Synpolydactyly and HOXD13 polyalanine repeat: addition of 2 alanine residues is without clinical consequences

<p>Abstract</p> <p>Background</p> <p>Type II syndactyly or synpolydactyly (SPD) is clinically very heterogeneous, and genetically three distinct SPD conditions are known and have been designated as SPD1, SPD2 and SPD3, respectively. SPD1 type is associated with expansion mutations in <it>HOXD13</it>, resulting in an addition of ≥ 7 alanine residues to the polyalanine repeat. It has been suggested that expansions ≤ 6 alanine residues go without medical attention, as no such expansion has ever been reported with the SPD1 phenotype.</p> <p>Methods</p> <p>We describe a large Pakistani and an Indian family with SPD. We perform detailed clinical and molecular analyses to identify the genetic basis of this malformation.</p> <p>Results</p> <p>We have identified four distinct clinical categories for the SPD1 phenotype observed in the affected subjects in both families. Next, we show that a milder foot phenotype, previously described as a separate entity, is in fact a part of the SPD1 phenotypic spectrum. Then, we demonstrate that the phenotype in both families segregates with an identical expansion mutation of 21 bp in <it>HOXD13</it>. Finally, we show that the HOXD13 polyalanine repeat is polymorphic, and the expansion of 2 alanine residues, evident in unaffected subjects of both families, is without clinical consequences.</p> <p>Conclusion</p> <p>It is the first molecular evidence supporting the hypothesis that expansion of ≤ 6 alanine residues in the HOXD13 polyalanine repeat is not associated with the SPD1 phenotype.</p

Comparison of Sonographic Quantitative Assessment of Splenomegaly in Thalassemia Patients Receiving Whole Blood and Packed Red Cell Transfusions

Objective: An observational cross-sectional study to assess sonographic splenomegaly quantitatively in thalassemia patients grouped with respect to transfusion given whole blood vs packed red cells. Methods: A study was conducted among 330 patients equally divided into two groups, undergoing an abdominal ultrasound examination with a transducer frequency ranging from 3-5 MHz during the period December 2021 to August 2022. An independent t-test was applied to compare the splenic volume in thalassemia patients given whole blood transfusions versus packed red cells transfusions, and Cohen's d was used to indicate the standardized difference between two ultrasound splenic volume means. Results: The mean splenic volume of the patients who received whole blood cells was 320.62 ± 219.05 cm3, which is greater than the patients who received packed red cells, whose mean was 60.72 ± 58.72 cm3, The splenomegaly was quantitatively assessed in six age groups ranging from 1 to 3 years, 4 to 6 years, 7 to 9 years, 10 to 12 years, 13 to 15 years, and 16-18 years and mean splenic volume in each age group was compared to those receiving whole blood or packed red cells transfusion. there is a statistically significant difference between both transfusion receiving groups, having a larger Cohen’s d size effect of 1.62. Conclusion: Ultrasound is a reliable imaging modality for assessing splenic volume and linear parameters of the spleen with greater splenomegaly in thalassemia patients with whole blood transfusions than those with packed red cells when quantitatively assessed according to relevant age groups. Thalassemia patients should be transfused packed red cells to delay splenomegaly, that should be assessed sonographically

Distal junctional kyphosis in patients with Scheuermann’s disease: a retrospective radiographic analysis

Purpose To investigate the relationship between preoperative and postoperative spinopelvic alignment and occurrence of DJK/DJF. Study design/setting This was a retrospective observational cohort study. Patient sample The sample included 40 patients who underwent posterior correction of SK from January 2006 to December 2014. Outcome measures Correlation analysis between the preoperative and postoperative spinopelvic alignment parameters and development of DJK over the course of the study period were studied. Methods Whole spine X-rays obtained before surgery, 3 months after surgery and at the latest follow-up were analyzed. The following parameters were measured: maximum of thoracic kyphosis (TK), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lower instrumented vertebra (LIV) and LIV plumb line. Development of DJK was considered as the primary end point of the study. The patient population was split into a control and DJK group, with 34 patients and 6 patients, respectively. Statistic analysis was performed using unpaired t test for normal contribution and Mann–Whitney test for skew distributed values. The significance level was set to 0.05. Results DJK occurred in 15% (n = 6) over the study period. There was a significantly lower postoperative TK for the group with DJK (42.4 ± 5.3 vs 49.8 ± 6.7, p = 0.015). LIV plumb line showed higher negative values in the DJK group (−43.6 ± 25.1 vs −2.2 ± 17.8, p = 0.0435). Furthermore, postoperative LL changes were lower for the DJK group (33.84 ± 13.86% vs 31.77 ± 14.05, p < 0.0001.) The age of the patients who developed DJK was also significantly lower than that of the control group (16.8 ± 1.7 vs 19.6 ± 4.9, p = 0.0024.) Conclusions SK patients who developed DJK appeared to have a significantly higher degree of TK correction and more negative LIV plumb line. In addition, there may be a higher risk for DJK in patients undergoing corrective surgery at a younger age

Modulators of Prostate Cancer Cell Proliferation and Viability Identified by Short-Hairpin RNA Library Screening

There is significant need to identify novel prostate cancer drug targets because current hormone therapies eventually fail, leading to a drug-resistant and fatal disease termed castration-resistant prostate cancer. To functionally identify genes that, when silenced, decrease prostate cancer cell proliferation or induce cell death in combination with antiandrogens, we employed an RNA interference-based short hairpin RNA barcode screen in LNCaP human prostate cancer cells. We identified and validated four candidate genes (AKT1, PSMC1, STRADA, and TTK) that impaired growth when silenced in androgen receptor positive prostate cancer cells and enhanced the antiproliferative effects of antiandrogens. Inhibition of AKT with a pharmacologic inhibitor also induced apoptosis when combined with antiandrogens, consistent with recent evidence for PI3K and AR pathway crosstalk in prostate cancer cells. Recovery of hairpins targeting a known prostate cancer pathway validates the utility of shRNA library screening in prostate cancer as a broad strategy to identify new candidate drug targets

Classification and biomarker identification using gene network modules and support vector machines

<p>Abstract</p> <p>Background</p> <p>Classification using microarray datasets is usually based on a small number of samples for which tens of thousands of gene expression measurements have been obtained. The selection of the genes most significant to the classification problem is a challenging issue in high dimension data analysis and interpretation. A previous study with SVM-RCE (Recursive Cluster Elimination), suggested that classification based on groups of correlated genes sometimes exhibits better performance than classification using single genes. Large databases of gene interaction networks provide an important resource for the analysis of genetic phenomena and for classification studies using interacting genes.</p> <p>We now demonstrate that an algorithm which integrates network information with recursive feature elimination based on SVM exhibits good performance and improves the biological interpretability of the results. We refer to the method as SVM with Recursive Network Elimination (SVM-RNE)</p> <p>Results</p> <p>Initially, one thousand genes selected by t-test from a training set are filtered so that only genes that map to a gene network database remain. The Gene Expression Network Analysis Tool (GXNA) is applied to the remaining genes to form <it>n </it>clusters of genes that are highly connected in the network. Linear SVM is used to classify the samples using these clusters, and a weight is assigned to each cluster based on its importance to the classification. The least informative clusters are removed while retaining the remainder for the next classification step. This process is repeated until an optimal classification is obtained.</p> <p>Conclusion</p> <p>More than 90% accuracy can be obtained in classification of selected microarray datasets by integrating the interaction network information with the gene expression information from the microarrays.</p> <p>The Matlab version of SVM-RNE can be downloaded from <url>http://web.macam.ac.il/~myousef</url></p

Multiple micronutrient supplementation improves vitamin B12 and folate concentrations of HIV infected children in Uganda: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>The effect of multiple micronutrient supplementation on vitamin B₁₂and folate has hither to not been reported in African HIV infected children. This paper describes vitamin B₁₂and folate status of Ugandan HIV infected children aged 1-5 years and reports the effect of multiple micronutrient supplementation on serum vitamin B₁₂and folate concentrations.</p> <p>Methods</p> <p>Of 847 children who participated in a multiple micronutrient supplementation trial, 214 were assessed for vitamin B₁₂and folate concentrations pre and post supplementation. One hundred and four children were randomised to two times the recommended dietary allowance (RDA) of a 14 multiple micronutrient supplement (MMS) and 114 to a 'standard of care' supplement of 6 multivitamins (MV). Serum vitamin B₁₂was measured by an electrochemiluminescence immunoassay and folate by a competitive protein-binding assay using Modular E (Roche) automatic analyzer. Vitamin B₁₂concentrations were considered low if less than 221picomoles per litre (pmol/L) and folate if < 13.4 nanomoles per litre (nmol/L). The Wilcoxon Signed Ranks test was used to measure the difference between pre and post supplementation concentrations.</p> <p>Results</p> <p>Vitamin B₁₂was low in 60/214 (28%) and folate in 62/214 (29.0%) children. In the MMS group, the median concentration (IQR) of vitamin B₁₂at 6 months was 401.5 (264.3 - 518.8) pmol/L compared to the baseline of 285.5 (216.5 - 371.8) pmol/L, p < 0.001. The median (IQR) folate concentrations increased from 17.3 (13.5 - 26.6) nmol/L to 27.7 (21.1 - 33.4) nmol/L, p < 0.001. In the 'standard of care' MV supplemented group, the median concentration (IQR) of vitamin B₁₂at 6 months was 288.5 (198.8 - 391.0) pmol/L compared to the baseline of 280.0 (211.5 - 386.3) pmol/L while the median (IQR) folate concentrations at 6 months were 16.5 (11.7 - 22.1) nmol/L compared to 15.7 (11.9 - 22.1) nmol/L at baseline. There was a significant difference in the MMS group in both vitamin B₁₂and folate concentrations but no difference in the MV group.</p> <p>Conclusions</p> <p>Almost a third of the HIV infected Ugandan children aged 1-5 years had low serum concentrations of vitamin B₁₂and folate. Multiple micronutrient supplementation compared to the 'standard of care' supplement of 6 multivitamins improved the vitamin B₁₂and folate status of HIV infected children in Uganda.</p> <p>Trial registration</p> <p><url>http://ClinicalTrials.gov</url><a href="http://www.clinicaltrials.gov/ct2/show/NCT00122941">NCT00122941</a>)</p

Measurement of the top quark mass using the matrix element technique in dilepton final states

We present a measurement of the top quark mass in pp¯ collisions at a center-of-mass energy of 1.96 TeV at the Fermilab Tevatron collider. The data were collected by the D0 experiment corresponding to an integrated luminosity of 9.7  fb−1. The matrix element technique is applied to tt¯ events in the final state containing leptons (electrons or muons) with high transverse momenta and at least two jets. The calibration of the jet energy scale determined in the lepton+jets final state of tt¯ decays is applied to jet energies. This correction provides a substantial reduction in systematic uncertainties. We obtain a top quark mass of mt=173.93±1.84  GeV

Ethical, legal and social aspects of the approach in Sudan

The global malaria situation, especially in Africa, and the problems frequently encountered in chemical control of vectors such as insecticide resistance, emphasize the urgency of research, development and implementation of new vector control technologies that are applicable at regional and local levels. The successful application of the sterile insect technique (SIT) for the control of the New World screwworm Cochliomyia hominivorax and several species of fruit flies has given impetus to the use of this method for suppression or elimination of malaria vectors in some areas of Africa including Northern State of Sudan. The research and development phase of the Northern State feasibility study has been started. Sudanese stakeholders are working side-by-side with the International Atomic Energy Agency in the activities of this important phase. Several ethical, legal and social issues associated with this approach arose during this phase of the project. They need to be seriously considered and handled with care. In this paper, these issues are described, and the current and proposed activities to overcome potential hurdles to ensure success of the project are listed

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty