Investigation of the cardiac depressant effect of Caralluma tuberculate N.E.Br on isolated rabbit heart

Purpose: To investigate the histopathological and cardiac depressant effect of the aqueous methanol extract of Caralluma tuberculata N.E. Br (AMECT) (family: Asclepiadaceae)’ and to determine if there is a scientific basis for its cardiovascular diseases-related folkloric use. Methods: The effect of AMECT in different concentrations ranging from 0.00001 to 1.0 mg/mL were evaluated in isolated perfused rabbit heart to assess their effect on the force of contraction and heart rate using Langendorff’s apparatus. Atropine and adrenaline were used to identify the underlying mechanism of response produced by AMECT. The extract was studied for its possible mechanism in the absence and presence of atropine and adrenaline. In addition, sub-chronic toxicity and histopathological study of heart tissues in rats were assessed by administering 500 mg/kg of extract. Results: At all concentrations, AMECT produced significant (p < 0.001) negative ionotropic and negative chronotropic effects. The most significant effect was observed at 0.001 mg/mL and higher concentrations hence 0.001 mg/mL was selected for further studies. Pre-incubation with atropine did not significantly inhibit the effects of AMECT. However, AMECT significantly (p < 0.01) blocked the cardiac stimulant effect of adrenaline. In the histopathological studies, AMECT did not produce any significant cellular changes or signs of toxicity in the sub-chronic toxicity study. Conclusion: The cardiac-depressant responses of AMECT may involve the β-adrenergic receptors in the myocardium of isolated rabbit heart thus confirming the rationale for its use in ethnomedicine for cardiac diseases

Contributions to Nonparametric Predictive Inference with Right-Censored Data

A right-censored data set is most common in reliability and survival analyses. It occurs when a particular event of interest is not fully observed in an experiment and when there is no information provided about a random quantity except that it exceeds a certain value. Nonparametric Predictive Inference (NPI) is a frequentist statistical method based on only few assumptions. It focuses explicitly on future observations and uses imprecise probabilities, based on Hill's assumption A(n), to quantify uncertainty. NPI has been developed for several types of data, including right-censored data. However, NPI with right-censored data has only taken into consideration a single future observation. This thesis presents three contributions to NPI with right-censored data. First, some statistical methods on extreme values assume that the endpoint of the support is equal to the largest observed value in a data set. However, a question that may be of interest is whether, for some right-censored observations in a data set, their actual value might exceed the largest observed value. Secondly, the actuarial estimator provides information on the number of events and censorings at any given discrete point in time. The nature of this estimator is such that, at every time point (except if all people in the data set have died) there is right-censoring, the data themselves are not necessarily right-censored. A similar approach is followed here, but we aim to develop an alternative method to the actuarial estimator, based on NPI with right-censored data. The proposed method will be used to derive NPI lower and upper probabilities for a variety of events of interest. As an example application, we apply the newly developed method to obtain NPI lower and upper survival probabilities for reliability of systems. Thirdly, NPI has been developed for real-valued data that contain right-censored observations but only a single future observation was considered. There may be reasons to be interested in multiple future observations, and it is important that in the NPI approach such multiple future observations are not conditionally independent given the data. We extend NPI for right-censored data by considering two future observations. Particularly, we present NPI lower and upper probabilities for the event that both future observations are greater than time t. We apply the proposed method to system reliability. The results in this thesis widen the applicability of NPI for several real-world scenarios, while also suggesting new related topics for research

Modified Optimal Class of Newton-Like Fourth-Order Methods for Multiple Roots

Here, we propose optimal fourth-order iterative methods for approximating multiple zeros of univariate functions. The proposed family is composed of two stages and requires 3 functional values at each iteration. We also suggest an extensive convergence analysis that demonstrated the establishment of fourth-order convergence of the developed methods. It is interesting to note that some existing schemes are found to be the special cases of our proposed scheme. Numerical experiments have been performed on a good number of problems arising from different disciplines such as the fractional conversion problem of a chemical reactor, continuous stirred tank reactor problem, and Planck’s radiation law problem. Computational results demonstrates that suggested methods are better and efficient than their existing counterparts

Case report: Wolman disease in four-month infant, with pathogenic variant G87V in the Jazan region, Saudi Arabia

Background: Wolman disease (WD) severe lysosomal acid lipase is a rare, autosomal recessive lysosomal storage disease caused by the absence or deficiency of lysosomal acid lipase enzyme. This deficiency leads to the accumulation of cholesterol esters and triglycerides in multiple organs of the body. Jazan Region is the second smallest region of Saudi Arabia. It stretches 300 km (190 mi) along the southern Red Sea coast, just north of Yemen. It covers an area of 11,671 km² and has a population of 1,567,547 at the 2017 census. The region has the highest population density in the Kingdom and a high consanguinity marriage rate. Case Presentation: We report a rare case of WD, misdiagnosed by a surgeon to be pyloric stenosis, treated for a while as renal tubular acidosis, found to have typical WD presentation of malabsorption, hepatosplenomegaly, and adrenal calcification. Conclusion: This case report is the first report that described the existence of WD in the Jazan region up to date. [JBCGenetics 2019; 2(2.000): 139-142

A Reliable Auto-Robust Analysis of Blood Smear Images for Classification of Microcytic Hypochromic Anemia Using Gray Level Matrices and Gabor Feature Bank

Accurate blood smear quantification with various blood cell samples is of great clinical importance. The conventional manual process of blood smear quantification is quite time consuming and is prone to errors. Therefore, this paper presents automatic detection of the most frequently occurring condition in human blood—microcytic hyperchromic anemia—which is the cause of various life-threatening diseases. This task has been done with segmentation of blood contents, i.e., Red Blood Cells (RBCs), White Blood Cells (WBCs), and platelets, in the first step. Then, the most influential features like geometric shape descriptors, Gray Level Co-occurrence Matrix (GLCM), Gray Level Run Length Matrix (GLRLM), and Gabor features (mean squared energy and mean amplitude) are extracted from each of the RBCs. To discriminate the cells as hypochromic microcytes among other RBC classes, scanning is done at angles (0∘, 45∘, 90∘, and 135∘). To achieve high-level accuracy, Adaptive Synthetic (AdaSyn) sampling for imbalance learning is used to balance the datasets and locality sensitive discriminant analysis (LSDA) technique is used for feature reduction. Finally, upon using these features, classification of blood cells is done using the multilayer perceptual model and random forest learning algorithms. Performance in terms of accuracy was 96%, which is better than the performance of existing techniques. The final outcome of this work may be useful in the efforts to produce a cost-effective screening scheme that could make inexpensive screening for blood smear analysis available globally, thus providing early detection of these diseases

Severity and prevalence of allergic rhinitis among school children, Jazan Region Saudi Arabia

Background: Allergic diseases such as allergic rhinitis (AR) represent a global health problem, affecting 10–25% of the world population. There is clear evidence to support the concept that allergic diseases are influenced by genetic predisposition and environmental exposure. Objectives: To assess the severity and prevalence of AR among school children in Jazan Region, Saudi Arabia. Methods: This is a cross-sectional study using a modified International Study of Asthma and Allergies in Children (ISAAC) questionnaire. Results: The nasal blocking is considered to be one of the most common symptoms of AR. Regarding the frequency of AR-related symptoms which indicate severity in the last 12 months according to the gender, our statistical analysis results found that the severity regarding nasal symptoms varied from nasal block to disturbed sleep due to nasal block where 97 (6.9%) had nasal block, 109 (7.8%) had nasal block interfering with daily activities, 12.1% had nasal block resulting in breathing difficulties, and 67 (4.7%) had disturbed sleep due to nasal block/problem. About 258 (18.4%) of all population urgently visited the emergency department due to nasal problems. Sixty-four (4.5%) were admitted due to nasal problems and 92 (6.6%) missed school days due to nasal block. The prevalence in elementary and intermediate school was 209 (14.9) and 170 (12.2), respectively with P value of 0.013, according to gender of study population showed no statistical significance according to all parameters. The prevalence was higher among Saudi population, regarding education level the prevalence was higher among intermediate school children. Conclusion: In conclusion, it was clear that the prevalence of AR among Saudi school children is 27.1%. Living in urban areas, intermediate school education level, lowlander population are significant risk factors for the prevalence and severity of AR

Epidemiology of bronchial asthma among children in Jazan Region, Saudi Arabia

Context: Asthma is a global problem, its prevalence varies among different countries and cities and age groups. In children, asthma is one of the most common chronic diseases and one of the leading causes of morbidity and mortality. Aims: This study was conducted to estimate the prevalence of asthma among children in Jazan Region (JR), Saudi Arabia. Settings And Design: This is study conducted in Jazan region, saudi arabia among school age children. It is a cross-sectional study used a modified international study os asthma and allergy in children questionnaire. Subjects And Methods: The target study population were school age, witth sample size of 1200 distributed to all geographical areas. Statistical Analysis Used: The data had been entered and analyzed using Statistical Package for Social Sciences software version 22.0. Descriptive statistics (e.g., number, percentage) and analytic statistics using Chi-square tests (χ2) to test for the association and/or the difference between two categorical variables will be applied. A P < 0.05 was considered statistically significant. Results: The total study population was 1400, most of them were Saudi (1273, 90.9%). Male students were 840 (60.0%), and female students were 560 (40.0%). According to the residency, 811 (57.9%) students were lived in rural, 64.7% of them were male, and 589 (42.1%) of participants lived in urban area. Most of the students lived in plain area (840, 60.0%), and only 16.4% of them lived in mountain area in which 63.5% of them were male. Elementary school students account 54.1% of total students; about 63% of them were male. The prevalence of life-long wheezes was 17.7%. The prevalence of exercise-induced wheeze and wheeze during the last 12 months was 206 (14.7%) and 159 (11.4%), respectively. Students with the past medical history of bronchial asthma were 212 (15.1%), with no clear statistical significant difference in frequency between male and female (P = 0.161). Asthma was confirmed by doctor in 10% of participants. Conclusions: The prevalence of asthma among children in JR is slightly higher than those reported from local and regional reports

Novel Glu-based pyrazolo[3,4-d]pyrimidine analogues: design, synthesis and biological evaluation as DHFR and TS dual inhibitors

AbstractA novel series of multifunctional pyrazolo[3,4-d]pyrimidine-based glutamate analogs (6a–l and 7a,b) have been designed and synthesized as antifolate anticancer agents. Among the tested compounds, 6i exhibited the most potent anti-proliferative activity towards NSCLC, CNS, Ovarian, Prostate, Colon, Melanoma, Breast, and Renal cancers with good to weak cytostatic activity and non-lethal actions. 6i demonstrated higher selectivity for cancer than normal cells. 6i could significantly increase the accumulation of S-phase cells during the cell cycle distribution of cancer cells with high potency in the induction of apoptosis. The results unveiled that 6i probably acts through dual inhibition of DHFR and TS enzymes (IC50 = 2.41 and 8.88 µM, correspondingly). Docking studies of 6i displayed that N1-p-bromophenyl and C3-Methyl groups participate in substantial hydrophobic interactions. The drug-likeness features inferred that 6i met the acceptance criteria of Pfizer. Taking together, 6i could be a promising prototype for further optimization as an effective anticancer drug

Design, Synthesis, and Biological Evaluation of a Novel VEGFR-2 Inhibitor Based on a 1,2,5-Oxadiazole-2-Oxide Scaffold with MAPK Signaling Pathway Inhibition

Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 cell one-dose screening revealed that compounds 12a&ndash;c and 14a had the best MGI%, among the tested compounds. The target fluorinated compound 12b, as the most active one, showed better anticancer activity compared to the reference drug sorafenib, with IC50 values of 11.5, 11.6, and 13 &micro;M against the HepG-2, A2780CP, and MDA-MB-231 cell lines, respectively. Furthermore, compound 12b (IC50 = 0.092 &micro;M) had VEGFR-2-inhibitory activity comparable to that of the standard inhibitor sorafenib (IC50 = 0.049 &micro;M). Furthermore, the ability of compound 12b in modulating MAPK signaling pathways was investigated. It was found to decrease the level of total ERK and its phosphorylated form, as well as leading to the down-regulation of metalloproteinase MMP-9 and the over-expression of p21 and p27, thus leading to subG1 cell-cycle arrest and, thus, the induction of apoptosis. Additionally, compound 12b decreased the rate of wound healing in the absence of serum, in comparison to DMSO-treated cells, providing a significant impact on metastasis inhibition. The quantitative RT-PCR results for E-cadherin and N-cadherin showed lower expression of the neuronal N-cadherin and increased expression of epithelial E-cadherin, indicating the ability of 12b to suppress metastasis. Furthermore, 12b-treated HepG2 cells expressed a low level of anti-apoptotic BCL-2 and over-expressed proapoptotic Bax genes, respectively. Using the DAF-FM DA fluorescence probe, compound 12b produced NO intracellularly as efficiently as the reference drug JS-K. In silico molecular docking studies showed a structural similarity through an overlay of 12b with sorafenib. Interestingly, the drug-likeness properties of compound 12b met the expectations of Pfizer&rsquo;s rule for the design of new drug candidates. Therefore, this study presents a novel anticancer lead compound that is worthy of further investigation and activity improvement

Exploration of Succinimide Derivative as a Multi-Target, Anti-Diabetic Agent: In Vitro and In Vivo Approaches

Diabetes mellitus (DM) is counted among one of the leading challenges in the recent era, and it is a life-threatening disorder. Compound 4-hydroxy 3-methoxy phenylacetone (compound 1) was previously isolated from Polygonum aviculare. This compound was reacted with N-benzylmaleimide to synthesize the targeted compound 3. The purpose of this research is to exhibit our developed compound 3’s ability to concurrently inhibit many targets that are responsible for hyperglycemia. Compound 3 was capable of inhibiting α-amylase, α-glucosidase, and protein tyrosine phosphatase 1 B. Even so, outstanding in vitro inhibition was shown by the compound against dipeptidyl peptidase-4 (DPP-4) with an IC50 value of 0.07 µM. Additionally, by using DPPH in the antioxidant activity, it exhibited good antioxidant potential. Similarly, in the in vivo activity, the experimental mice proved to be safe by treatment with compound 3. After 21 days of examination, the compound 3 activity pattern was found to be effective in experimental mice. Compound 3 decreased the excess peak of total triglycerides, total cholesterol, AST, ALT, ALP, LDL, BUN, and creatinine in the STZ-induced diabetic mice. Likewise, the histopathology of the kidneys, liver, and pancreas of the treated animals was also evaluated. Overall, the succinimde moiety, such as compound 3, can affect several targets simultaneously, and, finally, we were successful in synthesizing a multi-targeted preclinical therapy