Longitudinal in vivo effects of growth hormone overexpression on bone in transgenic mice.

In this study we examined the effect of systemic overexpression of GH on bone in transgenic mice longitudinally in vivo over a period of 9 months. We observed substantially increased BMC in GH transgenic mice and a significant reduction in serum osteocalcin. GH effects on bone were strongly dependent on gender and developmental stage. INTRODUCTION: State-of-the-art bone marker and microimaging technology was applied in this longitudinal study to examine bone metabolism, BMC, bone density, and cortical bone structure over the life span of growth hormone (GH) transgenic (tg) mice. MATERIALS AND METHODS: Thirty-eight mice from four genetic groups (male, female, tg, and controls) were examined with DXA, and their femur and tibia were examined with peripheral QCT (pQCT). Osteocalcin (formation) and collagen cross-links (resorption) from serum and urine were also measured at postnatal weeks 3, 6, 9, 12, 18, 26, and 38. RESULTS: GH tg mice displayed a significant increase in body weight (up to 50%) and BMC (up to 90%), but serum osteocalcin was significantly reduced compared with controls. GH tg females (but not males) displayed increased trabecular density over controls up to week 12. In contrast, male (but not female) GH tg mice displayed a higher cortical cross-sectional area than controls. Cortical density was significantly lower in both male and female GH tg mice compared with control mice. CONCLUSIONS: The increase in BMC in GH tg mice is associated with reduced serum osteocalcin levels, indicating that bone turnover may be lower than in the control mice. On a structural level, bone responds to GH excess in a gender-specific manner, with alterations varying substantially between different developmental stages.     

Anatomic subdivisions in human temporal cortical neuronal activity related to recent verbal memory.

We identified functional anatomical subdivisions of human lateral and basal temporal cortex related to recent verbal memory for object names, text and auditory words. Extracellular neuronal activity was recorded during memory encoding compared to identification, during encoding, storage or recall retrieval stages of the memory task, during recognition memory, and during implicit memory as measured by repetition priming. Changes in frequency of activity during encoding were recorded from most neurons. In lateral temporal cortex, these encoding changes in the dominant hemisphere were more likely to be polymodal, whereas those in nondominant hemisphere were unimodal. There was substantial separation of neurons with changes in other aspects of memory, defining additional subdivisions. Inferior lateral and basal cortex were related to memory stages, and superior-posterior lateral cortex was related to implicit and recognition memory.     

Increased COVID-19 Lockdown Burden in Italian Adults with Gastrointestinal Diseases

Background: Coronavirus disease 2019 (COVID-19) causes not only severe illness but also detrimental effects associated with the lockdown measures. The present study aimed to evaluate reported lifestyle changes in a cohort of adults in Italy, including physical exercise, food choices, and psychological wellbeing, after two months of lockdown. Methods: A web survey on social media (Facebook and LinkedIn) of 32 multiple-choice questions aiming to evaluate the impact of the national COVID-19 lockdown in a sample of Italian adults. Results: We received 1378 complete responses (women 68.3%, mean age 39.5 ± 12.5 years). The percentage of participants reporting regular exercise decreased during lockdown (52 vs. 56.5%). The vast majority of people continued to consume the three traditional meals per day, but the consumption of meat, fish, and eggs significantly decreased. Women reported more frequent anxiety, sadness, fear, and feelings of insecurity than men. The factors predicting the worst outcome during the lockdown were being a woman, low education and income, gastrointestinal diseases. Conclusion: The lockdown has had a limited impact on food choices and physical exercise in Italian adults of our series, since most of them made an effort to improve their lifestyle. However, women with gastrointestinal diseases reported more frequent negative feelings and poor adaptation to the lockdown.     

COVID-19 in pediatric kidney transplantation: The Improving Renal Outcomes Collaborative

There are limited data on the impact of COVID-19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID-19 in pediatric KT patients. Twenty-two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS-CoV-2 by PCR. Testing indications included symptoms and/or potential exposures to COVID-19 (N = 134, 47.7%) and/or testing per hospital policy (N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID-19-positive patients, 16 were managed as outpatients, six received non-ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID-19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID-19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID-19 disease and excellent short-term outcomes.     

Toxicokinetics of soman: species variation and stereospecificity in elimination pathways

Blood levels of the four stereoisomers of the nerve agent C(+/-)P(+/-)-soman were analyzed gas chromatographically in anaesthetized, artificially respirated and atropinized rats, guinea pigs and marmosets at intravenous doses of C(+/-)P(+/-)-soman corresponding with 1-6 LD50. The relatively nontoxic C(+/-)P(+/-)-isomers disappear within a few minutes from the blood stream of all three species, whereas the levels of the highly toxic C(+/-)P(-)-isomers remain toxicologically relevant for periods of 50-100 min in three species of doses of 2-3 LD50. Elimination pathways were quantified using 14C-labeled soman stereoisomers. Whereas the C(+/-)P(+)-isomers are largely eliminated by way of enzymatic hydrolysis, the major elimination pathway for the C(+/-)P(-)-isomers is binding to various proteins, in competition with binding to target acetylcholinesterase. Intraspecies nonlinearity with dose in the toxicokinetics of the C(+/-)P(-)-isomers is related to heterogeneous reactivity of the binding sites. Interspecies nonlinearity is probably due to decreasing amounts of binding sites in the order rats greater than guinea pigs greater than primates, leading to increasing "toxico-availability" in the reversed order.     

Reactivation of acetylcholinesterase inhibited by methamidophos and analogous (di)methylphosphoramidates

Reactivation of electric eel acetylcholinesterase (AChE) inhibited by MeO(NH₂)P(O)SMe (methamidophos) and by MeS(NH₂)P(O)SMe was studied at pH 7.5 and 25° C. The former inhibited enzyme shows a rather rapid spontaneous reactivation (t_1/2=3.7 h); this reactivation is accelerated by 1 M of the bispyridinium oximes TMB4 and obidoxime, and, to a lesser extent, by the monopyridinium oximes P2S and its 1-benzyl analogue (benzyl-P2A). The latter inhibited enzyme shows rapid aging (t_1/2=0.6 h). Reactivation with 1 mM of the bispyridinium oximes is incomplete and reactivation with 1 mM of the monopyridinium oximes proceeds very slowly. These large differences between the properties of the two inhibited enzymes indicate that the methylthio group is the leaving group during inhibition of AChE by methamidophos. Additional support is afforded by the observation of induced aging of the former inhibited enzyme by thiourea.Upon comparison of the reactivation of AChE inhibited by methamidophos with that of AChE inhibited by an N-methyl analogue, cruf ornate, and an N,N-dimethyl analogue, tabun, it appears that the rate of spontaneous reactivation decreases with increasing alkylation of the P-NH₂ group. Whereas benzyl-P2A is somewhat less active than P2S for reactivation of AChE inhibited by methamidophos, it is superior to P2S for reactivation of AChE inhibited by crufomate and also superior to P2S and to the bispyridinium oximes for AChE inhibited by tabun.     

Rifampicin reverses nicardipine effect inducing uncontrolled essential hypertension

Dihydropyridine calcium‐channel blockers are a known substrate for the cytochrome P450 isoform 3A4. Rifampicin, an antitubercular agent, is one of the most potent inducers of hepatic and intestinal CYP3A4 thus increasing dihydropyridine metabolism. We report a case of a 67‐year‐old hypertensive female treated with a four‐drug antihypertensive regimen including a dihydropyridine (nicardipine 50 mg bid), who was admitted for septic arthritis of the knee requiring antibiotic treatment with teicoplanin 400 mg od and rifampicin 600 mg bid. Six days after rifampicin initiation, she presented with Posterior Reversible Encephalopathy Syndrome due to uncontrolled hypertension. We hypothesized that disequilibrium of previously controlled hypertension was partially due to nicardipine ineffectiveness. Plasma nicardipine concentration was assessed through high‐performance liquid chromatography 5 hours after coadministration of the two drugs and proved undetectable.