Impedance cardiography using the Sramek-Bernstein method: accuracy and variability at rest and during exercise. 1. Sramek and Bernstein's method of impedance cardiography is a simple, non-invasive and inexpensive computerised way of measuring stroke volume and systolic time intervals. In this study measurements made using the method were compared with those found simultaneously using established reference techniques. 2. In healthy volunteers there was no significant bias (d) and narrow 95% limits of agreement (d +/- 2s) when impedance and mechanophonocardiographic measurements of pre-ejection period (PEP, d = 0.3, d + 2s = 7.3, d-2s = -6.6 ms), ventricular ejection time (VET, d = 1.5, d + 2s = 17.7, d-2s = 14.6 ms) and PEP/VET ratio were compared. 3. In critically ill patients there was moderate agreement between impedance and thermodilution measurements of stroke volume (d = 8.1 (P < 0.05), d + 2s = 35.5, d-2s = -19.4 ml) and drug-induced changes in stroke volume were accurately detected. 4. In healthy volunteers agreement between impedance and dye dilution measurements of stroke volume was moderate, and similar at rest and during exercise (d = 3.4, d-2s = -31.1, d + 2s = 37.9 ml), however impedance underestimated exercise-induced increases in stroke volume (P < 0.05). 5. In patients with coronary heart disease impedance measurements correlated with angiographic left ventricular ejection fraction included the PEP/VET ratio (r = -0.81), stroke volume index (r = 0.65) and Heather index (r = 0.58, all P < 0.001), however the PEP/VET ratio could not be used to estimate the left ventricular ejection fraction with sufficient accuracy. 6. This impedance method provides reproducible semi-quantitative measurements of cardiac performance and blood flow. Its use for making pharmacodynamic measurements can be justified when invasive methods are considered inappropriate.


Clinical, radiological, and functional evaluation following acute stroke. 1. There are currently no proven treatments for cerebral infarction or intracerebral haematoma. Drug testing is at an exciting phase, however, and thrombolytic and neuroprotective agents appear to have the potential to rescue ischaemic cerebral tissue. The heterogeneous nature of stroke demands adequate patient assessment by clinical and radiological study, with standardised approaches to the measurement of recovery. 2. Previous studies have not fulfilled these stringent criteria, impairing interpretation and inter-study comparison. The needs of drug studies in the acute phase following stroke are discussed in this review.


Therapeutic interventions in acute stroke. 1. Potential therapies for ischaemic stroke include agents to reduce oedema, to improve cerebral perfusion, to reduce excitotoxic damage, to minimise free-radical induced injury and to reduce complications such as deep venous thrombosis. 2. Of the anti-oedema drugs, steroids are ineffective and possibly dangerous; intravenous glycerol is unproven. 3. Haemodilution to reduce whole blood viscosity and improve perfusion is ineffective. Thrombolytic drugs have not been adequately tested but several randomised multicentre trials are now commencing. Early treatment and CT scanning are essential. 4. Anticoagulants and antiplatelet drugs may have wide applicability but have not been tested in the acute phase of stroke. A multi-centre trial will address this issue. 5. Neuronal cytoprotection offers exciting prospects for acute stroke treatment. Antagonists of glutamate at the NMDA receptor, calcium and sodium channel blocking agents and free radical scavenging drugs have potent effects experimentally. Several agents are now reaching clinical trials. The calcium antagonist nimodipine has been disappointing in large scale trials but some studies were flawed by late treatment. 6. Successful treatment of acute stroke is likely to combine several approaches. 7. Therapeutic trials in stroke must include CT scanning, early treatment and a multicentre approach to achieve large numbers of patients.


Co-regulation of phenytoin and tolbutamide metabolism in humans. 1. The disposition of phenytoin and tolbutamide was compared in eighteen healthy young adults separately administered single therapeutic doses (sodium phenytoin 300 mg, tolbutamide 500 mg) of the two drugs. 2. Within the group, ratios of ranges of total and unbound areas under the plasma concentration-time curves were similar for both drugs. 3. There were significant (P < 0.001) correlations between total (r = 0.88) and unbound (r = 0.86) areas under the plasma phenytoin and tolbutamide concentration-time curves. 4. The results are consistent with the involvement of the same cytochrome P-450 isoenzyme(s) in the metabolism of tolbutamide and phenytoin.


The pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in haemodialysis patients. 1. The pharmacokinetics of and therapeutic response to recombinant human erythropoietin (rcEPO) were studied in 12 patients under chronic haemodialysis on a thrice weekly intravenous rcEPO treatment scheme. The kinetics of rcEPO were also assessed after a subcutaneous injection during the initial period and during maintenance treatment. RcEPO was measured in plasma by radioimmunoassay. 2. After the first i.v. dose plasma erythropoietin concentrations were best described by a monoexponential disposition function with a mean (+/- s.d.) elimination half-life of 5.4 +/- 1.7 h. The volume of distribution was 70 +/- 5.2 ml kg-1 and the clearance was 10.1 +/- 3.5 ml h-1 kg-1 (n = 12). 3. After 3 months of continuous therapy, the plasma half-life of rcEPO decreased by 15% (P < 0.05, mean half-life during steady state: 4.6 +/- 2.8 h), while mean clearance and volume of distribution remained constant. 4. After the first s.c. injection the mean (+/- s.d.) absorption time was 22 +/- 11 h and systemic availability was 44 +/- 7%. 5. Changes in haemoglobin concentrations were described by a linear additive dose-response model, defined by an efficacy constant (Keff) and the mean erythrocyte lifetime (MRTHb). The sample mean (+/- s.d.) Keff was 0.043 +/- 0.017 g dl-1 Hb per 1000 units rcEPO and MRTHb was 10.02 +/- 1.75 weeks. The net effect of rcEPO treatment was described by the area under the unit-dose-response curve (AUEC) with a mean (+/- s.d.) value of 0.45 +/- 0.23 g dl-1 weeks. 6. RcEPO clearance showed a significant positive correlation (r2 = 0.41) with the effectiveness of rcEPO therapy, as measured by the parameters Keff or AUEC.


A study of the interaction of omeprazole and warfarin in anticoagulated patients. 1. Thirty-five patients on continuous therapy with warfarin were given omeprazole 20 mg once daily and placebo each for 3 weeks according to a two-centre randomised double-blind cross-over design. 2. Blood samples were obtained once weekly during the run-in and follow-up periods as well as during the first 2 weeks of each treatment period, and twice during the last week of each treatment period. Plasma concentrations of R- and S-warfarin were measured by h.p.l.c. and the anticoagulant effect was assessed using the Trombotest. 3. Twenty-eight patients were evaluated. The mean plasma concentration of R-warfarin was increased by 9.5% during omeprazole treatment compared with placebo, while that of S-warfarin, the more active isomer, was unaffected. The coagulation time was not significantly changed (106 s during omeprazole and 98 s during placebo). Corresponding TT-values (Trombotest) were 8.8 and 9.9 (NS).


Blood cyclosporin concentrations and the short-term risk of lung rejection following heart-lung transplantation. 1. The relationship between blood cyclosporin concentration (CyACb) and a patient's risk of organ rejection following heart-lung (HL) transplantation was investigated. 2. Longitudinal data were collected for 90 days post-operation for 31 HL transplant recipients. Following exploratory analysis, a multiple logistic regression model with a binary outcome variable representing presence or absence of lung rejection (as defined on biopsy findings and/or intention to treat) in the next 5 days was fitted to the data. 3. A significant interaction between time post-transplant and CyACb was found. During weeks 1-3, the relative risk (RR) of rejection per unit increase in log(e) (5-day mean CyACb) was reduced: RR = 0.29, 95% confidence interval (CI) = (0.12, 0.72). After 3 post-operative weeks, this trend was reversed: RR = 1.61, 95% CI = (0.96, 2.70). Increases in cyclosporin dose (CyAD) and in coefficient of variation (CV) for both CyAD and CyACb over the previous 10 days significantly increased the risk of rejection: RR per unit increase in log(e) (5-day mean CyAD) = 2.72, 95% CI = (1.18, 6.25); RR per increase of 10% (i.e. from, say, 20% to 30%) in the CV for CyAD = 1.20, 95% CI = (1.07, 1.36); RR if the CV for CyACb > 40% = 1.51, 95% CI = (1.01, 2.27). Administration of high dose steroids in the previous 5 days was found to protect against further rejection: RR if steroid treatment was given = 0.23, 95% CI = (0.13, 0.38).(ABSTRACT TRUNCATED AT 250 WORDS)


Trials of the bronchodilator activity of the isoenzyme-selective phosphodiesterase inhibitor AH 21-132 in healthy volunteers during a methacholine challenge test. 1. An approximately steady-state reduction of specific airway conductance was induced in normal human subjects by means of a methacholine individualized loading+maintenance dose regime. Tested against this background bronchoconstriction, the mixed type III/IV phosphodiesterase inhibitor AH 21-132, ingested in doses up to 90 mg, had no detectable bronchodilator activity. 2. AH 21-132, infused intravenously over 15 min, evoked short-lived bronchodilatation at doses of 20 and 40 mg, without affecting blood pressure or heart rate. 3. AH 21-132, mixed 1:18.5 by weight with sucrose, dissolved in saline, nebulized and inhaled in doses between 2 and 24 mg of AH 21-132, produced dose-dependent bronchodilation. The ED50 was estimated as 9.2 mg AH 21-132. The peak relief of imposed bronchoconstriction was 80% and the apparent half-time of removal of AH 21-132 from its site of action was 25 min. 4. Inhaled, nebulized, hypertonic sucrose had a minor bronchodilator action. 5. AH 21-132, by intravenous and inhaled routes of administration, provides relief of methacholine-induced bronchoconstriction.


The effect of genetically engineered glucagon on glucose recovery after hypoglycaemia in man. To compare the effect on glucose recovery after insulin-induced hypoglycaemia of intramuscular genetically engineered glucagon, intramuscular glucagon from pancreatic extraction and intravenous glucose, we examined 10 healthy subjects during blockage of glucose counterregulation with somatostatin, propranolol and phentolamine. Each subject was studied on three separate occasions. Thirty min after a bolus injection of 0.075 iu soluble insulin per kilogram body weight the subjects received one of the following treatments: 1 mg glucagon from pancreatic extraction intramuscularly; 1 mg genetically engineered glucagon intramuscularly; and 25 g glucose intravenously, respectively. The two glucagon preparations induced an equally rapid increase in plasma glucose. This was due to an abrupt (within 4 min) and equal increase in glucose appearance rate. The increases in both plasma glucose and in glucose appearance rate were far more protracted after i.m. glucagon than after i.v. glucose. These results suggest that genetically engineered glucagon and glucagon from pancreatic extraction have a similar effect on hepatic glucose production rate. Due to the protracted effect of intramuscular glucagon, a combined treatment consisting of both intravenous glucose and intramuscular glucagon may be more effective in the treatment of hypoglycaemia than any of these given alone.


Trimethoprim, alone or in combination with sulphamethoxazole, decreases the renal excretion of zidovudine and its glucuronide. Trimethoprim and trimethoprim-sulphamethoxazole (co-trimoxazole) are often prescribed in HIV patients treated with zidovudine. The pharmacokinetics of zidovudine, after a dose of 3 mg kg-1 by constant rate intravenous infusion over 1 h were evaluated in nine HIV patients in an open, randomized, three-phase crossover study, without and with trimethoprim (150 mg) and trimethoprim-sulphamethoxazole (160 and 800 mg). The metabolic clearance of zidovudine was not significantly influenced by trimethoprim-sulphamethoxazole and trimethoprim. However, the renal clearance of zidovudine was decreased by 58 and 48%, respectively, and that of its glucuronide by 27 and 20% (P < 0.05). The fraction of the dose excreted as the parent compound fell by 47 and 39% and the metabolic ratio by 48 and 43% (P < 0.05). This kinetic drug interaction, apparently due solely to trimethoprim, may only be clinically important when hepatic glucuronidation is also impaired by liver disease or inhibited by other drugs.


Photosensitive psoriasis.

Photosensitive psoriasis. Photosensitive psoriasis is rare. The prevalence among psoriasis patients was estimated to be 5.5%. Photosensitive psoriatics have a statistically significant higher frequency of skin type I, a heredity of photosensitivity, advanced age, and psoriasis affecting hands compared with nonphotosensitive psoriatics. Half of the patients with photosensitive psoriasis have polymorphous light eruption (PLE), with psoriasis appearing as a secondary phenomenon in the PLE lesions. The other half slowly develop psoriasis after sun exposure but without preceding PLE. These reaction patterns may be confirmed with phototesting. Photochemotherapy is effective treatment for photosensitive psoriasis.


Optimal efficacy of topical corticoids in psoriasis. Topical corticoids remain the mainstay of treatment for mild psoriasis. In recent years certain valuable modifications of this mode of treatment have emerged. Clobetasol propionate was found to induce the highest immediate response if applied as intensive pulse therapy and possibly also to induce longer remissions than other compounds. Once-daily application of betamethasone dipropionate in optimized vehicle and mometasone furoate were at least as effective as repeated applications of several other compounds. There are indications of a dissociation of potency and side effects for mometasone furoate. Thus, corticoid therapy now can be tailored to suit more closely the needs of the patients than was possible previously.


Home ultraviolet phototherapy.

Home ultraviolet phototherapy. Home UV phototherapy is extremely popular with many psoriasis patients. However, it is essential that they understand the need for regular skin examination by the dermatologist. Patients with psoriasis are not trained nor are many nondermatologist physicians to recognize the early features of many skin cancers, and continued home UV therapy in the presence of such skin cancers is clearly unwise for the safety of that patient. The use of UVA tanning salon treatments in the therapy of psoriasis is usually unsuccessful and is extremely unwise with concomitant psoralen and drug therapy. This is to be discouraged, and the patient should always be treated with PUVA in the dermatologist's office with carefully monitored UVA machines and staff trained in the administration of PUVA phototherapy.


PUVA: how to use it for maintenance.

PUVA: how to use it for maintenance. The selection of optimal maintenance therapy for psoriasis needs great dermatologic skill. The choice between topical therapy, photochemotherapy (PUVA), UVB, and immunomodulating regimens alone or in combinations is a balance between cost and benefit. The effectiveness of healing and the tendency to relapse stands against convenience and access of therapy, the patients' motivation, and not least, the risks of side effects. The effective PUVA-maintenance must be reserved for patients who do not experience clearing of their disease on mild topical and UVB regimens.


Practical use of retinoids in psoriasis. In two decades, retinoids have nearly revolutionized some aspects of dermatologic practice. The dramatic response of severe acne to isotretinoin therapy is equally matched at times by the rapid response of pustular psoriasis treated with etretinate. Many other psoriatic patients, especially those who have failed the standard therapeutic regimens, have immensely benefited by the addition of retinoids to the therapeutic armamentaria. The use of etretinate or acitretin where available has repeatedly shown their utility, general safety, and cost effectiveness. Additionally, the advent of combination therapy with UV light has allowed better response using less retinoid and less light, eg, in retinoid-light combinations. With careful attention to the safety profile of retinoids, especially in the area of pregnancy prevention, a powerful therapy option is available for even the most recalcitrant patients. These responses would be sufficient reason for interest in retinoids but, when coupled with the exciting developments in molecular biology of retinoids, lead one to look with excitement on the dermatologic horizon for a new generation of significant breakthroughs.


Can maintenance cyclosporine be used in psoriasis without decreasing renal function? Nephrotoxicity attributable to cyclosporine therapy is dose dependent and unlikely to occur in psoriasis treatment protocols using less than 5 mg/kg/d in otherwise healthy patients. Any long-term or maintenance protocol should include regular monitoring of urea nitrogen/creatinine levels and blood pressure. Cyclosporine is a potent drug, and it is reasonable to monitor its administration to otherwise healthy psoriasis patients with yearly measurement of glomerular filtration rate (GFR), especially in elderly patients or patients with diminished renal reserve (eg, diabetes). There is no convincing evidence of irreversible renal dysfunction in psoriasis patients on low-dose cyclosporine protocols, nor is there evidence that cyclosporine in low doses in completely safe or banal. Therefore, we suggest monitoring GFR at 3, 6, and 12 months after initiating therapy, provided serum creatinine level is stable. If serum creatinine level increases by > 30% over baseline, GFR should be monitored more frequently and the dose of cyclosporine adjusted if there is a persistent decrease.


Development and resolution of Pneumocystis carinii pneumonia in severe combined immunodeficient mice: a morphological study of host inflammatory responses. The development and resolution of naturally-acquired Pneumocystis carinii pneumonia was studied in a severe combined immunodeficient (SCID) mouse model by light and electron microscopies. Initial infection was evident in 3-week-old SCID mice and started as focal alveolar colonization in the areas near terminal airways. Pronounced pulmonary inflammation occurred in animals of 10 weeks or older and the infection intensity reached a plateau in animals 12 weeks of age. At this stage of disease, the histopathological features of P. carinii infection in SCID mice were similar to those of immunodeficient man. Reconstitution of SCID mice with immunocompetent spleen cells at day 0 induced substantial pulmonary inflammation that was evident already by day 7 and most severe and extensive by day 12. The clearance of P. carinii did not begin until after day 12 and was almost completed by day 17. Alveolar macrophages in mice killed between days 12 and 15, at the time when P. carinii are being rapidly cleared, appeared active but phagocytosis of P. carinii was not commonly observed by either light or electron microscopy. These results suggest that (1) the presence of non-lymphoid inflammatory cells in SCID mice is not sufficient to control P. carinii infection; (2) the clearance of P. carinii from the lungs of reconstituted SCID mice requires local recruitment of large numbers of inflammatory cells with an active appearance; and (3) intracellular killing of P. carinii by phagocytosis does not appear to be a major mechanism in host defences against P. carinii infection in this model.


The effect of thionaphthene-2-carboxylic acid (TNCA) on bone structure in the rat: a histomorphometric study. Thionaphthene-2-carboxylic acid (TNCA) has been shown to decrease osteoclast-mediated bone resorption in vitro and has shown efficacy in animal models of hypercalcaemia of malignancy. In this study, the effects of TNCA on the tibial proximal epiphysis and the sternum have been quantified by image analysis in rats administered the drug orally for 90 days at 75, 125 or 250 mg/kg/day. The amount of bone in the subepiphyseal area and sternum was increased in a dose-related manner. TNCA exerted a biphasic effect on the height of the epiphyseal plate. It was stimulatory at the low dosage and inhibitory at the high dose. This study constitutes the first of its kind to demonstrate the in-vivo effect of TNCA on the bones of rats.


Induction of contact sensitivity by cell-associated immunocomplexes requires activation of the early complement components. Lymph node cells collected from CBA/J mice 4 days after painting the skin with picryl chloride behave like antigen presenting cells and induce contact sensitivity when injected into naive recipient mice. The immunizing capacity of these '4-day' cells is due to T cells which carry on their membrane hapten-IgM immunocomplexes. Incubation of the cells with complement from mouse strains that express high C4 serum levels (C4H), abolishes their immunizing capacity. This effect is related to the activation of the early components of the classical complement pathway, as supported by experiments using C3 and C4-depleted or C5 and C6-genetically deficient mouse sera. The detection of different amounts of C3b and C4b on the surface of 4-day T cells after incubation with C4L and C4H sera supports the possibility that membrane bound activated complement components could modify the immunizing capacity of these cells. Results herein reported suggest that membrane-bound C3b and C4b are not per se inhibitory but interfere with the residual complement activating capacity of 4-day T cells. The role of complement activation by 4-day T cells is pivotal as complement depletion of recipient mice by cobra venom factor (CVF) inhibits the immunizing capacity of untreated 4-day T cells, while 4-day T cells treated with complement in vitro and injected together with C4a anaphylatoxin are able to immunize recipient mice.


Morphology of rejection in experimental pancreas transplantation and its modification by cyclosporin A administration. Histology of pancreas transplant rejection is complicated by non-specific appearances related to undrained exocrine secretions. Using a rat model of pancreas transplantation with exocrine drainage into the urinary tract, morphology of acute rejection has been studied with minimal interference from non-specific change. Unmodified acute rejection was complete after 7-9 days. Intralobular lymphocytic infiltration, which differentiated allografts from isografts, was present 5 days after transplantation and lymphocytic infiltration of islets and blood vessel walls developed between 5th and 7th days. Cyclosporin A immunosuppression of allografts resulted in marked attenuation of the cellular infiltrate. The nature of the infiltrate and its suppression with cyclosporin A indicated an allograft reaction.


Phenotypic modulation of perisinusoidal cells following acute liver injury: a quantitative analysis. Expression of the alpha-(smooth muscle) isoform of actin (alpha-SMA) by non-parenchymal cells in rat liver was studied following induction of acute liver injury using a single sublethal dose of carbon tetrachloride (CCl4). In normal liver, alpha-SMA immunoreactivity was identified in the smooth muscle cells of hepatic arteries and in the walls of portal and hepatic vein branches. Occasional alpha-SMA-containing stellate shaped cells were found in acinar zone 3 but most perisinusoidal cells (PSCs) did not express this protein. In CCl4-treated animals, there was an increase in the number of immunoreactive cells in perivenular zones, reaching a peak at day 3 following exposure to the toxin. These cells were morphologically identical to desmin-positive PSCs and the kinetics of the responses of alpha-SMA-positive and desmin-positive cells were similar. In en face labelling experiments, evidence of co-expression of alpha-SMA and desmin by non-parenchymal cells was obtained, although some desmin-positive PSCs did not appear to express alpha-SMA. These results suggest that PSCs rapidly undergo phenotypic modulation in response to acute liver injury with acquisition of alpha-SMA expression. It is proposed that these phenotypic changes coincide with functional alterations, such activated 'myofibroblast-like' cells being responsible for the enhanced matrix protein synthesis necessary for tissue repair.


Transmission of dengue virus-induced helper signal to B cell via macrophages. The helper T cells (TH) generated in dengue type 2 virus (DV) infection of mice produce a soluble helper cytokine (HF) which enhances the clonal expansion of DV-specific IgM antibody plaque forming cells (PFC). The present study was undertaken to investigate the mechanism of transmission of the helper signal from TH and HF to B cells. It was observed that TH could transmit the helper signal to B cells by direct cell to cell contact, but HF could not do so without the presence of live macrophages (M phi). HF was adsorbed by both heat killed and live M phi but the former could not transmit it to B cells. Both the polypeptide chains of HF bind to M phi. HF remains on the surface of M phi and can be retrieved completely by contact with B cells for 40 min. The helper signal from TH or HF-adsorbed M phi could not be transmitted to B cells when they were separated from each other by a cell impermeable membrane. The enhancement of PFC count is greater when the signal is transmitted by HF-adsorbed M phi as compared to that by TH alone. Thus, even with lower frequency of TH a significant number of B cells may be triggered with the help of HF and M phi. The findings thus show that the DV-specific helper signal could be transmitted only by a close physical contact of the plasma membranes of the signal presenting cells (TH or HF-adsorbed M phi) and B cells.


Interferon-gamma increases macrophage phospholipid polyunsaturation: a possible mechanism of endotoxin sensitivity. Incubation of murine macrophages or the macrophage-like cell line P388D with interferon-gamma in vitro induced a significant increase in the polyunsaturated fatty acid content of phosphatidylethanolamine. These increases were time and dose-dependent, being maximal at 12 hours and with 5000 U/ml interferon and were inhibited in the presence of anti-interferon-gamma monoclonal antibody. Interferon-gamma induced a significant increase in linoleate in peritoneal macrophages while in the cell line arachidonate was significantly increased. These results are of interest because such increases in the polyunsaturated fatty acid content of phosphatidylethanolamine were previously shown by us to be associated with increased sensitivity to endotoxin in mice in vivo. The implications for interferon-gamma sensitizing to endotoxin are discussed.


An immunohistochemical study of mesothelial cell seeding for knitted Dacron. Six greyhounds underwent bilateral femoral artery replacement with knitted Dacron, one side seeded with omental digest at graft preclotting, the other acting as an unseeded control. Grafts were removed at 24 hours and two months. Tissue was examined using a monoclonal antibody (MNF116) directed against a broad range of human cytokeratins to differentiate mesothelial cells (MC) from microvascular endothelial cells (MEC), which stained only with a polyclonal antibody directed against von Willebrand Factor (anti-vWF). Cells released from omentum by collagenase stained with MNF116 and reacted poorly with anti-vWF. Identical cells were observed to be within the interstices of seeded but not control knitted Dacron. Few remained in seeded grafts (n = 2) removed at 24 hours and none at two months (n = 4).


Gilles de la Tourette's syndrome: a case study. Tourette's Syndrome was first described by Gilles de la Tourette in 1885. Previously thought to be a rare neuropsychiatric disorder, its prevalence is now estimated at 0.05%. In Canada, this would mean approximately 12,000 people are affected. The rapid growth of knowledge in the neurosciences has led to better understanding and treatment of this disorder. Tourette's Syndrome is characterized by motor tics, usually beginning in the face and progressing to other areas, and by vocal tics, such as hissing, snorting, and barking. Fifty percent also develop copralalia. The age of onset is between 2 and 15 years of age but its complex symptomatology and its waxing and waning course delays diagnosis. This paper will describe the disease process including etiology, signs and symptoms, and treatment. The main focus will be on a case study which will depict how this syndrome affected the life of one woman. The multidisciplinary approach required to assist the severely affected individual to return to her family following successful treatment will be described.


Strategies for intervention and research with children or adolescents who have a parent with multiple sclerosis. Parents with multiple sclerosis worry about effects their illness may have on their children. This stress can be a factor in exacerbating parental illness, yet little conclusive research exists about this population of children. In most instances their existence is not even recorded within the medical records of their parents. Children with chronically ill parents have been described by some as constrained, depressed and antisocial. In contrast, other authors, including this researcher, have concluded that these children are more empathetic and are advanced in friendship concept development compared to the general population. Implications for nursing research and nursing care are presented.


Effect of wound location, orientation, direction, and postoperative time on unsutured corneal wound healing morphology in monkeys. Clinical observation suggests the location, orientation, direction, and postoperative time of unsutured corneal wounds may affect healing. We studied wound depth, deviation, width, and healing phases in central to peripheral portions of superior and inferior transverse incisions, and centripetal and centrifugal semiradial incisions. Healing phases were quantified by the amount of epithelial plug elimination and by fibroblast orientation to the wound. Healing rates varied among individual monkeys. Complete stromal wound closure was seen as early as 2.5 months postoperative, whereas epithelial plugs were present up to 11 months. Average depth did not differ between superior (61.7% +/- 13.4%) and inferior transverse incisions (66.3% +/- 8.2%) (p > .1); all incisions deviated toward the limbus (28.9 degrees +/- 19.9 degrees and 31.0 degrees +/- 19.8 degrees) (p > .1). Superior transverse wounds showed advanced healing compared to mate inferior wounds (p < .05). Compared to centrifugal wounds, centripetal wounds had greater depth (48.1% +/- 7.3% versus 76.0% +/- 7.0%) (p < .0005), greater width (17.2 microns +/- 4.5 microns versus 27.8 microns +/- 6.9 microns) (p < .01), and earlier healing phases (p < .025). With longer postoperative time intervals, fibroblast orientation appeared to change from a relatively perpendicular to a parallel orientation to the wound. Transverse incisions may be difficult to perform perpendicular to the corneal surface. Superior transverse wounds may heal faster than mate inferior wounds, and centrifugal radial wounds may heal faster than centripetal wounds. Differences in semiradial wound morphology may be related primarily to incision depth and postoperative time; incision direction may also affect wound healing.


Stability of refraction and visual acuity during 5 years in eyes with simple myopia. The PERK Study Group. Normal ranges of variability of refraction and visual acuity in adult myopic eyes are needed as a reference standard for assessing the stability of refractive corneal surgery. We measured the changes in spectacle-corrected visual acuity and cycloplegic refraction during 5 years for the unoperated eye of 82 patients aged 21 to 57 years in the Prospective Evaluation of Radial Keratotomy Study. The changes were compared for contact lens and non-contact lens wearers. We also compared the 5-year cycloplegic and manifest refractions for these unoperated eyes. Of 77 eyes, 44% gained or lost one Snellen line and 48% experienced no change in spectacle-corrected visual acuity between baseline and 5 years. Only one eye (1%) lost two lines, and 7% gained two lines. The refractive change was less than 1.00 D for 84% of the 37 non-contact lens wearing eyes. Only 13% became more myopic by at least 1.00 D (maximum increase in myopia, 2.00 D), and 3% became less myopic by 1.00 D. Of 45 contact lens wearing eyes, 38% became more myopic by at least 1.00 D. The 5-year manifest refraction was 0.50 D to 1.50 D more myopic than the cycloplegic refraction for 37% of eyes. We recommend using two or more Snellen lines as the standard for a meaningful change in spectacle-corrected visual acuity in operated eyes, and 1.00 D as a meaningful cutoff for stability of refraction. The wearing of contact lenses can confound the results of stability studies. The difference between the cycloplegic and manifest refractions suggests that the cycloplegic refraction should be used in planning for refractive surgery.


A new procedure for evaluating smoothness of corneal surface following 193-nanometer excimer laser ablation. The routine technique for evaluating the smoothness of an excimer laser keratectomy has been scanning electron microscopy (SEM). However, this method suffers from tissue shrinkage and surface artifacts, and evaluates the surface only in a qualitative manner. In our study, we used a Zygo microscope to quantitatively assess the smoothness of the excimer laser ablated corneas, without complicated tissue processing. Five rabbit eyes and five PMMA blocks underwent 193-nanometer excimer laser ablations (5.00-millimeter diameter and 80-micrometer depth). The ablation zones of the corneas were trephined and fixated prior to the measurement. The surface smoothness was measured under the Zygo and characterized by two surface parameters (Ra and RMS). After measurement, the corneal and PMMA samples were processed for SEM. The Ra and RMS (mean +/- SD) for the ablated corneas are 183.33 +/- 20.6 and 240.06 +/- 23.10 nm, respectively; for the PMMA blocks, 79.49 +/- 23.02 and 96.45 +/- 27.16 nm, respectively. There are significant differences of Ra and RMS between the ablated corneas and PMMA blocks (p < .01), indicating the ablated corneal surfaces are rougher than the ablated PMMA surfaces. Qualitatively, SEM correlated well with the results of the Zygo measurements. We found this technique to be a simple, accurate, and reproducible means of objectively assessing the surface smoothness following excimer laser ablation. Combined use of the Zygo and SEM enables more complete evaluation of the ablated corneal surface.


Nutritional intake, height and weight of 11-12-year-old Northumbrian children in 1990 compared with information obtained in 1980. There is little age-specific information on changes in dietary intake over time in this country, yet this is valuable in assessing the effectiveness of health education programmes particularly in vulnerable groups such as adolescents. In 1990, 379 children aged 12 years completed two 3 d dietary records. They were interviewed by one dietitian on the day after completion of each diary to verify and enlarge on the information provided and, with the aid of food models, obtain a quantitative record of food intake. Nutrient intake was calculated using computerized food tables. These children attended the same seven Middle schools in Northumberland as 405 children of the same age who recorded their diet using the same method, 10 years previously. Heights and weights were also recorded in both studies in the same manner. Comparing the nutrient intakes in 1990 with 1980, energy intake fell in the boys (to 8.6 MJ) but not in the girls (8.3 MJ). The contribution of fat to energy intake was unchanged at about 40% (about 90 g/d). Likewise, intake of sugars was unchanged at about 22% of energy (about 118 g/d). Calcium intake remained the same in the girls (763 mg/d in 1990) but fell in the boys (786 mg/d in 1990). Iron, vitamin C and unavailable carbohydrate intakes increased in both sexes, and the nutrient density of the diet improved in all sex and social-class groups. However, a social trend evident in 1980 still existed in 1990 with low social groups having the poorest-quality diet. It is concluded that there is little evidence of substantial progress towards improving the diet of adolescents in this country.


Iowa PK Press for donor corneas--a comparative study of donor corneal shape. A new cornea press for cutting donor corneal buttons from the endothelial side, the Iowa PK Press, is described. Major modifications of the Bourne Press include a spring-activated piston without lateral sway, a centering device for a Teflon cutting pad, and the ability to accommodate a wider range of trephine sizes (6.2 mm to 10.0 mm). The Iowa PK Press was compared with the Bourne Corneal Press and trephination by hand in a series of 15 donor cornea trephinations. Measurements taken from photographs of the buttons included endothelial diameter, epithelial diameter, and edge angles. The Iowa PK press cut buttons that had a slightly larger epithelial and endothelial diameter when compared to hand trephination (p < .05, analysis of variance) with less undercutting of the endothelial surface. There was no statistically significant difference in epithelial and endothelial diameters, eccentricity, or edge angles between the two presses. The Iowa PK Press is more versatile than the Bourne Press in terms of the potential range of diameter of corneal buttons that can be created.


Modifying diets to satisfy nutritional requirements using linear programming. A computational method for constructing individually acceptable diets by modifying a chosen diet to meet nutritional requirements is described. The effects on food quantities of imposing different nutrient requirements on a sample diet are demonstrated and techniques which can ensure the acceptability to the individual of the modified diet are described. The starting point in the calculation is the person's current dietary intake. This is modified using linear programming methods which make the smallest changes to the food quantities to meet specific targets. Sequential modification can be used to identify changes that are acceptable to the individual. The computer program has been developed in collaboration with practising dietitians and is in use in some leading UK hospitals.


Astigmatism after cataract extraction: 6-year follow up of 6.5- and 12- millimeter incisions. Cataract surgery and cataract surgeons have long realized that the surgical wound induces a significant change in the astigmatic properties of the eye postoperatively. In efforts to avoid or minimize these changes, there has been a progressive shift toward smaller incision sizes. However, that incision size which renders the eye astigmatically neutral has yet to be completely defined. This article will examine the long-term behavior of planned extracapsular surgical wounds (chord length 12 mm) and phacoemulsification wounds (chord length 6.5 mm), as well as look at potential animal models for defining how smaller incisions behave. One hundred thirty-eight eyes of patients whose average age was 75 years have been followed for up to 6 years. Both vector and scalar analyses of the induced postoperative cylinder were evaluated. Additionally, the astigmatic properties of 10 nonhuman primate eyes which had phacoemulsification surgery were followed for 1 year. Finally, incisions of smaller chord lengths, as small as 2.5 mm, were examined in the nonhuman primate model. We demonstrated that with vector analysis, the induced cylindrical change with phacoemulsification wounds (6.5 mm) was 1.20 +/- 0.60 diopters and with planned extracapsular wounds was 2.20 +/- 1.30 D. In all cases, a significant against-the-rule shift was observed which was independent of the amount of surgically induced with-the-rule astigmatism at the time of surgery. Vector analysis was more appropriate because it demonstrated the against-the-rule shift for both patients whose preoperative cylinder was "with-the-rule" as well as those who were preoperatively "against-the-rule." In humans with 6.50-millimeter scleral incisions, these changes were completely stable 2 to 6 months postoperatively depending on the cylinder induced at the time of surgery. Experiments were also carried out in monkeys demonstrating that similar types of surgical wounds induced roughly the same amount of induced against-the-rule cylindrical shift (1.40 +/- 1.00 D), suggesting that this model is appropriate for looking at the behavior of cataract wounds in general. Smaller wounds in the nonhuman primate showed that 3.5- and 2.5-millimeter wounds were astigmatically neutral whereas 4.5-millimeter wounds and larger were not. Although the later study was performed with corneal incisions, whereas the studies mentioned earlier were all performed with scleral incisions, it is felt that this model could define that incision size which is neutral and that further work utilizing this model with other wound locations might be clinically helpful. Although the long-term behavior of 6.5-millimeter phacoemulsification wounds was generally stable, a small clinically insignificant shift did occur several years after the initial surgical procedure (0.30 D). Animal modeling, although difficult and costly, could provide relevant data in defining the specific size and placement of surgical wounds for cataract surgery.


Evaluation of the nutritive value of yellow rice in rats and broiler chicks. Yellow discoloration often develops in rice kernels during post-harvest storage, due possibly to fungal activity. The present study examined the changes in nutrient composition taking place during yellowing of rice, and the effects of feeding rats and broiler chicks on a moderately yellow rice at 600 g/kg diet. Nitrogen content was found to be higher in rice grains that had become more yellow, only part of the increase being in non-protein-N; however, relative to crude protein (N x 6.25) the concentrations of lysine, methionine, cystine and arginine were lower. There were no significant differences between white and yellow rice in the food intake, weight gain and efficiency of food utilization (EFU) of rats and chicks when diets were formulated to contain similar nutrient concentrations, or the same basal ingredient composition. Diet pelleting increased food intake and weight gain in both animal species, but reduced dry matter and energy digestibility in rats; effects on nutrient retention in chicks were largely non-significant. Liver weights of rats and chicks and pancreas weights of chicks were unaffected by yellow rice; however, chicks fed on mash had a larger pancreas on average than those fed on pellets. Thus, whilst the nutrient composition of rice is altered during yellowing, a moderately yellow rice is unlikely to produce major adverse effects when fed to rats and broiler chicks.


Hypersensitivity following excimer laser ablation through the corneal epithelium. From our preliminary study, we found corneal hypersensitivity after excimer laser. To study the effects of corneal epithelial wound healing on corneal sensitivity, we investigated the recovery of corneal sensitivity following excimer laser and manual epithelial debridement. The corneal epithelium of the right eye of New Zealand white rabbits (n = 19) was manually debrided and the left eye was ablated with the excimer laser (5 Hz, 160 mJ/cm2, 47-micrometer depth). The wound-healing rate was measured up to 46 hours. Corneal sensitivity was measured for 10 weeks. There was no significant difference in the wound-healing rate, but at 36 hours there was a reduction in wound-healing rate of the excimer ablated corneas. In the laser-ablated cornea, sensitivity rapidly increased to a normal level by day 5, and then it continued to increase gradually and reached a maximum at day 42. Thereafter, it retained a higher level than normal up to 10 weeks. There were significant differences in the recovery of sensitivity following excimer ablation and manual debridement. These results show the development of a lasting enhanced sensitivity in the cornea after excimer laser ablation, suggesting the need to conduct further studies of neural plasticity and sensory thresholds following interventions on the corneal surface.


Changes in insulin-receptor mRNA levels in skeletal muscle and brown adipose tissue of weanling rats during fasting and refeeding. Tissue-specific alterations in insulin sensitivity occur in response to fasting and refeeding, as part of the integrated adaptive mechanisms employed to adjust to major changes in nutritional status. In the present study the effects of fasting and refeeding on insulin-receptor, actin and myosin mRNA levels in skeletal muscle, and insulin-receptor and uncoupling-protein mRNA in brown adipose tissue of rats have been examined. Insulin-receptor mRNA levels increased markedly in both skeletal muscle and brown adipose tissue after a 40 h fast, the increase being greater in brown fat (8-fold) than in muscle (2-fold). On refeeding for 4 h, the insulin-receptor mRNA level in both tissues declined rapidly to control levels. An increase in insulin-receptor mRNA level was also observed in brown adipose tissue after a 16 h fast, although not in skeletal muscle. In contrast to the insulin-receptor mRNA, the level of the mRNA for the mitochondrial uncoupling protein declined markedly in brown adipose tissue during a 40 h fast. These results indicate that insulin-receptor mRNA levels are modulated in response to the alterations in nutritional status that occur during fasting and refeeding; this may reflect a nutritional influence on transcription of the receptor-protein gene.


Energy supplementation reverses changes in the basal metabolic rates of chronically undernourished individuals. The objective of the present study was to examine the influence of energy supplementation and its cessation thereafter on the basal metabolic rates (BMR) of chronically undernourished individuals. Seven apparently healthy males were supplemented daily with 3.35 MJ (15 g protein, 35 g fat, 105 g carbohydrate) for 12 weeks. The average gain in body-weight was 1.9 kg (body fat, 58%; fat-free mass (FFM), 42%). The rise in BMR exceeded that accounted for by the increases in FFM during the 12 weeks of supplementation and was attributed to increases in the amount and activity of the visceral tissue as well as to an added cost of lipogenesis. At 12 weeks after cessation of the supplement, body-weights and FFM had decreased to presupplementation levels. BMR at this stage were significantly lower than at the 12th week of supplementation, when expressed per kg FFM or when adjusted for FFM using an analysis of covariance. These results suggest an increase in the metabolic efficiency during this negative energy balance period. The study demonstrates that, in the chronically undernourished, the changes in BMR are reversible and, hence, physiologically important to the process of adaptation to low-energy intakes.


The effects of varying protein and energy intakes on the growth and body composition of pigs. 1. The effects of energy intake at constant, high protein intake. The objective of the present experiment was to define the form of the relationship between varying levels of energy intake at constant, high protein intake and the performance of young pigs. By doing so it was expected that we could distinguish between four models that predict the pig's responses to its diet as rates of protein and lipid retention. Forty young pigs were assigned at 12 kg live weight either to an initial slaughter group (n 8) or to one of four allowances of starch intake at a constant intake of a high-protein feed (with 345 g crude protein (nitrogen x 6.25)/kg food). Half the pigs were killed after 4 weeks and half after 8 weeks on the treatments; at each slaughter point on each treatment half the pigs were entire males and half were females. Increasing the intake of starch (energy) resulted in significant increases in the rates of live weight, empty-body, protein and lipid gains of pigs slaughtered at both stages. There was no minimum positive lipid:protein ratio in the gain of the pigs. Male pigs deposited more protein and less lipid than females but this effect of sex on protein and lipid retention was seen only on the two highest allowances of starch intake. The calculated efficiency of protein utilization increased with increasing starch intake up to a maximum of 0.81, when probably the energy:protein in the diet became non-limiting. The results led to the rejection of two of the models that predict the rates of protein and lipid retention as responses to protein and energy intake, but the two remaining models could not be rejected, at least qualitatively.


The effects of varying protein and energy intakes on the growth and body composition of pigs. 2. The effects of varying both energy and protein intake. The objective of the experiment was to define the form of the relationship between varying levels of protein and energy intake and the performance of young pigs. Forty-four young-pigs were assigned at 12 kg live weight for 6 weeks either to an initial slaughter group (n 8) or to one of the nine feeding treatments (n 4); three allowances of a high-protein food with 355 g crude protein (nitrogen x 6.25; CP)/kg (P1, P2, P3) at three levels of feeding (L, M and H). Each feeding level was met by supplementing the allowance of feed P with the appropriate amount of starch and each treatment had two males and two females. The rate of protein deposition was not affected by feeding level at the two lowest allowances of basal feed P (P1 and P2), but it increased with increasing the feeding level for the pigs on treatment P3. Males deposited more protein than females, but this effect was more pronounced with treatment P3. The rate of lipid deposition increased with each increase in the level of feeding and decreased with increasing the allowance of feed P. The calculated efficiency of protein utilization (ep) was expressed as a function of the energy:protein ratio in the feed (MJ metabolizable energy/kg digestible CP). The best model to describe the relationship was a linear-plateau model, with the maximum value for ep of 0.814 at 73 MJ/kg. This relationship provided the basis of a model that could predict the response of a growing pig to its diet as rates of protein and lipid retention.


Depletion of delta 9 desaturase (EC 1.14.99.5) enzyme activity in growing rat during dietary protein restriction. The effects of protein restriction on delta 9 desaturase (EC 1.14.99.5) activity were studied in growing rats. A control group was fed on a balanced diet (200 g casein/kg; BD) for 28 d. The experimental group was fed on the low-protein diet (20 g casein/kg; LP) for 26 d, then refed the balanced diet (BD-R) for 2 d. Rats were born to and suckled from normally fed dams. The enzyme activity was measured after 2 and 14 d of LP, and 26 d of LP plus 2 d of BD-R, by incubations in vitro of hepatic microsomal pellets with [1-14C]steric acid. The results indicated a decreased delta 9 desaturase activity after 2 and 14 d of LP of -33 and -43% respectively. Refeeding for 2 d was sufficient to super-repair this activity (+66%). The fatty acid composition of total liver lipids and microsomal phosphatidylethanolamines (PE) and phosphatidylcholines (PC) were also investigated; 18:0 decreased in total liver lipids at 14 d of LP, when 18:1n-9 increased. Stearic acid (18:0) increased in PC at 2 d of LP and in PE at 14 d of LP; oleic acid (18:1n-9) did not change. Therefore, it is concluded that a defect occurred in the bioconversion of 18:0 into 18:1n-9 by delta 9 desaturation during protein depletion. As oleic acid is accumulated in total liver lipids during LP, we speculate that this is due to a decreased oxidation or transport of this fatty acid.


Effects of n-3 fatty acids on postprandial triacylglycerol and hormone concentrations in normal subjects. The present study reports results from two investigations to determine effects of a 6-week period of moderate n-3 fatty acid supplementation (2.7 g/d) on fasting and on postprandial triacylglycerol and metabolic hormone concentrations in response to standard test meals. In the first study postprandial responses were followed for 210 min after an early morning test meal challenge; in the second study responses to an evening test meal were followed during the evening and overnight for a total period of 12 h. In both studies postprandial triacylglycerol responses to the test meals were significantly reduced after compared with before fish-oil supplementation. In the second study the triacylglycerol peak response seen between 200 and 400 min in subjects studied before supplementation with fish oils was almost completely absent in the same subjects after 6 weeks of n-3 fatty acid supplementation. Analysis of fasting concentrations of metabolites and hormones was carried out on the combined data from the two studies. There were no significant differences in total, low-density-lipoprotein- or high-density-lipoprotein-cholesterol concentrations during fish-oil supplementation, although there was considerable individual variation in cholesterol responses to the supplement. Concentrations of Apo-B and Apo-A1 were unchanged during supplementation with fish oils. Fasting and early morning postprandial GIP concentrations were lower in subjects taking fish oils, possibly due to acute effects of fish-oil capsules taken on the evening before the studies. In both studies fasting insulin and glucose and postprandial insulin concentrations remained unchanged following fish-oil supplementation. The results do not support the view that triacylglycerol-lowering effects of n-3 fatty acids are due to modulation of insulin secretion mediated via the enteroinsular axis. Further studies are required to determine the precise mechanism by which fish oils reduce both fasting and postprandial triacylglycerol concentrations.


Replacement of dietary fat with palm oil: effect on human serum lipids, lipoproteins and apolipoproteins. Thirty-eight male volunteers participated in a double-blind cross-over trial evaluating the effect of replacing the usual sources of saturated fat in the Dutch diet (animal fats and hydrogenated oils) by palm oil, which is virtually free of cholesterol and trans-fatty acids, on serum lipids, lipoproteins and apolipoproteins. Maximum (about 70%) replacement had no significant effect on serum total cholesterol or most lipoprotein fractions, but resulted in an 11% increase in serum high-density-lipoprotein (HDL)2-cholesterol relative to the control (P2 = 0.01). The palm-oil diet also caused an 8% decrease in low-density-lipoprotein (LDL):HDL2 + HDL3-cholesterol ratio (P2 = 0.02) as well as a 9% decrease in triacylglycerols in the low-density-lipoprotein fractions (P2 = 0.01). Palm oil consumption resulted in a 4% increase in serum apolipoprotein AI (P2 = 0.008) and a 4% decrease in apolipoprotein B (P2 = 0.01) relative to the control diet; the B:AI apolipoprotein ratio was decreased by 8% (P2 < 0.0001). These results were not significantly affected by the different lipoprotein E phenotypes of the volunteers. Although the observed differences were relatively modest, the present study, nonetheless, indicates that dietary palm oil, when replacing a major part of the normal fat content in a Dutch diet, may slightly reduce the lipoprotein- and apolipoprotein-associated cardiovascular risk profiles.


Influence of ascorbic acid supplementation on copper metabolism in rats. An attempt was made to unravel further the mechanism by which high dietary concentrations of ascorbic acid influence copper metabolism. The addition of ascorbic acid to the diet of rats caused about a twofold increase in plasma ascorbate concentrations and reduced group mean plasma and tissue concentrations of Cu. The effect of 10 g ascorbic acid/kg diet was greater than that of 1 g/kg. Ascorbic acid feeding reduced blood haemoglobin concentrations and packed cell volume values. Dietary ascorbic acid caused a significant decrease in apparent Cu absorption from the intestine. Ascorbate, intravenously administered together with 64Cu, caused an increase in 64Cu in the liver. Ascorbate, at concentrations occurring in plasma after ascorbic acid feeding, promoted the uptake of 64Cu by isolated hepatocytes. Thus, ascorbate stimulated the efficiency of hepatic uptake of Cu. Ascorbate, intravenously administered together with 64Cu, stimulated accumulation of 64Cu in bile of rats with a bile duct cannula. In rats fed on ascorbic acid, intravenously administered 64Cu was recovered in bile at increased rates. Dietary ascorbic acid enhanced the recovery of intraperitoneally administered 64Cu in faeces. The ascorbate-induced stimulation of biliary 64Cu excretion may reflect an increased hepatic uptake of 64Cu and be caused by an increased specific activity of Cu in liver pools. It is suggested that dietary ascorbic acid reduces tissue Cu concentrations primarily by interfering with intestinal Cu absorption. Ascorbate increases the efficiency of hepatic uptake of Cu, but this effect may not be causatively related with the reduced tissue Cu concentrations after ascorbic acid feeding.


A study of whole-body isotope dilution of [14C]ascorbic acid in guinea-pigs with graded ascorbate intakes. The purpose of the present study was first to assess the extent to which unlabelled ascorbate in the diet of guinea-pigs can exchange with labelled ascorbate within their organs when the dietary intake is varied over a wide range, and second to determine whether the retention of label might be used to assess either the amount of ascorbate intake or its biological availability where these are not known. The retention of [14C]ascorbate in the body and in various organs of guinea-pigs were, therefore, measured following a 13 d period of graded dietary intakes of ascorbate. It was found first, that the amount of label retained in each of the organs, 13 d after the initial dose of labelled ascorbate, was much more closely related to the amount of ascorbate intake after labelling than to the intake (and tissue ascorbate levels) before and at the time of labelling. Second, most of the individual internal organs exhibited a constant relationship between the specific activity at 13 d and the dietary intake, except for brain which was flushed to a smaller extent. Third, in agreement with several previous studies a high proportion of the radioactive label in the tissues was found to be still present in ascorbate. The specific activity of column-purified ascorbate was very similar to the estimated specific activity in the crude extract, which implies that it may be possible to estimate specific activities (or stable isotope enrichments) at certain sites without rigorous isolation procedures. Fourth, the amount of radioactivity appearing in the urine 2 d before killing the animals was correlated with the amount of ascorbate intake and with tissue specific activities, suggesting that intakes (or bioavailability) might be predicted from the patterns of label-appearance in the urine.


Evaluation of inert markers for the determination of ileal and faecal apparent digestibility values in the pig. A series of experiments was designed to evaluate inert markers employed in studies of ileal and faecal apparent digestibilities of nitrogen and amino acids in pigs fitted with simple 'T' piece cannulas. Trial 1 assessed the palatability of diets containing (a) 5 g chromic oxide/kg, (b) 1 and (c) 5 g titanium dioxide/kg at two levels of feeding. The results indicated that there were slight problems in terms of period of feed consumption associated with diets (a) and (c), but that these effects were transitory and disappeared following acclimatization, although higher levels of feeding may compound the problem. Trial 2 estimated N balance, faecal apparent digestibility of amino acids as determined by both total collection and ratio of markers, ileal apparent digestibility of amino acids and recovery of markers using diets containing (a) 1 and (b) 5 g Cr2O3/kg, (c) 1 and (d) 5 g TiO2/kg. An additional assessment of acid-insoluble lignin present within the diet was also undertaken. Cr2O3 was associated with the lowest recovery, whilst calculations based on TiO2 gave lower standard errors. Trial 3 examined diurnal variation in digesta sampling and its effect on faecal apparent digestibility of N and amino acids. There were no evident effects. In general, it was concluded that the most appropriate marker to use in studies of this nature was TiO2 at a rate of 1 g/kg.


Effect of vitamin A deficiency and Newcastle disease virus infection on IgA and IgM secretion in chickens. The effect of vitamin A deficiency or the lentogenic La Sota strain of Newcastle disease virus (NDV) infection, or both, on immunoglobulin (IgA and IgM) levels in bile and plasma were investigated. In addition, tissue distribution of IgA-, IgG- and IgM-containing cells was studied to establish the source of these Ig. Chickens (1-d-old) with limited vitamin A reserves were fed ad lib. on diets containing either marginal or adequate levels of vitamin A. At 4 weeks of age, half the chickens in each group were infected with NDV. The number of IgA- and IgM-containing cells was not significantly affected by vitamin A deficiency, demonstrating that neither class-switching nor homing of Ig-containing cells is influenced by vitamin A deficiency. Although bile IgM levels were not significantly different in vitamin A-deficient chickens compared with normal chickens, IgA levels were significantly lower. This decrease was even more pronounced in deficient NDV-infected chickens, despite the higher number of IgA-containing cells found in these birds. These results, together with the slightly increased levels of IgA in plasma of vitamin A-deficient chickens, suggest that the hepatobiliary transport of IgA is impaired by vitamin A deficiency and possibly also by NDV infection, although disturbed secretion by IgA-containing cells cannot be excluded.


Effect of casein, casein phosphopeptides and calcium intake on ileal 45Ca disappearance and temporal systolic blood pressure in spontaneously hypertensive rats. Paracellular 45Ca absorption and temporal systolic blood pressure (SBP) measurements were recorded in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats fed on casein (C) and soya-bean-protein isolate (S) diets, containing 20 (H), 5 (H) and 0.5 (L) g Ca/kg. Similar measurements were also taken in SHR rats only fed on C-M and S-M diets supplemented with 30 g caseinophosphopeptides (CPP)/kg. Absorption of 45Ca from the ileal loop was equivalent in both SHR and WKY animals and largely affected by the level of dietary Ca. In addition, animals fed on C diets exhibited significantly (P < 0.05) greater ileal absorption of 45Ca compared with S-fed animals. This result was attributed to the presence of CPP and a greater (P < 0.05) proportion of soluble 45Ca in the contents of the ileum. Animals fed on S diets supplemented with CPP confirmed this finding. The SBP of SHR rats was higher (P < 0.01) than WKY controls after 9-10 weeks of age. The temporal pattern of observed hypertension was independent of dietary influence in the SHR. The severity of hypertension in SHR rats was affected only by dietary Ca deficiency, and not by Ca supplementation or CPP enhancement of Ca bioavailability. These findings suggest that tryptic digestion products of casein in milk can enhance Ca bioavailability by increasing Ca solubility; however, this action had no effect in reducing hypertension in SHR.


Nutritional evaluation of the trypsin (EC 3.4.21.4) inhibitor from cowpea (Vigna unguiculata Walp.). The effect of feeding rats purified cowpea (Vigna unguiculata Walp.) trypsin (EC 3.4.21.4) inhibitor in a semi-synthetic high-quality diet based on lactalbumin (10 g inhibitor/kg) for 10 d was a moderate reduction in the weight gain of rats in comparison with controls, despite an identical food intake in the two groups. The reduction in the growth rate was about 20% on a live weight basis. However, the corresponding value calculated from the weight of dry carcasses was less, only about 7%, probably because the water content of the body of the two groups of rats was different. Although most of the cowpea trypsin inhibitor (CpTI) was rapidly broken down in the digestive tract, its inclusion in the diet led to a slight, though significant, increase in the nitrogen content of faeces but not of urine. Accordingly, the net protein utilization of rats fed on inhibitor-containing diets was also slightly depressed while their energy expenditure was elevated. In agreement with results obtained for the protease inhibitors of soya bean, the slight anti-nutritional effects of CpTI were probably due mainly to the stimulation of the growth and metabolism of the pancreas. Thus, the nutritional penalty for increased insect-resistance after the transfer of the cowpea trypsin inhibitor gene into food plants is slight in the short-term.


The digestibility in piglets of faba bean (Vicia faba L.) as affected by breeding towards the absence of condensed tannins. Seed samples from two near-isogenic faba bean (Vicia faba L.) lines were examined for the levels of so-called anti-nutritional factors (ANF). From the ANF known to be present in faba beans, trypsin inhibitor activity, functional lectins, condensed tannins and pyrimidine glycosides were analysed. It was concluded that the lines differed only in the content of condensed tannins being < 0.5 g/kg and 5.2 (SD 0.2) g/kg for the low (LT)- and high (HT)-tannin lines respectively. In addition, the level of pyrimidine glycosides in the LT line was slightly higher than that in the HT line. The LT line showed a reduced proportion of the seed coat (105 v. 119 g/kg) and a lower seed weight (0.85 v. 1.01 g). The apparent ileal and faecal digestibility values of dry matter and nitrogen from the HT and LT line were determined for piglets which were fed on diets containing chromium oxide as a marker. The mean apparent ileal and faecal digestibility values for dry matter for the LT line were 0.694 and 0.889 and for N 0.828 and 0.879 respectively. For the HT line, these values were approximately 0.05 and 0.10 lower (P > 0.05). A multienzyme technique was used to predict the in vitro protein digestibility (IVPD) of the two lines. The IVPD of the LT line was 0.965 and about 0.05 higher than the HT line, confirming the difference in digestibility as measured in vivo. The present study shows the positive effects on digestibility of removal of condensed tannins in faba beans which was achieved by plant breeding.


Use of birth control pills and condoms among 17-19-year-old adolescents in Norway: contraceptive versus protective behaviour? This article addresses the relationship between sexual risk behaviour and contraceptive behaviour, and considers whether adolescents who use condoms are practising birth control or STD protective behaviour. The material comprised a representative sample of 3000 Norwegians aged 17-19 years. Data were collected by anonymous self-administered questionnaires. The response-rate was 63%. At the first sexual intercourse 51% of the adolescents used condoms and 7% birth control pills. At the most recent intercourse 31% used condoms and 38% the pill. Use of the pill was widespread among adolescents with high coital frequency and few coital partners. Use of condoms was not particularly widespread among adolescents who reported a relatively large number of coital partners. Irrespective of the number of years they had been coitally active there was no significant difference between those who intended to use condoms at the next sexual intercourse and those who did not as regards their beliefs about condoms as protection against STDs, HIV and unintended pregnancies. The results from this study indicate that the majority of adolescents who use contraception do this for protection against unintended pregnancy and not for protection against STDs. The preference for the pill may make teenagers less prepared to practise STD protective behaviour in specific situations.


AIDS dementia-related psychosis: is there a window of vulnerability? Human immunodeficiency virus (HIV) frequently enters the central nervous system (CNS) soon after infection, and frequently produces a wide variety of neurologic, cognitive, and psychiatric complications. Although, the entire spectrum of psychiatric illnesses may be seen in individuals with HIV infection, most are probably not directly caused by the virus. Psychiatric manifestations that are the direct result of HIV infection are usually seen in the setting of HIV-associated dementia. In this paper, it is proposed that these psychiatric manifestations of HIV infection can be phenomenologically separated into positive and negative symptoms. Negative symptoms are deficit states presenting as cognitive, social, or motivational deterioration; positive symptoms are psychotic or manic states that may occur in the course of the dementing illness. It is further purposed that there is a window of vulnerability to psychosis or mania that occurs relatively early in the dementing process. Consequently, advancing dementia would be expected to be associated with remission of psychosis.


Differences in HIV-related knowledge and attitudes between Caucasian and 'Asian' men in Glasgow. There is little available information about the possible differences in HIV-related knowledge and attitudes between ethnic majority and minority groups. Questionnaires were completed by 490 Caucasian males and 243 males with origins in the Indian subcontinent ('Asian') living in Glasgow. There were small differences between the samples regarding knowledge of modes of transmission of HIV or perceived adequacy of personal knowledge. The 'Asian' men, however, were much more likely to indicate reluctance to use services also used by people with HIV and to feel that people with AIDS only had themselves to blame. They were also much less likely to feel at risk of becoming infected with HIV. The differences were not related to age. These marked differences, apparently unrelated to knowledge are important and require further exploration.


Selling sex: female street prostitution and HIV risk behaviour in Glasgow. Female prostitutes have often been seen as a major source of HIV infection. In this paper we report on a study of HIV-related risk behaviour among street prostitutes in Glasgow. This paper is based on street interviews using a standardized schedule with 68 women. We focus on the extent of HIV testing amongst the women, travel, the sexual services provided, the use of condoms with clients and private partners, and the extent of drug injecting and equipment sharing by the women. It is shown that female street prostitution within Glasgow is, at present, unlikely to be associated with significant heterosexual spread of HIV as most commercial sex is with a condom. However, some risk activities are continuing. Additionally, prostitutes report worrying rates of condom failure with clients. It is suggested that attention should switch away from an exclusive focus on women selling sexual services to target the men who purchase sex. These data indicate that much of the pressure for these women to provide unprotected sex comes from their clients.


Maintenance of open gay relationships: some strategies for protection against HIV. The role of sexual exclusivity (monogamy) in relation to HIV, and the use of rule making in non-exclusive (open) relationships, are discussed. Data from interviews with 387 homosexually active men are presented. The most common sexual/relational configuration amongst these men is that of open relationships. Sexual non-exclusivity was found to be associated with longer relationships, and a greater age difference between partners. The strategies some of these men are using to maintain sexually non-exclusive relationships are outlined. These rules pertain both to interpersonal dynamics and HIV prevention. Differing epidemiological significance of the rules and some implications for health education are discussed.


The Edinburgh cohort of HIV positive drug users: who are they and who cares for them? Between 1983 and 1984, it is estimated that over 1,000 injection drug users in Edinburgh were infected with HIV. The social and demographic characteristics of 300 HIV positive drug users attending a medical clinical between 1987 and 1991 have been recorded. Nearly all were unemployed, poorly educated and living in council-owned accommodation; one third were female, 17% of whom were caring for a child. Half the cohort lived with a partner, and one fifth with parents; there were no differences between symptomatic and asymptomatic patients. During the study, 45 patients died, mostly from AIDS or an AIDS-related condition. HIV positive drug users are not socially isolated, but they are heavily dependent on family support in the community.


The origin of clinical laboratories.

The origin of clinical laboratories. Clinical laboratories are a main attribute of clinical chemistry. Their historical development is therefore of great interest in the history of clinical chemistry. The results of a study are given which was undertaken to trace the establishment of clinical laboratories in central Europe, mainly in France, England and in the German-speaking countries. Presuppositions for the creation of these laboratories were: (i) The idea that the results of laboratory examinations can be used as "chemical signs" in medical diagnosis, and (ii) a new concept of disease which was the result of the "birth of the clinic" at the end of the 18th century. The study shows that the development of clinical laboratories began 200 years ago. Up to the end of the 19th century, three development phases can be distinguished: an early phase from 1790 to 1840, a phase of institutionalization from 1840 to 1855, and a phase of extension between 1855 and 1890. To characterize these three phases, the foundation of the laboratories, the layout of the laboratory rooms, their equipment and instrumentation, and the usual staff are described with the aid of typical examples.


Liver transplantation in a boy with acute porphyria due to aminolaevulinate dehydratase deficiency. The clinical and biochemical outcome of a liver transplantation in a seven-year-old boy with acute porphyria due to aminolaevulinate dehydratase deficiency is described. Before transplantation standard liver function tests were normal and the rationale for transplantation was that the new liver would reduce the metabolic disturbance and thus avert the porphyric symptoms. During the year after the transplantation, the functioning of the new liver has been excellent. Basal excretion of porphyrin and porphyrin precursors has remained unchanged but, with the new liver transplant the patient has been able to withstand several porphyrinogenic challenges without increasing the excretion. Episodes of neurological and respiratory crises may have been due to persistent porphyric vulnerability. Alternatively, two early attacks may have been caused by neurotoxic effects of cyclosporin in combination with the existing damage to nervous tissue.


Renal sorbitol, myo-inositol and glycerophosphorylcholine in streptozotocin-diabetic rats. The polyols, sorbitol and myo-inositol, seem to be involved in the development of diabetic complications of different organs. High concentrations of both polyols were found in kidney medulla in addition to trimethylamines. To investigate the influence of diabetes mellitus on the regulation of both polyols and glycerophosphorylcholine in kidney, these osmolytes were quantitated enzymatically along the corticopapillary axis in untreated, streptozotocin-diabetic and insulin-treated streptozotocin-diabetic rats. In control animals three individual osmolyte patterns were found: a steep gradient of sorbitol in the papilla, increasing amounts of glycerophosphorylcholine from the outer medulla to the papilla, and nearly equal amounts of myo-inositol in the renal medulla, decreasing towards the cortex. Diabetic rats exhibit an up to fourfold increase of inner medullary sorbitol, whereas myo-inositol was only elevated in the outer medulla. Glycerophosphorylcholine was lowered in the papillary tip and elevated in the outer medulla and cortex. Insulin treatment reduced sorbitol to a concentration between those of diabetic and control rats, caused a restoration of glycerophosphorylcholine in the papillary tip and outer medulla to control values, and increased cortical myo-inositol. These data confirm previous in vitro data, which show that papillary sorbitol specifically increases in hyperglycaemic states, thereby counteracting the increased extracellular tonicity due to elevated tissue glucose concentrations. Imbalance of extra- vs intracellular osmolality during insulin treatment may be involved in the pathomechanism of renal papillary necrosis.


The physiological and pathophysiological basis of glomerular permeability for plasma proteins and erythrocytes. The barrier function of glomerular capillaries in vivo, which prevents the leakage of plasma proteins and cellular elements, depends on the basic morphological and electro-chemical fine structure of the glomerular capillary wall, and on a functional barrier maintained by components obtained from blood, which effect the definitive barrier against the leakage of plasma proteins and cellular elements. The functional component of the barrier may explain the variability and some of the phenomena known as functional proteinuria. A certain size and number of morphological "defects" are thought to represent the normal condition, but under pathological conditions they may increase in size and number, resulting in a shift to an increasing permeability for higher molecular mass proteins; also an increase of the size and number of larger defects may enable more red cells to pass the barrier compared with the normal condition. These defects are different from the minimal glomerular lesions which are due to charge defects in the glomerular capillary membrane, primarily the lamina rara interna and the lamina rara externa of the basement membrane.


Glomerular changes in diabetes mellitus. Ultrastructural, immunohistochemical and biochemical studies have improved our knowledge on the events occurring during the development of diabetic late complications. Immunohistochemical investigations of diabetic kidneys, using antibodies against various components of the extracellular matrix, showed increased collagen type IV (alpha 1,alpha 2-chain) deposition in the mesangial matrix, and a decrease of heparan sulphate proteoglycan in the mesangial matrix and glomerular basement membrane. Changes in matrix components seem to be the underlying cause of the alterations in renal function, as reflected by albuminuria and proteinuria. The occurrence of collagen type III in late diffuse glomerulosclerosis has been interpreted as an irreversible change in glomerular structure. The extent of alteration of the extracellular matrix correlates to a certain extent with the severity of nephropathy of the individual subject. The studies performed to date support the hypothesis that hyperglycaemia, whatever its origin, is the primary cause of diabetic late complications, although the pathobiochemical mechanisms are not yet fully understood. Increased intra- and extracellular levels of glucose and its derivatives are thought to contribute to diabetic tissue dysfunction. Three pathobiochemical theories are favoured in the current discussion: i) the polyol pathway ii) non-enzymatic glycation of proteins iii) direct influence of hyperglycaemia on the synthesis of matrix components. The evidence for the participation of the polyol pathway in the pathogenesis of diabetic nephropathy comes mainly from animal data using aldose reductase inhibitors, but only limited data are available for humans, so that the significance of this pathomechanism cannot yet be determined.(ABSTRACT TRUNCATED AT 250 WORDS)


Role of glomerular proteinases in the evolution of glomerulosclerosis. Recent studies suggest that proteolytic enzymes located within the glomerulus are involved in the degradation of extracellular matrix components. In the present investigation glomerular proteinase activities were followed in a variety of non-immune-mediated renal diseases as well as during different dietary manipulations. Azocaseinolysis was significantly reduced in the obese Zucker rat compared with lean littermates (pH 5.4:8.9 +/- 0.4 vs 11.4 +/- 0.7; pH 7.4:5.8 +/- 0.7 vs 9.3 +/- 0.6 arb. U/mg protein). When the glomerular proteolytic capacity was measured in old rats, again a significant decline in proteolysis was observed (pH 5.4:9.8 +/- 0.8 vs 17.7 +/- 0.8; pH 7.4:6.4 +/- 0.7 vs 11.7 +/- 0.5 arb. U/mg protein). In Goldblatt hypertensive rats the unclipped kidney, which is exposed to high blood pressure, revealed lower glomerular azocaseinolytic activity compared with the contralateral clipped kidney (pH 5.4:8.1 +/- 0.4 vs 12.9 +/- 0.5 arb. U/mg protein). In parallel, the cathepsin B content was also diminished in glomeruli from kidneys exposed to hypertension. When proteinases were followed in glomeruli from intact kidneys of rats fed protein-modified diets (fraction of casein 0.05, 0.20 or 0.60) a significant fall in the activities of cysteine proteinases, e.g. cathepsin B (casein 0.05:1,498 +/- 110 vs casein 0.60:914 +/- 84 microU/micrograms DNA), as well as metalloproteinases, e.g. collagenase (casein 0.05:233 +/- 14 vs casein 0.60:137 +/- 11 microU/micrograms DNA), occurred. These data indicate that in both early and late stages of glomerulosclerosis, proteolytic activities within the glomerulus tend to be reduced, which could allow extracellular matrix accumulation. Moreover, changes in dietary protein intake resulted in profound alterations of glomerular proteinases.(ABSTRACT TRUNCATED AT 250 WORDS)


Adenosine deaminase restores the ability of atrial natriuretic peptide to induce glomerular hyperfiltration in low-sodium rats. Administration of a large dose of atrial natriuretic peptide is associated with an increase in glomerular filtration rate, diuresis and natriuresis in normal-sodium rats. However, glomerular hyperfiltration induced by atrial natriuretic peptide is markedly decreased in low-sodium rats. Glomerular insensitivity to atrial natriuretic peptide may be due to increased activity of the renin-angiotensin system in low-sodium rats and to an accompanying hypersensitivity to adenosine. The results indicate that attenuated glomerular responses to atrial natriuretic peptide are restored by the administration of adenosine deaminase in low-sodium rats. Moreover atrial natriuretic peptide markedly increases the urinary excretion of adenosine deaminase, which may be due to increased permeability of glomeruli to the enzyme.


Glycation of serum albumin and its role in renal protein excretion and the development of diabetic nephropathy. The present study was designed to investigate whether microalbuminuria at the onset of diabetic nephropathy might be partially due to the glycation of serum albumin. It is postulated elsewhere (Ghiggeri et al., Proc. Eur. Dial. Transplant. Assoc. 21 (1984) 633-636) that the glycation of serum albumin and the subsequent cationization may induce microalbuminuria. To investigate whether a relationship exists between the amount of glycated albumin in its cationized form and the development, and progression of diabetic nephropathy, the urinary excretion of glycated albumin was studied in diabetic patients. The diabetic patients (type I and II diabetes) were divided into groups according to their albumin excretion rates: group I diabetics had a normal albumin excretion (n = 30, x = 4.2 mg/12 h); group II diabetes displayed microalbuminuria (n = 17, x = 38.6 mg/12 h); group III diabetics displayed macroalbuminuria (n = 21, x = 582.5 mg/12 h). The fraction of glycated albumin in serum (Glyco Gel Test Kit) was 0.032 in group I, 0.042 in group II, and 0.038 in group III, all these values were significantly higher than the value for the controls (0.014%; n = 17, 2 alpha = 0.001) as measured with the Glyco Gel Test Kit. The concentration of glycated albumin in the urine of the controls and group I was below the detection limit. Urine in group II contained only a glycated albumin fraction of 0.0002 of total albumin, and the fraction for group III was 0.0008. Isoelectric focussing (IEF) and chromato-focussing revealed native albumin with an isoelectric point of 4.7-4.9, and anionic glycated albumin with a pI of 3.0-4.2.(ABSTRACT TRUNCATED AT 250 WORDS)


Carbohydrate and lipid metabolism of the renal tubule in diabetes mellitus. Diabetic nephropathy not only involves vascular and glomerular changes but also affects tubular metabolism, structure and function. Under acute insulin withdrawal the tubular size increases with glomerular hyperfiltration. Insulin like growth factor 1 (IGF1) has been found to be a candidate mediator involved under these conditions. Tubular carbohydrate metabolism is characterized by gluconeogenesis in the proximal tubule, glycolytic enzymes in the distal segments and high aldose reductase activity in the structures of the renal papilla. In the diabetic state, gluconeogenesis is stimulated by changes of the acid base status. Mitochondrial glucose oxidation is decreased by inhibition of pyruvate dehydrogenase activity through preferential oxidation of fatty acids and ketone bodies. The increase in glycogen in distal tubule cells and sorbitol accumulated in papillary structures can be explained by the high extracellular glucose supply under diabetic conditions. Fatty acids taken up in excess of tubular energy needs accumulate in the nephron as triacylglycerols, mainly in the proximal convoluted tubule. Fatty acid oxidation is inhibited by ketone bodies in proximal and outer medullary tubules, leading to preferential oxidation of the latter under ketotic conditions. Ammonia formed during tubular metabolism of glutamine increases in metabolic acidosis but is suppressed by ketone bodies, leading to a nitrogen sparing effect of ketone bodies. All acute metabolic derangements are abolished, and normal metabolism reestablished by adequate insulin treatment in vivo.


Distribution of cathepsins B and L in the kidney and their role in tubular protein absorption. Intralysosomal proteinase activity, due to cathepsins B and L, was measured in microdissected segments of rat nephron, using Z-Phen-Arg-7-amido-4-methylcoumarin as the substrate. Cathepsin B was determined with Z-Arg-Arg-7-amido-4-methylcoumarin. The enzymes cleave on the carboxy side of arginine and release free 7-amino-4-methylcoumarin, which is highly fluorescent and can be measured at very low concentrations in small volumes. Enzyme activities were measured in three individual microdissected segments of the proximal tubule and in six different segments of the distal tubule. Experiments were performed in normal non-proteinuric rats and in several rat models of glomerular proteinuria. The distributions of cathepsin activities along the nephron were similar. In all groups, the convoluted part of the proximal tubule had enzyme activities three times higher than in the remaining segments of the nephron. In the last millimeter of the pars convoluta and in the pars recta of the proximal tubule, enzyme activities were two to three times higher in proteinuric animals. These findings suggest that in proteinuric animals the increase in the protein load delivered to the proximal tubules selectively stimulated cathepsin B and L activities in the last millimeter of the pars convoluta and in the pars recta of the proximal tubule, presumably because of an increase in protein uptake, and that cathepsins B and L participate in lysosomal digestion of protein reabsorbed from the glomerular ultrafiltrate via endocytosis.


Measurement of N-acetyl-beta-glucosaminidase and its isoenzymes in urine methods and clinical applications. 1. N-Acetyl-beta-glucosaminidase is the most widely used urinary enzyme assay for the assessment of renal disease and the detection of nephrotoxicity. 2. An increase in N-acetyl-beta-glucosaminidase activity in urine is a sensitive test for renal tubular damage, since its relative molecular mass (M(r) > 130,000) precludes its filtration by the glomerulus and it is the most active of the glycosidases found in the lysosomes in the proximal tubule. 3. The analytical methods available for the determination of urinary N-acetyl-beta-glucosaminidase include fluorometric, colorimetric, spectrophotometric and a dipstick test. 4. The isoenzyme profile of N-acetyl-beta-glucosaminidase in urine varies at different stages of renal disease and damage. In particular there are increases in the B and I2 forms which may reflect perturbation of the cellular biosynthetic processes. 5. The value of N-acetyl-beta-glucosaminidase assays in various areas of medicine is briefly discussed and attention paid to its future role.


A new strategy for characterizing proteinuria and haematuria from a single pattern of defined proteins in urine. Prerenal, glomerular, tubulointerstitial and postrenal proteinurias and haematurias are usually differentiated by a number of non-invasive and invasive diagnostic procedures. We have applied a new analytical strategy based on the observation that different urine protein patterns are excreted in normal, prerenal, renal and postrenal proteinurias and haematurias. When analysed by turbidimetric procedures urine albumin, IgG, alpha 1-microglobulin and alpha 2-macroglobulin can be used as marker proteins to characterize the degree of glomerular permeability, tubular protein reabsorption and postrenal bleeding respectively. Primary glomerulopathies (selective and non-selective) and tubulointerstitial nephropathies can be differentiated by plotting the excretion rates of IgG or alpha 1-microglobulin against that of albumin. Postrenal contaminations are detected by quantitative turbidimetric assay of the high molecular weight proteins, alpha 2-macroglobulin and IgG. In postrenal bleeding, with albumin concentrations above 100 mg/l, the relative excretion rates of these proteins were proportional to their plasma concentrations. In glomerular haematurias, however, the ratios to albumin were much lower. The optimal discriminating ratio was found to be 2.0 x 10(-2) for alpha 2-macroglobulin/albumin and 2 x 10(-1) for IgG/albumin. Tubulointerstitial involvement in haematuria is characterized by elevated alpha 1-microglobulin excretion rates, with alpha 2-macroglobulin/albumin ratios below 2.0 x 10(-2) and IgG/albumin ratios above 2 x 10(-1). The reported procedure allows the exclusion and differentiation of clinically relevant proteinurias and haematurias in a single urine specimen.


Intestinal alkaline phosphatase as an indicator of effects on the S3-segment of the human proximal tubule. A specific monoclonal antibody (IAP250) raised against human intestinal alkaline phosphatase was used to study the expression of this isoenzyme in human renal tissue and its release into urine.


Exogenous progesterone and progestins as used in estrous synchrony regimens do not mimic the corpus luteum in regulation of luteinizing hormone and 17 beta-estradiol in circulation of cows. Our working hypothesis was that the low concentrations of progesterone (P4) and synthetic progestins administered in hormonal regimens to control estrous cycles of cows would have similar effects on secretion of LH and 17 beta-estradiol (E2). In addition, we hypothesized that concentrations of exogenous P4 typical of the midluteal phase of the estrous cycle and the corpus luteum (CL) would have similar effects on LH and E2, and the effects would be different from those of synthetic progestins and low concentrations of P4. Cows (n = 29) were randomly assigned to one of five treatment groups: 1) one Progesterone Releasing Intravaginal Device (1PRID; n = 6); 2) two PRIDs (2PRID; n = 6); 3) norgestomet, as in Syncro-Mate-B regimen (SMB; n = 6); 4) melengestrol acetate (MGA; 0.5 mg/day; n = 5); and 5) control (CONT; n = 6). Treatments were administered for 9 days (Day 0 = initiation of treatment). All cows from 1PRID, 2PRID, SMB, and MGA groups were injected with prostaglandin F2 alpha (PGF2 alpha) on Days 2 and 5 of the treatment period to regress CL. Cows in the 1PRID and SMB groups were also administered exogenous estrogen according to the respective estrous synchronization protocol for these products. Daily blood samples were collected from Day 0 to 35 to determine concentrations of P4. On Day 8, blood samples were collected at 15-min intervals for 24 h to determine pattern of LH secretion. On Day 9, all treatments ceased and cows in the CONT group received injections of PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)


Changes in concentrations of follicular inhibin alpha and beta A subunit messenger ribonucleic acids and inhibin immunoactivity during preovulatory maturation in the pig. Ovarian tissues were collected from 5 pigs on each of days 1, 3, 5, and 7 after withdrawal of an orally active progestin to determine changes in follicular inhibin subunit mRNAs during preovulatory maturation. Follicles (N = 146) were aspirated for fluid and homogenized in guanidinium isothiocyanate for RNA isolation. Follicular RNA and inhibin alpha and beta A subunit mRNA standards were dot-blotted, hybridized with [32P]-cDNA probes, and quantified by densitometry. Mean concentrations of alpha mRNA (pg/micrograms of RNA) increased (p < or = 0.05) by 140% as healthy follicles grew from medium (3-5 mm) to large (> 5 mm). Inhibin immunoactivity was greater (p < or = 0.05) in large than medium follicles. In contrast, mean concentrations of inhibin beta A subunit mRNA did not differ between healthy medium and large follicles. However, both alpha mRNA and beta A mRNA increased (p < or = 0.05) linearly as follicular diameter increased from 3 to 5 mm on Day 1 and from 3 to 9 mm on Day 3. On Day 5, alpha mRNA remained elevated, but was not significantly correlated with diameter. In contrast, beta A mRNA decreased linearly (p < 0.05) as diameter increased from 6 to 11 mm on Day 5. The molar ratio alpha mRNA to beta A mRNA was 20:1 in healthy, large follicles on Days 3 and 5. Mean concentration of alpha mRNA in large follicles decreased (p < 0.05) by 72% between Days 5 and 7, while beta A mRNA decreased to non-detectable levels on Day 7.(ABSTRACT TRUNCATED AT 250 WORDS)


Influence of sexual maturity of donor on in vivo survival of transferred porcine embryos. A study was conducted to determine whether embryos recovered from first-estrous (pubertal) and second-estrous gilts differed in survival when transferred to first- or third-estrous recipients. Embryos were recovered surgically from first- and second-estrous donors 48-72 h postmating and 6-10 normal embryos/zygotes (1-4 cells) were transferred to oviducts (3-5 embryos/ampulla) of nonmated synchronous first- (n = 40) or third- (n = 15) estrous recipients. Blood samples were collected from the jugular vein of recipient gilts on Days 3, 12, and 30 of gestation and the sera were analyzed for progesterone and free (unconjugated) estrogens by use of radioimmunoassays. Recipient gilts were subsequently slaughtered between Days 30 and 40 to assess embryonic losses. Mean number of ovulations was lower among first-estrous vs. third-estrous recipients (8.9 +/- 0.7 vs. 11.4 +/- 0.7; p < 0.05). Percentage of recipients that maintained pregnancy was similar between first- and third-estrous gilts (67.5 vs. 60.0%) and recovery of total conceptuses (normal and degenerating) resulting from transfer of one-cell- and cleavage-stage embryos did not differ among first- vs. third-estrous gilts (76.1 vs. 78.2%). Similarly, percentage of viable fetuses in first-estrous gilts that were pregnant from transfer of one-cell- and cleavage-stage embryos was not different from that of third-estrous gilts (69.3 vs. 75.6%). Percentages of total conceptuses and viable fetuses in first- and third-estrous gilts that were recipients of cleavage-stage embryos only also did not differ (p > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Urethral glands of the male mouse contain secretory component and immunoglobulin A plasma cells and are targets of testosterone. The occurrence and possible functions of mucosal immunity in the male urogenital tract have not been extensively investigated. In this study we used immunolabeling to localize secretory component (SC) and immunoglobulin (Ig) A in the urogenital tract of the male mouse. SC was located in the ventral prostate, while SC and IgA plasma cells were both detected in the urethral glands in the pelvic and bulbous portions of the urethra. SC and IgA were not observed elsewhere in the urogenital tract. We also examined the ventral prostate and urethral glands of sham-castrated, oil-treated castrated, and testosterone-treated castrated mice. There was a striking reduction in the size of the ventral prostate and urethral glands in oil-treated castrates compared to the other two groups, based on gross and histological morphology. Morphometric analysis showed that the cell and nuclear sizes of the urethral gland acinar cells were reduced after castration and restored to normal size by testosterone treatment. Androgen receptors (AR) were localized in the nuclei of urethral gland cells by immunocytochemistry using anti-AR antibodies. Labeling of SC and IgA plasma cells was similar in the urethral glands and ventral prostates of sham- and testosterone-treated castrates, but was reduced or absent at these sites in oil-treated castrates. These studies show that the ventral prostate and urethral glands may be sites for secretory immunity in the male murine urogenital tract, and that the urethral glands are targets for testosterone.