Wnt5a Promotes Lysosomal Cholesterol Egress and Protects Against Atherosclerosis.

BACKGROUND: Impairment of cellular cholesterol trafficking is at the heart of atherosclerotic lesions formation. This involves egress of cholesterol from the lysosomes and 2 lysosomal proteins, the NPC1 (Niemann-Pick C1) and NPC2 that promotes cholesterol trafficking. However, movement of cholesterol out the lysosome and how disrupted cholesterol trafficking leads to atherosclerosis is unclear. As the Wnt ligand, Wnt5a inhibits the intracellular accumulation of cholesterol in multiple cell types, we tested whether Wnt5a interacts with the lysosomal cholesterol export machinery and studied its role in atherosclerotic lesions formation. METHODS: We generated mice deleted for the Wnt5a gene in vascular smooth muscle cells. To establish whether Wnt5a also protects against cholesterol accumulation in human vascular smooth muscle cells, we used a CRISPR/Cas9 guided nuclease approach to generate human vascular smooth muscle cells knockout for Wnt5a. RESULTS: We show that Wnt5a is a crucial component of the lysosomal cholesterol export machinery. By increasing lysosomal acid lipase expression, decreasing metabolic signaling by the mTORC1 (mechanistic target of rapamycin complex 1) kinase, and through binding to NPC1 and NPC2, Wnt5a senses changes in dietary cholesterol supply and promotes lysosomal cholesterol egress to the endoplasmic reticulum. Consequently, loss of Wnt5a decoupled mTORC1 from variations in lysosomal sterol levels, disrupted lysosomal function, decreased cholesterol content in the endoplasmic reticulum, and promoted atherosclerosis. CONCLUSIONS: These results reveal an unexpected function of the Wnt5a pathway as essential for maintaining cholesterol homeostasis in vivo.

Bone Marrow Metastasis in Clear Cell Renal Cell Carcinoma: A Case Study.

Clear cell renal cell carcinoma (RCC) is the most frequently reported renal cell neoplasm, which commonly metastasizes to the lungs, bones, lymph nodes, liver, adrenal gland and/or brain. It is usually diagnosed as an incidental finding on radiological imaging, which can further be confirmed by histological examination of the neoplastic tissue. Bone marrow metastasis of renal cell tumors is a rare event and very few cases have been reported. Here we report an unusual case of a 68-year-male who presented with lytic bone lesions on imaging. This raised the suspicion of a bone marrow involvement by a hematolymphoid malignancy or metastatic disease and a bone marrow biopsy was performed. Incidentally, the biopsy revealed infiltration of bone marrow by clear cell RCC. The patient was referred to the oncology clinic where further workup was done which revealed a primary renal tumor.

Acute Myeloid Leukemia with t(8;21)(q22;q22) and Trisomy 4: A Rare Occurrence in a Female Child.

Acute myeloid leukemia (AML) with balanced translocation t (8;21) is one of the most frequent chromosomal abnormalities and carries a favorable clinical outcome. However, according to a literature review, additional chromosomal aberrations can affect the overall disease prognosis. Trisomy 4 is a rare numerical abnormality in AML patients with t (8;21), which can be associated with c-KIT gene involvement. In adults, c-KIT mutation carries an unfavorable clinical outcome; however, its incidence and clinical importance in the pediatric population are still under scrutiny. Here, we report a case of AML with t(8;21) and trisomy 4 in an eight-year-old female child and the clinical course of the disease.

Author Correction: Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation.

ShcA is an adaptor protein that binds to the cytoplasmic tail of receptor tyrosine kinases and of the Low Density Lipoprotein-related receptor 1 (LRP1), a trans-membrane receptor that protects against atherosclerosis. Here, we examined the role of endothelial ShcA in atherosclerotic lesion formation. We found that atherosclerosis progression was markedly attenuated in mice deleted for ShcA in endothelial cells, that macrophage content was reduced at the sites of lesions, and that adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) were severely reduced. Our data indicate that transcriptional regulation of ShcA by the zinc-finger E-box-binding homeobox 1 (ZEB1) and the Hippo pathway effector YAP, promotes ICAM-1 expression independently of p-NF-κB, the primary driver of adhesion molecules expressions. In addition, ShcA suppresses endothelial Akt and nitric oxide synthase (eNOS) expressions. Thus, through down regulation of eNOS and ZEB1-mediated ICAM-1 up regulation, endothelial ShcA promotes monocyte-macrophage adhesion and atherosclerotic lesion formation. Reducing ShcA expression in endothelial cells may represent an obvious therapeutic approach to prevent atherosclerosis.

Oral Health Practices Among Pakistani Physicians.

Introduction In most healthcare models, the first interaction of a patient is with a general physician. The inspection of the oral cavity is a mandatory component of the general physical examination performed by a physician. This helps detect any oral pathology and make suitable referrals. Therefore, adequate oral health awareness is essential for physicians. Our study aimed at evaluating the oral health practices among physicians working in a private teaching setup in Islamabad, Pakistan. Methods A cross-sectional study involving 144 physicians teaching undergraduate medical students at Shifa College of Medicine and its affiliated hospital, Shifa International Hospital, was conducted. Participants were interviewed through a self-designed questionnaire. Later, each participant demonstrated their teeth brushing technique on a standard model of the oral cavity, which was assessed against a checklist conforming to the modified bass technique. A video clip showing the aforementioned brushing technique was shown at the end of the interview. The collected data was analyzed on IBM's statistical package for the social sciences (SPSS) version 21.  Results Toothpaste was the top choice (97.2%) of teeth cleaning tool with 69% participants brushing their teeth two times a day and 56.9% using toothbrushes with bristles of medium texture. The use of mouthwash (32.6%) and dental floss (11.1%) was considerably low. Dental caries and teeth discoloration were seen in 46.5% and 43.8% physicians, respectively. An alarmingly low number of physicians (31.9%) claimed to have read guidelines regarding oral health. This translated into most participants (78.5%) visiting a dentist only when needed. Only 4.9% participants performed all components of the modified bass technique to clean teeth on the oral cavity model, with up to 22.9% unable to perform a single step accurately.  Conclusion The oral health knowledge and practices of physicians were found to be suboptimal and necessitate the integration of oral health awareness in the medical curriculum. A multiprofessional approach with physicians in crucial roles is required to address the burden of dental diseases globally.

Blood Diathesis in a Patient of Rare Blood Group 'Bombay Phenotype'.

Bombay blood group or Oh phenotype is a rare autosomal recessive phenotype within the ABO blood grouping system. It occurs due to a mutation in the H gene that produces H antigen on red blood cells (RBCs). Individuals with two mutant H genes lack H antigen on RBCs and have anti-H antibodies in serum. At the time of blood grouping, this blood group mimics O blood group but it shows incompatibility with O group blood during cross matching. Several studies have reported an association of decreased von Willebrand factor (VWF) levels in plasma with ABO blood groups. Here we report a case of a 19-year-old male, who was labelled as Bombay phenotype and later found to have markedly reduced plasma VWF levels.

Transfusion Transmissible Infections: Maximizing Donor Surveillance.

Introduction The World Health Organization (WHO) recommends that all blood transfusion services must screen donated blood for human immunodeficiency virus (HIV) one and two, hepatitis B, hepatitis C and syphilis. A mandatory screening for malaria is also warranted in malaria endemic areas. Our study aimed at analyzing the prevalence and different diagnostic methods of screening transfusion transmitted infections (TTIs) in replacement and voluntary, non-remunerated donors in the blood bank of a tertiary care hospital in Islamabad, Pakistan. Methods The cross-sectional, descriptive study was conducted on 30,470 blood donors from July 2015 to October 2017, in the blood bank of a 500-bed teaching hospital in Islamabad. Initially all blood donors were screened for HIV one, HIV two, hepatitis B and hepatitis C by serological testing. The seronegative samples were further tested by nucleic acid amplification test (NAT). Malaria was screened using immuno-chromatographic antigen-detection tests, while treponema pallidum was screened by electrochemiluminescence immunoassay to detect treponema pallidum (TP) antibodies. All infected blood and blood products were discarded and donors were contacted. The donors were deferred from blood donation according to WHO guidelines. They were also counselled and referred to the infectious diseases clinic. The collected data was analyzed on IBM's statistical package for the social sciences (SPSS) version 21. Results The results revealed that amongst the 30,470 donors, 997 (3.27%) donors were found infected with one or more TTI while 29,473 (96.73%) donors were found safe. Individuals who tested positive on serology for hepatitis B were 322 (1.06%), hepatitis C were 392 (1.29%) and HIV were 49 (0.16%). The seronegative donors were tested by NAT. NAT on seronegative samples showed that 10 (0.03%) donors tested positive for hepatitis B virus deoxyribonucleic acid, while only three (0.01%) were positive for hepatitis C ribonucleic acid. No donor was found positive for HIV by NAT testing. Syphilis testing revealed a frequency of 228 (0.75%) positive results while only five (0.02%) donors were found infected with malaria. Conclusion The results testify that standardized blood component screening can save transmission of infections through blood transfusion. They also establish the superiority of NAT screening over serological tests in decreasing the residual risk of transfusion transmitted infections.