Disease-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1.

SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers. However, the defect of mutant SF3B1 is unknown. Here, we analyzed RNA sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3' splice sites. To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1 and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes. Strikingly, SUGP1 knockdown completely recapitulated the splicing errors, whereas SUGP1 overexpression drove the protein, which our data suggest plays an important role in branchsite recognition, into the mutant spliceosome and partially rescued splicing. Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1. Our study demonstrates that SUGP1 loss is a common defect of spliceosomes with disease-causing SF3B1 mutations and, because this defect can be rescued, suggests possibilities for therapeutic intervention.

SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes.

SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ∼25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 WT and mutant cell lines, normal human CD34 cells, and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature down-regulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia, and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.

BDNF/TrkB activators in Parkinson's disease: A new therapeutic strategy.

Parkinson's disease (PD) is a neurodegenerative disorder of the brain and is manifested by motor and non-motor symptoms because of degenerative changes in dopaminergic neurons of the substantia nigra. PD neuropathology is associated with mitochondrial dysfunction, oxidative damage and apoptosis. Thus, the modulation of mitochondrial dysfunction, oxidative damage and apoptosis by growth factors could be a novel boulevard in the management of PD. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase type B (TrkB) are chiefly involved in PD neuropathology. BDNF promotes the survival of dopaminergic neurons in the substantia nigra and enhances the functional activity of striatal neurons. Deficiency of the TrkB receptor triggers degeneration of dopaminergic neurons and accumulation of α-Syn in the substantia nigra. As well, BDNF/TrkB signalling is reduced in the early phase of PD neuropathology. Targeting of BDNF/TrkB signalling by specific activators may attenuate PD neuropathology. Thus, this review aimed to discuss the potential role of BDNF/TrkB activators against PD. In conclusion, BDNF/TrkB signalling is decreased in PD and linked with disease severity and long-term complications. Activation of BDNF/TrkB by specific activators may attenuate PD neuropathology.

Molecular insights into expression and silencing of resistance determinants in Staphylococcus aureus.

OBJECTIVE: This study aimed to investigate the status of antimicrobial-resistant strains of Staphylococcus aureus in Pakistan, their association in terms of co-occurrence with the biofilm-forming genes, resistance profiling and associated discrepancies in diagnostic methods. METHODOLOGY: A total of 384 milk samples from bovine was collected by using convenient sampling technique and were initially screened for subclinical mastitis, further preceded by isolation and confirmation of S. aureus. The S. aureus isolates were subjected to evaluation of antimicrobial resistance by phenotypic identification using Kirby-Bauer disc diffusion method, while the genotypic estimation was done by polymerase chain reaction to declare isolates as methicillin, beta-lactam, vancomycin, tetracycline, and aminoglycoside resistant S. aureus (MRSA, BRSA, VRSA, TRSA, and ARSA), respectively. RESULTS: The current study revealed an overall prevalence of subclinical mastitis and S. aureus to be 59.11% and 46.69%, respectively. On a phenotypic basis, the prevalence of MRSA, BRSA, VRSA, TRSA, and ARSA was found to be 44.33%, 58.49%, 20.75%, 35.84%, and 30.18%, respectively. The results of PCR analysis showed that 46.80% of the tested isolates were declared as MRSA, 37.09% as BRSA, and 36.36% as VRSA, while the occurrence of TRSA and ARSA was observed in 26.31% and 18.75%, respectively. The current study also reported the existence of biofilm-producing genes (icaA and icaD) in 49.06% and 40.57% isolates, respectively. Lastly, this study also reported a high incidence of discrepancies for both genotypic and phenotypic identification methods of resistance evaluation, with the highest discrepancy ratio for the accA-aphD gene, followed by tetK, vanB, blaZ, and mecA genes. CONCLUSION: The study concluded that different antibiotic resistance strains of S. aureus are prevalent in study districts with high potential to transmit between human populations. The study also determined that there are multiple resistance determinants and mechanisms that are responsible for the silencing and expression of antibiotic resistance genes.

U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-mRNA 3' End Formation.

Recurrent mutations in the splicing factor U2AF35 are found in several cancers and myelodysplastic syndrome (MDS). How oncogenic U2AF35 mutants promote transformation remains to be determined. Here we derive cell lines transformed by the oncogenic U2AF35(S34F) mutant and identify aberrantly processed pre-mRNAs by deep sequencing. We find that in U2AF35(S34F)-transformed cells the autophagy-related factor 7 (Atg7) pre-mRNA is abnormally processed, which unexpectedly is not due to altered splicing but rather selection of a distal cleavage and polyadenylation (CP) site. This longer Atg7 mRNA is translated inefficiently, leading to decreased ATG7 levels and an autophagy defect that predisposes cells to secondary mutations, resulting in transformation. MDS and acute myeloid leukemia patient samples harboring U2AF35(S34F) have a similar increased use of the ATG7 distal CP site, and previous studies have shown that mice with hematopoietic cells lacking Atg7 develop an MDS-like syndrome. Collectively, our results reveal a basis for U2AF35(S34F) oncogenic activity.

Dual role of mesenchymal stem/stromal cells and their cell-free extracellular vesicles in colorectal cancer.

Colorectal cancer (CRC) is one of the main causes of cancer-related deaths. However, the surgical control of the CRC progression is difficult, and in most cases, the metastasis leads to cancer-related mortality. Mesenchymal stem/stromal cells (MSCs) with potential translational applications in regenerative medicine have been widely researched for several years. MSCs could affect tumor development through secreting exosomes. The beneficial properties of stem cells are attributed to their cell-cell interactions as well as the secretion of paracrine factors in the tissue microenvironment. For several years, exosomes have been used as a cell-free therapy to regulate the fate of tumor cells in a tumor microenvironment. This review discusses the recent advances and current understanding of assessing MSC-derived exosomes for possible cell-free therapy in CRC.

Nanoparticle Augmentation of Adhesive Systems: Impact on Tensile Strength in Fiberglass Post Placement within Root Dentin.

BACKGROUND Modification of the glass fiber post (GFP) with titanium dioxide or silver particles can improve the durability and reliability of dental treatments for ensuring long-term success. This research assessed the tensile bond strength (TBS) of an adhesive system used for cementing GFPs into root dentin following the incorporation of nanoparticles of titanium dioxide (NTiO2) and silver (NAg). MATERIAL AND METHODS Sixty human maxillary canines were prepared to create a 10-mm intra-radicular space for post placement from the cementoenamel junction. The specimens were randomly allocated into 2 groups (a non-thermocycling group and a thermocycling group). Each group was divided into 3 subgroups (10 samples each) according to the adhesive system used (adhesive system devoid of any addition, adhesive system including 1% NAg, and adhesive system infused with 1% NTiO2). TBS tests were conducted and recorded in MPa using a Universal Testing Machine, with an axial load applied at a rate of 0.5 mm/min until failure. The TBS for both groups (non-thermocycling and thermocycling) was measured in megapascals (MPa), and the failure type was recorded. The data were statistically analyzed using one-way analysis of variance (ANOVA) and Tukey's test with P.

The prevalence of probable overactive bladder and associated risk factors among medical students in Jordan: a cross-sectional study.

BACKGROUND: To discuss the impact of overactive bladder (OAB) on medical students. overactive bladder. is a chronic condition that causes sudden and intense urges to urinate, which can have significant physical and psychological effects on patients' lives. The prevalence of OAB among medical students is relatively high, with some studies reporting rates as high as 35.4%. This research aims to shed light on the prevalence rates and risk factors associated with OAB among medical students in Jordan. METHODS: A cross-sectional study was conducted using an online self-reported questionnaire as the study tool. The questionnaire collected the sociodemographic, health, and academic characteristics of medical students, as well as the new 7-item OABSS score. RESULTS: Out of the total sample of medical students surveyed (n = 525), 44.5% reported experiencing symptoms of OAB. Furthermore, the analysis also revealed that there was a significant difference in the prevalence of OAB between the ages of medical students. In addition, the study also found that there was a significant association between OAB symptoms and basic years, positive history of diagnostic UTI, positive history of recent trauma, high stress, and taking certain medications. CONCLUSIONS: The study highlights the need for further research in this area and emphasizes the possible implications of OAB for medical students, including the need for additional support and resources to manage the condition.

The prevalence of sedentary behavior among university students in Saudi Arabia.

BACKGROUND: A considerable body of research has demonstrated that reducing sitting time benefits health. Therefore, the current study aimed to explore the prevalence of sedentary behavior (SB) and its patterns. METHODS: A total of 6975 university students (49.1% female) were chosen randomly to participate in a face-to-face interview. The original English version of the sedentary behavior questionnaire (SBQ) was previously translated into Arabic. Then, the validated Arabic version of the SBQ was used to assess SB. The Arabic SBQ included 9 types of SB (watching television, playing computer/video games, sitting while listening to music, sitting and talking on the phone, doing paperwork or office work, sitting and reading, playing a musical instrument, doing arts and crafts, and sitting and driving/riding in a car, bus or train) on weekdays and weekends. RESULTS: SBQ indicated that the total time of SB was considerably high (478.75 ± 256.60 and 535.86 ± 316.53 (min/day) during weekdays and weekends, respectively). On average, participants spent the most time during the day doing office/paperwork (item number 4) during weekdays (112.47 ± 111.11 min/day) and weekends (122.05 ± 113.49 min/day), followed by sitting time in transportation (item number 9) during weekdays (78.95 ± 83.25 min/day) and weekends (92.84 ± 100.19 min/day). The average total sitting time of the SBQ was 495.09 ± 247.38 (min/day) and 58.4% of the participants reported a high amount of sitting time (≥ 7 hours/day). Independent t-test showed significant differences (P ≤ 0.05) between males and females in all types of SB except with doing office/paperwork (item number 4). The results also showed that male students have a longer daily sitting time (521.73 ± 236.53 min/day) than females (467.38 ± 255.28 min/day). Finally, 64.1% of the males reported a high amount of sitting time (≥ 7 hours/day) compared to females (52.3%). CONCLUSION: In conclusion, the total mean length of SB in minutes per day for male and female university students was considerably high. About 58% of the population appeared to spend ≥7 h/day sedentary. Male university students are likelier to sit longer than female students. Our findings also indicated that SB and physical activity interventions are needed to raise awareness of the importance of adopting an active lifestyle and reducing sitting time.

ASXL1 mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms.

Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMAs) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5- AZA could also extend the rationale of this treatment concept to high-risk MDS. In this study, we performed a comprehensive in vitro assessment of alvocidib and 5-AZA effects in n=45 high-risk MDS patients. Our data revealed additive cytotoxic effects of the combination treatment. Mutational profiling of MDS samples identified ASXL1 mutations as predictors of response. Further, increased response rates were associated with higher gene-expression of the pro-apoptotic factor NOXA in ASXL1 mutated samples. The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.

Cost and quality of operational larviciding using drones and smartphone technology.

BACKGROUND: Larval Source Management (LSM) is an important tool for malaria vector control and is recommended by WHO as a supplementary vector control measure. LSM has contributed in many successful attempts to eliminate the disease across the Globe. However, this approach is typically labour-intensive, largely due to the difficulties in locating and mapping potential malarial mosquito breeding sites. Previous studies have demonstrated the potential for drone imaging technology to map malaria vector breeding sites. However, key questions remain unanswered related to the use and cost of this technology within operational vector control. METHODS: Using Zanzibar (United Republic of Tanzania) as a demonstration site, a protocol was collaboratively designed that employs drones and smartphones for supporting operational LSM, termed the Spatial Intelligence System (SIS). SIS was evaluated over a four-month LSM programme by comparing key mapping accuracy indicators and relative costs (both mapping costs and intervention costs) against conventional ground-based methods. Additionally, malaria case incidence was compared between the SIS and conventional study areas, including an estimation of the incremental cost-effectiveness of switching from conventional to SIS larviciding. RESULTS: The results demonstrate that the SIS approach is significantly more accurate than a conventional approach for mapping potential breeding sites: mean % correct per site: SIS = 60% (95% CI 32-88%, p = 0.02), conventional = 18% (95% CI - 3-39%). Whilst SIS cost more in the start-up phase, overall annualized costs were similar to the conventional approach, with a simulated cost per person protected per year of $3.69 ($0.32 to $15.12) for conventional and $3.94 ($0.342 to $16.27) for SIS larviciding. The main economic benefits were reduced labour costs associated with SIS in the pre-intervention baseline mapping of habitats. There was no difference in malaria case incidence between the three arms. Cost effectiveness analysis showed that SIS is likely to provide similar health benefits at similar costs compared to the conventional arm. CONCLUSIONS: The use of drones and smartphones provides an improved means of mapping breeding sites for use in operational LSM. Furthermore, deploying this technology does not appear to be more costly than a conventional ground-based approach and, as such, may represent an important tool for Malaria Control Programmes that plan to implement LSM.

Elevated total and direct bilirubin are associated with acute complicated appendicitis: a single-center based study in Saudi Arabia.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency and up to our knowledge no previous studies have been conducted in Saudi Arabia particularly at Qassim region and this study aimed to determine a total and direct bilirubin as a predictor of acute complicated appendicitis. METHODS: Observational retrospective study that included patients admitted under the general surgery department with a diagnosis of acute appendicitis at King Saud Hospital, Unaizah, Saudi Arabia. Data on age, gender, BMI, diabetes mellitus, total and direct bilirubin, AST, ALT, sodium, and WBCs levels were obtained. RESULT: Among the overall study population of 158 patients, the age median [IQR] was 24.5 [19-31], males were 99 (62.7%), and complicated appendicitis was 33 (20.9%). The multivariable analysis revealed that both elevated total and direct bilirubin are associated with complicated appendicitis (aOR = 3.79, 95% CI: 1.67-8.48, P = 0.001) and (aOR = 4.74, 95% CI: 2.07-10.86, P < 0.001) respectively. A receiver operating characteristic curve showed the best cutoff value of total and direct bilirubin as ≥ 15 µmol/L and ≥ 5 µmol/L respectively, with a sensitivity of 57.6%, and specificity of 73.6% for elevated total bilirubin, and a sensitivity of 54.6%, and specificity of 80% for elevated direct bilirubin. CONCLUSION: Elevated total and direct bilirubin are associated with acute complicated appendicitis in this setting. However, it should be supportive factor for acute complicated appendicitis and not considered as standalone diagnostic test.

A Novel Image Classification Method Based on Residual Network, Inception, and Proposed Activation Function.

In deeper layers, ResNet heavily depends on skip connections and Relu. Although skip connections have demonstrated their usefulness in networks, a major issue arises when the dimensions between layers are not consistent. In such cases, it is necessary to use techniques such as zero-padding or projection to match the dimensions between layers. These adjustments increase the complexity of the network architecture, resulting in an increase in parameter number and a rise in computational costs. Another problem is the vanishing gradient caused by utilizing Relu. In our model, after making appropriate adjustments to the inception blocks, we replace the deeper layers of ResNet with modified inception blocks and Relu with our non-monotonic activation function (NMAF). To reduce parameter number, we use symmetric factorization and 1×1 convolutions. Utilizing these two techniques contributed to reducing the parameter number by around 6 M parameters, which has helped reduce the run time by 30 s/epoch. Unlike Relu, NMAF addresses the deactivation problem of the non-positive number by activating the negative values and outputting small negative numbers instead of zero in Relu, which helped in enhancing the convergence speed and increasing the accuracy by 5%, 15%, and 5% for the non-noisy datasets, and 5%, 6%, 21% for non-noisy datasets.

Outdoor biting and pyrethroid resistance as potential drivers of persistent malaria transmission in Zanzibar.

BACKGROUND: Low-level of malaria transmission persist in Zanzibar despite high coverage of core vector control interventions. This study was carried out in hot-spot sites to better understand entomological factors that may contribute to residual malaria transmission in Zanzibar. METHODS: A total of 135 households were randomly selected from six sites and consented to participate with 20-25 households per site. Mosquito vector surveillance was carried out indoors and outdoors from 6:00 pm-7:00 am using miniaturized double net trap (DN-Mini™). Additional collections were done indoors using mouth aspirators to retrieve resting mosquitoes from wall and ceiling surfaces, and outdoors using resting bucket and pit traps. All collected mosquitoes were morphologically and genetically (PCR) analysed in the laboratory. All collected anopheline and blood-fed mosquitoes were analysed for sporozoite infection and blood meal host preferences by Circumsporozoite Protein ELISA and blood meal ELISA, respectively. The differences between indoor and outdoor mosquito biting rates were analysed using generalized linear mixed models. Levels of resistance to commonly used insecticides were quantified by WHO susceptibility tests. RESULTS: Out of 704 malaria vectors collected across 135 households, PCR analysis shows that 98.60% were Anopheles arabiensis, 0.6% Anopheles merus and 0.6% Anopheles gambiae sensu stricto. Sporozoite ELISA analysis indicates that all mosquitoes were negative for the malaria parasite. The results show that more An. arabiensis were collected outdoor (~ 85%) compared to indoor (~ 15%). Furthermore, large numbers of An. arabiensis were caught in outdoor resting sites, where the pit trap (67.2%) collected more mosquitoes compared to the outdoor DN-Mini trap (32.8%). Nearly two-thirds (60.7%) of blood-fed mosquitoes had obtained blood meals from non-human hosts. Mosquitoes displayed non-uniform susceptibility status and resistance intensity among the tested insecticides across the study sites to all WHO recommended insecticides across the study sites. CONCLUSION: This study suggests that in contexts such as Zanzibar, testing of novel techniques to complement indoor protection and targeting outdoor biting and/or resting mosquitoes, may be warranted to complement existing interventions and contribute to malaria elimination efforts. The study highlights the need to implement novel interventions and/or adaptations of strategies that can target outdoors biting mosquitoes.

Gene-edited stem cells enable CD33-directed immune therapy for myeloid malignancies.

Antigen-directed immunotherapies for acute myeloid leukemia (AML), such as chimeric antigen receptor T cells (CAR-Ts) or antibody-drug conjugates (ADCs), are associated with severe toxicities due to the lack of unique targetable antigens that can distinguish leukemic cells from normal myeloid cells or myeloid progenitors. Here, we present an approach to treat AML by targeting the lineage-specific myeloid antigen CD33. Our approach combines CD33-targeted CAR-T cells, or the ADC Gemtuzumab Ozogamicin with the transplantation of hematopoietic stem cells that have been engineered to ablate CD33 expression using genomic engineering methods. We show highly efficient genetic ablation of CD33 antigen using CRISPR/Cas9 technology in human stem/progenitor cells (HSPC) and provide evidence that the deletion of CD33 in HSPC doesn't impair their ability to engraft and to repopulate a functional multilineage hematopoietic system in vivo. Whole-genome sequencing and RNA sequencing analysis revealed no detectable off-target mutagenesis and no loss of functional p53 pathways. Using a human AML cell line (HL-60), we modeled a postremission marrow with minimal residual disease and showed that the transplantation of CD33-ablated HSPCs with CD33-targeted immunotherapy leads to leukemia clearance, without myelosuppression, as demonstrated by the engraftment and recovery of multilineage descendants of CD33-ablated HSPCs. Our study thus contributes to the advancement of targeted immunotherapy and could be replicated in other malignancies.

Deep Ensemble Fake News Detection Model Using Sequential Deep Learning Technique.

Recently, fake news has been widely spread through the Internet due to the increased use of social media for communication. Fake news has become a significant concern due to its harmful impact on individual attitudes and the community's behavior. Researchers and social media service providers have commonly utilized artificial intelligence techniques in the recent few years to rein in fake news propagation. However, fake news detection is challenging due to the use of political language and the high linguistic similarities between real and fake news. In addition, most news sentences are short, therefore finding valuable representative features that machine learning classifiers can use to distinguish between fake and authentic news is difficult because both false and legitimate news have comparable language traits. Existing fake news solutions suffer from low detection performance due to improper representation and model design. This study aims at improving the detection accuracy by proposing a deep ensemble fake news detection model using the sequential deep learning technique. The proposed model was constructed in three phases. In the first phase, features were extracted from news contents, preprocessed using natural language processing techniques, enriched using n-gram, and represented using the term frequency-inverse term frequency technique. In the second phase, an ensemble model based on deep learning was constructed as follows. Multiple binary classifiers were trained using sequential deep learning networks to extract the representative hidden features that could accurately classify news types. In the third phase, a multi-class classifier was constructed based on multilayer perceptron (MLP) and trained using the features extracted from the aggregated outputs of the deep learning-based binary classifiers for final classification. The two popular and well-known datasets (LIAR and ISOT) were used with different classifiers to benchmark the proposed model. Compared with the state-of-the-art models, which use deep contextualized representation with convolutional neural network (CNN), the proposed model shows significant improvements (2.41%) in the overall performance in terms of the F1score for the LIAR dataset, which is more challenging than other datasets. Meanwhile, the proposed model achieves 100% accuracy with ISOT. The study demonstrates that traditional features extracted from news content with proper model design outperform the existing models that were constructed based on text embedding techniques.

Ocimum basilicum L. Methanol Extract Enhances Mitochondrial Efficiency and Decreases Adipokine Levels in Maturing Adipocytes Which Regulate Macrophage Systemic Inflammation.

Excessive storage of lipids in visceral or ectopic sites stimulates adipokine production, which attracts macrophages. This process determines the pro- and anti-inflammatory response regulation in adipose tissue during obesity-associated systemic inflammation. The present study aimed to identify the composition of Ocimum basilicum L. (basil) seed extract and to determine its bio-efficacy on adipocyte thermogenesis or fatty acid oxidation and inhibition of lipid accumulation and adipokine secretion. Ocimum basilicum L. seed methanol extract (BSME) was utilized to analyze the cytotoxicity vs. control; lipid accumulation assay (oil red O and Nile red staining), adipogenesis and mitochondrial-thermogenesis-related gene expression vs. vehicle control were analyzed by PCR assay. In addition, vehicle control and BSME-treated adipocytes condition media were collected and treated with lipopolysaccharide (LPS)-induced macrophage to identify the macrophage polarization. The results shown that the active components present in BSME did not produce significant cytotoxicity in preadipocytes or macrophages in the MTT assay. Furthermore, oil red O and Nile red staining assay confirmed that 80 and 160 µg/dL concentrations of BSME effectively arrested lipid accumulation and inhibited adipocyte maturation, when compared with tea polyphenols. Gene expression level of adipocyte hyperplasia (CEBPα, PPARγ) and lipogenesis (LPL)-related genes have been significantly (p ≤ 0.05) downregulated, and mitochondrial-thermogenesis-associated genes (PPARγc1α, UCP-1, prdm16) have been significantly (p ≤ 0.001) upregulated. The BSME-treated, maturing, adipocyte-secreted proteins were detected with a decreased protein level of leptin, TNF-α, IL-6 and STAT-6, which are associated with insulin resistance and macrophage recruitment. The "LPS-stimulated macrophage" treated with "BSME-treated adipocytes condition media", shown with significant (p ≤ 0.001) decrease in metabolic-inflammation-related proteins-such as PGE-2, MCP-1, TNF-α and NF-κB-were majorly associated with the development of foam cell formation and progression of atherosclerotic lesion. The present findings concluded that the availability of active principles in basil seed effectively inhibit adipocyte hypertrophy, macrophage polarization, and the inflammation associated with insulin resistance and thrombosis development. Ocimum basilicum L. seed may be useful as a dietary supplement to enhance fatty acid oxidation, which aids in overcoming metabolic complications.

Course and Predictors of Visual Outcome of Idiopathic Intracranial Hypertension.

Idiopathic intracranial hypertension (IIH) is a clinical syndrome characterised by headache and papilloedema that can lead to significant visual morbidity. There are few studies in the literature about the visual outcome of IIH. We have reviewed the record of 76 patients with IIH according to the modified Dandy criteria. There was a significant improvement in the Humphrey 24-2 mean deviation (MD) in the study eyes (worse affected eye at presentation) in both the medically treated group (+2.0 dB; from -5.60 dB at baseline to -3.60 dB at final follow-up, p < .01) and in the fellow eyes in the medically treated group (+1.70 dB, from -4.40 dB at baseline to -2.74 dB at final follow-up, p < .01). Higher papilloedema grade (beta -0.66, p < .001) and age (p < .02) were inversely correlated with the final visual field MD in the study eye. The visual outcome for the IIH patients in our study was predominantly favourable, but patients with high-grade papilloedema had a worse visual prognosis and required more aggressive treatment.

Ocular Myasthenia: Clinical Course and the Diagnostic Utility of Assaying Acetylcholine Receptor Antibodies.

Myasthenia gravis (MG) is an autoimmune disease that causes neuromuscular junction transmission defect and has a predilection for the with neuromuscular junction transmission defect and predilection for extra-ocular and eyelid muscles. Most cases of ocular MG (OMG) convert later to generalised MG (GMG). Assaying acetylcholine receptor antibodies (AchRA) has been used to diagnose MG, but the reported sensitivity in OMG is lower (50%) than in GMG. We report the clinical course and the diagnostic yield of assaying AchRA in a Kuwaiti cohort of patients with OMG. We carried out a retrospective review of 47 patients diagnosed with OMG who were tested for AchRA. Ancillary tests included the ice test, single-fibre electromyography (SFMEG), and repetitive nerve stimulation electromyography (RNS). Progression to GMG occurred in 51% of OMG patients with a mean time to progression of 12.1 months (range 4 to 20 months). AchRAs were positive in 46 of 47 cases (98%), while SFEMG was positive in 31 of 34 cases (91.1%). Older age (44.25 years versus 38 years, p < .05) and higher AchRA titre (2.0 nmol/L versus 1.27 nmol/L, p < .05) were significantly associated with conversion to GMG. We have found a high rate of AchRA seropositivity in relatively younger subjects of OMG. Higher AchRA titres and older age were associated with conversion to GMG, usually within the first 2 years.

Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study.

Glioblastoma is a fast-growing primary brain tumor observed in adults with the worst prognosis. Preclinical studies have demonstrated the encouraging anticancer activity of statins. This study evaluated the efficacy of atorvastatin in combination with standard therapy in patients with glioblastoma. In this prospective, open-label, single-arm, phase II study, patients were treated with atorvastatin in combination with the standard glioblastoma therapy comprising radiotherapy and temozolomide. The primary endpoint was progression-free survival (PFS) at 6 months (PFS-6). Among 36 patients enrolled from January 2014 to January 2017, the median age was 52 (20-69) years; 22% of the patients were aged ≥60 years, and 62% were male. Patients received atorvastatin for a median duration of 6.2 (0.3-28) months. At a median follow-up of 19 months, the PFS-6 rate was 66%, with a median PFS of 7.6 (5.7-9.4) months. In terms of Grade ≥ 3 hematological adverse events, thrombocytopenia and neutropenia occurred in 7% and 12% of patients, respectively. In multivariate analyses, high baseline low-density lipoprotein levels were associated with worse survival (P = 0.046). Atorvastatin was not shown to improve PFS-6. However, this study identified that high low-density lipoprotein levels are an independent predictor of poor cancer-related outcomes. Future clinical trials testing statins should aim to enroll patients with slow-growing tumors.Clinical trial information: NCT0202957 (December 12, 2013).