Dual Action of miR-125b As a Tumor Suppressor and OncomiR-22 Promotes Prostate Cancer Tumorigenesis.

MicroRNAs (miRs) are a novel class of small RNA molecules, the dysregulation of which can contribute to cancer. A combinatorial approach was used to identify miRs that promote prostate cancer progression in a unique set of prostate cancer cell lines, which originate from the parental p69 cell line and extend to a highly tumorigenic/metastatic M12 subline. Together, these cell lines are thought to mimic prostate cancer progression in vivo. Previous network analysis and miR arrays suggested that the loss of hsa-miR-125b together with the overexpression of hsa-miR-22 could contribute to prostate tumorigenesis. The dysregulation of these two miRs was confirmed in human prostate tumor samples as compared to adjacent benign glandular epithelium collected through laser capture microdissection from radical prostatectomies. In fact, alterations in hsa-miR-125b expression appeared to be an early event in tumorigenesis. Reverse phase microarray proteomic analysis revealed ErbB2/3 and downstream members of the PI3K/AKT and MAPK/ERK pathways as well as PTEN to be protein targets differentially expressed in the M12 tumor cell compared to its parental p69 cell. Relevant luciferase+3'-UTR expression studies confirmed a direct interaction between hsa-miR-125b and ErbB2 and between hsa-miR-22 and PTEN. Restoration of hsa-miR-125b or inhibition of hsa-miR-22 expression via an antagomiR resulted in an alteration of M12 tumor cell behavior in vitro. Thus, the dual action of hsa-miR-125b as a tumor suppressor and hsa-miR-22 as an oncomiR contributed to prostate tumorigenesis by modulations in PI3K/AKT and MAPK/ERK signaling pathways, key pathways known to influence prostate cancer progression.

Access to community-based mental healthcare and psychosocial support within a disaster context.

After a large-scale humanitarian disaster, 30-50% of victims develop moderate or severe psychological distress. Rates of mild and moderate mental disorders increase by 5-10% and severe disorders by 1-2%. Those with such disorders need access to mental healthcare. Primary care clinics are appropriate due to their easy accessibility and the non-stigmatising environment. There is a consensus among experts that the mental health effects of disaster are best addressed by existing services, that is, through capacity building rather than by establishing parallel systems. Mental health interventions in emergencies should begin with a clear vision for the long-term advancement of community services.

Factors associated with parental adaptation to having a child with a cleft lip and/or palate: the impact of parental diagnosis.

OBJECTIVE: To investigate the impact of parental diagnosis of cleft lip and/or palate on factors associated with parental adaptation to having a child with a cleft. DESIGN: A mixed-methodological, quasi-experimental, causal-comparative research design. PARTICIPANTS: A total of 27 parents born with a cleft lip and/or palate and 27 parents born without a cleft lip and/or palate completed the study measures. OUTCOME MEASURES: The Ways of Coping Questionnaire, the Connor-Davidson Resilience Scale, the Interpersonal Support Evaluation List, and the Posttraumatic Growth Inventory were included along with a researcher-designed, cleft-specific questionnaire. RESULTS: The cleft-specific questionnaire revealed that parents born with a cleft lip and/or palate reported feelings of guilt significantly more often than did parents without a cleft lip and/or palate. Parents without a cleft reported feeling anxious significantly more often than did parents born with a cleft lip and/or palate. The qualitative aspect of the study yielded further between-group differences. The feeling that their own cleft-related experiences influenced their adjustment to having a child with a cleft emerged as a dominant theme for parents born with a cleft; whereas, parents without a cleft lip and/or palate highlighted the importance of accurate information and positive interactions with clinicians in facilitating adjustment to their situation. No significant between-group differences were found on the standardized measures; however, the study's small sample size increases the risk of type II error and may account for the lack of significant findings. CONCLUSIONS: These findings appear to provide support for the widely held clinical opinion that parental diagnosis of cleft lip and/or palate impacts how parents cope with and adjust to their child's diagnosis.

Post-disaster recovery: a case study of human resource deployment in the health sector in post-conflict Kosovo.

INTRODUCTION: A professional understanding of disasters, paired with the need for health service development, can provide opportunities for the recovery and improvement of the health sector. Investment in training capacity ranks among the top priorities of a recovering health sector. The recovery and development of primary healthcare delivery systems has been implemented by various international and local health players in the aftermath of conflicts around the world. However, human resource development in the post-conflict environment has not been evaluated and/or published appropriately in the medical literature. OBJECTIVE: In this retrospective, descriptive study, the authors describe the strategy and evaluate the effectiveness of a field-based training program for primary healthcare doctors implemented by the US-based international non-governmental organization, the International Medical Corps, after the conflict in Kosovo in 1999. METHODS: A six-month, comprehensive education and training program on primary healthcare issues was delivered to 134 Kosovar primary healthcare physicians in 10 Kosovo municipalities in 1999 and 2000. Qualitative and quantitative data were collected. The qualitative methods included open-ended, semi-structured, key informant interviews, structured focus groups, and unstructured participant observations. The quantitative method was multiple-choice knowledge tests. RESULTS: The education and training program proved to be culturally appropriate and well-accepted by local communities. The program met its overall objective to refresh the knowledge of primary care doctors on various primary healthcare issues and set the stage for further strengthening and development of primary health services and their required human resources in Kosovo. CONCLUSIONS: The comprehensive education and training of primary healthcare doctors in Kosovo was a feasible, much appreciated, and effective intervention implemented in a difficult post-conflict environment. This training was one of the early steps in the modernization of primary healthcare services in Kosovo. Later, primary health care was strengthened by the introduction of a Department of Family Medicine at the university, which includes a residency program. The intervention described in this study has the potential to be reproduced in other post-disaster environments, especially in resource-poor settings with long-time troubled health sectors in developing countries.

Second generation sequencing allows for mtDNA mixture deconvolution and high resolution detection of heteroplasmy.

AIM: To use parallel array pyrosequencing to deconvolute mixtures of mitochondrial DNA (mtDNA) sequence and provide high resolution analysis of mtDNA heteroplasmy. METHODS: The hypervariable segment 1 (HV1) of the mtDNA control region was analyzed from 30 individuals using the 454 GS Junior instrument. Mock mixtures were used to evaluate the system's ability to deconvolute mixtures and to reliably detect heteroplasmy, including heteroplasmic differences between 5 family members of the same maternal lineage. Amplicon sequencing was performed on polymerase chain reaction (PCR) products generated with primers that included multiplex identifiers (MID) and adaptors for pyrosequencing. Data analysis was performed using NextGENe® software. The analysis of an autosomal short tandem repeat (STR) locus (D18S51) and a Y-STR locus (DYS389 I/II) was performed simultaneously with a portion of HV1 to illustrate that multiplexing can encompass different markers of forensic interest. RESULTS: Mixtures, including heteroplasmic variants, can be detected routinely down to a component ratio of 1:250 (20 minor variant copies with a coverage rate of 5000 sequences) and can be readily detected down to 1:1000 (0.1%) with expanded coverage. Amplicon sequences from D18S51, DYS389 I/II, and the second half of HV1 were successfully partitioned and analyzed. CONCLUSIONS: The ability to routinely deconvolute mtDNA mixtures down to a level of 1:250 allows for high resolution analysis of mtDNA heteroplasmy, and for differentiation of individuals from the same maternal lineage. The pyrosequencing approach results in poor resolution of homopolymeric sequences, and PCR/sequencing artifacts require a filtering mechanism similar to that for STR stutter and spectral bleed through. In addition, chimeric sequences from jumping PCR must be addressed to make the method operational.

Gastric rupture with pneumoperitoneum after mouth-to-nose breathing in an infant.

BACKGROUND: Gastric rupture with resulting tension pneumoperitoneum occurs rarely in infants. It may be associated with resuscitative efforts. OBJECTIVES: This report presents a unique case of gastric rupture and illustrates the factors necessary for prompt recognition and treatment. CASE REPORT: The patient was a 16-week-old infant with nasal congestion whose father had attempted to clear her nose by a mouth-to-mouth-and-nose maneuver. The alert and attentive patient presented to the Emergency Department in respiratory distress, with marked abdominal distention. She was diagnosed with a massive tension pneumoperitoneum, which was decompressed by needle aspiration. A laceration of the lesser curvature of the stomach was repaired at laparotomy; the patient recovered uneventfully. CONCLUSION: Tension pneumoperitoneum is rarely seen but has key defining elements. A simple procedure is critical to relief of the condition.

Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies.

Hematopoietic stem cell transplantation (HSCT) is a highly successful treatment for severe congenital immunodeficiencies. However, some studies have suggested that children may experience cognitive difficulties after HSCT. This large-scale study assessed cognitive and behavioral function for the cohort of children treated by HSCT at one center between 1979 and 2003 to determine the frequency and severity of problems and to identify risk factors. A total of 105 patients were assessed on standardized measures of cognitive and emotional and behavioral function together with a control group of unaffected siblings. The average IQ for the cohort was 85 (95% confidence interval, 81-90), significantly lower than both the population average of 100 (P < .001) and unaffected siblings. Multivariate analysis indicated that the underlying genetic defect, diagnosis of adenosine deaminase-deficient severe combined immunodeficiency, and consanguinity were associated with worse outcome but that age at transplantation and chemotherapy conditioning were not. Children treated by HSCT for severe immunodeficiency have an increased risk of long-term cognitive difficulties and associated emotional and behavioral difficulties. The specific genetic diagnosis, consanguinity, and severe clinical course are associated with poor outcome. Long-term follow-up of these patients should include screening to identify and manage these problems more effectively.