Genetic approaches identify differential roles for alpha4beta2* nicotinic receptors in acute models of antinociception in mice.

The effects of nicotine on the tail-flick and hot-plate tests were determined to identify nicotinic receptor subtypes responsible for spinally and supraspinally mediated nicotine analgesia in knockin mice expressing hypersensitive alpha(4) nicotinic receptors (L9'S), in seven inbred mouse strains (C57BL/6, DBA/2, A/2, CBA/2, BALB/cByJ, C3H/HeJ, and 129/SvEv), and in two F1 hybrids (B6CBAF1 and B6D2F1). L9'S heterozygotes were approximately 6-fold more sensitive to the antinociceptive effects of nicotine than the wild-type controls in the hot-plate test but not in the tail-flick assay. Large differences in the effects of nicotine were also observed with both tests for the seven mouse strains. A/J and 129 mice were 6- to 8-fold more sensitive than CBA and BALB mice. In addition, B6CBAF1 hybrid mice were even less sensitive than CBA mice. Nicotinic binding sites were measured in three spinal cord regions and the hindbrain of the inbred strains. Significant differences in cytisine-sensitive, high affinity [(125)I]epibatidine binding site levels (alpha(4)beta(2)(*) subtypes), but not in (125)I-alpha-bungarotoxin binding (alpha(7)(*) subtypes), were observed. Significant negative correlations between cytisine-sensitive [(125)I]epibatidine binding and nicotine ED(50) for both tests were noted. Our results indicate that alpha(4)beta(2)(*) acetylcholine nicotinic receptors (nAChR) are important in mediating nicotine analgesia in supraspinal responses, while also showing that alpha(4)beta(2)(*)-nAChR and at least one other nAChR subtype appear to modulate spinal actions.

Autosomal recessive polycystic kidney disease in adulthood.

BACKGROUND: Renal cysts arising from collecting ducts, congenital hepatic fibrosis, and recessive inheritance characterize autosomal recessive polycystic kidney disease (ARPKD). The disorder usually manifests in infancy, with a high mortality rate in the first year of life. For the patients who survive the neonatal period, the probability of being alive at 15 years of age ranges from 50 to 80%, with 56--67% of them not requiring renal replacement therapy at that stage. Some develop portal hypertension. Long-term outcome of adults escaping renal insufficiency above age 18 is largely unknown. METHOD: In consecutive patients with ARPKD and autonomous renal function at age 18, clinical course of kidney and liver disease in adulthood and status at last follow-up were evaluated. Progression of renal insufficiency was assessed by the rate of decline of creatinine clearance, according to Schwartz's formula before age 18 and Cockcroft and Gault formula thereafter. Severity of liver involvement was estimated by imaging techniques, liver function tests, and endoscopy. RESULTS: Sixteen patients from 15 families were included. ARPKD was diagnosed between 1 day and 13 years of age. From diagnosis, mean follow-up period lasted 24+/-9 years. Before age 18, nine patients (56%) were hypertensive, nine (56%) had renal failure, and four (25%) had portal hypertension. Beyond age 18, no additional patient became hypertensive, and another five developed progressive renal insufficiency; altogether, the mean yearly decline of creatinine clearance was 2.9+/-1.6 ml/min. Portal hypertension was recognized in two additional patients. Four patients experienced gastro-oesophageal bleeding, while recurrent cholangitis or cholangiocarcinoma developed in one case each. At the end of follow-up, 15/16 patients (94%) were alive at a mean age of 27 (18--55) years. Two patients had a normal renal function, 11 had chronic renal insufficiency, one was on regular dialysis, and two had functioning kidney grafts. Four patients had required a porto-systemic shunt. CONCLUSIONS: A subset of ARPKD patients with autonomous renal function at age 18 experiences slowly progressive renal insufficiency. With prolonged renal survival, complications related to portal hypertension are not rare, requiring careful surveillance and appropriate management.

Outcome of cadaver kidney transplantation in 23 patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (DM) is a growing cause of end-stage renal failure worldwide. Yet, only a minority of type 2 diabetics are considered today for kidney transplantation (KT). The scarcity of data on the outcome of such patients after KT prompted us to review our experience. METHODS: Between 1 January 1983 and 30 June 1996, 23 patients with type 2 DM received a first cadaver KT at a mean age of 57+/-9 (41-73) years, after a dialysis period ranging from 5 to 72 (mean 25+/-18) months. Only nine patients had a history of coronary and/or peripheral vascular disease before KT. All were given cyclosporin- or tacrolimus-based immunosuppression. Post-KT follow-up ranged from 4 to 181 (mean 70+/-38) months. Outcome analysis focused on the impact of cardiovascular complications. RESULTS: Patient survival at 1, 5 and 8 years was 91, 83 and 76% respectively. Death was due to infection in three patients and to a cardiovascular event in two. The actuarial risk of coronary, cerebrovascular, peripheral vascular, and any cardiovascular event after KT was 14, 13, 9 and 30% at 1 year, 20, 13, 50 and 58% at 5 years, and 20, 46, 66 and 72% at 8 years respectively. Post-KT hospital readmissions averaged 10 days/patient-year and were mostly related to the management of peripheral vascular disease. CONCLUSION: KT is an excellent therapeutic option for selected patients with type 2 DM. Peripheral vascular disease is the leading cause of morbidity following KT. KT should be considered in type 2 diabetics with a low/medium cardiovascular risk.

Toxic effects of MPP(+) and MPTP in PC12 cells independent of reactive oxygen species formation.

MPTP is a toxin presumed to damage dopamine-secreting neurons by an oxygen free radical-mediated mechanism. Two steps in MPTP metabolism are the primary candidates for oxygen free radical generation: (a) MPTP oxidation to MPP(+) by a monoamine oxidase and (b) NADH dehydrogenase inhibition by MPP(+). In order to test the idea that MPTP toxicity is mediated by oxygen free radicals, we assessed lipid peroxidation and the effects of antioxidants in dopaminergic PC12 cells treated with MPTP or MPP(+). For comparison purposes, we also examined the effects of the pro-oxidant tert-butyl-hydroperoxide (TBHP) and of the dopaminergic toxin 6-hydroxydopamine (6-OHDA) in PC12 cells. MPTP and MPP(+), unlike TBHP, failed to induce lipid peroxidation in PC12 cells after a 4-h exposure. All toxins tested (MPTP, MPP(+), TBHP and 6-OHDA) caused a dose-dependent decrease in [(3)H]dopamine ((3)H-DA) uptake in PC12 cultures. The hydroperoxide scavengers glutathione and N-acetyl-cysteine and the superoxide and peroxide scavenger EUK-134 protected PC12 cells from TBHP- and 6-OHDA-induced decrease in (3)H-DA uptake. However, no protection by these antioxidants at various concentrations and time regimens was observed against MPTP- or MPP(+)-induced decreases in (3)H-DA uptake in PC12 cells. In addition, incubation of PC12 cells with the energy-rich substrate, NADH, attenuated MPP(+)-induced decrease in (3)H-DA uptake. These results suggest that MPTP-induced toxicity in dopaminergic PC12 cell cultures, does not involve oxygen free radical production, but rather may be caused by impairment in energy metabolism.

Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety.

Knock-in mice were generated that harbored a leucine-to-serine mutation in the alpha4 nicotinic receptor near the gate in the channel pore. Mice with intact expression of this hypersensitive receptor display dominant neonatal lethality. These mice have a severe deficit of dopaminergic neurons in the substantia nigra, possibly because the hypersensitive receptors are continuously activated by normal extracellular choline concentrations. A strain that retains the neo selection cassette in an intron has reduced expression of the hypersensitive receptor and is viable and fertile. The viable mice display increased anxiety, poor motor learning, excessive ambulation that is eliminated by very low levels of nicotine, and a reduction of nigrostriatal dopaminergic function upon aging. These knock-in mice provide useful insights into the pathophysiology of sustained nicotinic receptor activation and may provide a model for Parkinson's disease.

Acute interstitial nephritis and fatal Stevens-Johnson syndrome after propylthiouracil therapy.

We report a case of acute interstitial nephritis and fatal Stevens-Johnson syndrome in a 90-year-old woman with amiodarone-induced hyperthyroidism, who had been treated for 5 weeks with propylthiouracil (PTU). On admission, the patient exhibited acute renal failure and generalized macular purpuric eruption. Acute interstitial nephritis and Stevens-Johnson syndrome were diagnosed and PTU withdrawn. Although renal function recovered after PTU withdrawal and corticosteroid therapy, the patient's condition worsened, and she died after developing multiple organ failure. Acute interstitial nephritis seems to be rarely associated with PTU therapy. Moreover, a literature review suggested that this could represent the first published report of a Stevens-Johnson syndrome developing during PTU therapy.

Transgenic mice neuronally expressing baculoviral p35 are resistant to diverse types of induced apoptosis, including seizure-associated neurodegeneration.

Apoptosis is a cell-suicide process that appears to play a central role not only during normal neuronal development but also in several neuropathological disease states. An important component of this process is a proteolytic cascade involving a family of cysteine proteases called caspases. Caspase inhibitors have been demonstrated to be effective in inhibiting neuronal cell death in various apoptotic paradigms. We have created transgenic mice that neuronally express the baculoviral caspase inhibitor p35. Neuronal expression of the p35 protein was found to confer functional caspase inhibitory activity and prevent apoptosis in isolated cerebellar granular cultures induced to undergo apoptosis either via staurosporine treatment or through withdrawal of extracellular potassium. Neuronal expression of p35 was also found to attenuate neurodegeneration associated with the excitotoxic glutamate analogue kainic acid (KA) in vitro and in vivo. Organotypic hippocampal cultures isolated from p35 transgenics demonstrated lowered caspase activity and decreased apoptosis compared with wild type when exposed to KA. In vivo injection of KA also produced decreased caspase activity and cell death in p35 transgenics vs. wild type. These results suggest that the presence of p35 in neurons in vivo is protective against various types of apoptosis, including seizure-related neurodegeneration, and that caspases may be attractive potential targets for preventing neuronal injury associated with diseases such as epilepsy. These mice also provide a valuable tool for exploring the role of caspases in other neuropathological conditions in which apoptosis has been implicated.

Polycystic kidney disease: <<30 ans après>>.

Major progress has been achieved in autosomal dominant polycystic kidney disease in the last 30 years; Progress in imaging procedures has been decisive for diagnosis (by ultasonography), management of kidney and liver complications (by CT scan), and investigation and sometimes management of intracranial aneurysms (by MRI-angiography and endovascular treatment procedures). On the other hand, progress in molecular genetics has led to the identification of PKD1 and PDK2 genes, and their respective gene products, polycystin 1 and 2. A two-hit model for cyst formation has recently been put forward. The link between the gene defects and cyst fluid formation and progression is still unknown. In addition, cystic and non-cystic lesions coexist in the disease, underlining that the primary molecular defect is located upstream of the mechanism of cyst formation.

Recurrent fulminant anti-glomerular basement membrane nephritis at a 7-year interval.

True recurrence of anti-glomerular basement membrane (anti-GBM) nephritis is very rare, both in native kidneys and after renal transplantation. We report the recurrence of fulminant anti-GBM nephritis in a kidney graft recipient after the spontaneous withdrawal of immunosuppressive treatment more than 5 years after renal transplantation. The initial episode of anti-GBM nephritis had destroyed the native kidneys 7 years earlier. Circulating anti-GBM antibodies had disappeared for 14 months at the time of transplantation and reappeared with recurrence. This observation challenges the concept of anti-GBM nephritis as a single-shot illness and emphasises the need to consider the possibility of recurrence, even in the long term, among patients who underwent transplantation for anti-GBM nephritis.

On the energetic cost of sociality.

Measurements of oxygen consumption from ant colonies of various sizes of Odontomachus bauri, Camponotus rufipes and Zacryptocerus depressus showed a complex and nonlinear relationship between colony size and energy consumption per unit mass. Results show that at certain critical colony sizes, the colonies energy consumption is larger than the sum of the average energy requirement of the individually workers, and near maximal colony sizes, the energy consumption of the colony per unit mass tends exponentially to that of the average individual worker. We propose that social complexity is related to energy consumption in a discontinuous manner and is bound by both, negentropy content of a society and social optimization mechanisms.

High and low molecular weight rabbit secretory components. Evidence for the deletion of the second and third domains in the smaller polypeptide.

Rabbit secretory components exist in two forms which differ in apparent mass by about 25 kDa. Each of these two forms were reduced, carboxymethylated, and extensively digested with trypsin. The resulting peptides were purified by reverse-phase high performance liquid chromatography and characterized by NH2- and COOH-terminal sequence determination and/or amino acid analysis. They were aligned with the protein sequence predicted from the cDNA nucleotide sequence encoding the rabbit poly(Ig) receptor (Mostov, K. E., Friedlander, M., and Blobel, G. (1984) Nature 308, 37-43). All peptides belonging to the fourth and fifth domains except one (positions 488-496) were accounted for in both forms. In addition, limited tryptic proteolysis of the native low Mr secretory components produced the intact 18-kDa NH2-terminal domain (positions 1-117) and the 30-kDa fragment encompassing the fourth and fifth domains. These results suggest that the smaller polypeptide derives from the larger secretory component form by the deletion of the second and third domains.