Three Dimensional Electrical Impedance Tomography

The electrical resistivity of mammalian tissues varies widely and is correlated with physiological function. Electrical impedance tomography (EIT) can be used to probe such variations in vivo, and offers a non-invasive means of imaging the internal conductivity distribution of the human body. But the computational complexity of EIT has severe practical limitations, and previous work has been restricted to considering image reconstruction as an essentially two-dimensional problem. This simplification can limit significantly the imaging capabilities of EIT, as the electric currents used to determine the conductivity variations will not in general be confined to a two-dimensional plane. A few studies have attempted three-dimensional EIT image reconstruction, but have not yet succeeded in generating images of a quality suitable for clinical applications. Here we report the development of a three-dimensional EIT system with greatly improved imaging capabilities, which combines our 64-electrode data-collection apparatus with customized matrix inversion techniques. Our results demonstrate the practical potential of EIT for clinical applications, such as lung or brain imaging and diagnostic screening

Effectiveness of counseling for anxiety and depression in mothers of children ages 0-30 months by community workers in Karachi, Pakistan: a quasi experimental study

<p>Abstract</p> <p>Background</p> <p>The prevalence of anxiety/depression is quite high during the perinatal period but unfortunately its detection and treatment have been less than satisfactory. Moreover, many women are reluctant to take pharmacotherapy for fear of excretion of drugs into their breast milk. This study assesses the effectiveness of counseling from minimally trained community health workers in reducing anxiety/depression, the rate of recurrence and the interval preceding recurrence in women during first two and a half years after childbirth.</p> <p>Methods</p> <p>In a quasi-experimental study, community women from two under-privileged communities were trained in data gathering, teaching healthy child-rearing practices, basic counseling skills, and screening for anxiety/depression by using an indigenously developed questionnaire, the Aga Khan University Anxiety and Depression Scale (AKUADS). The diagnosis was further confirmed by a clinical psychologist using DSM IV criteria. After obtaining consent, 420 women were screened and 102 were identified as having anxiety/depression. Screening was carried out after 1, 2, 6, 12, 18, 24 and 30 months of a live birth. Only 62 out of 102 agreed to be counseled and received eight weekly sessions. AKUADS was re-administered at 4 weeks and 8 weeks after the beginning of counseling; this was followed by the clinical psychologist's interview for confirmation of response. After recovery, screening was continued every 3 months for detection of recurrence throughout the study period. Out of the women who had declined counseling 12 agreed to retake AKUADS after 4 and 8 weeks of diagnosis. Independent samples t-test, chi-square test, Repeated Measures ANOVA and Kaplan Meier technique were used for the analysis.</p> <p>Results</p> <p>A significant decline in level of anxiety/depression was found in both the counseled and the non-counseled groups at 4 and 8 weeks (p-value < 0.001) but the counseled group fared better than the non-counseled for recovery, reduction in the rate of recurrence and increase in the duration before relapse.</p> <p>Conclusions</p> <p>As our results cannot be generalized; further studies need to be carried out, to assess the benefit of incorporating minimal counseling skills in the training of community health workers.</p

Elimination of Endogenous Toxin, Creatinine from Blood Plasma Depends on Albumin Conformation: Site Specific Uremic Toxicity & Impaired Drug Binding

Uremic syndrome results from malfunctioning of various organ systems due to the retention of uremic toxins which, under normal conditions, would be excreted into the urine and/or metabolized by the kidneys. The aim of this study was to elucidate the mechanisms underlying the renal elimination of uremic toxin creatinine that accumulate in chronic renal failure. Quantitative investigation of the plausible correlations was performed by spectroscopy, calorimetry, molecular docking and accessibility of surface area. Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination. The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding. These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state

Age-Specific Differences in Oncogenic Pathway Deregulation Seen in Human Breast Tumors

Purpose. To define the biology driving the aggressive nature of breast cancer arising in young women. Experimental Design. Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young ≤45 years; older ≥65 years), 411 eligible patients (n = 200≤545 years; n = 211≥65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. Results. In comparing deregulation of oncogenic pathways between age groups, a higher probability of P13K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of P13K, Myc, and β-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of P13K, Myc and β-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value. Conclusion. Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation. Copyright

Deficiency in Nucleotide Excision Repair Family Gene Activity, Especially ERCC3, Is Associated with Non-Pigmented Hair Fiber Growth

We conducted a microarray study to discover gene expression patterns associated with a lack of melanogenesis in non-pigmented hair follicles (HF) by microarray. Pigmented and non-pigmented HFs were collected and micro-dissected into the hair bulb (HB) and the upper hair sheaths (HS) including the bulge region. In comparison to pigmented HS and HBs, nucleotide excision repair (NER) family genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, XPA, NTPBP, HCNP, DDB2 and POLH exhibited statistically significantly lower expression in non- pigmented HS and HBs. Quantitative PCR verified microarray data and identified ERCC3 as highly differentially expressed. Immunohistochemistry confirmed ERCC3 expression in HF melanocytes. A reduction in ERCC3 by siRNA interference in human melanocytes in vitro reduced their tyrosinase production ability. Our results suggest that loss of NER gene function is associated with a loss of melanin production capacity. This may be due to reduced gene transcription and/or reduced DNA repair in melanocytes which may eventually lead to cell death. These results provide novel information with regard to melanogenesis and its regulation

Role of genetic polymorphisms in tumour angiogenesis

Angiogenesis plays a crucial role in the development, growth and spread of solid tumours. Pro- and anti-angiogenic factors are abnormally expressed in tumours, influencing tumour angiogenesis, growth and progression. Polymorphisms in genes encoding angiogenic factors or their receptors may alter protein expression and/or activity. This article reviews the literature to determine the possible role of angiogenesis-related polymorphisms in cancer. Further research studies in this potentially crucial area of tumour biology are proposed

Pre-referral rectal artesunate in severe malaria: flawed trial

<p>Abstract</p> <p>Background</p> <p>Immediate injectable treatment is essential for severe malaria. Otherwise, the afflicted risk lifelong impairment or death. In rural areas of Africa and Asia, appropriate care is often miles away. In 2009, Melba Gomes and her colleagues published the findings of a randomized, placebo-controlled trial of rectal artesunate for suspected severe malaria in such remote areas. Enrolling nearly 18,000 cases, the aim was to evaluate whether, as patients were in transit to a health facility, a pre-referral artesunate suppository blocked disease progression sufficiently to reduce these risks. The affirmative findings of this, the only trial on the issue thus far, have led the WHO to endorse rectal artesunate as a pre-referral treatment for severe malaria. In the light of its public health importance and because its scientific quality has not been assessed for a systematic review, our paper provides a detailed evaluation of the design, conduct, analysis, reporting, and practical features of this trial.</p> <p>Results</p> <p>We performed a checklist-based and an in-depth evaluation of the trial. The evaluation criteria were based on the CONSORT statement for reporting clinical trials, the clinical trial methodology literature, and practice in malaria research. Our main findings are: The inclusion and exclusion criteria and the sample size justification are not stated. Many clearly ineligible subjects were enrolled. The training of the recruiters does not appear to have been satisfactory. There was excessive between center heterogeneity in design and conduct. Outcome evaluation schedule was not defined, and in practice, became too wide. Large gaps in the collection of key data were evident. Primary endpoints were inconsistently utilized and reported; an overall analysis of the outcomes was not done; analyses of time to event data had major flaws; the stated intent-to-treat analysis excluded a third of the randomized subjects; the design-indicated stratified or multi-variate analysis was not done; many improper subgroups were analyzed in a post-hoc fashion; the analysis and reporting metric was deficient. There are concerns relating to patient welfare at some centers. Exclusion of many cases from data analysis compromised external validity. A bias-controlled reanalysis of available data does not lend support to the conclusions drawn by the authors.</p> <p>Conclusions</p> <p>This trial has numerous serious deficiencies in design, implementation, and methods of data analysis. Interpretation and manner of reporting are wanting, and the applicability of the findings is unclear. The trial conduct could have been improved to better protect patient welfare. The totality of these problems make it a flawed study whose conclusions remain subject to appreciable doubt.</p

Cancer Genomics Identifies Regulatory Gene Networks Associated with the Transition from Dysplasia to Advanced Lung Adenocarcinomas Induced by c-Raf-1

Background: Lung cancer is a leading cause of cancer morbidity. To improve an understanding of molecular causes of disease a transgenic mouse model was investigated where targeted expression of the serine threonine kinase c-Raf to respiratory epithelium induced initialy dysplasia and subsequently adenocarcinomas. This enables dissection of genetic events associated with precancerous and cancerous lesions. Methodology/Principal Findings: By laser microdissection cancer cell populations were harvested and subjected to whole genome expression analyses. Overall 473 and 541 genes were significantly regulated, when cancer versus transgenic and non-transgenic cells were compared, giving rise to three distinct and one common regulatory gene network. At advanced stages of tumor growth predominately repression of gene expression was observed, but genes previously shown to be upregulated in dysplasia were also up-regulated in solid tumors. Regulation of developmental programs as well as epithelial mesenchymal and mesenchymal endothelial transition was a hall mark of adenocarcinomas. Additionaly, genes coding for cell adhesion, i.e. the integrins and the tight and gap junction proteins were repressed, whereas ligands for receptor tyrosine kinase such as epi- and amphiregulin were up-regulated. Notably, Vegfr- 2 and its ligand Vegfd, as well as Notch and Wnt signalling cascades were regulated as were glycosylases that influence cellular recognition. Other regulated signalling molecules included guanine exchange factors that play a role in an activation of the MAP kinases while several tumor suppressors i.e. Mcc, Hey1, Fat3, Armcx1 and Reck were significantly repressed. Finally, probable molecular switches forcing dysplastic cells into malignantly transformed cells could be identified. Conclusions/Significance: This study provides insight into molecular pertubations allowing dysplasia to progress further to adenocarcinoma induced by exaggerted c-Raf kinase activity

Markers of progression in early-stage invasive breast cancer: a predictive immunohistochemical panel algorithm for distant recurrence risk stratification

Accurate distant metastasis (DM) prediction is critical for risk stratification and effective treatment decisions in breast cancer (BC). Many prognostic markers/models based on tissue marker studies are continually emerging using conventional statistical approaches analysing complex/dimensional data association with DM/poor prognosis. However, few of them have fulfilled satisfactory evidences for clinical application. This study aimed at building DM risk assessment algorithm for BC patients. A well-characterised series of early invasive primary operable BC (n=1902), with immunohistochemical (IHC) expression of a panel of biomarkers (n=31) formed the material of this study. Decision tree algorithm was computed using WEKA software, utilising quantitative biomarkers’ expression and the absence/presence of distant metastases. Fifteen biomarkers were significantly associated with DM, with six temporal subgroups characterised based on time-to-development of DM ranging from 15 years of follow-up. Of these 15 biomarkers, 10 had a significant expression pattern where Ki67LI, HER2, p53, N-cadherin, P-cadherin, PIK3CA and TOMM34 showed significantly higher expressions with earlier development of DM. In contrast, higher expressions of ER, PR, and BCL2, were associated with delayed occurrence of DM. DM prediction algorithm was built utilising cases informative for the 15 significant markers. Four risk groups of patients were characterised. Three markers; p53, HER2 and BCL2 predicted the probability of DM, based on software-generated cut-offs, with a precision rate of 81.1% for positive predictive value and 77.3%, for the negative predictive value. This algorithm reiterates the reported prognostic values of these three markers and underscores their central biologic role in BC progression. Further independent validation of this pruned panel of biomarkers is therefore warranted