Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment

Strategies that increase homing to the bone marrow and engraftment efficacy of ex?vivo expended CD34(+) cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34(+) cells cultured with cytokines. In the presence of NAM, the fraction of CD34(+)CD38(-) cells increased and the fraction of differentiated cells (CD14(+), CD11b(+), and CD11c(+)) decreased. CD34(+) cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD(+)-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34(+) cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not?inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest?a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the?clinical utility of NAM for ex?vivo expansion of functional CD34(+) cells.     

Behavioral Outcomes Following Laparoscopic Sleeve Gastrectomy Performed After Failed Laparoscopic Adjustable Gastric Banding

A healthy diet and good eating behaviors are essential components of long-term success in weight maintenance after bariatric surgery. Although rates of revised bariatric surgery have increased, data on subsequent behavioral outcomes are sparse. The aim of our study was to investigate behavioral outcomes following revised laparoscopic sleeve gastrectomy (R-LSG) that was indicated for failed laparoscopic adjustable gastric banding and compare with outcomes following primary laparoscopic sleeve gastrectomy (P-LSG). Twelve patients who underwent R-LSG and 25 patients who underwent P-LSG between 2007 and 2009 in our medical center completed a questionnaire that assessed weight loss, eating behaviors, physical activity, food tolerance, and satisfaction. The average time elapsed since the operation was 18 months for both groups. In the R-LSG group, more patients reported non-normative eating patterns and less healthy food selection than in the P-LSG group. Food tolerance and satisfaction were also lower after R-LSG. Engagement in regular physical activity increased from 0 to 16.7 % in the R-LSG group and from 8 to 33 % in the P-LSG group. After R-LSG, 58 % reported eating at scheduled times, compared with 85 % after P-LSG. Levels of healthy food selection, food tolerance, normative eating patterns, and physical activity were lower in the R-LSG group than in the P-LSG group. This study highlights the need to develop pre- and post-surgery treatment that would promote better behavioral outcomes in the growing number of individuals undergoing repeat bariatric surgery.     

Waste of skin in elliptical excision biopsy of non-melanomatous skin cancer

Our objective was to quantify the skin wasted during elliptical excision biopsy. This is defined as the difference between the excised elliptical area and the area of the original lesion. We used geometrical calculations of 26 excisional biopsy specimens from patients with non-melanomatous malignant tumours. Relative to the lesion area, the largest waste of skin measured was 230% and the smallest was 34% with a mean of 130%. We conclude that for better preservation of tissue when closing circular defects, patterns other than an ellipse should be adopted.     

Oral myiasis: a case report and literature review

Myiasis is the infestation of tissues and organs of animals and humans by certain Dipteran fly larvae. This phenomenon is well documented in the skin, especially among animals and people in tropical and subtropical areas. Oral myiasis is a rare condition and can be caused by several species of Dipteran fly larvae and may be secondary to serious medical conditions. Upon removal of the larvae, the tissues seem to recover with no subsequent complications and with no need for further treatment. Here we describe a case of oral myiasis within the gingiva of a healthy young man caused by the larvae of Wohlfahrtia magnifica (Family Sarcophagidae), in which infection may have been due to ingestion of infested flesh. Reviewing the literature revealed that most cases of oral myiasis tend to be multiple and to occur in anterior segments of the jaws rather than in posterior segments as in the case we describe here.     

Evaluation of the effectiveness of a novel gait trainer in increasing the functionality of individuals with motor impairment: A case series

Regaining the ability to independently ambulate following a physical disability can increase functional ability and participation of patients in daily life. Gait trainers are assistive devices that enable body support and provide safety during gait. However, most conventional gait trainers are pre-configured to a constant position, therefore not suitable for practicing sit-to-stand function, and require assistance from a caregiver in order to mount the device from a sitting position. We therefore evaluated the effectiveness of a dynamically-adjusting gait trainer, designed to provide independence and safety during gait and various activities, in both lab setting and at home in four subjects (one female, three males, ages 32–79 years) with limited ambulation. Spatiotemporal parameters and gait symmetry were recorded, as well as activity levels, actual use of device, and satisfaction. Although gait parameters and physical activity levels were not notably improved, and in one case were worsened, three subjects reported positive experience with the gait trainer. The new gait trainer may have advantages in supporting users with limited mobility during walking and various functions and decrease the risk for falls. A longer practice time and individual fitting process are recommended for better accommodation to the new possibilities.     

From the Cover: Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.Inherited mutations in BRCA1 and BRCA2 predispose to high risks of breast and ovarian cancer. Among female mutation carriers, presymptomatic surgical measures significantly reduce morbidity and mortality (1, 2). In particular, risk-reducing salpingo-oophorectomy (i.e., the removal of ovaries and fallopian tubes from a woman without ovarian cancer) reduces risk both of breast cancer and of ovarian cancer, as well as overall mortality (1). However, for many mutation carriers identified following their first cancer diagnosis, genetic testing was not previously indicated because family history did not suggest inherited cancer predisposition (3–5, 6). From a prevention perspective, it is a missed opportunity to identify a woman as a BRCA1 or BRCA2 mutation carrier only after she develops cancer.Among Ashkenazi (European) Jews (AJ), three mutations, BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, account for the great majority of inherited cancer risk due to BRCA1 and BRCA2 (7). In the AJ population, 2.5% of persons carry one of these three mutations (8), and the mutations account for 11% of breast cancer (3) and 40% of ovarian cancer (9, 10). These observations suggest that genetic testing in the AJ population for these mutations fulfills WHO criteria for population screening (11, 12): The disease is an important public health burden to the target population; prevalence and attributable risk of disease due to the mutations are known; and effective interventions exist. However, one necessary piece of information remains unknown: What is the disease risk to mutation carriers ascertained from the general population, rather than carriers identified based on family history (13)?Previous studies assessing cancer risks due to mutations in BRCA1 and BRCA2 ascertained carriers through high-incidence families (14), through a single index case with breast or ovarian cancer (3, 15) or through both affected and unaffected carriers (16). In a 1997 study of AJ volunteers, most index cases had no previous cancer diagnosis, but the percentage of index cases with a family history of breast cancer was approximately double that of unselected AJs (17). In principle, these strategies could have yielded risk estimates different from those of carriers ascertained from the local host population, if cancer risk in BRCA1 or BRCA2 carriers were influenced by familial factors other than the BRCA1 or BRCA2 mutation, such as modifier genes or shared environment (18). In addition, in almost all of these studies, risk estimates were based on imputing carrier status, rather than on direct genetic testing of BRCA1 and BRCA2. This year, the Recommendation Statement on BRCA Testing from the US Preventive Services Task Force recommended against population screening for BRCA1 and BRCA2 mutations, because cancer risk to mutation carriers in the general population was not yet known (19). To address this gap, in this study we assessed breast and ovarian cancer risks in confirmed carriers of BRCA1 and BRCA2 mutations ascertained from the general population. The study was undertaken in the AJ population, because screening for only three founder mutations is sufficient to capture nearly all inherited cancer risk in this population due to BRCA1 and BRCA2 (7).