Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes.

For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.

Uncovering the growing burden of enteric fever: A molecular analysis of Salmonella Typhi antimicrobial resistance.

Enteric fever, a persistent public health challenge in developing regions, is exacerbated by suboptimal socioeconomic conditions, contaminated water and food sources, and insufficient sanitation. This study delves into the antimicrobial susceptibility of Salmonella Typhi, uncovering the genetic underpinnings of its resistance. Analyzing 897 suspected cases, we identified a significant prevalence of typhoid fever, predominantly in males (58.3 %) and younger demographics. Alarmingly, our data reveals an escalation in resistance to both primary and secondary antibiotics, with cases of multi-drug resistant (MDR) and extensively drug-resistant (XDR) S. Typhi reaching 14.7 % and 43.4 %, respectively, in 2021. The Multiple Antibiotic Resistance (MAR) index exceeded 0.2 in over half of the isolates, signaling widespread antibiotic misuse. The study discerned 47 unique antibiotic resistance patterns and pinpointed carbapenem and macrolide antibiotics as the remaining effective treatments against XDR strains, underlining the critical need to preserve these drugs for severe cases. Molecular examinations identified blaTEM, blaSHV, and blaCTX-M genes in ceftriaxone-resistant strains, while qnrS was specific to ciprofloxacin-resistant variants. Notably, all examined strains exhibited a singular mutation in the gyrA gene, maintaining wild-type gyrB and parC genes. The erm(B) gene emerged as the primary determinant of azithromycin resistance. Furthermore, a distressing increase in resistance genes was observed over three years, with erm(B), blaTEM and qnrS showing significant upward trends. These findings are a clarion call for robust antimicrobial stewardship programs to curtail inappropriate antibiotic use and forestall the burgeoning threat of antibiotic resistance in S. Typhi.

Dyslipidemia and impaired liver function biomarkers in patients with hepatitis B liver cirrhosis.

Objective: This study was conducted to determine changes in lipid metabolism and liver enzyme status among HBV-positive patients with liver cirrhosis. Methods: A total of 300 HBV-positive patients with liver cirrhosis and 200 healthy controls were included in this case-control study. The patients were recruited from several tertiary care hospitals in Lahore from March to October 2021. Their blood samples were collected and analyzed for HBsAg, HBeAg, liver function biomarkers, and serum lipids. Liver cirrhosis was confirmed by ultrasonography and liver biopsy. The data were analyzed with chi-square test, Student's t-test, logistic regression, and ROC curve analysis. Results: Serum liver function biomarkers were significantly higher, and serum lipid levels were substantially lower, in HBV-infected patients with liver cirrhosis than in controls. No significant associations of sex and age with dyslipidemia were observed in patients with cirrhosis. Grading and staging scores for liver cirrhosis were negatively associated with total cholesterol levels. Moreover, sex and high levels of liver enzymes were significant risk factors associated with dyslipidemia in HBV-positive patients with liver cirrhosis. The optimum cut-off values of liver enzymes and serum lipids for the prognosis of liver cirrhosis exceeded normal ranges. Conclusion: Serum lipid concentrations may serve as a clinical index to assess liver damage in HBV-positive patients.

BBIBP-CorV (Sinopharm) vaccination- induced immunity is affected by age, gender and prior COVID-19 and activates responses to spike and other antigens

Long-term solutions against SARS-CoV-2 infections require understanding of immune protection induced by different vaccine COVID-19 formulations. We investigated humoral and cellular immunity induced by Sinopharm (BBIBP-CorV) in a region of high SARS-CoV-2 seroprevalence. Levels of IgG antibodies to SARS-CoV-2 spike protein and its receptor-binding domain (RBD) were determined 24-weeks. Cellular immunity was investigated using a commercially available IFN-{gamma} release assay to SARS-CoV-2 spike (Ag1 and 2) and extended genome antigens (Ag3). Increasing IgG seropositivity to Spike protein and RBD was observed post-vaccination. Seropositivity was reduced in those over 50 years and raised in females and those with prior COVID-19. After 20 weeks post-vaccination, only one third of participants had positive T cell responses to SARS-CoV-2 antigens. Prior COVID-19 impacted IFN{gamma} responses, with reactivity enhanced in those infected earlier. The frequency of IFN{gamma} responses was highest to extended genome antigen set. Overall, BBIBP-CorV- induced antibody responses were impacted by age, gender and prior COVID-19. Cellular immunity was present in a limited number of individuals after 20 weeks but was enhanced by prior infection. This suggests the need for booster vaccinations in older individuals. BBIBP-CorV-induced cellular activation is broader than to spike, requiring further study to understand how to monitor vaccine effectiveness.

Rohingya Boat Refugees at Bay of Bengal and Obligations of the South East Asian States Under Soft Law.

The 1951 Refugee Convention and the 1967 Protocol are the only binding international instruments under which the parties of the instruments agree to protect refugees. However, there are gaps in the existing protection mechanisms for refugees at sea. Moreover, the South East Asian States are non-parties to the 1951 Refugee Convention; the States argue that they have no treaty obligation to accept Rohingya boat refugees. In this context, this article revisits the traditional view of 'soft laws', suggesting a fresh look at 'soft laws' regarding boat refugees. This article argues that even though the States are non-parties to international refugee law, the South East Asian States are members of the UN General Assembly, IMO, and ExCom. These international bodies have adopted numerous resolutions, guidelines and conclusions on refugee protection at sea; therefore, the States have international obligations to boat refugees according to Article 38(1)(C) of the Statute of the International Court of Justice 1945, the general principle of international law.

1,4-Disubstituted 1H-1,2,3-Triazoles for Renal Diseases: Studies of Viability, Anti-Inflammatory, and Antioxidant Activities.

Inflammation is a hallmark of many metabolic diseases. We previously showed that ferrocene-appended 1H-1,2,3-triazole hybrids inhibit nitric oxide (NO) production in in vitro models of lipopolysaccharide-induced inflammation in the BV-2 cell. In the present study, we explored the viability, anti-inflammatory, and antioxidant potential of ferrocene-1H-1,2,3-triazole hybrids using biochemical assays in rat mesangial cells (RMCs). We found that, among all the ferrocene-1H-1,2,3-triazole hybrids, X2-X4 exhibited an antioxidant effect on mitochondrial free radicals. Among all the studied compounds, X4 demonstrated the best anti-inflammatory effect on RMCs. These results were supplemented by in silico studies including molecular docking with human cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (COX-2) enzymes as well as absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling. Besides, two new crystal structures of the compounds have also been reported. In addition, combining the results from the inducible nitric oxide synthase (iNOS), cPLA2, COX-2, and matrix metalloproteinase-9 (MMP-9) enzymatic activity analysis and NO production also confirmed this argument. Overall, the results of this study will be a valuable addition to the growing body of work on biological activities of triazole-based compounds.

Weakly Coupled Piezoelectric MEMS Resonators for Aerosol Sensing.

This paper successfully demonstrates the potential of weakly coupled piezoelectric MEMS (Micro-Electro-Mechanical Systems) gravimetric sensors for the detection of ultra-fine particulates. As a proof-of-principle, the detection of diesel soot particles of 100 nanometres or less is demonstrated. A practical monitoring context also exists for diesel soot particles originating from combustion engines, as they are of serious health concern. The MEMS sensors employed in this work operate on the principle of vibration mode-localisation employing an amplitude ratio shift output metric for readout. Notably, gains are observed while comparing parametric sensitivities and the input referred stability for amplitude ratio and resonant frequency variations, demonstrating that the amplitude ratio output metric is particularly suitable for long-term measurements. The soot particle mass directly estimated using coupled MEMS resonators can be correlated to the mass, indirectly estimated using the condensation particle counter used as the reference instrument.

Association of hypertension and dyslipidaemia with increasing obesity in patients with Type 2 Diabetes Mellitus

The study was performed to estimate the association of hypertension and dyslipidaemia with increasing body weight and obesity in Type II diabetics of Lahore, Pakistan. An observational study was conducted by enrolling 2708 obese diabetics from four diabetes care centres of Lahore, Pakistan. Data was collected for a period of 7 months. Associations were estimated using chi-square, binary and multinomial logistic regression. Data suggested that blood pressure, systolic and diastolic, exhibited continual increase with increasing body weight and obesity class in diabetes patients with 41.8% increase in the prevalence of hypertension in obesity class III subjects (OR; 1.91, p=0.02). Likewise, triglycerides and total cholesterol exhibited continual increase in their mean values with increasing obesity, i-e., an overall increase in the prevalence of dyslipidaemia of 27.2% in obesity class 3 subjects (OR; 1.94, p=0.29). Taken together, this data suggested that hypertension is potentially associated with increasing obesity in diabetics, while dyslipidaemia demonstrated plausible association only with obesity class 3.

Can we link foot ulcer with risk factors in diabetics? A study in a tertiary care hospital.

OBJECTIVE: Although many studies worldwide explained the risk factors for developing Diabetic Foot Ulceration (DFU), little has been done to assess medical factors in DFU formation and link them in patients of Pakistan. This study aimed to link the DFU with different risk factors. METHODS: This descriptive cross-sectional retrospective study was conducted in Diabetes Endocrine and Metabolic Centre / Post Graduate Medical Institute / Lahore General Hospital. Data of all patients presenting between July 2017 to June 2018 were analyzed for risk factors. Analysis was done on SPSS version 21. RESULTS: Total of 3301 patient were seen during this period, out of which 2052 patient data was picked up as it was complete in respect to the information needed. Middle age, Male gender, Type 2 diabetes, and Hypertension, were insignificantly co-related. High waist circumference, Comorbidity like Neuropathy, Dyslipidemia, Greater body mass index, Poor compliance with Medication and type of medication used (combination of oral and injectable) were found statistically significant predictor for DFU. However retinopathy was not found to be a risk factor of DFU. This result was statistically significant. CONCLUSION: Factors like obesity, waist circumference, combination of oral along with injectable therapies, neuropathy, dyslipidemia, retinopathy and poor compliance with medication were statistically significant and can be strongly linked with diabetic foot ulcer. Middle age, Male gender, Type 2 diabetes, and Hypertension were insignificantly co-related. However, further studies are needed in larger population to support these findings.

Microstructure core photonic crystal fiber for gas sensing applications.

In this paper, a highly sensitive gas sensor based on the microstructure core and cladding photonic crystal fiber (PCF) is presented over the wavelength range from 1.3 to 2.2 µm, which is advantageous for sensor fabrication. The guiding properties of the proposed structure are dependent on geometrical parameters and wavelengths, which are numerically investigated by using a finite element method (FEM). Introducing the microstructure core makes it possible to obtain higher relative sensitivity and achieves low confinement loss. Moreover, it can be shown that increasing the diameter of the air holes in the microstructure core and decreasing the size of hole to hole space (pitch), the relative sensitivity is enhanced. In addition, the confinement loss is reduced by increasing the value of the diameter of the air holes in the cladding. Simulation results reveal that for the optimum design of the proposed PCF it is possible to obtain the highest relative sensitivity of about 42.27% at the wavelength λ=1.33 µm for the absorption line of methane (CH4) and hydrogen fluoride (HF) gases. In this case, the confinement loss of the fiber is 4.78345×10-6 dB/m.

Protein detection with potentiometric aptasensors: a comparative study between polyaniline and single-walled carbon nanotubes transducers.

A comparison study on the performance characteristics and surface characterization of two different solid-contact selective potentiometric thrombin aptasensors, one exploiting a network of single-walled carbon nanotubes (SWCNTs) and the other the polyaniline (PANI), both acting as a transducing element, is described in this work. The molecular properties of both SWCNT and PANI surfaces have been modified by covalently linking thrombin binding aptamers as biorecognition elements. The two aptasensors are compared and characterized through potentiometry and electrochemical impedance spectroscopy (EIS) based on the voltammetric response of multiply charged transition metal cations (such as hexaammineruthenium, [Ru(NH3)6](3+)) bound electrostatically to the DNA probes. The surface densities of aptamers were accurately determined by the integration of the peak for the reduction of [Ru(NH3)6](3+) to [Ru(NH3)6](2+). The differences and the similarities, as well as the transduction mechanism, are also discussed. The sensitivity is calculated as 2.97 mV/decade and 8.03 mV/decade for the PANI and SWCNTs aptasensors, respectively. These results are in accordance with the higher surface density of the aptamers in the SWCNT potentiometric sensor.

Preparation, structure and spasmolytic activities of some derivatives of harmine series of alkaloids.

Keeping in view the interesting chemistry and pharmacological importance of harmine series of bases -- the beta-carboline alkaloids, a number of new derivatives of tetrahydroharmine and harmalol have been prepared and characterized through spectral studies. Some of these derivatives showed spasmolytic activity. It was observed that all the N-acyl tetrahydroharmine derivatives are stable, not labile and no ring opening occurs in these compounds, as reported recently.