Ubiquitin Regulation of Trk Receptor Trafficking and Degradation.

The regulation of Trk receptors is critical for orchestrating multiple signalling pathways required for developing and maintaining neuronal networks. Activation of Trk receptors results in signalling, internalisation and subsequent degradation of the protein. Although ubiquitination of TrkA by Nedd4-2 has been identified as an important degradation pathway, much less is known about the pathways regulating the degradation of TrkB and TrkC. Critical to the interaction between TrkA and Nedd4-2 is a PPxY motif present within TrkA but absent in TrkB and TrkC. Given the absence of this interaction motif, it remains to be determined how TrkB and TrkC are ubiquitinated. Here we report that the adaptor protein Ndfip1 can interact with all three Trk receptors and show for TrkB the recruitment of Nedd4-2 through PPxY motifs present in Ndfip1. Ndfip1 mediates the ubiquitination of TrkB, resulting in receptor trafficking predominantly on Rab7 containing late endosomes, highlighting a pathway for TrkB degradation at the lysosome. In vitro, overexpression of Ndfip1 increased TrkB ubiquitination and decreased viability of BDNF-dependent primary neurons. In vivo, conditional genetic deletion of Ndfip1 increased TrkB in the brain and resulted in enlargement of the granular cell layer of the dentate gyrus.

A Retrospective Review Of Tinea Capitis Infection

Background: Tinea capitis (TC), a fungal infection of the scalp, hair follicles and hair shafts, is common among the paediatric population especially under tropical conditions1. The etiological factors vary between different regions of the world. Clinical presentation of tinea capitis varies widely from non-inflammatory to severe, painful inflammatory lesions. Aim: To look into the clinical manifestations, causative agents and the treatment pattern for tinea capitis in Penang Hospital. Methods: A retrospective study of all patients who were treated clinically for tinea capitis in Penang Hospital from January 2011 to June 2013. Results: There were a total of thirty nine patients treated for tinea capitis during this period. Tinea capitis was found to be most common in the 7-12 year age group (44%) with a male to female ratio of 2:1. Non-inflammatory type (54%) was more common then the inflammatory type. Twenty seven of them (69%) had positive fungal culture of their pluck hair roots. The most common dermatophyte detected was Microsporum canis (92%) followed by Trichophyton rubrum (4%) and Trichophyton metagraphyte (4%). Thirty-one (80%) of them were treated with griseofulvin at a dose of 10-15mg / kg /day. The rest were treated with itraconazole, terbinafine or fluconazole. All of them responded well to the treatment. In this cohort only one patient, has a second episode of infection a year later. He is a child who was concomitantly undergoing chemotherapy for acute lymphoblastic leukaemia. Conclusion: Tinea capitis is predominantly an infection of pre-adolescent children and M. canis was the most common dermatophyte isolated.

Significance of relaxin-2 expression in hepatocellular carcinoma: relation with clinicopathological parameters.

BACKGROUND: A number of putative roles, including the modulation of tumor growth, neovascularization, metastasis and oncogenic progression, have been correlated to relaxin-2 overexpression. However, the clinical significance of relaxin-2 expression in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the expression of relaxin-2 in HCC and determine its correlation with tumor progression and prognosis. PATIENTS AND METHODS: 180 HCC patients who had undergone curative liver resection were selected and immunohistochemistry was performed to analyze relaxin-2 expression in the respective tumors. RESULTS: Immunohistochemistry confirmed relaxin-2 overexpression in HCC tissues compared with their adjacent nonneoplastic tissues (p < 0.01). Additionally, immunostaining showed more relaxin-2 positive cells in the higher tumor grade (III) than in the lower tumor stage (I, II; p = 0.026). Moreover, HCC patients with high relaxin-2 expression were significantly associated with lower 5-year overall survival (p < 0.01) and lower 5-year disease-free survival (p < 0.01), respectively. Furthermore, immunostaining showed more relaxin-2 positive cells in the tumor recurrence (ETR) patients than non-ETR patients (p = 0.001). The Cox proportional hazards model further showed that relaxin-2 was an independent poor prognostic factor for both 5-year disease-free survival (hazards ratio [HR] = 1.872, 95% confidence interval [CI] = 1.18-5.146, p = 0.023) and 5-year overall survival (HR = 3.637, CI = 1.443-7.15, p = 0.001) in HCC. CONCLUSIONS: Our data suggest for the first time that the overexpression of relaxin-2 protein in HCC tissues is of predictive value on tumor progression and poor prognosis.

Adequacy of Care in patient with Psoriasis (ADECAP) Study

Introduction: Psoriasis is a chronic recurrent inflammatory skin disease and poses a lifelong burden. Psoriasis is now considered a systemic inflammatory disease. Increasing epidemiological studies have established the role of psoriasis as an independent risk factor in the development of metabolic syndrome and its components. This has led to changes in standard of care recommendations for patients with psoriasis. We conducted a clinical audit on “adequacy of care in patient with psoriasis”. Objective: To examine current trend of practice in the treatment of adults with psoriasis in Dermatology clinic (tertiary referral centre), Penang Hospital. This study also aims to determine the adequacy of care in psoriasis patients in general, and those on systemic agents in specific. Method: A retrospective study examined all adult psoriasis patients who visited Dermatology Clinic, Penang Hospital within 1st July - 31st July 2009. Only those who have been on follow-up for at least 1 year were included in the study. Demographic characteristics, disease burden and details of psoriasis management were documented and analysed. Standards were derived from recommendations of the British Association of Dermatologists (BAD) and American Academy of Dermatology (AAD). Results: Of the 112 patients, 67 were males (59.8%). The mean age of patients was 48.8 years. Fifty (44.6%) were Chinese, 35 Malay (31.3%), 26 Indians (23.2%) and 1 foreigner (0.9%). The mean frequency of clinic visit was 8.2. Forty-seven patients required systemic agents to achieve better disease control. Eighty-three (74.1%) patients were offered “Psoriasis Education Programme”. Percentage of patients who had their severity scoring done by using the DLQI, BSA & Pain score were 73.2%, 90.2% and 85.7% respectively. Only less than 50% of our patients were offered “Metabolic Syndrome Risk Factors Screening”. Of those on systemic agents, only 87.2% and 46.8% of patients, had their baseline and follow up blood investigations done respectively. Conclusion: The care of psoriasis patients in Dermatology Clinic, Penang Hospital is still not adequate. Particular areas of concern include blood monitoring for those on systemic agents and screening for metabolic syndrome risk factors. Remedial measures: Guidelines have been designed to create awareness and to educate doctors and patients on psoriasis and its association with metabolic syndrome. This includes a flow chart / tables to facilitate monitoring and screening of patients. Patients will be given pamphlets on the general knowledge on psoriasis, treatments and the risk of co-morbidities.

Churg Strauss Syndrome in a 40 year old woman

Cutaneous vasculitis is a common manifestation of many systemic diseases. In the setting of asthma, eosinophilia and multiple disparate signs and symptoms, more serious cause of vasculitis like Churg-Strauss syndrome (CSS) should always be considered.

Global analysis of gene expression patterns in developing mouse neocortex using serial analysis of gene expression.

Molecular inventories of the developing mouse neocortex before and after birth were generated using the global gene expression profiling tool serial analysis of gene expression (SAGE). Libraries were generated from embryonic day 15 and postnatal day 1 mouse neocortex and more than 40,000 tags were collected (20,211 and 22,001 tags, representing 11,706 and 12,402 transcripts, respectively). Comparison of the two libraries resulted in the identification of 321 transcripts that were differentially expressed (P < 0.05). Differential expression was independently verified for selected genes by Northern blotting, and in situ hybridization revealed spatial expression patterns in the neocortex. Differentially expressed transcripts included genes known to be important in neocortical development (e.g., brain factor 1, neuroD2, and Id2), genes not previously associated with neocortical development (such as brahma-related gene 1, receptor for activated C-kinase I, hypermethylated in cancer 2, and Evi9), and genes of unknown identity or function.

Nonrandom X chromosome inactivation in mouse embryos carrying Searle's T(X;16)16H translocation visualized using X-linked LACZ and GFP transgenes.

Only the morphologically normal X chromosome is inactivated in female mice heterozygous for Searle's X-autosome translocation, T(X;16)16H. Here we performed a visual study of the primary and secondary events that culminate in the completely nonrandom inactivation of the X in female embryos having this translocation. The data we have obtained so far indicate that the initial choice of the future inactive X chromosome is biased, with the degree of skewing somewhere between 70:30% and 90:10% in favor of the morphologically normal X chromosome. The majority of genetically unbalanced cells that inactivate a translocated X chromosome are quickly eliminated from the embryo proper by E8.5, although the survival of such cells is sporadically observed thereafter. The initial nonrandom choice demonstrated in this study supports the contention that the T(X;16)16H translocation disrupts one of the loci involved in the randomness of the choice of the future inactive X chromosome. Although the HMG-LACZ transgene in H253 stock mice is an excellent marker of X chromosome inactivation, the present study suggests that it is infrequently de-repressed on the inactive X chromosome.