Unaltered brain membranes after prolonged intake of highly oxidizable long-chain fatty acids of the (n-3) series

Feeding rats a diet enriched in n-3 polyunsaturated fatty acids (Menhaden oil) increased the content in eicosapentaenoic acid 20:5 n-3 of brain phospholipids. Conversely 22:4 n-6 was reduced. These changes were not associated with alterations in either vitamin E concentration or glutathione peroxidase and catalase activities in cerebrum and cerebellum. No increase in peroxidative damage was found. Interestingly the major very-long-chain fatty acids (22:6 n-3 and 22:5 n-3) were not affected.     

46,XY gonadal dysgenesis: evidence for autosomal dominant transmission in a large kindred

46,XY gonadal dysgenesis is characterized by abnormal testicular determination. We describe a large kindred in which various disorders of sexual development were observed, ranging from completely female phenotype without ambiguities of the external genitalia (five cases) to men with isolated penile or perineal hypospadias (four cases), including two cases with moderate virilization and one case with ambiguity of the external genitalia. Histologic examination of gonadal tissue was performed on seven subjects. These findings were suggestive of complete gonadal dysgenesis in one patient, partial gonadal dysgenesis in three patients, and mixed gonadal dysgenesis in three patients. Four patients developed gonadal tumors (two gonadoblastoma, two dysgerminoma, and one immature teratoma, i.e., one patient had a dysgerminoma with some areas of gonadoblastoma). All affected subjects had no other congenital anomalies or dysmorphic features. Analysis of families with several affected individuals with 46,XY gonadal dysgenesis implied an X-linked mode of inheritance because of the apparent absence of male-to-male transmission. However, a sex-limited autosomal dominant mode of inheritance affecting only XY individuals could not be ruled out. Analysis of the pedigree we report indicated an autosomal dominant mode of inheritance because of male-to-male transmission. This kindred supports the involvement of at least one autosomal gene in non-syndromic 46,XY gonadal dysgenesis.     

Neuropathological Diagnostic Criteria for Creutzfeldt-Jakob Disease (CJD) and Other Human Spongiform Encephalopathies (Prion Diseases)

Neuropathological diagnostic criteria for Creutzfeldt-Jakob disease (CJD) and other human transmissible spongiform encephalopathies (prion diseases) are proposed for the following disease entities: CJD - sporadic, iatrogenic (recognised risk) or familial (same disease in 1st degree relative): spongiform encephalopathy in cerebral and/or cerebellar cortex and/or subcortical grey matter; or encephalopathy with prion protein (PrP) immuno-reactivity (plaque and/or diffuse synaptic and/or patchy/perivacuolar types). Gerstmann-Sträussler-Scheinker disease (GSS) (in family with dominantly inherited progressive ataxia and/or dementia): encephalo(myelo)pathy with multicentric PrP plaques. Familial fatal insomnia (FFI) (in member of a family with PRNP178 mutation): thalamic degeneration, variable spongiform change in cerebrum. Kuru (in the Fore population). Without PrP data, the crucial feature is the spongiform change accompanied by neuronal loss and gliosis. This spongiform change is characterised by diffuse or focally clustered small round or oval vacuoles in the neuropil of the deep cortical layers, cerebellar cortex or subcortical grey matter, which might become confluent. Spongiform change should not be confused with non-specific spon-giosis. This includes status spongiosus (“spongiform state”), comprising irregular cavities in gliotic neuropil following extensive neuronal loss (including also lesions of “burnt-out” CJD), “spongy” changes in brain oedema and metabolic encephalopathies, and artefacts such as superficial cortical, perineuronal, or perivascular vacuolation; focal changes indistinguishable from spongiform change may occur in some cases of Alzheimer's and diffuse Lewy body diseases. Very rare cases might not be diagnosed by these criteria. Then confirmation must be sought by additional techniques such as PrP immunoblotting, preparations for electron microscopic examination of scrapie associated fibrils (SAF), molecular biologic studies, or experimental transmission.     

Involvement of the catecholaminergic system in glucagon-induced thermogenesis in Muscovy ducklings (Cairina moschata)

Physiological studies have shown that glucagon is a potential mediator of nonshivering thermogenesis (NST) in birds. The present work was undertaken in order to investigate whether the observed thermogenesis results from a direct action of glucagon on avian thermoregulatory mechanisms or in fact requires the participation of other agents such as catecholamines. Our experiments were performed using cold-acclimated (CA) ducklings which developed muscle NST. A comparison was made with thermoneutral (TN) ducklings of the same age. Our principal results showed that: (1) at ambient temperature (25 degrees C), circulating norepinephrine (NE) was markedly decreased in CA ducklings (-42%), while circulating epinephrine (E) did not undergo any consistent change; (2) in CA and TN ducklings, an intraperitoneal injection of glucagon (360 microg x kg(-1)) was followed after 10 min by prominent lipolysis and a large increase in circulating NE (4- to 6-fold) and E (14- to 17-fold), which was sustained for at least 1 h. The elevation of circulating NE was less pronounced in CA ducklings. The thermogenic action of glucagon in birds is probably indirect and involves at least the mobilization of lipids and sympatho-adrenal stimulation. The changes in peripheral noradrenergic activity during cold acclimation could be associated with adaptive changes leading to NST.     

Contribution of BK Ca2+-activated K+ channels to auditory neurotransmission in the Guinea pig cochlea

Large-conductance calcium-activated potassium (BK) channels are known to play a prominent role in the hair cell function of lower vertebrates where these channels determine electrical tuning and regulation of neurotransmitter release. Very little is known, by contrast, about the role of BK channels in the mammalian cochlea. In the current study, we perfused specific toxins in the guinea pig cochlea to characterize the role of BK channels in cochlear neurotransmission. Intracochlear perfusion of charybdotoxin (ChTX) or iberiotoxin (IbTX) reversibly reduced the compound action potential (CAP) of the auditory nerve within minutes. The cochlear microphonics (CM at f1 = 8 kHz and f2 = 9.68 kHz) and their distortion product (DPCM at 2f1-f2) were essentially not affected, suggesting that the BK specific toxins do not alter the active cochlear amplification at the outer hair cells (OHCs). We also tested the effects of these toxins on the whole cell voltage-dependent membrane current of isolated guinea pig inner hair cells (IHCs). ChTX and IbTX reversibly reduced a fast outward current (activating above -40 mV, peaking at 0 mV with a mean activation time constant tau ranging between 0.5 and 1 ms). A similar block of a fast outward current was also observed with the extracellular application of barium ions, which we believe permeate through Ca2+ channels and block BK channels. In situ hybridization of Slo antisense riboprobes and immunocytochemistry demonstrated a strong expression of BK channels in IHCs and spiral ganglion and to a lesser extent in OHCs. Overall, our results clearly revealed the importance of BK channels in mammalian cochlear neurotransmission and demonstrated that at the presynaptic level, fast BK channels are a significant component of the repolarizing current of IHCs.     

Measurement of the vasoconstrictive substances endothelin,angiotensin II,and thromboxane B2 in cold storage solution can reveal previous renal ischemic insults

In a rat model, the left kidney was subjected to 60 min of normothermic ischemia followed by 15 min of reperfusion, whereas the right kidney, serving as a paired control, was not rendered ischemic. Both kidneys were then perfused in situ with either Euro-Collins (EC) solution (n=12) or University of Wisconsin (UW) solution (n=6) for 10 min. Each kidney was then harvested and stored at 4°C in its respective solution. After 24 and 48 h of cold storage, the following vasoactive substances were measured in the preservation media: endothelin (ET), angiotensin II (A-II), thromboxane (B₂) (TxB₂), and prostaglandin I₂ (PGI₂). After 24 h in EC solution, left kidneys uniformly produced significantly higher concentrations of each vasoactive substance than right kidneys: ET 1.64±0.3 pg/ml vs 0.82±0.1 pg/ml (P0.009); A-II 20.8±6.2 pg/ml vs 7.75+2.3 pg/ml (P0.007); TxB₂ 100.8±17.7 pg/ml vs 40.1±11.7 pg/ml (P0.04); PGI₂ 638.3±41.1 pg/ml vs 318.3±36.4 pg/ml (P0.001), respectively. At 48 h, a similar pattern of results was obtained as the kidney continued to produce TxB₂ and prostacyclins during the 24–48 h period. In the UW solution, basal levels of ET and A-II were lower than those in EC solution, but similarly increased after initial ischemia. At 24 h, the concentrations produced by the left and right kidneys were as follows: ET 0.66±0.1 pg/ml vs 0.48±0.1 pg/ml (P0.14); A-II 10.36±3.7 pg/ml vs 2.14±0.7 pg/ml (P0.006); TxB₂ 178±53 pg/ml vs 52±23.1 pg/ml (P0.001); and PGI₂ 448.3±49 pg/ml vs 323±44.3 pg/ml (P0.01), respectively. After 48 h, the range of concentrations of each substance was similar to that obtained after 24 h. In further studies, the concentrations of ET and A-II were measured in solution previously used to preserve human kidneys (n=7). The mean concentration of ET and A-II in these samples was 3.82±1.14 pg/ml and 21.3±9.2 pg/ml, respectively, whereas in control media both substances were below the limits of detection. These results demonstrate that vasoconstrictive substances can be measured in the preservation media after a kidney has been stored cold and that higher concentrations are found when the organ has been subjected to prior normothermic ischemia. The measurement of these vasoactive substances before transplantation may reveal that the kidney has been subjected to previous ischemic events. Moreover, these vasoactive substances could be involved in the early recovery of renal function after kidney transplantation.     

A Retrospective Assessment of Canadian Preterm Birth Prevention Efforts: 1979–1999

Objectives: To assess the achievements and effectiveness of efforts to reduce preterm deliveries through the collaborative efforts of funding agencies, scientists, obstetricians, pediatricians, and health care providers in Canada. Methods: Chronological review of studies carried out in Canada within the past two decades using several methodological approaches, including randomized clinical trials, surveys of women and physicians, and prospective cohort studies. Results: Tertiary prevention by treatment of spontaneous preterm labor with beta-agonists was effective in delaying delivery by 48 hr compared with placebo. Ongoing studies tested the comparative efficacy of oxytocin antagonists to beta-adrenergic agents. Recently, nitric oxyde donors have been tested. Secondary prevention using various approaches showed that high-risk factors could not be modified by these interventions. Before applying primary prevention approaches, surveys disclosed the lack of knowledge among both physicians and pregnant women. Conclusion: A recent Canadian consensus meeting emphasized the potential for success by using multidisciplinary, community-based health promotion approaches to prevent preterm labor; enhancing basic research in predictive markers such as cervical change, infection/inflammation, and psychosocial stress; and increasing political involvement of health decision makers.     

Randomized, Prospective, Controlled Study Comparing Radical Prostatectomy Alone and Neoadjuvant Androgen Withdrawal in the Treatment of Localized Prostate Cancer

Purpose

A prospective, multicenter, randomized study was done to test the hypothesis that neoadjuvant androgen withdrawal decreases the incidence of positive margins following radical prostatectomy for localized prostate cancer.

Materials and Methods

Observations were made of 213 patients randomized to undergo radical prostatectomy alone (101) or to receive a 12-week course of 300 mg. cyproterone acetate daily followed by surgery (112). Groups were similar at baseline in terms of clinical stage, serum prostate specific antigen and Gleason score. Of 192 patients available for efficacy analysis 9 had stage T1b, 8 stage T1c, 63 stage T2a, 36 stage T2b and 76 stage T2c disease.

Results

One or more positive surgical margins were found in 59 of 91 patients (64.8 percent) in the surgery only group compared to 28 of 101 (27.7 percent) in the cyproterone acetate group (p = 0.001). Patients who received preoperative therapy had a statistically significantly lower rate of apical margin involvement than those who did not (17.8 versus 47.8 percent, respectively, p less than 0.0001). There was no statistically significant difference in surgical (p = 0.8645) or postoperative (p = 0.173) complications between the 2 groups.

Conclusions

Neoadjuvant androgen withdrawal with a 12-week course of 300 mg. cyproterone acetate daily results in a lower rate of positive margins without adversely affecting postoperative recovery. The impact on patient survival will be determined by long-term followup.     

Management of soft tissue sarcomas (STS) in first isolated local recurrence: a retrospective study of 83 cases.

PURPOSE: To analyze the management and clinical outcome of patients treated for a first isolated local recurrence of soft tissue sarcomas (trunk or extremities) and to identify prognosis factors. METHODS AND MATERIAL: Between 1980 and 1999, 83 adult patients were included in the study. Mean age was 61 years. Mean tumor size was 6 cm. Most sarcomas were located in extremities (n=74), were deep (n=60), and proximal (n=53); 30 involved nerves or vessels. Histologic subtypes were mainly grade 2 (42%) or 3 (36%) histiocytofibrosarcomas (49%) and liposarcomas (20%). Surgical treatment of recurrences consisted in wide excision (29 cases), marginal resection (43 cases), 5 patients requiring amputation. Final results were R0 (n=33), R1 (n=47) or R2 (n=3) resection. Besides surgery, 6 patients received neo-adjuvant and 7 others adjuvant chemotherapy. Twenty three patients received post-operative external beam radiotherapy (EBRT) (mean dose 55 Gy) and 26 interstitial 192Ir low dose rate brachytherapy (BCT) (mean dose 45 Gy for BCT alone, 22 Gy when associated with EBRT), 19 patients being re-irradiated. RESULTS: Mean follow up was 13 years. Thirty-seven (45%) patients relapsed, 62% of whom presenting an isolated local recurrence. Nineteen patients developed distant metastases. Multivariate analysis showed only tumor depth (P=0.05) and re-resection for primary R1 resection (P=0.018) being independent prognosis factors for tumor control, radiotherapy (EBRT and/or BCT) being significant in univariate analysis (P=0.05). Overall survival rate was 73%, 54%, and 47% at, respectively, 3.5 and 10 years, and was 65%, 35% and 32% after a further local recurrence. Multivariate analysis showed trunk (P=0.0001) or inferior extremity locations (P=0.023), symptomatic (P=0.001), high grade (P=0.01), deep (P=0.01) tumors, and the occurrence of a further local failure (P=0.004) as unfavorable characteristics for overall survival. CONCLUSIONS: A first isolated local recurrence of STS increases mainly the risk of a subsequent local relapse. Quality of local treatment is decisive. When a conservative treatment is feasible, it should combine surgical resection and radiotherapy, BCT being the best suited in previously irradiated patients. Efforts have to be pursued to increase quality of the treatment of primary tumors, at best performed in centers that have expertise in this field.