Analyzing the role of cannabinoids as modulators of Wnt/β-catenin signaling pathway for their use in the management of neuropathic pain

Neuropathic pain is a debilitating form of treatment-resistant chronic pain caused by damage to the nervous system. Cannabinoids have been known for suppressing neuropathic pain by modulating the endo cannabinoid system. Since the canonical Wnt/β-catenin signaling has recently been implicated in pain sensation, we investigated the impact of major cannabinoids (1–6) from the leaves of Cannabis sativa and an epoxy derivative of compound 2, here upon referred to as 2a, on modulating Wnt/β-catenin signaling pathway. The results presented in this study show that compound 1, 2 and 2a exhibited potent inhibitory activity against Wnt/β-catenin pathway in a dose-dependent manner. Compound 2a was seen to inhibit this pathway at slightly lower concentrations than its parent molecule 2, under similar conditions. Taken together, compound 1, 2 and 2a, by virtue of their inhibition of Wnt/β-catenin signaling pathway, could be developed as effective neuroprotective agents for the management of neuropathic pain.     

Health Risk Assessment of Consumption of Heavy Metals in Market Food Crops from Sialkot and Gujranwala Districts,Pakistan

This study was performed to investigate the potential health risk of heavy metals (HMs) through consumption of market food crops (MFCs) in the Sialkot and Gujranwala districts, Pakistan. Both study areas are located in industrialized regions of the country, where atmospheric pollution is a problem and irrigation of food crops is mostly practiced on the use of wastewater/contaminated water. For the purpose of this study, MFCs samples were collected and assessed for HMs (Cr, Ni, Cd, Pb, Mn, Cu, Zn, and Fe) by using flame atomic absorption spectrophotometry. Concentration of HMs such as Pb and Cd exceeded the Food and Agriculture/World Health Organization's recommended limits in all MFCs, while Cr in most of the vegetables of the Sialkot and Gujranwala districts also exceeded that limit. The health risk index was >1 in Triticum aestivum for Pb and Cd intake in the Sialkot district and only Pb in the Gujranwala district. Therefore, this study suggests pretreatment of wastewater and its utilization for lawns and green belts irrigation, rather than for food crops. This study also suggests a regular monitoring of HMs in the irrigation water, subsequent soil, air, and MFCs in order to prevent or reduce health hazards.     

A Cross-Sectional Survey of Knowledge,Attitude and Practices Related to Cutaneous Leishmaniasis and Sand Flies in Punjab,Pakistan

Background

Recent outbreaks of cutaneous leishmaniasis make the disease a public health concern in Punjab, Pakistan. The knowledge of how the population perceives the disease and its vector is essential in order to design an effective management strategy, but such studies are rare in Pakistan.

Methodology/Principal Findings

The present study was based on a cross-sectional self-administered survey comprising 250 household samples collected from five localities including Bhawalpur, Multan, Jhang, Faisalabad and Lahore. The results revealed that the respondents had a poor knowledge of the vector and disease. Few of the respondents were aware about the identification of sand flies, their breeding place, biting time, transmission of leishmaniasis and control measures. Skin infection and sandflies as the main disease symptom and vector of the disease, respectively, were known to some of the respondents. Some believed that summer was the main peak incidence of the disease and it could be transmitted from man to man via contact. However, most of the respondents believed that the disease could be cured. Admission to hospitals, cleanliness and use of bed nets were the treatment measures for the disease in suspected patients, whereas some thought that the use of bed nets could be helpful in preventing leishmaniasis infection.

Conclusions/Significance

Poor knowledge of the disease and its vector in the study population emphasize the need to initiate health education and awareness campaigns to minimize the risks of cutaneous leishmaniasis outbreaks in the future.     

A mouse model for human hearing loss DFNB30 due to loss of function of myosin IIIA

The motor protein myosin IIIA is critical for maintenance of normal hearing. Homozygosity and compound heterozygosity for loss-of-function mutations in MYO3A, which encodes myosin IIIA, are responsible for inherited human progressive hearing loss DFNB30. To further evaluate this hearing loss, we constructed a mouse model, Myo3a ^KI/KI , that harbors the mutation equivalent to the nonsense allele responsible for the most severe human phenotype. Myo3a ^KI/KI mice were compared to their wild-type littermates. Myosin IIIA, with a unique N-terminal kinase domain and a C-terminal actin-binding domain, localizes to the tips of stereocilia in wild-type mice but is absent in the mutant. The phenotype of the Myo3a ^KI/KI mouse parallels the phenotype of human DFNB30. Hearing loss, as measured by auditory brainstem response, is reduced and progresses significantly with age. Vestibular function is normal. Outer hair cells of Myo3a ^KI/KI mice degenerate with age in a pattern consistent with their progressive hearing loss.     

Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in middle eastern families

Background

Identification of genes responsible for medically important traits is a major challenge in human genetics. Due to the genetic heterogeneity of hearing loss, targeted DNA capture and massively parallel sequencing are ideal tools to address this challenge. Our subjects for genome analysis are Israeli Jewish and Palestinian Arab families with hearing loss that varies in mode of inheritance and severity.

Results

A custom 1.46 MB design of cRNA oligonucleotides was constructed containing 246 genes responsible for either human or mouse deafness. Paired-end libraries were prepared from 11 probands and bar-coded multiplexed samples were sequenced to high depth of coverage. Rare single base pair and indel variants were identified by filtering sequence reads against polymorphisms in dbSNP132 and the 1000 Genomes Project. We identified deleterious mutations in CDH23, MYO15A, TECTA, TMC1, and WFS1. Critical mutations of the probands co-segregated with hearing loss. Screening of additional families in a relevant population was performed. TMC1 p.S647P proved to be a founder allele, contributing to 34% of genetic hearing loss in the Moroccan Jewish population.

Conclusions

Critical mutations were identified in 6 of the 11 original probands and their families, leading to the identification of causative alleles in 20 additional probands and their families. The integration of genomic analysis into early clinical diagnosis of hearing loss will enable prediction of related phenotypes and enhance rehabilitation. Characterization of the proteins encoded by these genes will enable an understanding of the biological mechanisms involved in hearing loss.     

Assessment of an index of biological integrity (IBI) to quantify the quality of two tributaries of river Chenab,Sialkot, Pakistan

Nullah Aik and Nullah Palkhu, two tributaries of river Chenab, were investigated for the assessment of fish habitat degradation as indicator of stream health. Fish abundance data were collected from 18 sites from September 2004 to April 2006 to develop multimetric indices for fish assemblage integrity and to detect the intensity of habitat degradation. A total of 12 metrics were calculated on the basis of taxonomic richness, habitat preference, trophic guild, stress tolerance and origin of species to develop stepped and continuous index of biological integrity (IBI) criteria. Cluster analysis (CA) classified sites based on species composition into three groups, viz., reference, moderately impaired and impaired groups. Non-metric multidimensional scaling (NMDS) was applied to identify underlying ecological gradient to highlight the habitat degradation. NMDS segregated two sites as less impaired, five sites as moderately impaired and eleven sites as impaired groups. Axes 1 and 2 explained a total variation of 53.3%. First axis explained the level of habitat impairment, whereas axis 2 indicated species richness along longitudinal gradient of streams. Sites located upstream of Nullah Aik showed higher IBI scores which dropped to its lowest in downstream sites near Sialkot city. Lowest values of IBI of sites in close proximity of city indicated the role of anthropogenic activities in catchment areas. The results indicated that variability in water chemistry can be related as a function of stream sites impairments (i.e., unimpaired, moderately impaired, and severely impaired). Water quality parameters showed strong correlation with IBI scores. Significantly negative correlation of IBI scores with COD, TDS, turbidity, Fe, Cr, Zn and positive correlation with DO and pH was found. The results can be used for restoration and future management of small streams passing through urban areas of Pakistan. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Handling editor: J. A. Cambray     

Managing soft tissue sarcomas in a developing country: are prognostic factors similar to those of developed world?

ABSTRACT: BACKGROUND: Managing soft tissue sarcomas (STS) in a developing country with limited financial resources and a poor health referral system is a challenge. Presenting late, these extremity STS are prone to recurrence despite apparently complete resection. This study aimed to explore and compare the impact of clinico-pathological factors on recurrence and survival in Pakistan with the corresponding figures quoted from the developed world. METHODS: An institutional review was performed on all patients with primary STS of the extremities operated on between 1994 and 2008. The prognostic influence of clinical, pathologic, and treatment variables on local recurrence free survival (LRFS), metastasis free survival (MFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression analysis and Kaplan Meier survival curves. RESULTS: A total of 84 patients with a mean age of 41.8 +/- 21.9 years were included in the study. The local recurrence rate was 14.3% after a median of 6 (mean 7.4) months. Metastases occurred in 7 patients (8.3%) and 65 patients were alive without evidence of disease after a mean follow-up of 52.6 +/- 39.8 months. Tumor size > 5 cm, grade 3 tumors and margin < 10 mm significantly increased local recurrence rates. A margin >= 10 mm and age < 45 years significantly enhanced cumulative survival. Significant multivariate risk factors for metastases were margin < 10 mm and tumor grade G3. CONCLUSIONS: Despite a poor health referral system in our country, our results are no different from those reported from the developed world. Surgical margins and tumor grade prognostically influenced LRFS, MFS and OS.