Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion is among the strongest known genetic risk factors for neuropsychiatric disorders, including autism and schizophrenia. Brain imaging studies have reported disrupted large-scale functional connectivity in people with 22q11 deletion syndrome (22q11DS). However, the significance and biological determinants of these functional alterations remain unclear. Here, we use a cross-species design to investigate the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. We find that LgDel mice, an established mouse model of 22q11DS, exhibit age-specific patterns of functional MRI (fMRI) dysconnectivity, with widespread fMRI hyper-connectivity in juvenile mice reverting to focal hippocampal hypoconnectivity over puberty. These fMRI connectivity alterations are mirrored by co-occurring developmental alterations in dendritic spine density, and are both transiently normalized by developmental GSK3ß inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous hyper- to hypoconnectivity reconfiguration occurs also in human 22q11DS, where it affects hippocampal and cortical regions spatially enriched for synaptic genes that interact with GSK3ß, and autism-relevant transcripts. Functional dysconnectivity in somatomotor components of this network is predictive of age-dependent social alterations in 22q11.2 deletion carriers. Taken together, these findings suggest that synaptic-related mechanisms underlie developmentally mediated functional dysconnectivity in 22q11DS.

A prospective study of religion/spirituality and depressive symptoms among adolescent psychiatric patients.

OBJECTIVE: Previous research has uncovered relationships between religion/spirituality and depressive disorders. Proposed mechanisms through which religion may impact depression include decreased substance use and enhanced social support. Little investigation of these topics has occurred with adolescent psychiatric patients, among whom depression, substance use, and social dysfunction are common. METHOD: 145 subjects, aged 12-18, from two psychiatric outpatient clinics completed the Beck Depression Inventory-II (BDI-II), the Fetzer multidimensional survey of religion/spirituality, and inventories of substance abuse and perceived social support. Measures were completed again six months later. Longitudinal and cross-sectional relationships between depression and religion were examined, controlling for substance abuse and social support. RESULTS: Of thirteen religious/spiritual characteristics assessed, nine showed strong cross-sectional relationships to BDI-II score. When perceived social support and substance abuse were controlled for, forgiveness, negative religious support, loss of faith, and negative religious coping retained significant relationships to BDI-II. In longitudinal analyses, loss of faith predicted less improvement in depression scores over 6 months, controlling for depression at study entry. LIMITATIONS: Self-report data, clinical sample. CONCLUSIONS: Several aspects of religiousness/spirituality appear to relate cross-sectionally to depressive symptoms in adolescent psychiatric patients. Findings suggest that perceived social support and substance abuse account for some of these correlations but do not explain relationships to negative religious coping, loss of faith, or forgiveness. Endorsing a loss of faith may be a marker of poor prognosis among depressed youth.

Supplementation with gum arabic fiber increases fecal nitrogen excretion and lowers serum urea nitrogen concentration in chronic renal failure patients consuming a low-protein diet.

In chronic renal failure (CRF), plasma concentrations of the products of protein metabolism are increased. Current dietary management is to prescribe a decrease in protein intake. The use of dietary fiber to increase fecal excretion of retained metabolites in CRF may be a beneficial adjunct to a low-protein diet (LPD). Colonic bacteria ferment dietary fiber, providing them with energy for growth and nitrogen incorporation, in turn, increasing nitrogen excretion in feces. Sixteen CRF patients consuming an LPD were randomly assigned to receive a supplement of a highly fermentable fiber, gum arabic (50 g/d), or a placebo (1 g pectin/d) in a prospective, single-blind, crossover design. Fecal bacterial mass and fecal nitrogen content were significantly increased during supplementation with gum arabic compared with the baseline LPD or supplementation with pectin. Serum urea nitrogen was significantly decreased during supplementation with gum arabic compared with the baseline LPD or supplementation with pectin. Nitrogen balance did not change significantly.

Adequacy of continuous ambulatory peritoneal dialysis: morbidity and mortality in chronic peritoneal dialysis.

Mortality for hemodialysis patients tends to be in excess of 20% per year, and it is generally agreed that outcome for continuous ambulatory peritoneal dialysis patients is comparable. Several investigators have suggested recently that continuous ambulatory peritoneal dialysis, as commonly practiced, may not provide adequate therapy, especially for larger patients and for those with no residual renal function. Unfortunately, a dose-response curve relating the amount of dialysis delivered and clinical outcome for continuous ambulatory peritoneal dialysis patients has not been constructed. Several methods of quantifying the dose of peritoneal dialysis are described. Both cross-sectional and longitudinal studies are reviewed. The conclusions of these studies are of limited value, however, because of their retrospective nature and the limited number of patients enrolled. Nevertheless, in aggregate, these studies suggest that survival may be improved by higher doses of dialysis. They also suggest that while malnutrition is relatively common in this patient population, higher doses of Kt/V are associated with higher protein intake (as measured by protein catabolic rate). Serum albumin is recognized as a strong predictor of clinical outcome and the protein catabolic rate may correlate directly with Kt/V, but there are studies that support and others that refute a correlation between Kt/V and serum albumin. Definitive answers to these questions are likely to be available in the near future. Two large multicenter studies are currently under way. Preliminary results may be available in the near future.

Sleep disordered breathing in ESRD: acute beneficial effects of treatment with nasal continuous positive airway pressure.

Complaints about sleep and daytime alertness are common in ESRD patients. Eight consecutive ESRD patients with a sleep complaint were studied with all-night polysomnography. All were found to have significant sleep apnea with a mean apnea/hypopnea index (AHI) of 64 +/- 41.6 episodes per hour of sleep (range 7.5 to 140/hr of sleep). The majority of apneas were of the central or mixed variety causing severe fragmentation of sleep and frequent awakenings. Treatment was attempted with nasal continuous positive airway pressure (NCPAP). NCPAP was highly successful in six of the eight patients, reducing the mean AHI to normal or near normal levels (6.0 +/- 3.8/hr of sleep, P < 0.02 vs. baseline). The quality of sleep was significantly improved with statistically significant decreases in light stage 1 sleep, and nocturnal oxygenation improved with statistically significant increases in low SaO2 values. Five of six responders reported that they awoke feeling more alert and fewer times from sleep. The etiology of sleep apnea in ESRD is unknown although the frequent central apneas suggest a dysfunction of central respiratory control resulting from the effects of renal failure. Sleep-related complaints in patients with ESRD are likely to result from sleep apnea, a sleep disorder that can be diagnosed with polysomnography and treated with NCPAP.

Suppression of renal vein renin profiles by mannitol prophylaxis: implications in the evaluation of renovascular hypertension.

Renal arteriography with concomitant renal vein renin profiling remains the diagnostic standard for evaluating the anatomic and physiologic significance of stenotic renal artery lesions in hypertensive patients. False-negative renal vein renin profiles with failure of lateralization in patients with anatomically apparent high-grade stenosis complicate the diagnostic process. Mannitol is frequently administered prophylactically to minimize the risk of dye nephropathy in these patients. Yet, the potential effects of mannitol on renal vein renin profiling in man have not been previously reported. Seven patients with renovascular hypertension were studied prospectively to determine changes in renal vein renin profiles before and after mannitol prophylaxis. Despite captopril stimulation, all patients demonstrated significant renin suppression leading to the loss of renin lateralization in patients with unilateral renovascular hypertension. In 60% of the patients, renal vein renin ratios fell to below the standard 1.5 to 1 ratio after mannitol infusion. In patients with bilateral renovascular disease, the least stenotic side suppressed completely, while the more stenotic side suppressed partially. Percent suppression analysis showed a mean suppression of 56.8% on the stenotic side versus 8.2% on the noninvolved side (P less than 0.002). In every study, suppression equaled or exceeded 32% on the involved side and was less than this on the noninvolved side. Thus, the degree of renin suppression following mannitol infusion may prove to be an important tool in the diagnosis of clinically significant stenotic lesions. The mechanism of mannitol-induced suppression remains undefined, but appears independent of volume expansions or dilutional effects. The inhibitory effects of mannitol on renin profiles can obscure the diagnosis of underlying renovascular hypertension.

Urea kinetic analysis and clinical outcome on CAPD. A five year longitudinal study.

The present study, along with some recent studies, suggests that there is an organic link between the amount of dialysis a patient receives and his/her nutritional status. The latter, as reflected by serum albumin, is predictive of survival on CAPD. It is clear, therefore, that urea kinetic analysis is a powerful tool for prescribing and monitoring therapy in CAPD patients.

Successful treatment of postparathyroidectomy hypocalcemia using continuous ambulatory intraperitoneal calcium (CAIC) therapy.

Severe, recalcitrant hypocalcemia and hungry bone syndrome can complicate parathyroidectomy in end-stage renal disease patients. Treatment with prolonged and massive doses of intravenous calcium, with calcitriol supplementation, is often necessary, but potentially dangerous and may prolong hospitalization. Three CAPD patients (including 1 with malabsorption) were safely treated by adding 1 to 3 ampules (10-30 mL) of 10% calcium gluconate solution to each bag of dialysate for up to 29 months. Continuous ambulatory intraperitoneal calcium (CAIC) therapy was initiated postoperatively and continued on an outpatient basis until the patients' hungry bone syndrome resolved and serum calcium normalized. Complications such as visible dialysate precipitation or an increased rate of peritonitis were not observed. Mean total calcium uptake was approximately 137 to 226 mg/exchange. We conclude that CAIC therapy is a safe, effective treatment both for CAPD patients with postparathyroidectomy hypocalcemia with hungry bone syndrome, as well as in patients with hypocalcemia secondary to malabsorption.

Hydrothorax in continuous ambulatory peritoneal dialysis: successful treatment with intrapleural tetracycline and a review of the literature.

Recurrent hydrothorax complicating peritoneal dialysis has been considered a contraindication to continuing peritoneal dialysis. In the continuous ambulatory peritoneal dialysis (CAPD) population this problem has generally required a change of dialytic modality. Talc poudrage has been attempted to ameliorate the problem but has met with limited success. We report a successful case of intrapleural instillation of tetracycline to induce a pleural symphysis and prevent recurrence of peritoneal dialysis-related hydrothorax in a patient who refused any alternative mode of dialysis. We also review the literature, pathophysiology, epidemiology, diagnosis, and management of this compromising problem.

Acid-base balance in continuous ambulatory peritoneal dialysis.

Metabolic acidosis was demonstrated in a group of anuric CAPD patients. Dialysate HCO3- loss was the major determinant of a negative base balance of 26.4 +/- 23.5 mMol/day. Bicarbonate supplementation corrected the acidosis. A primary respiratory alkalosis was also present in several patients.

Plasma pyridoxal-5'-phosphate levels and clinical correlations in chronic hemodialysis patients.

Plasma pyridoxal-5'-phosphate (PLP) was measured by a specific method in 45 stable, chronic hemodialysis patients and 13 normal adults. Despite oral pyridoxine supplements (1 to 5 mg/day) a majority (64%) of patients had low levels. The difference between normals (8.5 +/- 3.7 ng/ml) and dialysis patients (3.6 +/- 3.6 ng/ml) was significant at P less than 0.01. Plasma PLP appeared to decrease with increasing duration of time on dialysis therapy. In vivo clearance studies as well as pre- and postdialysis plasma levels indicated that PLP was not removed by the dialyzer. Mean plasma PLP levels were normal in patients with stable motor nerve conduction velocity and a low transfusion requirement and low in those with decreasing motor nerve conduction velocity or a high transfusion requirement but the difference between the means in each group was not statistically significant. High oral doses of pyridoxine (100 to 200 mg/day) but not low doses (1 to 5 mg/day) restored PLP levels to normal in a majority of patients after 2 weeks.