Obesity with associated developmental delay and/or learning disability in patients exhibiting additional features: Report of novel pathogenic copy number variants

Obesity is a major threat to public health worldwide, and there is now mounting evidence favoring a role for the central nervous system (CNS) in weight control. A causal relationship has been recognized in both monogenic (e.g., BDNF, TRKB, and SIM1 deficiencies) and syndromic forms of obesity [e.g., Prader–Willi syndrome (PWS)]. Syndromic obesity arising from chromosomal abnormalities, that typically also affect learning and development, are often associated with congenital malformations and behavioral characteristics. We report on nine unrelated patients with a diagnosis of learning disability and/or developmental delay (DD) in addition to obesity that were found to have copy number variants (CNVs) by single nucleotide polymorphism array‐based analysis. Each patient also had a distinct and complex phenotype, and most had hypotonia and other neuroendocrine issues, such as hyperphagia and hypogonadism. Molecular and clinical characterization of these patients enabled us to determine with confidence that the CNVs we observed were pathogenic or likely to be pathogenic. Overall, the CNVs reported here encompassed a candidate gene or region (e.g., SIM1) that has been reported in patients associating obesity and DD and/or intellectual disability (ID) and novel candidate genes and regions. © 2013 Wiley Periodicals, Inc.     

The development and validation of the hypertension evaluation of lifestyle and management knowledge scale

Hypertension knowledge is an integral component of the chronic care model. A valid scale to assess hypertension knowledge and self-management skills is needed. The hypertension evaluation of lifestyle and management (HELM) scale was developed as part of a community-based study designed to improve self-management of hypertension. Participants included 404 veterans with hypertension. Literature review and an expert panel were used to identify required skills. Items were generated and pilot tested in the target population. Validity was assessed through comparisons of performance with education, health numeracy, print numeracy, patient activation and self-efficacy, and hypertension control. The HELM knowledge scale had 14 items across 3 domains: general hypertension knowledge, lifestyle and medication management, and measurement and treatment goals. Scores were positively associated with education (0.28, P<.0001), print health literacy (0.21, P<.001), health numeracy (0.17, P<.001), and patient activation (0.12, P=.015) but no association was found with diastolic or systolic blood pressure. The HELM knowledge scores increased following the educational intervention from baseline (mean, 8.7; standard deviation, 2.2) to 12-month follow-up (mean, 9.2, standard deviation, 2.2; P<.001). We conclude that the HELM provides a valid measure of the knowledge required for patients to take an active role in the chronic disease management of hypertension.     

Serum Markers for Predicting Abdominal Surgery Outcomes in Patients with Cirrhosis

Background

Determinants of adverse events for cirrhotic patients undergoing abdominal surgery have not been adequately assessed. Child–Turcotte–Pugh (CTP) and Model for End-Stage Liver Disease (MELD) have estimated perioperative outcomes with inconsistent results. Our study sought to combine novel serum markers with CTP and MELD to improve prognostication of 30-day postoperative mortality or liver transplant in cirrhotic patients undergoing abdominal surgery.

Methods

A review was performed on 120 cirrhotic patients undergoing nonhepatic abdominal surgeries at Mount Sinai Medical Center from 2001–2011. Preoperative serum markers were evaluated by logistic regression and receiver–operator characteristics. Prognostic ability of scoring systems was assessed using Youden’s J statistic (J).

Results

Albumin and hematocrit were independently predictive of 30-day mortality or transplant with optimal cutoff values of albumin at <3.05 mg/dl and hematocrit at <35.55 %. Adding these criteria to CTP>A, CTP>B, MELD?≥?10, MELD?≥?15, and MELD?≥?20 improved sensitivity and specificity by an average of 6.1 and 32.1 %, respectively. The highest J values resulted from combining novel criteria with CTP>A (sensitivity, 80 %; specificity, 82 %; p?<?0.01; J, 0.63) and MELD?≥?10 (sensitivity, 63 %; specificity, 90 %; p?<?0.01; J, 0.53).

Conclusion

Augmenting CTP and MELD with albumin and hematocrit significantly improved the identification of cirrhotic patients at risk of 30-day mortality or transplantation following nonhepatic abdominal surgery.     

The astrocyte in multiple sclerosis revisited

Among the constituent cell types of the multiple sclerosis (MS) plaque, the astrocyte has been the least considered as a player in the pathogenesis of the lesion. Traditionally, it has been assigned a secondary scarring role with little or no role in lesion formation or repair. However, the recent upsurge of interest in the demyelinating condition neuromyelitis optica (NMO) has resulted in NMO being identified as the first disease of myelin in which primary damage to astrocytes, resulting from a humoral immune response that forms against the water channel aquaporin‐4, has been documented. This finding in NMO prompted us to re‐examine data and material from cases of MS displaying active lesions. Our reappraisal revealed unambiguous early damage to perivascular astrocyte end‐feet and to hypertrophic astrocytes in the adjacent parenchyma, but whether this was a primary event was difficult to evaluate due to concomitant edema and inflammation in these acute lesions. The astrocyte damage was long‐lasting since resolving lesions displaying remyelination also showed defects in the integrity of the astrocytic covering around blood vessels. Analysis of our findings and of the astrocytic literature supports multiple roles for the astrocyte in the evolution of changes encountered in MS depending upon lesion stage and lesion topography. At variance with the somewhat inhibitory role of the astrocyte is the abundant and growing evidence for this cell to actively participate in both lesion development and repair. We propose that the unequivocal selective early involvement of the astrocyte in MS lesions may have therapeutic relevance. © 2013 Wiley Periodicals, Inc.     

Neuropathic ulcers in leprosy treated with intralesional platelet‐rich plasma

Neuropathic ulcers in leprosy represent a therapeutic challenge for clinicians. Chronic ulcers affect patient health, emotional state and quality of life, causing considerable morbidity and mortality in addition to contributing to significant health care costs. The pathogenesis is mainly related to the abnormally increased pressure in areas such as the sole of the foot, secondary to lack of sensation and deformities induced by peripheral sensory‐motor neuropathy. Conventional treatment of these wounds can be slow due to their chronic inflammatory state and the senescence of local reparative cells. Platelet‐rich plasma (PRP) may restore the healing process, leading to a reparative phase. We present two patients with four neuropathic leprosy ulcers that have responded satisfactory to PRP treatment. PRP therapy has been growing as a viable treatment alternative for chronic ulcers. However, stronger scientific evidence is required to support its potential benefit for use in chronic wounds.     

Randomized trial of technology-assisted self-monitoring of blood glucose by low-income seniors: improved glycemic control in type 2 diabetes mellitus

Self-monitoring of blood glucose (SMBG) has been recommended for people with type 2 diabetes mellitus. This trial tested an automated self-management monitor (ASMM) that reminds patients to perform SMBG, provides feedback on results of SMBG, and action tips for improved self-management. This delayed-start trial randomized participants to using the ASMM immediately (IG), or following a delay of 6 months (DG). Glycated hemoglobin (HgbA1c) level and survey data was collected at home visits every 3 months. 44 diabetic men and women, mean age 70, completed the 12-month trial. Baseline HgbA1c was 8.1 % ± 1.0, dropping to 7.3 ± 1.0 by 9 months, with a 3-month lag in the DG (F = 3.56, p = 0.004). Decrease in HgbA1c was significantly correlated to increased frequency of SMBG, R = 0.588, p < 0.01. Providing older diabetics with objective immediate contingent feedback resulted in more frequent SMBG that correlated with better glycemic control. This type of technology may provide real-time feedback not only to patient users, but to the health care system, allowing better integration of provider recommendations with patient-centered action.     

Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome

The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D+HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.     

Absorption des médicaments lors de syndrome du grêle court

Short bowel syndrome (SBS) occurs when a patient is left with less than 200 cm of functional small intestine. Drug absorption is mostly a passive process and can be affected by the surface area of the remaining gastrointestinal tract. Oral medication absorption is often impaired and larger doses, or other administration routes may be required. Although patients with SBS do need pharmacotherapy for symptoms associated with their pathology or for other comorbidities, there are few published case reports on drug absorption, and few studies have been conducted in small patients’ samples. Moreover, due to the highly heterogeneous nature of this patient population, it is difficult to directly apply the findings of the published literature to specific patients. Drug dosages should be guided by the monitoring of clinical endpoints and/or of biomarkers.     

alpha- and epsilon-protein kinase C activity during smooth muscle cell apoptosis in response to gamma-radiation

The use of gamma-radiation in treatment of pelvic cancer is associated with injury of healthy surrounding tissues and disorders of intestinal motility; however, the cellular mechanisms involved are unclear. We tested the hypothesis that exposure of visceral smooth muscle cells (SMCs) to gamma-radiation induces apoptosis via activation of specific protein kinase C (PKC) isoforms. Cultured SMCs and slices from guinea pig ileum smooth muscle longitudinal layer (GPISMLL) were exposed to 10 to 50 Gy. Flow cytometry in gamma-radiated SMCs showed increased percentage of cells in the sub-G(0)/G(1) phase, a hallmark of apoptosis. gamma-Radiation-induced reduction in cell survival was partially but significantly alleviated with the PKC inhibitors. Sections of gamma-irradiated GPISMLL showed DNA fragmentation and apoptotic bodies analyzed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling method, whereas the plasma and nuclear membranes were preserved. Confocal microscopy in gamma-radiated SMCs labeled with annexin V-fluorescein showed an increase in apoptotic cells and phosphatidylserine externalization. Contraction of GPISMLL strips in response to KCl and acetylcholine was reduced in tissues exposed to 30 and 50 Gy. gamma-Radiation of GPISMLL caused an increase in PKC activity in the particulate fraction, a decrease in the cytosolic fraction, and increased particulate/cytosolic PKC activity ratio. Western blot analysis revealed significant amounts of alpha- and epsilon-PKC in the cytosolic fraction of control GPISMLL. gamma-Radiation caused an increase in the amount of alpha- and epsilon-PKC in the particulate fraction and a decrease in the cytosolic fraction. Data suggest that gamma-radiation induces apoptosis, growth arrest, and contractile dysfunction in visceral SMCs of GPISMLL via activation and translocation of alpha- and epsilon-PKC isoforms.