Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome.

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

Utilizing Bayesian inference in accelerated testing models under constant stress via ordered ranked set sampling and hybrid censoring with practical validation.

This research investigates the application of the ordered ranked set sampling (ORSSA) procedure in constant-stress partially accelerated life-testing (CSPALTE). The study adopts the assumption that the lifespan of a specific item under operational stress follows a half-logistic probability distribution. Through Bayesian estimation methods, it concentrates on estimating the parameters, utilizing both asymmetric loss function and symmetric loss function. Estimations are conducted using ORSSAs and simple random samples, incorporating hybrid censoring of type-I. Real-world data sets are utilized to offer practical context and validate the theoretical discoveries, providing concrete insights into the research findings. Furthermore, a rigorous simulation study, supported by precise numerical calculations, is meticulously conducted to gauge the Bayesian estimation performance across the two distinct sampling methodologies. This research ultimately sheds light on the efficacy of Bayesian estimation techniques under varying sampling strategies, contributing to the broader understanding of reliability analysis in CSPALTE scenarios.

A multi-task learning model for predicting drugs combination synergy by analyzing drug-drug interactions and integrated multi-view graph data.

This paper proposes a multi-task deep learning model for determining drug combination synergistic by simultaneously output synergy scores and synergy class labels. Initially, the two drugs are represented using a Simplified Molecular-Input Line-Entry (SMILE) system. Chemical structural features of the drugs are extracted from the SMILE using the RedKit package. Additionally, an improved Multi-view representation is proposed to extract graph-based drug features. Furthermore, the cancer cell line is represented by gene expression. Then, a three fully connected layers are learned to extract cancer cell line features. To investigate the impact of drug interactions on cell lines, the drug interaction features are extracted from a pretrained drugs interaction network and fed into an attention mechanism along with the cancer cell line features, resulting in the output of affected cancer cell line features. Subsequently, the drug and cell line features are concatenated and fed into an attention mechanism, which produces a two-feature representation for the two predicted tasks. The relationship between the two tasks is learned using the cross-stitch algorithm. Finally, each task feature is inputted into a fully connected subnetwork to predict the synergy score and synergy label. The proposed model 'MutliSyn' is evaluated using the O'Neil cancer dataset, comprising 38 unique drugs combined to form 22,737 drug combination pairs, tested on 39 cancer cell lines. For the synergy score, the model achieves a mean square error (MSE) of 219.14, a root mean square error (RMSE) of 14.75, and a Pearson score of 0.76. Regarding the synergy class label, the model achieves an area under the ROC curve (ROC-AUC) of 0.95, an area under the precision-recall curve (PR-AUC) of 0.85, precision of 0.93, kappa of 0.61, and accuracy of 0.90.

Reliability analysis of the triple modular redundancy system under step-partially accelerated life tests using Lomax distribution.

Triple modular redundancy (TMR) is a robust technique utilized in safety-critical applications to enhance fault-tolerance and reliability. This article focuses on estimating the distribution parameters of a TMR system under step-stress partially accelerated life tests, where each component included in the system follows a Lomax distribution. The study aims to analyze the system's reliability and mean residual lifetime based on the estimated parameters. Various estimation techniques, including maximum likelihood, percentile, least squares, and maximum product of spacings, are explored. Additionally, the optimal stress change time is determined using two criteria. An illustrative example supported by two actual data sets is presented to showcase the methodology's application. By conducting Monte Carlo simulations, the assessment of the estimation methods' effectiveness reveals that the maximum likelihood method outperforms the other three methods in terms of both accuracy and performance, as indicated by the numerical outcomes. This research contributes to the understanding and practical implementation of TMR systems in safety-critical industries, potentially saving lives and preventing catastrophic events.

Duplex Hemodynamic Parameters of Both Superior and Inferior Thyroid Arteries in Evaluation of Thyroid Hyperfunction Disorders.

Background: Thyrotoxicosis may be caused by Graves' disease or destructive thyroiditis. Differentiation between causes of thyrotoxicosis is crucial as management will differ. 99mTechnetium (Tc)-pertechnetate thyroid scintigraphy is currently the gold standard for this purpose, however, is expensive and uses ionizing radiation. Objective: To evaluate the role of color flow Doppler Ultrasound (CDU) of the superior thyroid (STA) and inferior thyroid arteries (ITA) as an inexpensive, non-invasive tool that can aid in differentiating between Graves' disease and thyroiditis and compare it with thyroid scintigraphy. Methods: Sixty-nine patients with newly-diagnosed thyrotoxicosis and 30 controls were enrolled. Thyroid functions, thyroid scintigraphy, and CDU of STA and ITA with measurements of peak systolic velocity (PSV) and end diastolic velocity (EDV), were performed. According to thyroid scintigraphy results, patients were divided into two groups: 42 patients with Graves' disease and 27 patients with thyroiditis. Results: PSV and EDV of both STA and ITA were significantly higher in patients with Graves' disease than thyroiditis (p-values <0.001). The STA-PSV had an equal sensitivity and specificity of 66.7%; cut-off value 76.57 cm/s, while those of STA-EDV were 73.8%, and 77.8% respectively; cut-off value 28.22 cm/s. ITA-PSV had a sensitivity and specificity of 76.2% and 77.8%, respectively; cut-off value 62.12 cm/s), while those of ITA-EDV were 78.6% and 77.8%, respectively; cut-off value 5.22 cm/s. Conclusion: CDU parameters of the STA and ITA could be used as an alternative to thyroid scintigraphy for discriminating between Graves' disease and thyroiditis.

Occurrence and clinical characteristics of occult hepatitis C virus infection in hemodialysis units at Ismailia, Egypt.

BACKGROUND AND AIMS: Occult hepatitis C infection is defined as the presence of hepatitis C virus RNA in peripheral blood mononuclear cells (PBMC) ± hepatocytes in the absence of HCV-RNA in serum. It has been a lot of debate and controversy in recent years and not discussed well. This issue has not been discussed or investigated in Egypt, especially in patients on hemodialysis in Ismailia. This study is the first one to investigate the prevalence of occult HCV infection in large populations of chronic hemodialysis (CHD) patients in Ismailia, Egypt. METHODS: Our study is cross-sectional analytic and included 204 CHD patients; who are negative for HCV infection. Sensitive commercial real-time assay was used to detect HCV-RNA in PBMC. In our study, the presence of genomic HCV-RNA in PBMCs of all these patients was detected by real-time PCR. On the other hand, 22 patients on hemodialysis with an established diagnosis of chronic hepatitis C virus infection were included as a control group and examined by real-time PCR was used to evaluate HCV infection. RESULTS: Occult HCV infection is defined as the presence of HCV-RNA in PBMNCs in patients on chronic hemodialysis, and it was found in 14/204 (7%) of the patients. Patients who were on CHD for a longer time are susceptible to occult HCV infection, and their mean alanine aminotransferase levels are significantly higher during the last 3 months before study entry. In comparison, chronic HCV patients have elevated bilirubin, aspartate transferase and alanine transferase than occult HCV infection. CONCLUSIONS: The prevalence of occult HCV infection was 7% in our CHD patients. No available data are showing the virulence of this form of virus. However, further studies in other geographic populations with high HCV endemicity are needed to clarify the significance of occult HCV infection in these patient groups, in addition to test for the presence of negative antigenomic strand to confirm or disconfirm the reliability of occult HCV.

Prevalence of gastrointestinal nematodes, parasite control practices and anthelmintic resistance patterns in a working horse population in Egypt.

BACKGROUND: Anthelmintic resistance is commonly reported in horse populations in developed countries, but evidence in some working horse populations is either lacking or inconclusive. OBJECTIVES: To estimate prevalence of GI nematode infections in working horses in Egypt and to evaluate strongyle resistance to ivermectin, doramectin and fenbendazole. STUDY DESIGN: Cross-sectional study. METHODS: Faecal egg count was performed on 644 working horses from 2 provinces in Egypt. A short questionnaire about horse signalment and worming history was completed for each horse. Horses identified with ≥50 strongyle type egg/g (n = 146) underwent faecal egg count reduction testing (FECRT) following treatment with ivermectin (n = 33), doramectin (n = 33) or fenbendazole (n = 30). Risk factors for strongyle (≥200 egg/g) and Parascaris equorum (>0 egg/g) infection were investigated using multivariable logistic regression analyses. RESULTS: The prevalence of low (0-199 epg), medium (200-500 epg) and high (>500 epg) strongyle infection was 88.4%, 5.9% and 5.8%, respectively. P. equorum eggs were detected in 5.1% (n = 33) of horses. Strongyle FECR was 100%, 99.97% and 100% following treatment with ivermectin, doramectin and fenbendazole respectively. Anthelmintic treatment in the 12 months preceding examination was associated with reduced likelihood of strongyle infection (odds ratio [OR] = 0.26, 95% confidence interval [CI] = 0.14, 0.47, P < .001). The likelihood of P. equorum infection was significantly associated with horses' age (OR = 0.78, 95% CI = 0.69, 0.90; P < .001). Male horses were more likely to have P. equorum infection (OR = 2.86, 95% CI = 1.37, 5.93, P = .005). MAIN LIMITATIONS: Nonrandomised selection of study areas and larval cultures was unsuccessful for some samples. CONCLUSIONS: There were low prevalence of strongyle and P. equorum infection and no evidence of macrocyclic lactones or benzimidazole resistance in strongyles in the studied working horse population.

Surgical versus Non-Surgical Management of Obstructive Sleep-disordered Breathing in Children: A Meta-analysis.

BACKGROUND: Obstructive sleep-disordered breathing (OSDB) is a term for several chronic conditions in which partial or complete cessation of breathing occurs many times throughout the night, resulting in fatigue or daytime sleepiness that interferes with a person's functions and reduces the quality of life. OBJECTIVE: Comparing the effectiveness of surgical versus non-surgical treatment of OSDB in children in clinical trials through a meta-analysis study. PATIENTS AND METHODS: A number of available studies and abstracts concerning the surgical versus non-surgical treatment of OSDB in children were identified through a comprehensive search of electronic databases. Data were abstracted from every study in the form of a risk estimate and its 95% confidence interval. RESULTS: The current study revealed that there was a statistically significant improvement in the surgically treated patients rather than non-surgically treated patients regarding the quality of life. CONCLUSION: The current meta-analysis reports a significant clinical improvement in the surgical (adenotonsillectomy) group as compared to the non-surgical group, in terms of disease specific quality of life, and healthcare utilization in spite of the availability of only one study.

Therapeutic efficacy of olfactory stem cells in rotenone induced Parkinsonism in adult male albino rats.

BACKGROUND: Olfactory stem cells (OSCs) are found in the olfactory mucosa and olfactory bulb and have the capacity to proliferate and differentiate along multiple tissue lineages. Rotenone; widely used insecticide has a neurodegenerative effect on the dopaminergic cells of substantia nigra (SN) of midbrain producing Parkinsonism. The aim of this study is to isolate rat OSCs from olfactory mucosa and olfactory bulb, culture these OSCs in suitable medium to allow for their proliferation to be used in the treatment of Parkinsonism induced by rotenone. METHODS: The characteristics of OSCs, the effects of rotenone on the SN of midbrain and the curative effect of OSCs on the substantia nigra were determined morphologically, immunohistochemically, and by transmission electron microscopy. PKH 26; immunofluorescent dye was used as a cell tracer to locate the transplanted cells in host midbrain. RESULTS: OSCs were spindle shaped with irregular processes, and were positive for CD44 and Nestin and negative for CD34. Subcutaneous rotenone produced Parkinsonism through producing degeneration of the dopaminergic cells of SN of the midbrain. Transplantation of OSCs produced restoration of the normal structure of SN and dopaminergic cells and improves the clinical manifestations of Parkinsonism. CONCLUSION: These results indicate that, the isolated rat OSCs can proliferate and expand in vitro when culture in suitable medium and these cells can exert therapeutic effects in Parkinsonism by recruitment in SN and restoration of the structure and function of dopaminergic cells.

Clinical audit of ectopic pregnancy.

OBJECTIVE: The aim of this study was to determine the risk factors of ectopic pregnancy in cases presented to the Woman's Health Hospital (WHH) in Assuit University, and to perform clinical audit on strategies for management of ectopic pregnancy in the WHH. METHODS: This descriptive hospital based study was conducted at the Woman's Health Hospital (WHH) of Assuit University (Egypt). There were 210 patients who were admitted to the WHH with the diagnosis of ectopic pregnancy in the period between February 1, 2015 through the end of October 2015. Data were analyzed by SPSS version 21, using descriptive statistics, Mann-Whitney U test, and Chi square. RESULTS: Ectopic pregnancy affects woman in the reproductive age. There are many risk factors that increase the chance of its occurrence; however, it may also occur in the absence of any risk factors (14.0%). Internal VD (72.5%) is the most frequent risk factor; other risk factors include history of abortion, previous CS, ovulation induction, history of infertility, or previous history of EP. CONCLUSION: Clinical audit is an important item of any adequate health care. As regards to the clinical audit of EP management, we are not adhering to the guidelines.

Insulin resistance and prediabetes in hepatitis C virus patients.

BACKGROUND: Egypt has the highest prevalence of hepatitis C virus (HCV) infection in the world and is facing an epidemic of type 2 diabetes mellitus. The objective of this study was to assess the prevalence of insulin resistance (IR) and prediabetes among HCV patients. METHODS: A cross-sectional case-control study was performed on 188 HCV patients admitted to the Internal Medicine Department in Menoufia University Hospital during the period from May to August 2014. Seventy persons were taken as controls. Body mass index (BMI), serum fasting glucose and fasting insulin were determined. IR was calculated by the Homeostasis Model for Assessment of Insulin Resistance (HOMA-IR), where a value of >2.0 was considered as IR and that >4.0 was considered as prediabetic state. RESULTS: Prediabetes was significantly higher among HCV group compared with the control group. Serum fasting glucose, fasting insulin and HOMA-IR levels were significantly higher among prediabetic HCV group compared with both non-prediabetic HCV and control groups. CONCLUSIONS: HCV patients should be assessed for IR and prediabetes in their routine evaluation to avoid the double burden of diabetes mellitus and HCV.

The role of anti-Mullerian and inhibin B hormones in the evaluation of 46,XY disorders of sex development.

OBJECTIVE: To assess the sensitivity and specificity of anti-Mullerian hormone (AMH) and inhibin B for diagnosis of 46,XY disorders of sex development (DSD). PATIENTS AND METHODS: The study included 43 patients of 46,XY DSD and compared them with 43 healthy, male, age matched controls. All patients underwent karyotyping, assessment of testosterone, dihydrotestosterone (DHT) and Δ4-androstendione (Δ4A) basal and after human chorionic gonadotropin (HCG) testing. Basal dehydroepiandrosterone (DHEA) was measured. Ultrasonograghy was also done and some cases underwent laparoscopy or gonadal biopsies. Basal AMH and inhibin B were measured in both cases and controls. RESULTS: The mean age of patients was 5.16±4.24 years. There were significant correlations between basal AMH and HCG stimulated testosterone and DHT (r=0.64; p<0.001 and r=0.52; p<0.001, respectively). Also, significant positive correlations were found between inhibin B and HCG as well as stimulated testosterone and DHT (r=0.62; p<0.001 and r=0.44; p=0.003, respectively). A highly significant correlation was found between AMH and inhibin B (r=0.78; p<0.001). The sensitivity of AMH was (96.6%), specificity (60.7%), NPV (89.5%) and PPV (83.6%). Best cut-off value was (27.11 IU/mL) while overall accuracy was (85%). The sensitivity of inhibin B was (96.6%), specificity (67.9%), NPV (90.5%), PPV (86.2%), and best cut-off value was (41.9 IU/mL) with an overall accuracy (87%). CONCLUSION: AMH and inhibin B are valuable, and reliable noninvasive parameters for the detection of functioning testicular tissues in prepubertal patients.

Novel mutations of the nucleophosmin (NPM-1) gene in Egyptian patients with acute myeloid leukemia: a pilot study.

UNLABELLED: Mutations of the nucleophosmin (NPM-1) gene have been reported in 50-60% of acute myeloid leukemia (AML) patients with normal karyotype. This work was designed to study the prevalence and nature of NPM1 gene mutations in a group of Egyptian patients with AML to get an idea about the profile of NPM1 gene mutations in our society. In 45 previously untreated patients with de novo AML, peripheral blood and/or bone marrow samples from all patients were subjected to microscopic morphologic examination, cytochemical analysis, immunophenotyping and karyotyping. Patients with normal cytogenetic results were selected for molecular analysis of NPM1 exon 12 by PCR amplification followed by DNA sequencing of the amplified product. Twenty-one patients (46.7%) had abnormal karyotype: six cases with t(15;17), five cases with t(8;21), five cases had trisomy 8, two cases carrying inv(3) and three cases had monosomy 7. The remaining 24 patients (53.3%) had normal karyotype. These patients were then subjected to molecular analysis. Out of these 24 patients with normal karyotype, mutant NPM-1 was detected in 11 patients (45.8%) by DNA sequencing; 2 cases showed type A mutation, 2 cases were harboring [ins 1015-1019 (CACG)], with point mutation [1006C>G], while the remaining 7 cases showed heterozygous deletion of nt A [del 1178 (A)]. CONCLUSION: Two novel NPM1 gene mutations were detected among our study population of AML patients identified as: the insertion CACG associated with point mutation, deletion of one base, or associated with point mutation. NPM1 gene mutations may become a new tool for monitoring minimal residual disease in AML with normal karyotype. Whether these previously unreported NPM-1 mutations will confer the same better outcome as previously reported mutations is currently unknown and warrants a larger study. CONCLUSION: Two novel NPM1 gene mutations were detected among our study population of AML patients identified as: the insertion CACG associated with point mutation, deletion of one base, or associated with point mutation. NPM1 gene mutations may become a new tool for monitoring minimal residual disease in AML with normal karyotype. Whether these previously unreported NPM-1 mutations will confer the same better outcome as previously reported mutations is currently unknown and warrants a larger study.

Renal duplex doppler ultrasonography in patients with recurrent urinary tract infection.

Renal hemodynamics were studied using duplex Doppler ultrasonography in forty (33 females and 7 males; mean age: 12.1 +/- 5.3 years) normotensive patients with recurrent urinary tract infection and with no evidence of obstructive uropathy and age matched control group of 24 healthy children and adolescents. Resistivity index (RI) and pulsatility index (PI) in both arcuate (AA) and interlobar (IA) arteries were significantly higher in patients as compared to controls (P= 0.001, 0.01 respectively). Diastolic/systolic ratio (D/S) at the same levels of renal vasculature (AA and IA) was significantly lower in study patients as compared to their controls (P= 0.01, 0.001 respectively). Moreover, scarred renal units had higher RI and PI values as well as lower D/S ratio as compared to non scarred units (p= 0.01, 0.001, 0.001 respectively).). In conclusion, intra renal vascular resistivity is significantly increased in recurrent UTI patients particularly in those sustaining renal scarring. Further follow up studies are recommended to determine if duplex assessment of intrarenal vasculature could be useful as an ancillary diagnostic and/or prognostic technique in the evaluation and follow up of recurrent UTI.

INF-gamma, IL-5 and IgE profiles in chronic schistosomiasis mansoni Egyptian patients with or without hepatitis C infection.

The immune response against clinical forms of chronic schistosomiasis mansoni patients with or without HCV infection was evaluated by assays the serum levels of IFN-gamma and IL-5 for estimate the cell mediated immunity and IgE level to estimate the humoral immunity. This study included three patient groups. G.I included 25 patients with intestinal schistosomiasis, G.II included 15 patients with hepatosplenic schistosomiasis and G.III included 40 patients hepatosplenic schistosomiasis co-infected with HCV. Control G.IV included 15 healthy persons with matched age and sex. The intestinal group had high IFN-gamma (92%), normal level of IL-5 and IgE. The immune response was mainly 100% Th-1 response. The hepatosplenic patients had high IFN-gamma (26.7%), IL-5 (86.7%) and IgE (73.3%). The immune response was 73.4% Th-0, 13.3% Th-1 and 13.3% Th-2. The co-infected group had high IFN-gamma (62.7%), IL-5 (100%) and IgE (92.5%). The immune response was 62.5% Th-0 and 37.5% Th-2 immunity. The shift to Th-0 and Th-2 immunity as well as associated depression of Th-1 in mixed group of patients may be playing a role in the persistence and severity of both diseases. Such immunity defects add to decrease challenge against HCV clearance.