Paradoxical sleep deprivation and sleep recovery: effects on the hypothalamic-pituitary-adrenal axis activity, energy balance and body composition of rats

Numerous studies indicate that sleep deprivation alters energy expenditure. However, this conclusion is drawn from indirect measurements. In the present study, we investigated alterations of energy expenditure, body composition, blood glucose levels, plasma insulin, adrenocorticotropic hormone (ACTH) and corticosterone levels immediately after 4 days of sleep deprivation or after 4 days of sleep recovery. Rats were sleep deprived or maintained in a control environment (groups sleep-deprived/deprivation and control/deprivation). One half of these animals were sacrificed at the end of the deprivation period and the other half was transported to metabolic cages, where they were allowed to sleep freely (groups sleep-deprived/recovery and control/recovery). At the end of the sleep recovery period, these rats were sacrificed. After sleep deprivation, sleep-deprived rats exhibited loss of body weight, augmented energy expenditure and reduced metabolic efficiency compared to control rats. These alterations were normalised during the sleep recovery period. The body composition of sleep-deprived rats was altered insofar as there was a loss of fat content and gain of protein content in the carcass compared to control rats. However, these alterations were not reversed by sleep recovery. Finally, plasma levels of insulin were reduced during the sleep deprivation period in both control and sleep deprived groups compared to the recovery period. After the deprivation period, plasma ACTH and corticosterone levels were increased in sleep-deprived rats compared to control rats, and although ACTH levels were similar between the groups after the sleep recovery period, corticosterone levels remained elevated in sleep-deprived rats after this period. By means of direct measurements of metabolism, our results showed that sleep deprivation produces increased energy expenditure and loss of fat content. Most of the alterations were reversed by sleep recovery, except for corticosterone levels and body composition.     

Taurine potentiates presynaptic NMDA receptors in hippocampal Schaffer collateral axons

We have previously shown that activation of presynaptic N-methyl-d-aspartate (NMDA) receptors (NMDAR) enhances the amplitude of the presynaptic fibre volley (FV) evoked in Schaffer collateral axons of rat hippocampal slices, by a mechanism independent of extracellular Ca(2+). Here we compared the pharmacological characteristics of presynaptic NMDARs affecting axon excitability (activated by 10-300 microM NMDA for 10 min), with those mediating field excitatory postsynaptic potentials (NMDA-fEPSP). We found that NMDA-induced potentiation was completely inhibited by NVP-AAM077, an antagonist of NR2A-containing NMDAR, but not by ifenprodil, an NR2B-selective antagonist. The inhibitor of the glycine-binding site in NMDARs, 7-clorokynurenic acid (7-CK), was more potent against NMDA-fEPSP (IC(50) = 6.3 +/- 1.3 microM) than against the NMDA-induced FV potentiation (IC(50) = 26.5 +/- 1.3 microM). Moreover, both post- and presynaptic NMDAR-mediated phenomena were enhanced by glycine and d-serine, but taurine, an endogenous analogue of glycine, only enhanced the latter (EC(50) = 19 microM). Taurine was able to block the inhibitory effect of low doses of 7-CK on NMDA-induced FV potentiation, while glycine and d-serine only reduced the effects of higher concentrations of this drug. Surprisingly, the enhancing effect of taurine on NMDA-induced FV potentiation was blocked when it was co-applied with glycine. Furthermore, the glutamate released synaptically with a train of stimuli also increased FV amplitude by a mechanism dependent on NMDARs; this was potentiated by taurine but not by co-application of taurine and glycine. These results reveal that presynaptic NMDARs have unique properties that mediate the facilitation of axon excitability.     

Improving on National Quality Indicators of Breast Cancer Care in a Large Public Hospital as a Means to Decrease Disparities for African American Women

Background

In April 2007, the National Quality Forum (NQF) endorsed the first nationally recognized hospital-based performance measures for stage I, II, and III breast cancer. The purpose of this study was to document compliance with the 3 NQF breast quality indicators during 2 time intervals in a metropolitan public hospital.

Materials and Methods

Tumor registry and medical records were used to identify patient demographics and treatments before (2005–2006) and after (2008) implementations in 2007 as a result of the NQF audit. Program changes included: hiring a dedicated medical oncology nurse practitioner, requiring the radiation oncology case manager to attend weekly multidisciplinary conferences, educating Patient Navigators of the importance of multimodal care, and providing support groups for patients addressing importance of completion of all treatment options.

Results

A total of 213 female patients were diagnosed with and treated for stage I, II, or III breast cancer in 2005–2006 and 2008. Of these, 189 (89%) were African American (AA) women. Also, 70 patients of 86 (81.3%) received radiation therapy, 60 of 77 (77.9%) received or were considered for adjuvant chemotherapy, and 124 of 144 (86.1%) for hormonal therapy according to NQF indicators. After 2007, patients receiving radiation therapy increased from 75.8 to 95.8%. Patients receiving or considered for adjuvant chemotherapy or hormonal therapy increased from 73.7 to 93.7% and from 84.1 to 90.0%, respectively.

Conclusions

NQF breast cancer indicators provided a mechanism to improve compliance of multimodal treatment in our center. Raising awareness of these indicators in the multidisciplinary conference, hiring dedicated personnel, and educating patients has led to major improvements in breast cancer care.     

Video-assisted thoracoscopic lobectomy in the treatment of intralobar pulmonary sequestration

Pulmonary sequestration is a congenital malformation characterised by cystic, non-functioning embryonic lung tissue with vascularisation of an abnormal systemic artery. They are classified as intralobar (75%) and extralobar (25%) and are more common in the left lung and lower lobes (60-90%). We report two cases of intralobar pulmonary sequestration located in the lower lobe of the left lung which were subjected to video-assisted thoracoscopic surgery (VATS). Both patients had recurrent infections for which, after performing imaging tests, they were diagnosed with intralobar pulmonary sequestration in the left lower lobe, with an afferent arterial branch to the malformation from the aorta. A lower lobectomy was performed by video-assisted surgery, dividing the aberrant aortic artery with an endostapler. A single thoracic chest tube was placed and removed on postoperative day 2 and the patients were discharged on the same day. In both cases, the pathology examination revealed intralobar pulmonary sequestration. Pulmonary sequestrations are uncommon malformations that can be operated on using minimally invasive techniques, thereby permitting early discharge and a low rate of complications.     

Defective differentiation of regulatory FoxP3+ T cells by small-intestinal dendritic cells in patients with type 1 diabetes

OBJECTIVE

The gut environment modulates the pathogenesis of type 1 diabetes (T1D), but how it affects autoimmunity toward pancreatic β-cells, a self-tissue located outside the intestine, is still unclear. In the small intestine, lamina propria dendritic cells (LPDCs) induce peripheral differentiation of FoxP3⁺ regulatory T (Treg) cells. We tested the hypothesis that the intestinal milieu impinges on human T1D by affecting differentiation of FoxP3⁺ Treg cells.

RESEARCH DESIGN AND METHODS

We collected duodenal biopsies of 10 T1D patients, 16 healthy subjects, and 20 celiac individuals and performed a fluorescent-activated cell sorter analysis to measure percentages of various immune cell subsets, including CD4⁺ and CD8⁺ T cells, NK cells, γδ T cells, CD103⁺CD11c⁺ LPDCs, and CD4⁺CD25⁺FoxP3⁺CD127⁻ Treg cells. In parallel, we assessed the tolerogenic function (i.e., capacity to induce differentiation of FoxP3⁺ Treg cells) by LPDCs of T1D patients and control subjects.

RESULTS

Our analysis revealed a significant reduction in the percentage of intestinal CD4⁺CD25⁺FoxP3⁺CD127⁻ Treg cells in T1D patients compared with healthy subjects (P = 0.03) and celiac individuals (P = 0.003). In addition, we found that LPDCs from T1D patients completely lacked their tolerogenic function; they were unable to convert CD4⁺CD25⁻ T cells into CD4⁺CD25⁺FoxP3⁺CD127⁻ Treg cells.

CONCLUSIONS

Our data indicate that T1D patients have a reduced number of intestinal FoxP3⁺ Treg cells as a result of their defective differentiation in the gut. These findings suggest that intestinal immune regulation is not only calibrated to tolerate commensal bacteria and food components but also is instrumental in maintaining immune tolerance toward pancreatic β-cells and preventing T1D.Type 1 diabetes (T1D) is a destructive islet β-cell specific autoimmune disease resulting from a yet undefined interaction between genetic and environmental factors (1). A dramatic increase in T1D incidence was recorded in most developed countries in the past 40 years (e.g., a threefold increase in Western countries) (2,3). The steady and rapid increase in T1D incidence cannot be ascribed to genetic variations and, thus, it must be related to environmental changes. Environmental agents such as viral infections (i.e., enteroviruses and rotaviruses) (4,5), reactions to dietary antigens (i.e., cow’s milk and gluten) (6–8), and microbiota alterations (9) that act at the intestinal level have been observed in association with, or as risk factors for, the development of T1D. The observation that development of clinical diabetes in patients is preceded by intestinal alterations such as increased permeability, immune activation, and ultrastructural abnormalities of the epithelium (10–16) provides additional evidence on the crucial role of the gut environment in human T1D. Although existing evidence is suggestive of a causative link between the gut milieu and the pathogenesis of T1D, it is still unclear whether and by which mechanism(s) a dysfunction in the intestine promotes autoimmunity elsewhere (i.e., in the pancreatic β-cells) and if it does, how this process occurs.Important immune regulatory mechanisms reside in the intestinal mucosa. FoxP3⁺ regulatory T (Treg) cells, a Treg cell subset that is instrumental to controlling T1D (17), arise centrally in the thymus and peripherally in the gut (18). Specifically, lamina propria CD103⁺CD11c⁺ dendritic cells (LPDCs) are responsible for extrathymic FoxP3⁺ Treg cell development and expansion (18,19). Considering the key immune regulatory role of FoxP3⁺ Treg cells, it is clear that their defective peripheral differentiation in the gut could lead to failure of self-tolerance and autoimmune disease, particularly in tissues such as pancreatic islets and lymph nodes that are directly connected to the intestinal mucosa and gut-associated lymphoid tissue (20).Here we demonstrate that the extrathymic differentiation of FoxP3⁺ Treg cells by gut-resident CD103⁺CD11c⁺ dendritic cells (DCs) is selectively impaired in humans affected by T1D. Our findings indicate that organ-specific autoimmune diseases such as T1D could be initiated and possibly maintained by virtue of changes in peripheral FoxP3⁺ Treg cell differentiation and/or expansion in the gut.     

Transient urethral obstruction predisposes to ascending pyelonephritis and tubulo-interstitial disease: studies in rats

Chronic tubulo-interstitial disease, an important cause of end-stage renal disease, often results from the combined effects of a disturbed urinary outflow tract and urinary tract infection. Acute unilateral ureteral obstruction in rats rapidly induces foci of medullary necrosis, confined to the region of the papilla and fornices. This injury may provide a nidus for bacterial invasion and may invoke reactive and regenerative changes, ultimately leading to chronic pyelonephritis and tubulo-interstitial nephropathy. To explore this possibility, adult rats underwent renal morphological evaluation 2–7 days following transient 24-h unilateral ureteral obstruction. In some experiments the bladder was inoculated with bacteria (10⁸–10⁹ cfu/ml Escherichia coli in 0.5 ml) after release of ureteral obstruction, with subsequent cultures obtained from the pelvis of both kidneys and from the urinary bladder. Morphologic evaluation of perfusion-fixed kidneys, 2–7 days after the release of 24-h ureteral obstruction disclosed papillary necrosis, urothelial proliferation, marked inner-stripe interstitial expansion, and fibrosis and proximal tubular (S₃) dilatation. The lateral (perihilar region) was predominantly affected, with lesions spreading from the fornices. There was some progression of interstitial fibrosis during the postobstructive time course or following more prolonged ureteral obstruction. By contrast, infection hardly contributed to the tubulointerstitial changes. In rats subjected to infection, cultures were positive in all 15 postobstructive kidneys, as opposed to five contralateral kidneys (P < 0.0001). Viable counts from the postobstructive kidney were also higher than those from the contralateral side (79,000 ± 12,000 vs 2900 ± 1600 cfu/ml, mean ± SEM, P < 0.0001), and were comparable to those obtained from the bladder (77,000 ± 13,000 cfu/ml). We conclude that transient ureteral obstruction predisposes to ascending pyelonephritis and to tubulointerstitial disease. This vulnerability may relate to altered urodynamics and medullary tissue destruction. Received: 28 December 1999 / Accepted: 28 September 2000     

Clinical and imaging correlations of Treacher Collins syndrome: report of two cases.

Mandibulofacial dysostosis (Treacher Collins Syndrome) is an autosomal dominant genetic disorder that probably derives from inhibition of the facial structures from the first and second branchial arches. The facial pattern of the syndrome is a convex facial profile with a prominent nose above a retruded chin. The eyes are deformed by antimongoloid slant of the palpebral fissures and facial bones are hypoplastic. The alterations are caused by mutation in gene 5q32-33.1, which encodes the nucleolar phosphoprotein treacle. Computed tomography images are able to demonstrate craniofacial bones, allowing the morphological analysis of these bones in individuals with complex deformities. The purpose of this paper is to present the results of a clinical and computed tomography investigation of two patients with Treacher Collins syndrome.     

Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis.

A controversy exists over whether the outcome of a hepatitis C virus (HCV)-infection-related liver transplant differs based on the calcineurin inhibitor (CNI) used. We have performed a systematic review and a subsequent meta-analysis evaluating tacrolimus (Tac)-based vs. cyclosporine A-based immunosuppression in HCV-infected liver transplant recipients. Searches were conducted to locate randomized controlled trials comparing Tac vs. cyclosporine A. Data on HCV liver transplant recipients were obtained, independently of whether the study was specifically designed for patients with this disease or not. A fixed effects model was used for statistical pooling of the relative risks (RR) for the different outcomes. A total of 5 articles (366 patients) fulfilled the inclusion criteria. Statistically significant differences between Tac-based vs. cyclosporine A-based therapies were not found for mortality (P = 0.11; RR = 0.72; 95% confidence interval [CI], 0.49-1.08), graft survival (P = 0.37; RR = 0.86; 95% CI, 0.61-1.21), biopsy-proven acute rejection (P = 0.65; RR = 0.91; 95% CI, 0.61-1.36), corticoresistant acute rejection (P = 0.26; RR = 2.25; 95% CI, 0.55-9.29), and fibrosing cholestatic hepatitis (P = 0.92; RR = 0.96; 95% CI, 0.41-2.26). In 1 study, no differences were detected regarding severe fibrosis at 1 yr. In conclusion, patient and graft survivals in HCV-positive liver transplant patients are similar independently of the CNI selected as basic immunosuppressant. Unfortunately, data on the severity of recurrence and effect on viremia are scarce. Well-designed randomized prospective studies are needed to determine whether there are differences between the 2 CNIs regarding these specific variables.     

Evaluation of methods based on creatinine and cystatin C to estimate glomerular filtration rate in chronic kidney disease

Purpose

Estimated glomerular filtration rate (GFR) is a useful tool for the detection of chronic kidney disease (CKD). Several methods have been proposed, but findings can vary in specific groups such as patients with diabetes, elderly and high and low body mass index and, also, with the stage of CKD. The objective of this study was comparing the accuracy of the currently used equations for estimating GFR with that of the gold standard technetium-(99m)-diethylene triamine pentaacetic acid (99mTc-DTPA).

Methods

We performed a cross-sectional study of 129 patients with all five CKD stages. GFR was estimated using the following: 24-h urine creatinine clearance, Cockcroft–Gault equation, MDRD equation, CKD-EPI equation, Hoek’s cystatin C equation, and isotopic 99mTc-DTPA (as gold standard). We evaluated agreement in the whole study population and according to age, sex, weight, and diabetes.

Results

All methods had good agreement. The best agreement was observed with the cystatin C [intraclass coefficient correlation (ICC) 95 % confidence interval (95 % CI), 0.87 (0.82–0.91)], followed by CKD-EPI [ICC 0.83 (0.77–0.88)]. Twenty-four-hour urine creatinine clearance showed the worst agreement in patients older than 65 years [ICC 0.70 (0.56–0.79)]. The Cockcroft–Gault equation showed the worst agreement in younger than 65 years [ICC 0.64 (0.42–0.79)]. The best agreement for classification in the correct CKD stage was with the cystatin C equation [κ = 0.80 (0.74–0.87)]. GFR was overestimated with all methods in CKD stages 4 and 5.

Conclusions

The methods used in clinical practice are adequate for classification of CKD. Cystatin C is the most accurate method, followed by CKD-EPI. The Cockcroft–Gault equation is not accurate in young patients. Twenty-four-hour urine creatinine clearance loses accuracy in patients aged older than 65 years.