Whole exome sequencing identifies a novel mutation in ASPM and ultra-rare mutation in CDK5RAP2 causing primary microcephaly in consanguineous Pakistani families

Background & objectives: Primary Microcephaly (MCPH) is a rare neurogenetic disease, manifesting congenitally reduced head circumference and non-progressive intellectual disability (ID). To date, twenty-eight genes with biallelic mutations have been reported for this disorder. The study aimed for molecular genetic characterization of Pakistani families segregating MCPH. Methods: We studied two unrelated consanguineous families (family A and B) presenting \u3e2 patients with diagnostic symptoms of MCPH, born to asymptomatic parents. We employed whole-exome sequencing (WES) of probands to find putative causal mutations. The candidate variants were further confirmed and analyzed for co-segregation by Sanger sequencing of all available members of each family. This study was conducted at Government College University, Faisalabad, Pakistan, and Cologne Center for Genomics (CCG), University of Cologne, Germany; during 2017-2020. Results: We identified a novel homozygous variant c.10097_10098delGA, p.(Gly3366Glufs*19) in exon 26 of ASPM gene in family A which presents with moderate intellectual disability, speech impairment, visual abnormalities, seizures, and ptyalism. Family B was found to segregate nonsense, homozygous variant c.448C\u3eT p.(Arg150*) in CDK5RAP2. The patients also exhibited mild to severe seizures without ptyalism that has not been previously reported in patients with mutations in the CDK5RAP2 gene. Conclusion: We report a novel mutation in ASPM and ultra-rare mutation in the CDK5RAP2 gene, both causing primary microcephaly. The study expands the mutational spectrum of the ASPM gene to 212, and also adds to the clinical spectrum of CDK5RAP2 mutations. It also demonstrated the utility of WES in the investigation and genetic diagnosis of genetically heterogeneous disorders like MCPH. These findings would aid in diagnostic and preventive strategies including carrier screening, cascade testing, and genetic counselling

Epidemiological Data of Neurological Disorders in Pakistan and Neighboring Countries: A Review

Neurological disorders are the impairments of nervous system and are an important and growing cause of morbidity, mortality, and disability. In addition to health costs, those suffering from these conditions are also frequently victimized of stigmatization and discrimination. Stigmatization further minimizes the patients\u27 access to treatment and social activities. These disorders, therefore, require special attention particularly in developing countries where unfortunately, the burden of these disorders remains largely unrecognized. Moreover, the burden imposed by such chronic neurological conditions in general can be expected to be particularly devastating in poor populations. These conditions are emerging as severe public health concerns in the developing countries due to the facts such as unawareness, Illiteracy, large numbers of people who are untreated, and unavailability of inexpensive but effective interventions. Regrettably, reliable population-based data from developing countries including Pakistan on the epidemiology of neurological disorders are extremely limited. Although, some information on epidemiological aspects of neurological diseases are available from some developing countries (Pakistan, Iran, India, Sri Lanka, Saudi Arabia and China) but disease prevalence and pattern are based on geographical, social, cultural, religious, and ethnic factors. In this review, w e critically analyzed data of 209 studies regarding the burden and prevalence of hypertension, depression, Stroke, Alzheimer\u27s disease (AD), epilepsy, and Parkinson\u27s disease (PD) in Pakistan and neighboring countries

Comparison of Essential Oil Yield, Chemical Composition and Biological Activities of Eucalyptus camaldulensis Leaf: Conventional Distillation versus Emerging Superheated Steam Distillation

Eucalyptus essential oil (EO) has significance economically since it is used in the medicinal and fragrance industries. The main objective of this study was to investigate the differences in yield, composition, antioxidant capacity, and antibacterial effectiveness of the EO extracted from Eucalyptus camaldulensis leaves. To achieve this, three distinct extraction techniques, namely steam distillation (SD), hydro distillation (HD), and superheated steam distillation (SHSD), were utilized to isolate the EO. The study aimed to analyze and compare these parameters among the three extraction methods. Based on the findings from the experiments, it has been found that using SHSD resulted in a higher EO yield than conventional techniques, and this SHSD produced a greater amount of EO in a shorter time. The EOs extracted using all three techniques have 1,8 cineole as the main constituent, according to gas chromatography-mass spectrometry (GC-MS) analysis results. All of the EOs demonstrated significant antioxidant capacities when tested in vitro using a variety of antioxidant assays. The EOs extracted through HD showed greater antibacterial activity among the other extraction processes, as evaluated by agar well diffusion and resazurin microtitre-plate assays. In conclusion, SHSD is more efficient for extracting EOs and antioxidant activity than traditional HD and SD

Neurological disorder burden in Faisalabad, Punjab-Pakistan:data from the major tertiary carecenters of the city

The burden of neurological disorders (NDs) in developing countries is 4-5%, compared to 10-11% in developed countries. This burden is rising in developing countries due to prolonged life expectancy, improved health facilities, easy access to diagnostic facilities, and a trend in urbanization. There is inadequate data about the epidemiology of major NDs in Pakistan and most available information are hospital-based estimations or physicians’ collected data

On Riemannian warped-twisted product submersions

In this paper, we introduce the concepts of Riemannian warped-twisted product submersions and examine their fundamental properties, including total geodesicity, total umbilicity and minimality. Additionally, we investigate the Ricci tensor of Riemannian warped-twisted product submersions, specifically about the horizontal and vertical distributions. Finally, we obtain Einstein condition for base manifold if the horizontal and vertical distributions of the ambient manifold is Einstein

Hepatoprotective effect of desi and kabuli cultivars of Cicer arietinum L (chick peas) against carbon tetrachloride-induced toxicity in rats

Purpose: To determine the hepatoprotective potential of ethanol extracts of desi and kabuli cultivars of Cicer arietinum L. (chick peas). Methods: Hepatotoxicity was induced in rats using oral administration of carbon tetrachloride (CCl4). The rats were then orally administered different doses of the ethanol extracts of desi and kabuli cultivars of Cicer arietinum L. for 21 days. Oxidative stress parameters and hepatoprotective profiles were determined in serum samples using standard procedures. The effect of the treatments on liver histology was also determined. Results: Administration of extracts of desi and kabuli cultivars of Cicer arietinum L. to CCl4 treated rats at a dose of 300 mg/kg resulted in a significant (p ≤ 0.05) decrease in oxidative stress parameters, whereas catalase activity significantly increased (p ≤ 0.05); on the other hand, ALT and AST levels were decreased significantly (p ≤ 0.05), when compared to the control group. Conclusion: High doses of Cicer arietinum L (desi and kabuli cultivars) seem to have hepatoprotective and antioxidant effects on CCl4-induced toxicity in rats. This finding underscores the therapeutic importance of Cicer arietinum L. as a plant with hepatoprotective properties. Keywords: Cicer arietinum, Phenolics, Hepatotoxicity, Chick peas, Catalas

EFFECT OF SURFACE PROFILE OF MILD STEEL SUBSTRATE UPON ADHESION STRENGTH OF WC-11%CO FLAME SPRAY COATING

Improving surface properties especially high wear and impact resistance is always an existing challenge for automotive, aerospace, defense and agriculture industries etc. Surface engineering has developed various processes and methods to encounter this problem using plasma spray, electric arc, HVOF, PVD and flame spray etc. Amongst them flame spray technique has its own features to produce cermet coatings on steel substrates. In the present study, behavior of WC-11%Co coatings deposited on Mild Steel by means of flame spray process has been studied. It was found that surface roughness of substrate plays a vital role in the adhesion of such type of coatings. Therefore, different surface roughness profiles on substrate were generated by blasting sand and steel grits of various sizes. Surface profilometer was used to evaluate the surface roughness of substrates while the adhesion strength of flame spray coatings was determined by Pull test. SEM/EDX was used to study the morphology of flame spray coated samples and hardness was measured by micro-Vickers hardness tester. The results illustrate the optimum values of surface roughness to achieve better properties of WC-11%Co coatings for various engineering applications

Ferula asafoetida Linn. is effective for early functional recovery following mechanically induced insult to the sciatic nerve of a mouse model

Purpose: To evaluate the effect of Ferula asafoetida (oleo gum resin powder) on sensory and motor functions retrieval on an induced sciatic nerve injury in a mouse model.Methods: A mechanical crush was inserted in the sciatic nerve of all the experimental mice after acclimatization. The mice were allocated to four groups; one normal chow group (control, n = 7) and three Ferula asafoetida chow groups (each n = 7) of different doses (50, 100 and 200 mg/kg). Muscle grip strength, muscle mass, and sciatic functional index were measured to evaluate the motor function regain, while sensory function regain was assessed by hot plate test. Oxidative stress and glycemic levels were measured by biochemical assays.Results: The findings of this study indicate that Ferula asafoetida 200 mg/kg has a highly significant (p≤ 0.001) ameliorating effect in terms of improved grip strength (77.7 ± 5.4 % for 200 mg/kg vs. 46 ± 5.1 % for control), reversal of SFI towards normal ( -34 ± 8.1 for 200 mg/kg group vs. –61 ± 6.1 for control), decrease in paw withdrawal latency (7.10 ± 0.06 s for 200 mg/kg group vs. 15 ± 0.5 s for control) on day 12 post-injury, as well as restoration of skeletal muscle mass towards normal. Interestingly, F. asafoetida chow 50 mg/kg and 100 mg/kg groups also impacted significant (p < 0.01) improvement in the ameliorative effect. However, the differences among all treatment groups in ameliorating recovery were not significant (p > 0.05). Moreover, comparatively improved (p < 0.0001) total antioxidant capacity along with reduced total oxidant status (p = 0.01) in the Ferula asafoetida chow (200 mg/kg) group, indicate the antioxidative effect of this plant. Furthermore, the treated mice (200 mg/kg) also expressedan improved glycemic level (p = 0.0005).Conclusion: Ferula asafoetida supplementation helps to accelerate both sensory and motor function retrieval following sciatic nerve injury. This  improvement is thought to be correlated with the antioxidant capacity of the plant. However, further investigations are required to identify the therapeutic principles responsible for the observed actions. Keywords: Sciatic nerve injury, Ferula asafoetida, Function recovery, Oxidative stress, Biochemical analysi

Beneficial effects of Trillium govanianum rhizomes in pain and inflammation

Trillium govanianum rhizome is used as an analgesic and anti-inflammatory remedy in traditional medicine in northern Pakistan. In an attempt to establish its medicinal value, the present research evaluated the analgesic and anti-inflammatory potential of T. govanianum. The in vivo anti-inflammatory activity of extract and fractions was investigated in the carrageenan induced paw edema assay. The in vitro suppression of oxidative burst of extract, fractions and isolated compounds was assessed through luminol-enhanced chemiluminescence assay. The in vivo analgesic activity was assayed in chemical and thermal induced nociceptive pain models. The crude methanol extract and its solvent fractions showed anti-inflammatory and analgesic responses, exhibited by significant amelioration of paw edema and relieve of the tonic visceral chemical and acute phasic thermal nociception. In the oxidative burst assay, based on IC50 , the crude methanol extract and n-butanol soluble fraction produced a significant inhibition, followed by chloroform and hexane soluble fractions as compared to ibuprofen. Similarly, the isolated compounds pennogenin and borassoside E exhibited significant level of oxidative burst suppressive activity. The in vivo anti-inflammatory and analgesic activities as well as the in vitro inhibition of oxidative burst validated the traditional use of T. govanianum rhizomes as a phytotherapeutic remedy for both inflammatory conditions and pain. The observed activities might be attributed to the presence of steroids and steroid-based compounds. Therefore, the rhizomes of this plant species could serve as potential novel source of compounds effective for alleviating pain and inflammation

Adaptive Filtering on GPS-Aided MEMS-IMU for Optimal Estimation of Ground Vehicle Trajectory

Fusion of the Global Positioning System (GPS) and Inertial Navigation System (INS) for navigation of ground vehicles is an extensively researched topic for military and civilian applications. Micro-electro-mechanical-systems-based inertial measurement units (MEMS-IMU) are being widely used in numerous commercial applications due to their low cost; however, they are characterized by relatively poor accuracy when compared with more expensive counterparts. With a sudden boom in research and development of autonomous navigation technology for consumer vehicles, the need to enhance estimation accuracy and reliability has become critical, while aiming to deliver a cost-effective solution. Optimal fusion of commercially available, low-cost MEMS-IMU and the GPS may provide one such solution. Different variants of the Kalman filter have been proposed and implemented for integration of the GPS and the INS. This paper proposes a framework for the fusion of adaptive Kalman filters, based on Sage-Husa and strong tracking filtering algorithms, implemented on MEMS-IMU and the GPS for the case of a ground vehicle. The error models of the inertial sensors have also been implemented to achieve reliable and accurate estimations. Simulations have been carried out on actual navigation data from a test vehicle. Measurements were obtained using commercially available GPS receiver and MEMS-IMU. The solution was shown to enhance navigation accuracy when compared to conventional Kalman filter