Process, rationale, and interventions of Pakistan's National Action Plan on Chronic Diseases

Most developing countries do not comprehensively address chronic diseases as part of their health agendas because of lack of resources, limited capacity within the health system, and the threat that the institution of national-level programs will weaken local health systems and compete with other health issues. An integrated partnership-based approach, however, could obviate some of these obstacles. In Pakistan, a tripartite public-private partnership was developed among the Ministry of Health, the nongovernmental organization (NGO) Heartfile, and World Health Organization. This was the first time an NGO participated in a national health program; NGOs typically assume a contractual role. The partnership developed a national integrated plan for health promotion and the prevention and control of noncommunicable diseases (NCDs), which as of January 2006 is in the first stage of implementation. This plan, called the National Action Plan on NCD Prevention, Control, and Health Promotion (NAP-NCD), was released on May 12, 2004, and attempts to obviate the challenges associated with addressing chronic diseases in countries with limited resources. By developing an integrated approach to chronic diseases at several levels, capitalizing on the strengths of partnerships, building on existing efforts, and focusing primary health care on chronic disease prevention, the NAP-NCD aims to mitigate the effects of national-level programs on local resources. The impact of the NAP-NCD on population outcomes can only be assessed over time. However, this article details the plan's process, its perceived merits, and its limitations in addition to discussing challenges with its implementation, highlighting the value of such partnerships in facilitating the missions and mandates of participating agencies, and suggesting options for generalizability.     

A family harboring homozygous FZD4 deletion supports the existence of recessive FZD4-related familial exudative vitreoretinopathy

Purpose: To document recessive FZD4-related familial exudative vitreoretinopathy.

Methods: Retrospective case series.

Results: Two brothers, the only two males among five siblings, had bilateral infantile retinal detachments and were referred for genetic counseling. Next-generation sequencing uncovered a homozygous FZD4 frameshift deletion in both affected brothers (c.40_49delCCCGGGGGCG; p.Pro14Serfs*44). None of the other immediate family members had clinical evidence for retinal disease, including the three family members who underwent confirmatory genetic testing and were found to be heterozygous for the mutation (both parents and one sister).

Conclusions: The findings in this family support the concept that some mutated FZD4 alleles can be associated with recessive rather than dominant disease.     

Pattern of ocular injuries in stone pelters in Kashmir valley

PurposeTo describe the pattern and types of ocular injuries in stone pelters in Kashmir valley during recent turmoil.DesignCross sectional study.MethodsSixty patients with different types of eye injuries were assessed between June–September 2010 and initial visual acuity was recorded. The injuries were classified according to Systems for Classifying Ocular Injuries (OTCS) and Ocular Trauma Score (OTS) was calculated in order to estimate the probability of follow-up visual acuity range.ResultsMost of the victims (75%) were young boys between 16–26 years with a mean age of 20.95, 95% of cases were males. The main cause of injury was stones (48.3%) and pellets (30%) besides rubber bullets, sling shots and tear gas shells.Most of the open-globe injuries due to stones were of Type B and A, Grade E, Zone II and III with Afferent Pupillary Defect (APD) in 30% of the cases. Closed-globe injuries were mostly of Type A, Grade C and D and Zone II and III.Most of the open-globe injuries due to pellets were of Type D, Grade D, Zone II and APD in 33.3%. Pellets Intra Ocular Foreign Body (IOFB) was in 41.6%. Most of the closed-globe injuries were of Type A, Grade D and E and of Zone III.Overall OTS of 1 was calculated in 16.6% and 3 in 53.3% of the cases.ConclusionIn stone pelting demonstrations eye injuries can result in visually significant trauma. Injuries due to pellets are mostly perforating and pellet IOFB, and both tend to have a very poor prognosis. OTS can be used to estimate visual prognosis.     

Antiemetic neurokinin-1 antagonist aprepitant and ifosfamide-induced encephalopathy.

We report the occurrence of an acute encephalopathy followingifosfamide infusion, that we believe directly triggered by aprepitant(Emend^TM, Merck & Co., Inc.). Aprepitant, the first neurokinin-1receptor antagonist, is a new antiemetic indicated for highlyand moderately emetogenic chemotherapy, in association with     

Thymoquinone Augments Cyclophosphamide-Mediated Inhibition of Cell Proliferation in Breast Cancer Cells

Objective: Cancer chemotherapy at the recommended doses is largely associated with toxicity, and also it is noteffective enough to reduce the advancement of the disease at lower doses. Thymoquinone (TQ) is an active compoundderived from black seeds (Nigella sativa) which exhibits anticancer activities. The aim of the present study was toinvestigate the synergistic effect of TQ alone and in combination with cyclophosphamide (cyclo), and to unravel therole of TQ in fatty acid synthase (FASN) mediated molecular signaling in Her2 + and Her2- breast cancer cell lines.Methods: The effect of TQ on the growth of Her2+ SKBR-3 and Her2- MDA-231 breast cancer lines were evaluatedas percent cell viability by cytotoxicity-based MTT assay. The analysis of cell cycle arrest was done through flowcytometryfollowed by Western blot and RT-PCR to detect signaling events in the cells. Results: The data showedthat TQ-cyclo (0.5mM-10μM) combination significantly inhibited the proliferation through the 5.49% and 57.72%accumulation of cells in sub-G1 and G1 respectively as 12% cells were shifted from G2/M phase in Her2+ breast cancercells. Similarly, TQ-cyclo (0.5mM-20μM) combination exhibited that the 16.6% cells were arrested in Sub-G1 and only3.54% cells were remained in G2/M phase as it was 22.89% in DMSO control in Her-2- breast cancers cells. ThoughTQ alone or in combination with cyclo alleviated the PI3K/Akt signaling by downregulating the phosphorylation of Aktand upregulating the PTEN, no changes was observed in FASN and Her-2 as well in both type of cells. The significantdecreased expression of cyclin D1 was found in TQ-cyclo combinations. Conclusion: The current findings suggestedthat TQ can alter the cell cycle progression and induce cell death independent of FASN mediated signaling. In terms ofclinical perspective, the present study clearly showed that TQ can broadly augment the effect of cyclo in breast cancercases irrespective of Her-2+ or Her-.     

Prognosticating metastatic osteosarcoma treated with uniform chemotherapy protocol without high dose methotrexate and delayed metastasectomy: a single center experience of 102 patients

Purpose

Data on prognostic factors in patients with metastatic osteosarcoma treated with uniform chemotherapy protocol are lacking. The objective of this study was to analyze demographic data, treatment outcome and prognostic factors for patients with metastatic osteosarcoma at our center treated with a uniform chemotherapy protocol without high dose methotrexate.

Methods

This is a single-institutional data review of patients treated between June 2003 and December 2012 with neoadjuvant chemotherapy, local site surgery followed by adjuvant chemotherapy and metastasectomy at completion of adjuvant chemotherapy.

Results

102 patients of metastatic osteosarcoma were treated with a median age of 18 years (range 8–48 years), male to female ratio of 3.3:1 and median symptom duration of 4 months. EFS and OS at 5 years were 12.7 ± 0.1 and 28.1 ± 0.1 %, respectively. On multivariate analysis, elevated serum alkaline phosphatase (p < 0.001) and number of metastasis >3 (p = 0.04) were predictive of lower EFS, whereas elevated serum alkaline phosphatase (p = 0.01), number of metastasis >3 (p = 0.05), and margin positivity (p < 0.001) were predictive of lower OS.

Conclusions

This is the largest data on metastatic osteosarcoma treated with a uniform chemotherapy protocol without high dose methotrexate. The data showed prognostic factors similar to what have been observed previously such as elevated serum alkaline phosphatase and >3 metastatic lesions in lung predicting inferior outcome. Notably our survival was comparable to data from other studies despite our practice of delaying metastasectomy to completion of chemotherapy rather than performing the same along with local site surgery.

     

Microglial VPAC1R mediates a novel mechanism of neuroimmune‐modulation of hippocampal precursor cells via IL‐4 release

Neurogenesis, the production of new neurons from neural stem/progenitor cells (NSPCs), occurs throughout adulthood in the dentate gyrus of the hippocampus, where it supports learning and memory. The innate and adaptive immune systems are increasingly recognized as important modulators of hippocampal neurogenesis under both physiological and pathological conditions. However, the mechanisms by which the immune system regulates hippocampal neurogenesis are incompletely understood. In particular, the role of microglia, the brains resident immune cell is complex, as they have been reported to both positively and negatively regulate neurogenesis. Interestingly, neuronal activity can also regulate the function of the immune system. Here, we show that depleting microglia from hippocampal cultures reduces NSPC survival and proliferation. Furthermore, addition of purified hippocampal microglia, or their conditioned media, is trophic and proliferative to NSPCs. VIP, a neuropeptide released by dentate gyrus interneurons, enhances the proliferative and pro‐neurogenic effect of microglia via the VPAC1 receptor. This VIP‐induced enhancement is mediated by IL‐4 release, which directly targets NSPCs. This demonstrates a potential neuro‐immuno‐neurogenic pathway, disruption of which may have significant implications in conditions where combined cognitive impairments, interneuron loss, and immune system activation occurs, such as temporal lobe epilepsy and Alzheimer's disease. GLIA 2014;62:1313–1327     

Abnormalities in motor cortical plasticity differentiate manifesting and nonmanifesting DYT1 carriers.

A mutation in the DYT1 gene causes dominantly inherited childhood-onset primary dystonia, but intriguingly, only 30 to 40% of those who carry the mutation ever develop symptoms. We have used the unique model provided by this group of patients to investigate the hypothesis that abnormalities in brain plasticity underlie the pathophysiology of primary dystonia. We recruited 8 DYT1 gene carriers with dystonia, 6 DYT1 gene carriers without dystonia, 6 patients with sporadic primary dystonia (torticollis), and 10 healthy control subjects. Groups were age-matched. We compared the effect in these groups of subjects of repetitive transcranial magnetic stimulation (rTMS) delivered to the motor cortex, by assessing changes in corticospinal excitability following rTMS. rTMS was given in the form of theta burst stimulation (TBS) using the inhibitory protocol "cTBS" (total of 300 pulses in 50-Hz bursts given every 5Hz). DYT1 gene carriers with dystonia and subjects with torticollis had a significantly prolonged response to rTMS in comparison with healthy subjects. In contrast, DYT1 gene carriers without dystonia had no significant response to rTMS. These data demonstrate an excessive response to an experimental "plasticity probing protocol" in subjects with dystonia, but a lack of response in genetically susceptible individuals who have not developed dystonia. These preliminary data suggest that the propensity to undergo plastic change may affect the development of symptoms in genetically susceptible individuals and that this may be an important mechanism in the pathogenesis of primary dystonia in general.     

Effect of β-endorphin on the contractile responses in mouse skeletal muscle

Tension development in response to direct and indirect electrical stimulation was studied in an isolated phrenic nerve hemidiaphragm preparation of the mouse. β-Endorphin (β-EP) caused an increase in the preparation of the mouse. β-Endorphin (β-EP) caused an increase in the response to low frequency stimulation of the nerve. Upon direct stimulation of the muscle the peptide had no effect. The actions of β-EP were abolished in the presence of the opioid antagonist naloxone and mimicked by β opioid agonists. Upon high frequency stimulation of the nerve, β-EP caused an increase in the initial, maximum, and mean tension. It also prevented the fall in the final tension seen in the control preparations with repeated periods of stimulation. The findings are consistent with β-EP having a role to improve neuromuscular function and deley fatigue, and indicate the possible therapeutic potential of opioid substances in conditions where muscle weakness is present. © John Wiley & Sons, Inc.