Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines

Vascular endothelial growth factor (VEGF) induces expression of Bcl-2 in tumor-associated microvascular endothelial cells. We have previously reported that up-regulated Bcl-2 expression in microvascular endothelial cells is sufficient to enhance intratumoral angiogenesis and to accelerate tumor growth. We initially attributed these results to Bcl-2-mediated endothelial cell survival. However, in recent experiments, we observed that conditioned medium from Bcl-2-transduced human dermal microvascular endothelial cells (HDMEC-Bcl-2) is sufficient to induce potent neovascularization in the rat corneal assay, whereas conditioned medium from empty vector controls (HDMEC-LXSN) does not induce angiogenesis. These results cannot be attributed to the role of Bcl-2 in cell survival. To understand this unexpected observation, we did gene expression arrays that revealed that the expression of the proangiogenic chemokines interleukin-8 (CXCL8) and growth-related oncogene-alpha (CXCL1) is significantly higher in HDMEC exposed to VEGF and in HDMEC-Bcl-2 than in controls. Inhibition of Bcl-2 expression with small interfering RNA-Bcl-2, or the inhibition of Bcl-2 function with small molecule inhibitor BL-193, down-regulated CXCL8 and CXCL1 expression and caused marked decrease in the angiogenic potential of endothelial cells without affecting cell viability. Nuclear factor-kappaB (NF-kappaB) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-kappaB down-regulated CXCL8 and CXCL1 expression levels. These results reveal a novel function for Bcl-2 as a proangiogenic signaling molecule and suggest a role for this pathway in tumor angiogenesis.     

Haploinsufficiency of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump, predisposes mice to squamous cell tumors via a novel mode of cancer susceptibility

A null mutation in one copy of the Atp2a2 or ATP2A2 gene, encoding sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), leads to squamous cell tumors in mice and to Darier disease in humans, a skin disorder that also involves keratinocytes. Here, we examined the time course and genetic mechanisms of tumor development in the mutant animals. Atp2a2+/- mice overexpressed keratins associated with keratinocyte hyperactivation in normal forestomachs as early as 2 months of age. By the age of 5 to 7 months, 22% of mutants had developed papillomas of the forestomach, and 89% of mutants older than 14 months had developed squamous cell papillomas and/or carcinomas, with a preponderance of the latter. Tumors occurred in regions that had keratinized epithelium and were subjected to repeated mechanical irritation. The genetic mechanism of tumorigenesis did not involve loss of heterozygosity, as tumor cells analyzed by laser capture microdissection contained the wild-type Atp2a2 allele. Furthermore, immunoblot and immunohistochemical analysis showed that tumor keratinocytes expressed the SERCA2 protein. Mutations were not observed in the ras proto-oncogenes; however, expression of wild-type ras was up-regulated, with particularly high levels of K-ras. Loss of the p53 tumor suppressor gene occurred in a single massive tumor, whereas other tumors had increased levels of p53 protein but no mutations in the p53 gene. These findings show that SERCA2 haploinsufficiency predisposes mice to tumor development via a novel mode of cancer susceptibility involving a global change in the tumorigenic potential of keratinized epithelium in Atp2a2+/- mice.     

Morbidity and mortality of deep sedation in outpatient bone marrow biopsy

Deep sedation is being provided at an increasing rate for patients undergoing bone marrow biopsy and aspiration (BMBA). The aim of this study was to establish the safety of deep sedation used for adults undergoing BMBA. A nonrandomized database analysis and retrospective review of patient records from January 1997 to December 2000 was performed; 5,811 patients were identified as having undergone their first outpatient BMBA. Outcome measures included 30-day mortality and same-day hospital admission; surrogate measures included need for a surgical procedure or receipt of red blood cells within the 48 hr following the BMBA. Patients who received intravenously administered midazolam, fentanyl, and propofol for maintenance of deep sedation plus infiltration of a local anesthetic (n = 2,604; 45%) comprised the deep sedation group; those who received infiltration of a local anesthetic but no intravenous sedation or analgesia (n = 3,207; 55%) comprised the local anesthesia group. Patients in the deep sedation group compared to those in the local anesthesia group were less likely to die within 30 days (0.69% vs. 1.34%, P = 0.018) and less likely to receive red blood cells (1.27% vs. 2.25%, P = 0.006). No other differences between the groups were found. Although the study was retrospective and nonrandomized, the results suggest that the use of deep sedation for outpatient BMBA is as safe as using local anesthesia.     

Practitioner characteristics and the treatment of children and adolescents with attention deficit hyperactivity disorder

Aim: To investigate whether recent Australian practice conforms to the draft 2009 National Health and Medical Research Council (NHMRC) guidelines on the management of attention deficit hyperactivity disorder. Methods: Data from the 2007 Special Review on Attention Deficit Hyperactivity Disorder in Children and Adolescents in New South Wales (NSW) were examined. Results: Two hundred seven approved stimulant prescribers in NSW responded to a detailed survey on treatment practice (including 121 paediatricians and 67 psychiatrists). Overall, the practice identified in this survey of NSW approved stimulant prescribers was consistent with that recommended in the draft NHMRC guidelines. Paediatricians were more likely to inform families of developmental therapies. Most prescribers (67%) considered stimulants to be the first line of treatment for at least half of their patients. Psychiatrists were more likely to use stimulants as first‐line treatments, while those recently qualified were less likely to prescribe. Half of the prescribers were willing to consider prescribing for children 4 years of age and younger. Paediatricians were more likely to consider prescribing to this age group, while those recently qualified were less likely. There were no significant differences in prescribing practice between child and adult psychiatrists. Most prescribers (67–97%) routinely monitored patients on stimulants for weight, height, blood pressure and academic progress. Psychiatrists were less likely to review these parameters than paediatricians, with this difference being largely due to adult psychiatrists. Conclusions: There are significant differences in prescribing practice between paediatricians and psychiatrists. These variations may reflect differing training programs and patient populations, and merit close consideration in any review arising from the publication of the recent NHMRC guideline.     

Ethics application protocols for multicentre clinical studies in Canada: A paediatric rheumatology experience

INTRODUCTION:

Individual institutions govern research ethics applications and each must administer and regulate their own protocols. Variations in ethics review procedures and expectations among centres impose impediments to efficiently conducting multicentre studies.

METHODS:

Observations relating to preparing multisite ethics documents for a study conducted by Canadian paediatric rheumatology investigators are described. Research ethics applications from the 12 participating centres were compared.

RESULTS:

Although the applications were similar in their content, they differed in their formatting. All applications shared a commitment to ensuring that the study conformed to exemplary ethical standards.

CONCLUSIONS:

There is wide variation in the multicentre clinical study ethics application process at the institutional level. Considering the common fundamental elements required by all ethics review boards, the present study conceptualized introducing a discipline-specific uniform ethics application process acceptable to all Canadian research ethics boards. This may be a more efficient strategy that could help lessen the burden of collaborative research.     

Childhood maltreatment among Hispanic women in the United States: an examination of subgroup differences and impact on psychiatric disorder

Prevalence rates of childhood maltreatment among Hispanic women in the United States are presented separately for nativity status and ethnic origin subgroups, and the associations between different types of maltreatment and the development of anxiety and depressive disorders are examined. Analyses used self-report data from 1,427 Hispanic women who participated in the National Latino and Asian American Survey. Foreign-born Hispanic women compared to U.S.-born Hispanic women reported significantly lower rates of sexual assault and witnessing interpersonal violence, and a significantly higher rate of being beaten. Ethnic subgroups reported similar rates of maltreatment, with the exception of rape. Bivariate analyses were remarkably consistent in that regardless of nativity status or ethnic subgroup, each type of maltreatment experience increased the risk of psychiatric disorder. In multivariate models controlling for all types of victimization and proxies of acculturation, having been beaten and witnessing interpersonal violence remained significant predictors of both disorders, but sexual abuse increased risk of anxiety only. A significant interaction effect of family cultural conflict and witnessing violence on anxiety provided very limited support for the hypothesis that acculturation moderates the influence of maltreatment on mental health outcomes. Implications for culturally relevant prevention and intervention approaches are presented.     

The accuracy and repeatability of an automatic 2D-3D fluoroscopic image-model registration technique for determining shoulder joint kinematics

Fluoroscopic imaging, using single plane or dual plane images, has grown in popularity to measure dynamic in vivo human shoulder joint kinematics. However, no study has quantified the difference in spatial positional accuracy between single and dual plane image-model registration applied to the shoulder joint. In this paper, an automatic 2D-3D image-model registration technique was validated for accuracy and repeatability with single and dual plane fluoroscopic images. Accuracy was assessed in a cadaver model, kinematics found using the automatic registration technique were compared to those found using radiostereometric analysis. The in vivo repeatability of the automatic registration technique was assessed during the dynamic abduction motion of four human subjects. The in vitro data indicated that the error in spatial positional accuracy of the humerus and the scapula was less than 0.30mm in translation and less than 0.58° in rotation using dual plane images. Single plane accuracy was satisfactory for in-plane motion variables, but out-of-plane motion variables on average were approximately 8 times less accurate. The in vivo test indicated that the repeatability of the automatic 2D-3D image-model registration was 0.50mm in translation and 1.04° in rotation using dual images. For a single plane technique, the repeatability was 3.31mm in translation and 2.46° in rotation for measuring shoulder joint kinematics. The data demonstrate that accurate and repeatable shoulder joint kinematics can be obtained using dual plane fluoroscopic images with an automatic 2D-3D image-model registration technique; and that out-of-plane motion variables are less accurate than in-plane motion variables using a single plane technique.     

Evaluation of Race by Cranial Index of Adult Human Skull in Maharastra Population

Biologists and physical anthropologists attempted to classify human being into races according to phenotypic variations. The latter are based either on one or two phenotypic characters therefore the outcome is unable to givq clear distinction among different races. Cranial index seems to be an important,tool, which may be used to identify the races in different geographical regions. 75 dried skulls collected from different part of Maharashtra were measured to determine the cranial index. Skulls were classified by the method of Montagu (1960)2 Average maximum cranial length and breadth were found to be 17.11 cm and 12.98 cm respectively and maximum & minimum cranial lengths were observed to be 18.50 and 16.60 cm and cranial breadths were noted to be 14.50 and 12.10 cm respectively. Average cranial index (mean ± SD) was 75.49 ± 3.95. In our study most of the skulls were grouped under the Mesocranial (46.66%) and Dolichocranial (42.66%) categorises when based on Montagu and Dolichocranial categorises when 56% based Comas'. As per the conclusion Maharashtrian population belongs to Indo-Dravidian race.