Progressive cerebellar tonsillar herniation with recurrent divergence insufficiency esotropia.

The Chiari malformations are characterized by herniation of posterior fossa contents through the foramen magnum. Chiari I malformation is currently defined as ectopia of the cerebellar tonsils more than 5 mm below the foramen magnum. Extension of the cerebellar tonsils up to 3 mm may be found in the normal population. Although Chiari malformations are congenital, symptoms often do not manifest until the third and fourth decades of life, or even later. Patients usually present with headache, lower cranial nerve palsies, downbeat nystagmus, ataxia, or dissociated anesthesia of the trunk and extremities. Definitive diagnosis is made by magnetic resonance imaging (MRI), which shows the compressed tonsils extending through the foramen magnum into the cervical subarachnoid space. One of the rare presenting signs of Chiari I malformations is acquired esotropia with a divergence insufficiency pattern. We report such a case in which the initial neuroimaging showed tonsillar herniation, but of insufficient magnitude to meet diagnostic criteria for Chiari I malformation. When the strabismus recurred after initially successful eye muscle surgery, follow-up scan showed progressive tonsillar herniation.     

Evaluation of endometrial changes and p53 expression in tamoxifen treated women: Comparision of various methods.

Objective: To compare transvaginal sonography (TVS), sonohysterography (SHG), hysteroscopy and endometrial aspiration (EA) and p53 expression in assessing endometrial abnormalities in women on tamoxifen. Methods: In a cross sectional study of 50 pre- and post-menopausal women receiving tamoxifen for > 2 years, all participants underwent TVS and EA. Those with endometrial thickness > 4 mm on TVS underwent hysteroscopy and SHG. Serum p53 antibody and p53 immunohistochemistry were tested in all women. Results: The sensitivity and specificity when compared with histopathology as the reference standard were as follows: TVS 100% and 33.3%, SHG 85.7% and 50%, hysteroscopy 92.8% and 80.8%, serum p53 50% and 83.3%, and p53 immunohistochemistry 57.1% and 61.1%. Prevalence of endometrial abnormalities was not significantly different in asymptomatic and symptomatic women. Conclusion: Tamoxifen-users require routine testing for endometrial evaluation. TVS followed by hysteroscopy and biopsy is an effective option. p53 expression correlates with histological abnormalities. Key words: Tamoxifen, Sonography, Sonohysterography, Hysteroscopy, Endometrium, p53.     

Alcohol use among physicians in a medical school in Nepal

Objective: The objective of the study was to know about the use of alcohol among physicians and factors that were related to it. Methods: This was a cross sectional study conducted among the physicians in a medical school of eastern Nepal. A semi structured questionnaire was used to collect information. Results: There were 55 subjects in the study. Half of them were between 35-45 years age group and one fourth among them were female. There were more than 88% physicians consuming alcohol for more than 10 years. One third used to preferred whisky as their favorites drink. Use of alcohol among them was due to peer pressure and to become a social human being. Most of them drink alcohol occasionally with an average amount 30-60ml in a sitting and usually in the evening. Most of the time, they use alcohol either in parties or at home. Conclusion: Alcohol use in Nepal is very much prevalent. The use of alcohol is socially accepted in many communities. Uses of alcohol by physicians have direct effect on their health as well as the health of many people because they are role model for many people. They are also in direct contact with the patients. Steps to council the physicians may reduce the consumption of alcohol. Key words: Alcohol, Nepal, Physicians, Dependence, Abuse.     

Continuing Medical Education Activity in Echocardiography

Article Title: Transesophageal Echocardiographic Assessment of Pulmonary Veins and Left Atrium in Patients Undergoing Atrial Fibrillation Ablation (Echocardiography 2011;28:774)     

The physical spacing between the von Willebrand factor D'D3 and A1 domains regulates platelet adhesion in vitro and in vivo

Essentials

• The role of von Willebrand factor (VWF) domains in regulating platelet adhesion was studied in vivo.
• Multimeric VWF with spacers at the N‐ and C‐terminus of VWF‐A1 were systematically tested.
• N‐terminal modified VWF avidly bound platelet GpIbα, causing VWD Type2B like phenotype in mice.
• Novel anti‐D'D3 mAbs suggest that changes at the D'D3‐A1 interface may be biologically relevant.

Summary

Background

Previous ex vivo studies using truncated VWF (von Willebrand factor) suggest that domain‐level molecular architecture may control platelet‐GpIbα binding function.

Objective

We determined if this is the case with multimeric VWF in vivo.

Methods

Full‐length human VWF (‘hV’) was modified with a 22‐amino acid mucinous stretch at either the N‐terminus of VWF‐A1 to create ‘hNV’ or C‐terminus to yield ‘hCV’. This extends the physical distance between VWF‐A1 and the adjacent domains by ~6 nm. Similar mucin inserts were also introduced into a human‐murine chimera (‘h[mA1]V’) where murine‐A1 replaced human‐A1 in hV. This yielded ‘h[mA1]NV’ and ‘h[mA1]CV’, with N‐ and C‐terminal inserts. The constructs were tested ex vivo and in vivo.

Results

Mucin insertion at the N‐terminus, but not C‐terminus, in both types of constructs resulted in >50‐fold increase in binding to immobilized GpIbα. N‐terminal insertion also resulted in greater shear‐induced platelet activation, more thrombus formation on collagen, enhanced platelet accumulation and slower platelet translocation on immobilized VWF in microfluidics assays. Hydrodynamic injection‐based expression of h[mA1]NV, but not h[mA1]V or h[mA1]CV, in VWF^?/? mice caused profound thrombocytopenia, reduced plasma VWF concentrations, lower multimer distribution, and incessant tail bleeding that is reminiscent of von Willebrand disease type 2B. Platelet plugs were noted in the portal veins and hepatic arteries. An anti‐D'D3 mAb DD3.3 that displays enhanced binding to VWF containing the N‐terminal mucin insert also exhibited increased binding to wild‐type VWF under shear and upon ristocetin addition.

Conclusion

Conformation changes at the VWF D'D3‐A1 interface may be a key regulator of thrombosis in vivo. Structural features at the A1‐A2 interface are likely of less significance.

     

Culturally competent primary care response for women of immigrant and refugee backgrounds experiencing family violence: A systematic review protocol

AimThis review will identify, critically appraise, and synthesise evidence on culturally competent approaches to the provision of primary care to women of immigrant and refugee backgrounds who experience family and domestic violence.BackgroundWomen from some immigrant and refugee backgrounds are known to be at a higher risk for harms from family and domestic violence. However, little is known about cultural competency in the provision of primary care for these women and how this enables, or hinders, clinicians in caring for them.Design/methodsA systematic review using Critical Interpretive Synthesis of quantitative, qualitative, and mixed-methods studies and grey literature that report cultural competency in the provision of primary care for women over 16 years of age experiencing family and domestic violence. Our search strategy will include electronic database searches, citation tracking, and grey literature searches. Two reviewers will independently carry out title, abstract, and full text screening using the Covidence software, then quality assessment, and data extraction. We will appraise quality using the Crowe Critical Appraisal Tool for quantitative and mixed methods studies; Quality Framework for qualitative studies; and the Authority, Accuracy, Coverage, Objectivity, Date, Significance checklist for grey literature. A qualitative critical synthesis of the included studies and grey literature will be completed.DiscussionCritical interpretive synthesis is an iterative method that allows reviewers to explore various foci of the concept in question and answer the research question posed at the outset comprehensively. The expected outcome of the review is an evidence-based model of culturally competent primary care related to family and domestic violence.     

Assessment of PI-RADS v2 categories ≥ 3 for diagnosis of clinically significant prostate cancer

Abdominal Radiology - To assess the diagnostic accuracy of PI-RADS v2 categories ≥ 3 to detect clinically significant prostate cancer (csPCa) against histopathology of...     

Parainfluenza virus‐3‐induced cytopathic effects on lung tissue and bronchoalveolar lavage fluid in a bone marrow transplant recipient

Parainfluenza virus type 3(PIV‐3) commonly causes respiratory tract infections in hematopoietic stem cell transplant (HSCT) patients. The majority of PIV‐3 infections develop in patients who have undergone stem cell transplantation from unrelated donors. From these patients, bronchoalveolar lavage (BAL) fluid and/or lung biopsies are often collected and sent for evaluation of infectious processes. However, cytologic findings associated with a PIV‐3 infection in BAL fluid have not been reported in the literature. We describe BAL cytology and lung biopsy findings in a patient who received an HSCT from a related donor and subsequently developed a PIV‐3 infection. This patient was noted to have scattered reticular‐nodular opacities in both lungs on computed tomogram scan and underwent transbronchial biopsy and BAL of the left lower lobe. Examination of the BAL fluid revealed scattered multinucleated giant cells intermixed with inflammatory cells. The lung biopsy showed organizing pneumonia associated with several multinucleated respiratory epithelial cells containing rare intracytoplasmic inclusions. Gram, periodic acid Schiff, Gomori methenamine silver, and acid fast stains on the biopsy specimen failed to reveal microorganisms. A sample of the BAL fluid sent for respiratory viral culture grew PIV‐3. These findings suggest that the presence of giant cells in transplant patients with organizing pneumonia should raise suspicion of a PIV‐3 infection. Diagn. Cytopathol. 2014;42:521–524. © 2013 Wiley Periodicals, Inc.     

Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects

RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights into the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival.Subject terms: Acute lymphocytic leukaemia, Acute myeloid leukaemia, Drug development, Targeted therapies