomethasone was evaluated. The PEFR was measured in the morning before bronchodilator administration, and symptoms were graded on a scale of 4 to 16, while albuterol and beclomethasone inhalations were electronically recorded. Three measures of compliance with the beclomethasone regimen were used: (1) mean daily compliance ([number of inhalations/number of prescribed inhalations] x 100); (2) underuse, ie, the percentage of days with less than the prescribed number of inhalations; and (3) overuse, ie, the percentage of days with greater than the prescribed number of inhalations. Mean daily compliance was 67 +/- 36 percent, while underuse was observed in 69 percent and overuse in 11 percent of the days. Despite clinical exacerbations in six of the ten patients and considerable variation in the severity indices, no significant relationship was found between the change in asthma severity and compliance with the beclomethasone regimen. These findings do not support the concept of severity-modulated compliance with inhaled corticosteroids.


Performance evaluation of three vaporizing humidifiers and two heat and moisture exchangers in patients with minute ventilation > 10 L/min. To compare the thermal and humidification capacity of three heated hot water systems (HHWSs) and two heat and moisture exchangers (HMEs) in ICU patients submitted to minute ventilation > 10 L/min. Prospective, controlled, randomized, not blinded study. ICU of a university hospital. ICU patients requiring controlled mechanical ventilation with minute ventilation > 10 L/min. Patients had to be sedated and paralyzed and had to require ventilation for more than four days. Following a randomized order, the patients were ventilated for 24-h periods with three HHWSs (Bennett Cascade 2 humidifier, Fisher-Paykel MR 460 and MR 600) and two HMEs (Pall Ultipor and Hygrobac filter). In each patient and for each 24-h period, absolute humidity, (AH), relative humidity (RH) of inspired gases, and tracheal temperature were obtained. Two HHWSs (Bennett and Fisher-Paykel MR 460) had a better thermal and humidification capacity than any other systems (p < 0.001). The hydrophobic HME (Pall filter) had a poor thermal and humidification capacity (RH: 79 +/- 8.7 percent; AH: 20.6 +/- 2.3 mg H2O/L). The hygroscopic filter (Hygrobac filter) had better thermal and humidification capacity than the Pall filter (RH: 92.5 +/- 3.6 percent; AH: 29.1 +/- 1.8 mg H2O/L; p < 0.001). Tracheal temperature was well preserved by all systems. The thermic and humidification capability of the Hygrobac filter declined over 24 h. Since the Pall filter could not achieve an AH > 25 mg H2O/L in any patient, it was not studied beyond the first measurement. The Hygrobac filter had a thermal and humidification capability closed to the two HHWSs (81 to 97 percent) but the capability declines over 24 h. The Pall filter had a poor capability (54 to 74 percent of that of HHWSs).


Inspiratory muscle training combined with general exercise reconditioning in patients with COPD. We compared, in a controlled clinical trial, the effect of specific inspiratory muscle training combined with general exercise reconditioning, for six months, with that of general exercise reconditioning alone on inspiratory muscle strength, endurance, and exercise performance in patients with COPD. Thirty-six patients were recruited into three groups; 12 patients received specific inspiratory muscle training combined with general exercise reconditioning, 12 patients underwent general exercise reconditioning alone, and the remaining 12 patients received no training. Specific inspiratory muscle training, for six months, improved the inspiratory muscle strength and endurance in patients with COPD. This training combined with general exercise reconditioning also provided improvement in exercise tolerance, and this improvement was significantly greater than that of general exercise reconditioning alone.


Inspiratory muscle training in patients with bronchial asthma. In patients with asthma, the respiratory muscles have to overcome the increased resistance while they become progressively disadvantaged by hyperinflation. We hypothesized that increasing respiratory muscle strength and endurance with specific inspiratory muscle training (SIMT) would result in improvement in asthma symptoms in patients with asthma. Thirty patients with moderate to severe asthma were recruited into 2 groups; 15 patients received SIMT (group A) and 15 patients were assigned to the control group (group B) and got sham training in a double-blind group-comparative trial. The training was performed using a threshold inspiratory muscle trainer. Subjects of both groups trained five times a week, each session consisted of 1/2-h training, for six months. Inspiratory muscle strength, as expressed by the PImax at RV, increased significantly, from 84.0 +/- 4.3 to 107.0 +/- 4.8 cm H2O (p < 0.0001) and the respiratory muscle endurance, as expressed by the relationship between Pmpeak and PImax from 67.5 +/- 3.1 percent to 93.1 +/- 1.2 percent (p < 0.0001), in patients of group A, but not in patients of group B. This improvement was associated with significant improvements compared with baseline for asthma symptoms (nighttime asthma, p < 0.05; morning tightness, p < 0.05; daytime asthma, p < 0.01; cough, p < 0.005), inhaled B2 usage (p < 0.05), and the number of hospital (p < 0.05) and sick-leave (p < 0.05) days due to asthma. Five patients were able to stop taking oral/IM corticosteroids while on training and one in the placebo group. We conclude that SIMT, for six months, improves the inspiratory muscle strength and endurance, and results in improvement in asthma symptoms, hospitalizations for asthma, emergency department contact, absence from school or work, and medication consumption in patients with asthma.


Quantitative assessment of dyspnea during exercise before and after bullectomy for giant bulla. Incremental exercise testing using a cycle ergometer was performed in eight patients with giant bulla before and after bullectomy to assess dyspnea. There was a significant positive linear relationship between dyspnea expressed in the Borg scale (BS) and oxygen consumption (VO2) during exercise in all subjects. From these correlations, we introduced the following three new parameters for quantitative assessment of dyspnea: the Borg scale slope (BSS); the threshold load of dyspnea (TLD); and the breakpoint load of dyspnea (BLD), representing the slope of the regression line, onset of dyspnea on the regression line, and the maximum oxygen consumption before the subjects interrupted exercise, respectively. After surgery, the BSS showed marked decrease, and the TLD and BLD showed significant increase. Therefore, the reduction in the dyspnea with peak exercise after surgery was thought to be, at least in part, based on the delay of dyspnea onset, the decrease in dyspnea sensitivity, and the improvement in exercise capacity. The improvement in dyspnea during exercise in patients with giant bulla after surgery was extensively evaluated by newly introduced parameters based on BS-VO2 regression line.


Pulse oximetry in the postoperative care of cardiac surgical patients. A randomized controlled trail. To demonstrate the utility of pulse oximetry in detecting clinically unapparent episodes of arterial desaturation in postoperative cardiac surgical patients and to evaluate the effect of pulse oximetry on ordering arterial blood gas analyses. Prospective, randomized, partially blinded comparison. Cardiothoracic surgical intensive care unit. 35 patients following elective cardiac surgical procedures. All patients were monitored continuously with pulse oximetry throughout their ICU course. In group 1 patients, the SpO2 data were available at the bedside. In group 2 patients, the SpO2 data were masked at the bedside and monitored at a remote location. Utilization of pulse oximetry allowed a significant reduction in arterial blood gas utilization in group 1 (group 1: 12.4 +/- 7.5 blood gas analyses per ICU admission vs group 2: 23.1 +/- 8.8; p = 0.0007) without adverse events. Clinically unapparent desaturations were detected in 7 of 15 patients in group 2. Pulse oximetry improves patient safety through the detection of clinically unapparent episodes of desaturation and can allow a reduction in the number of blood gas analyses utilized without adverse effects to the patient. This may allow a potential cost savings to the patient.


Cardiovascular risk factors in snorers. A cross-sectional study of 3,323 men aged 54 to 74 years: the Copenhagen Male Study. Former studies on the association between snoring and cardiovascular disease (CVD) have only partly taken established CVD risk factors into consideration. In the Copenhagen Male Study, 3,323 men aged 54 to 74 years were classified according to self-reported snoring habits. Eleven CVD risk factors were examined. The prevalence of snoring decreased with age, with a 50 percent higher frequency of snorers among the youngest quintile than among the oldest (p < 0.00001). Snoring, age adjusted, was positively associated with tobacco smoking (p < 0.001), alcohol consumption (p < 0.001), body mass index (BMI) (p < 0.0001), serum triglyceride level (p < 0.01), systolic blood pressure (p < 0.05) and nearly significantly associated with diastolic blood pressure (p = 0.07). Snorers were less physically active in leisure time than others (p < 0.01). The association between self-reported snoring and blood pressure disappeared when other factors, including BMI, were taken into consideration. No significant associations were found between snoring and social class, snoring and low- or high-density lipoprotein or between snoring and hypertension. We conclude that snoring is associated with major cardiovascular risk factors. Accordingly, it is evident that in studies on snoring and CVD, proper controlling for the influence of potential confounders is a sine qua non.


Measurement of mucociliary transport velocity in ventilated patients. Short-term effect of general anesthesia on mucociliary transport. The objectives of this study were to evaluate a method for measuring BTV in ventilated patients and to study the short-term effect of general anesthesia with midazolam, Fentanyl, pancuronium and O2:N2O on BTV. The study included phantom measurements on a bronchoscopy model and the determination of BTV in patients in a convenience sample trial. The study took place in a university hospital. Fourteen patients undergoing major abdominal surgery with planned postoperative mechanical ventilation were included in the study. All patients gave their written informed consent to participate in the study. Bronchial mucus transport velocity was measured with a small volume (0.05 to 0.08 ml) of technetium 99m-labeled albumin microspheres with an activity of 3 MBq. The radiolabeled bolus was deposited on the dorsal mucosal surface at the distal end of the right and left main bronchus via flexible bronchoscopy. The movement of the microspheres toward the trachea was visualized and recorded using a scintillation camera; quantitative evaluation utilized the condensed image. The technique was validated in a bronchoscopy model and in an intubated patient by moving a radioactive drop in a catheter through the main bronchi at velocities from 0 to 20 mm/min. The velocities determined by the image processing technique correlated well with the data by the model and patient determination (right bronchus, r = 1.0; left bronchus, r = 1.0). In seven ventilated patients, mechanical irritation by the fiberscope produced no significant effect on BTV. The BTV was measured preoperatively in seven conscious patients one day before surgery while they received local anesthesia with 10 ml of 1 percent lidocaine and postoperatively while they received intubation anesthesia. The preoperative and postoperative BTV values showed no significant differences (10.5; 5.7 to 13.7 mm/min; vs 9.7 (3.7 to 15.3) (median with range). By this method, bronchial transport velocity can be determined in a relatively short time in ventilated patients. General anesthesia with midazolam, Fentanyl, pancuronium and O2:N2O does not influence BTV.


Two-year bronchodilator treatment in patients with mild airflow obstruction. Contradictory effects on lung function and quality of life. In a two-year randomized controlled study, we studied the effects of bronchodilator treatment on the lung function and the quality of life in patients with mild airflow obstruction. The patients were randomly divided to receive either continuous or symptomatic bronchodilator treatment. Within these treatment groups, they received salbutamol in the first year and ipratropium bromide in the second or vice versa. In addition, the quality of life of the patients was compared to that of the general population. One hundred and forty-four patients completed the study. When compared to the general population, these patients showed a serious impairment in quality of life. No differences between the two drugs were found, but the results indicated that FEV1 decline in the continuously treated group was significantly larger than in the symptomatically treated group. However, this was not reflected in a significant deterioration of the quality of life in the continuous group as measured by means of the Nottingham Health Profile and the Inventory of Subjective Health. Decline in FEV1 showed no correlation with changes in quality of life scores. This may be due to a relatively rapid adjustment of the patients to a decline in FEV1, as a result of which it has no direct effect on the experienced quality of life. Another reason may be that continuous bronchodilation masks the worsening of the disease. This lack of awareness might in turn be caused by the continuous symptom relief of bronchodilators.


Inpatient management of status asthmaticus. We examined physician management of patients hospitalized for status asthmaticus at a university hospital. A retrospective review of consecutive admissions for status asthmaticus covering a 13-month period yielded 130 charts for review. We found that practice patterns with respect to documentation of severity of illness, medications, and documentation of efficacy of therapy fell short of the current state of knowledge with respect to treatment of asthma. Asthma is a treatable disease, and physician education needs to bridge the gap between current practice patterns and standards of optimal therapy as defined in the literature.


Effect of nasal continuous positive airway pressure on cardiac output and oxygen delivery in patients with congestive heart failure. We studied the acute hemodynamic effects of increasing nasal continuous positive airway pressure (CPAP) in 13 patients with acute decompensation of congestive heart failure. Heart rate, respiratory rate, pulmonary capillary wedge pressure, right atrial pressure, systemic blood pressure, and thermodilution cardiac outputs were measured at baseline, during, and after application of nasal CPAP at increasing pressures of 5, 10, and 15 cm H2O. Cardiac index, stroke volume, and oxygen delivery were calculated. Based on a significant change in cardiac output greater than or equal to 400 ml, seven patients were classified as responders, whereas six patients were considered to be nonresponders. In responders, significant increases were noted in cardiac index (2.5 +/- 0.7 to 2.9 +/- 0.9 L/min/m2), stroke volume (49 +/- 15 to 57 +/- 16 ml), and oxygen delivery (10.3 +/- 5.1 to 12.3 +/- 6.0 ml/min/kg) without a change in pulmonary capillary wedge pressure. In contrast, the nonresponders showed no significant change in any of the hemodynamic parameters. Improvement in cardiac output could not be predicted by any of the baseline hemodynamic or clinical variables, nor was it related to random variations since all variables returned to baseline after cessation of CPAP. Increase in stroke volume without a change in pulmonary capillary wedge pressure (preload) suggests either improved inotropic function of the left ventricle or reduced left ventricular afterload with CPAP. Thus, CPAP may offer a new noninvasive adjunct to improving left ventricular function and augmenting cardiac performance in a subset of patients with congestive heart failure.


Intracranial hemodynamics in sleep apnea. Intracranial pressure changes and poor cerebral perfusion have been reported in sleep apnea syndrome (SAS), but such studies have been limited due to lack of a reliable noninvasive study method. We determined the systolic (VS), diastolic (VD), and mean (VM) cerebral blood flow velocities of the middle cerebral artery in 23 individuals (12 severe SAS patients and 11 control subjects) using transcranial Doppler sonography before sleep, during sleep (NREM and REM) and upon awakening. All three velocities (VS = 87.4 cm/s compared to 104.7 cm/s, VD = 41.6 cm/s compared to 47.7 cm/s, and VM = 57.0 cm/s compared to 67.0 cm/s) were decreased in patients with SAS and VS and VM were significantly lower than in control subjects (p = 0.005 and p = 0.033, respectively). The end-tidal CO2 (PETCO2) in the SAS patients (47.3 mm Hg) compared to the control subjects (41.8 mm Hg) was significantly higher (p = 0.003). When the VM was adjusted to normalized CO2 using the Markwalder's equation, the reduction in velocity in patients with SAS (47.5 cm/s) compared to control subjects (63.0 cm/s) became more significant (p = 0.005). This study shows that cerebral blood flow velocities are lower in patients with SAS compared to control subjects and that transcranial Doppler sonography may be useful in such evaluations.