The role of Wnt signaling pathway in carcinogenesis and implications for anticancer therapeutics.

The Wnt proteins are a family of 19 secreted glycoproteins that occupy crucial roles in the regulation of processes such as cell survival, proliferation, migration and polarity, cell fate specification, body axis patterning and self-renewal in stem cells. The canonical pathway has been implicated in a variety of cancers. As such, it is only fair to conclude that therapies targeting the Wnt pathway may play an essential role in the future of anticancer therapeutics, both alone or in conjunction with traditional therapies.

Physician migration at its roots: a study on the factors contributing towards a career choice abroad among students at a medical school in Pakistan.

BACKGROUND: Physician migration, also known as "brain drain," results from a combination of a gap in the supply and demand in developed countries and a lack of job satisfaction in developing countries. Many push and pull factors are responsible for this effect, with media and internet playing their parts. Large-scale physician migration can pose problems for both the donor and the recipient countries, with a resulting reinforcement in the economic divide between developed and developing countries. The main objectives of our study were to determine the prevalence of migration intentions in medical undergraduates, to elucidate the factors responsible and to analyze the attitudes and practices related to these intentions. METHODS: This was a cross-sectional, observational, questionnaire-based study, conducted at Dow Medical College of Dow University of Health Sciences, Karachi, between January, 2012 and May, 2012. A total of 323 students responded completely. The questionnaire consisted of 3 sections, and was aimed at collecting demographic details, determining students' migratory intentions, evaluating reasons for and against migration and assessing attitudes and practices of students related to these intentions. RESULTS: Out of 323 respondents, 195 wanted to pursue their careers abroad, giving a prevalence rate of 60.4% in our sample. United States was the most frequently reported recipient country. The most common reasons given by students who wished to migrate, in descending order, were: lucrative salary abroad followed by quality of training, job satisfaction, better way of life, relatives, more opportunities, better working environment, terrorism in Pakistan, harassment of doctors in Pakistan, desire to settle abroad, more competition in Pakistan, better management, peer pressure, longer working hours in Pakistan, religious reasons, parent pressure, political reasons and favoritism in Pakistan. A considerable number of respondents had already started studying for licensing examinations, and were also planning of gaining clinical experience in their desired country of interest. CONCLUSION: Physician migration is a serious condition that requires timely intervention from the concerned authorities. If considerable measures are not taken, serious consequences may follow, which may pose a threat to the healthcare system of the country.

DeNeRD: high-throughput detection of neurons for brain-wide analysis with deep learning.

Mapping the structure of the mammalian brain at cellular resolution is a challenging task and one that requires capturing key anatomical features at the appropriate level of analysis. Although neuroscientific methods have managed to provide significant insights at the micro and macro level, in order to obtain a whole-brain analysis at a cellular resolution requires a meso-scopic approach. A number of methods can be currently used to detect and count cells, with, nevertheless, significant limitations when analyzing data of high complexity. To overcome some of these constraints, we introduce a fully automated Artificial Intelligence (AI)-based method for whole-brain image processing to Detect Neurons in different brain Regions during Development (DeNeRD). We demonstrate a high performance of our deep neural network in detecting neurons labeled with different genetic markers in a range of imaging planes and imaging modalities.

The spectrum of genetic mutations in breast cancer.

Breast cancer is the most common malignancy in women around the world. About one in 12 women in the West develop breast cancer at some point in life. It is estimated that 5%-10% of all breast cancer cases in women are linked to hereditary susceptibility due to mutations in autosomal dominant genes. The two key players associated with high breast cancer risk are mutations in BRCA 1 and BRCA 2. Another highly important mutation can occur in TP53 resulting in a triple negative breast cancer. However, the great majority of breast cancer cases are not related to a mutated gene of high penetrance, but to genes of low penetrance such as CHEK2, CDH1, NBS1, RAD50, BRIP1 and PALB2, which are frequently mutated in the general population. In this review, we discuss the entire spectrum of mutations which are associated with breast cancer.

Virus against virus (VIVI): a potential solution against HIV/AIDS.

Most therapeutic regimens are aimed at the use of pharmacologic agents or the induction of immunological response against the pathological agent. However, these methods tend to be insufficient for the management of some of the most debilitating infectious diseases. Here we present a novel therapeutic approach. It involves voluntary super-infection of a subject having HIV/AIDS with a virus (GBV-C), which to date has not been shown to be responsible for any pathology. It has been shown to counter, suppress or eradicate the agent responsible for the severe disease. Several studies demonstrate the role of different micro-organisms in influencing the growth of other pathogens in the human body. This hypothesis requires meticulous testing before its implementation on humans. If the trials are successful, the implications for this hypothesis are promising considering the compliance issues and adverse effects associated with current standard of HIV care.

Management of Anemia and other Hematologic Derangements in Patients with Chronic Kidney Disease.

INTRODUCTION: Chronic Kidney Disease (CKD) has adverse consequences on almost all body systems. The kidney does not function merely as an excretory organ, but participates in normal erythropoiesis, normal bone mineral deposition and blood pressure regulation. REVIEW: Anemia is prevalent in CKD with known deleterious effects on the car diovascular system. It is mostly due to erythropoietin deficiency, inhibition of erythropoiesis by uremic solutes, and reduction in red blood cell life span. Other possible causes include iron, B12 or folic acid deficiency or blood loss. Dysfunction of the endogenous erythropoietin is usually clinically evident once the glomerular filtration rate (GFR) falls below 20-25 ml/min. Treating anemia of CKD is based on correction of iron deficiency and replacement of decreased erythropoietin production by erythropoietin stimulating agents (ESA). Guidelines recommend targeting hemoglobin levels of no more than 10-12 g/dl since there is evidence of increased mortality and morbidity in patients with higher levels. Increased level of pro-coagulant biomarkers cause enhanced thrombotic activity in CKD patients which promotes ischemic cardiac events while platelet dysfunction leads to bleeding diathesis. If anticoagulation is indicated, low molecular weight heparins (LMWHs) offer certain advantage sbut the dosage needs to be adjusted with increasing grade of renal insufficiency. Antiplatelet agents are effective in averting shunt and catheter thrombosis, but not for avoiding the thrombosis of arteriovenous grafts. CONCLUSION: Health related quality of life in CKD patients can be improved by treating anemia. Newly available ESAs and the entry into the market of epoetinbiosimilars are expected to lead to improvements in the management of CKD and its complications.

Time intervals and associated factors of emergency treatment: first insight into Pakistani system.

The objective of this study is to determine the time interval from decision to seek medical help and arrival of the patients to the emergency department (ED). The duration of stay in ED was also calculated. This study also assesses factors responsible delayed presentation to hospital. This prospective study was conducted during day timings (9 am to 3 pm) from May 2012 to August 2012 in ED at Civil Hospital, Karachi. Patients older than 18 years and meeting the inclusion criteria were considered to be eligible for the study. Statistical analysis was done using SPSS version 17. The study sample consisted of 4,226 patients with a response rate of 96.5%. The median decision time was 146 minutes (IQR = 74-339), median transit time was 84 minutes (IQR = 42-188), median physician time was 58 minutes (IQR = 47-103), median diagnostic time was 148 minutes (IQR = 135-192), median transfer time was 155 minutes (IQR = 118-274) and the median ED LOS was 327 minutes (IQR = 209-488). Patient beliefs regarding spontaneous resolution of the symptoms was the most common reason (44.8%) cited for increased time spent in taking decision to seek medical help. Mode of transportation other than ambulance and traffic gridlock were the most common reasons found to be significantly associated with increased transit time (p < 0.05). The time intervals calculated from our study were found to be higher than studies reported from countries. This calls for urgent intervention for formulation of triage systems to improve patient treatment and satisfaction.

Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy.

Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra(-/-) mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/MΦ) cardiac infiltrates. Depletion of Ly6Chi MO/MΦ also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/MΦ in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A-fibroblast-GM-CSF-MO/MΦ axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.

Direct cardiovascular effects of glucagon like peptide-1.

Current gold standard therapeutic strategies for T2DM target insulin resistance or ß cell dysfunction as their core mechanisms of action. However, the use of traditional anti-diabetic drugs, in most cases, does not significantly reduce macrovascular morbidity and mortality. Among emerging anti-diabetic candidates, glucagon like peptide-1 (GLP-1) based therapies carry special cardiovascular implications, exerting both direct as well as indirect effects. The direct cardiovascular effects of GLP-1 and its analogs remain the focus of this review.

PARP inhibitors: current status and implications for anticancer therapeutics.

Poly(ADP-ribose) polymerases (PARPs) comprise of a large family of 17 proteins encoded by various genes which participate in genome maintenance, apoptosis, inflammatory responses and the regulation of gene expression programs. PARP inhibitors, as therapeutic agents, come into play acting on both PARP 1 and PARP 2. These drugs seem to target tumor cells in a moment of vulnerability when they are undergoing DNA repair. In the past few years this class of anti-cancer drug has been discovered to show a promising niche in the clinic.

Akt inhibitors: mechanism of action and implications for anticancer therapeutics.

Akt, better known as protein kinase B (PKB), is a serine/threonine-specific protein kinase which acts as mediator via PI3K/Akt pathway in many biological processes like glucose metabolism, apoptosis, cell differentiation and transcription. Akt1 gene amplification has been implicated in gastric carcinoma while Akt2 amplification has been linked with ovarian, pancreas, breast and stomach tumors. The use of Akt inhibitors as monotherapy or in combination with other anticancer drugs could be useful for combating drug resistance and improving response. Thus, comprehensive understanding of Akt and its linked signaling pathways (PI3K, PKB, mTOR etc.) is necessary to lead to newer drug development and use.

c-Met inhibitors.

c-Met is a receptor tyrosine kinase that encodes protein such as hepatocyte growth factor receptor (HGFR). Inappropriate activity of c-Met can cause wide variety of carcinomas. c-Met inhibitor are relatively new class of small molecules that inhibit the enzymatic activity of c-Met tyrosine kinase. Met inhibitors divided into two main classes: class I (SU-11274-like) and class II (AM7-like). The use of c-Met inhibitors with other therapeutic agents could be crucial for overcoming potential resistance as well as for improving overall clinical benefit. Met pathway inhibitors might be used in combination with other treatments, including chemo-, radio- or immunotherapy.

Health consequences of cricket - view from South Asia.

Although cricket has origins in the British Empire, it is followed as a religion in South Asia, probably due to the influence of the former during their rule. The sport is equally popular among all groups of the society, and is not subject to gender or age constraints. It marks the epitome of reverence and is considered a battle for self-esteem, not only for those playing, but for those watching as well. The intensity of emotional attachment with this sport renders certain public health benefits as well as drawbacks to the general masses.

Reasons for non-vaccination in pediatric patients visiting tertiary care centers in a polio-prone country.

BACKGROUND: The Expanded Program on Immunization (EPI) was initiated by World Health Organization (WHO) in 1974 in order to save children from life threatening, disabling vaccine-preventable diseases (VPDs). In Pakistan, this program was launched in 1978 with the main objectives of eradicating polio by 2012, eliminating measles and neonatal tetanus by 2015, and minimizing the incidence of other VPDs. However, despite the efforts of government and WHO, this program has not received the amount of success that was desired. Hence, the objectives of this study were to elucidate the main reasons behind not achieving the full immunization coverage in Pakistan, the awareness of children's attendant about the importance of vaccination, their attitudes, thoughts and fears regarding childhood immunization, and the major hurdles faced in pursuit of getting their children vaccinated. METHODS: This was an observational, cross-sectional, questionnaire-based study conducted during a one year period from 4th January, 2012 to 6th January, 2013 at the pediatric outpatient clinics of Civil Hospital (CHK) and National Institute of Child Health (NICH). We attempted to interview all the parents who could be approached during the period of the study. Thus, convenience sampling was employed. The parents were approached in the clinics and interviewed after seeking informed, written consent. Those patients who were not accompanied by either of their parents were excluded from the study. The study instrument comprised of three sections. The first section consisted was concerned with the demographics of the patient and the parents. The second section dealt with the reasons for complete vaccination or under-vaccination. The last section aimed to assess the knowledge, attitudes and beliefs of the respondents. RESULTS: Out of 1044 patients, only 713(68.3%) were fully vaccinated, 239(22.9%) were partially vaccinated while 92(8.8%) had never been vaccinated. The vaccination status showed statistically significant association with ethnicity, income, residence, number of children and paternal occupation (p < 0.05 for all). The most common provocative factor for vaccination compliance was mass media (61.9%). The most common primary reason for non-vaccination was lack of knowledge (18.1%), whereas the most common secondary reason for non-vaccination was religious taboos (31.4%). Majority of the respondents demonstrated poor knowledge of EPI schedules or VPDs. However, most believed that there was a need for more active government/NGO involvement in this area. CONCLUSION: The most common primary reason for non-vaccination, i.e. lack of knowledge, and the most common secondary reason, i.e. religious taboos, imply that there is dire need to promote awareness among the masses in collaboration with NGOs, and major religious and social organizations.