Prolonged survival with a remnant kidney

Surgical ablation of five-sixths renal mass in Munich-Wistar rats fed a high protein diet leads to focal sclerosis in the remnant kidney and progressive renal failure. Experimental data suggest that this injury results from intraglomerular hypertension and/or chronic glomerular hyperfiltration. Data in humans largely are limited to patients with unilateral renal agenesis or uninephrectomy, either for unilateral renal disease or for kidney transplant donation. Isolated case reports have documented focal sclerosis and progressive renal failure in two patients with a remnant kidney. To obtain data in humans with a remnant kidney, we surveyed more than 800 urologists and nephrologists in the United States and abroad. Criteria for inclusion in the study were (1) surgical resection (in one or more operations) resulting in the presence of a remnant kidney; and (2) an adequate period of follow-up, defined as 5 years or greater. A total of 13 patients were identified (from 13 different centers). Twelve patients had renal cancer and one had tuberculosis. Six patients were observed for 10 or more years postoperatively and all have stable serum creatinine levels of less than 270 mumol/L (3.0 mg/dL); two of these six patients are now more than 25 and 30 years postoperation. The other seven patients, observed for 5 to 7 years, have serum creatinine levels less than 270 mumol/L (3 mg/dL), while one has an increasing serum creatinine level. The two longest surviving patients both have undergone successful pregnancy with no overall change in serum creatinine. These observations demonstrate that it is possible for humans to survive more than 30 years with a stable serum creatinine, despite the presence of only a remnant kidney.     

Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial

Aims/hypothesis: The management of charcot neuroarthropathy, a severe disabling condition in diabetic patients with peripheral neuropathy, is currently inadequate with no specific pharmacological treatment available. We undertook a double-blind randomised controlled trial to study the effect of pamidronate, a bisphosphonate, in the management of acute diabetic Charcot neuroarthropathy. Methods: Altogether 39 diabetic patients with active Charcot neuroarthropathy from four centres in England were randomised in a double-blind placebo-controlled trial. Patients received a single infusion of 90 mg of pamidronate or placebo (saline). Foot temperatures, symptoms and markers of bone turnover (bone specific alkaline phosphatase and deoxypyridinoline crosslinks) were measured over the 12 months, in 10 visits. All patients also had standard treatment of the Charcot foot. Results: Mean age of the study group (59 % Type II (non-insulin-dependent) diabetes mellitus) was 56.3 ± 10.2 years. The mean temperature difference between active and control groups was 3.6 ± 1.7 °C and 3.3 ± 1.4 °C, respectively. There was a fall in temperature of the affected foot in both groups after 2 weeks with a further reduction in temperature in the active group at 4 weeks (active and placebo vs baseline; p = 0.001; p = 0.01, respectively), but no difference was seen between groups. An improvement in symptoms was seen in the active group compared with the placebo group (p < 0.001). Reduction in bone turnover (means ± SEM) was greater in the active than in the control group. Urinary deoxypyridinoline in the pamidronate treated group fell to 4.4 ± 0.4 nmol/mmol creatinine at 4 weeks compared with 7.1 ± 1.0 in the placebo group (p = 0.01) and bone-specific alkaline phosphatase fell to 14.1 ± 1.2 u/l compared with 18.6 ± 1.6 u/l after 4 weeks, respectively (p = 0.03). Conclusion/interpretation: The bisphosphonate, pamidronate, given as a single dose leads to a reduction in bone turnover, symptoms and disease activity in diabetic patients with active Charcot neuroarthropathy. [Diabetologia (2001) 44: 2032–2037] Received: 20 April 2001 and in revised form: 26 June 2001     

Miliary tuberculosis: A complication of intravesical BCG treatment

A case of miliary tuberculosis following intravesical bacillus Calmette-Guerin (BCG) treatment is described.     

4-Amido-2-carboxytetrahydroquinolines. Structure-activity relationships for antagonism at the glycine site of the NMDA receptor.

trans-2-Carboxy-5,7-dichloro-4-amidotetrahydroquinolines, evolved from the lead 5,7-dichlorokynurenic acid, have been synthesized and tested for in vitro antagonist activity at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Optimization of the 4-substituent has provided antagonists having nanomolar affinity, including the urea trans-2-carboxy-5,7-dichloro-4[[(phenylamino)carbonyl]amino]-1,2,3, 4-tetrahydroquinoline (35; IC50 = 7.4 nM vs [3H]glycine binding; Kb = 130 nM for block of NMDA responses in the rat cortical slice), which is one of the most potent NMDA antagonists yet found. The absolute stereochemical requirements for binding were found to be 2S,4R, showing that, in common with other glycine-site NMDA receptor ligands, the unnatural configuration at the alpha-amino acid center is required. The preferred conformation of the trans-2,4-disubstituted tetrahydroquinoline system, as shown by X-ray crystallography and 1H NMR studies, places the 2-carboxyl pseudoequatorial and the 4-substituent pseudoaxial. Modifications of the 4-amide show that bulky substituents are tolerated and reveal the critical importance for activity of correct positioning of the carbonyl group. The high affinity of trans-2-carboxy-5,7-dichloro-4-[1-(3-phenyl-2-oxoimidazolidinyl)]- 1,2,3,4-tetrahydroquinoline (55; IC50 = 6 nM) suggests that the Z,Z conformer of the phenyl urea moiety in 35 is recognized by the receptor. Molecular modeling studies show that the 4-carbonyl groups of the kynurenic acids, the tetrahydroquinolines, and related antagonists based on N-(chlorophenyl)glycine, can interact with a single putative H-bond donor on the receptor. The results allow the establishment of a three-dimensional pharmacophore of the glycine receptor antagonist site, incorporating a newly defined bulk tolerance/hydrophobic region.     

Stage I nonseminomatous germ-cell testicular cancer — management options and risk-benefit considerations

Summary The results obtained with primary retroperitoneal lymph-node dissection (RPLND) in 464 patients with clinical stage A nonseminomatous germ-cell (NSGC) testicular cancer over a period of 25 years (1965–1989) were reviewed. Results were analyzed in clinical terms and subdivided into early (1965–1978) and contemporary (1979–1989) findings so as to be comparable with series using radiotherapy or surveillance. Between 1965 and 1978 (86 clinical stage A patients), the overall relapse rate of 15% (n=13) was similar to that obtained in radiotherapy series but the survival (98.8% after RPLND) was superior to that achieved with irradiation (87%). From 1979 to 1989, 378 clinical stage A cases had primary RPLND, of whom 29% (n=111) had cancerous nodes. The relapse rate for pathological stage A patients (n=267) was 11% and two patients died. The rate of relapse for pathological stage B patients who did not receive adjuvant chemotherapy was 32%. No relapse was seen among 46 pathological stage B patients given postoperative adjuvant chemotherapy. The mortality of 0.7% observed among 378 clinical stage A RPLND cases was lower than the 2% value reported in surveillance series. Although not statistically significant, these consistent results reported for two eras (pre- and postplatinum) spanning a period of 25 years suggest a sound basis for the surgical approach. The anatomic and medical principles in oncology, which have supported this approach, remain cogent today. They are discussed herein. Now that nerve-sparing techniques have been developed, the one long-term morbidity of RPLND (i.e., anejaculation) can be avoided. It would seem appropriate to have nerve-sparing RPLND techniques in any armamentarium dealing with clinical stage A disease.     

Simulation studies of the CA3 hippocampal subfield modelled as an attractor neural network

Real neuronal networks in the brain utilize networks of neurons with graded not binary firing rates. A theoretical analysis of the operation of autoassociative networks with neurons with graded firing rates has therefore been developed. The present simulation study was performed in order to investigate the operation of such a network with values for the asymmetric diluted neuronal connectivity typical of some brain regions such as the hippocampus, which are outside the range to which the theoretical analysis strictly applies. We report that, in line with theoretical predictions, the amount of information that can be retrieved is relatively independent of the resolution of the stored patterns (binary, ternary, decimal, or fifty-fold). The implication of this is that if the network stores many graded patterns, which it can, then the retrieval quality of each of the patterns becomes low. The implications of this trade-off between the number of patterns stored and the retrieval quality of each pattern when graded firing rates are stored for understanding the operation of networks in the hippocampus are considered.     

Inhibition of the activation of Hageman factor (factor XII) by extracts of Schistosoma mansoni.

How intravascular helminth parasites evade host hemostatic defense mechanisms and survive within the circulating blood has not been adequately explained. Previous reports have described an inhibitor of the intrinsic clotting pathway in extracts of adult Schistosoma mansoni. Using a purified preparation of Hageman factor, we examined the ability of schistosome extracts and secretory products to inhibit the activation of human Hageman factor (factor XII) in an amidolytic assay. Both schistosome extracts and secretory products inhibited the activation of purified Hageman factor by more than 95%. Schistosome extracts inhibited activation of Hageman factor both by ellagic acid and by bovine sulfatides. In contrast, activated Hageman factor retained full activity in the presence of schistosome extracts as tested both on an amidolytic synthetic substrate and a natural substrate, plasma thromboplastin antecedent (factor XI). Our findings indicate that extracts and secretory products of adult Schistosoma mansoni contain a potent inhibitor of the activation of Hageman factor. Knowledge of a site at which schistosomes inhibit the intrinsic clotting pathway provides added insight into the mechanisms by which the parasites avoid the host hemostatic defense mechanisms.     

In vivo characterisation of a translational enhancer upstream from the coat protein open reading frame of potato virus S

Summary The 101 nucleotide region upstream from the ATG of the potato virus S (PVS) coat protein gene was isolated and the effect of this region on the translation of a downstream open reading frame analysed in vivo. Translation was monitored using the reporter genes B-glucuronidase (GUS) and luciferase (LUC). Translational enhancement was assayed transiently using DNA microprojectile bombardment into both leaf and pollen tissue and also by polyethylene glycol mediated transfection of tobacco protoplasts. In both cases the presence of this region resulted in a 2–3 fold increase in translation when compared to reporter expression with synthetic leader and authentic plant leader constructs. Tobacco plants stabily transformed with this PVS 101 nucleotide region and downstream GUS gene gave 4 times the level of translation over synthetic leader GUS control plants.     

Assessing Children's Conceptions of AIDS

Assessed intuitive theories of AIDS transmission through clinicalmethod interviews in a cross-sectional design for a sample of205 1st; 195 3rd; and 208 5th-grade students, balanced by sexand race (black/white). Analyses of relationships between thetypes of theories children held and their responses to closed-endquestions about transmission and willingness to interact witha person with AIDS supported the validity of the interview method.Grade differences were noted for knowledge of high-risk routes,rejection of misconceptions, and cohe-siveness and complexityof children's theories. Theories also differed by race and verbalabilities. Implications for most appropriate ways to assesschildren's understanding of illnesses and directions for futureresearch are discussed.