Crisis averted: a world united against the menace of multiple drug-resistant superbugs -pioneering anti-AMR vaccines, RNA interference, nanomedicine, CRISPR-based antimicrobials, bacteriophage therapies, and clinical artificial intelligence strategies to safeguard global antimicrobial arsenal.

The efficacy of antibiotics and other antimicrobial agents in combating bacterial infections faces a grave peril in the form of antimicrobial resistance (AMR), an exceedingly pressing global health issue. The emergence and dissemination of drug-resistant bacteria can be attributed to the rampant overuse and misuse of antibiotics, leading to dire consequences such as organ failure and sepsis. Beyond the realm of individual health, the pervasive specter of AMR casts its ominous shadow upon the economy and society at large, resulting in protracted hospital stays, elevated medical expenditures, and diminished productivity, with particularly dire consequences for vulnerable populations. It is abundantly clear that addressing this ominous threat necessitates a concerted international endeavor encompassing the optimization of antibiotic deployment, the pursuit of novel antimicrobial compounds and therapeutic strategies, the enhancement of surveillance and monitoring of resistant bacterial strains, and the assurance of universal access to efficacious treatments. In the ongoing struggle against this encroaching menace, phage-based therapies, strategically tailored to combat AMR, offer a formidable line of defense. Furthermore, an alluring pathway forward for the development of vaccines lies in the utilization of virus-like particles (VLPs), which have demonstrated their remarkable capacity to elicit a robust immune response against bacterial infections. VLP-based vaccinations, characterized by their absence of genetic material and non-infectious nature, present a markedly safer and more stable alternative to conventional immunization protocols. Encouragingly, preclinical investigations have yielded promising results in the development of VLP vaccines targeting pivotal bacteria implicated in the AMR crisis, including Salmonella, Escherichia coli, and Clostridium difficile. Notwithstanding the undeniable potential of VLP vaccines, formidable challenges persist, including the identification of suitable bacterial markers for vaccination and the formidable prospect of bacterial pathogens evolving mechanisms to thwart the immune response. Nonetheless, the prospect of VLP-based vaccines holds great promise in the relentless fight against AMR, underscoring the need for sustained research and development endeavors. In the quest to marshal more potent defenses against AMR and to pave the way for visionary innovations, cutting-edge techniques that incorporate RNA interference, nanomedicine, and the integration of artificial intelligence are currently under rigorous scrutiny.

Can velmanase alfa be the next widespread potential therapy for alpha-mannosidosis?

Alpha-mannosidosis (AM) is an autosomal recessive lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase. The disease is characterized by immunodeficiency, facial and skeletal abnormalities, impaired hearing, and intellectual disability. The clinical subtype of AM shows considerable variability in an individual, and at present, at least three clinical subtypes are suggested. Diagnosis is made by identification of deficiency of α-mannosidase activity in nucleated cells, like fibroblasts. The children are often born apparently normal as the disease is insidiously progressive, hence making early diagnosis essential. Along with supportive care, long-term therapeutic options include hematopoietic stem cell transplant, bone marrow transplantation, and enzyme replacement therapy. The possible benefits of these procedures must be weighed against the overall risk of procedure-related morbidity and mortality. Velmanase alfa is the first human recombinant form of alpha-mannosidase licensed and available for long-term enzyme replacement therapy. It is approved for treating non-neurologic manifestations of mild to moderate AM. The results obtained from different clinical trials provide evidence of the positive clinical effect of the recombinant enzyme on patients with AM. Different routes of diagnosis and unspecific initial symptoms of the disease lead to a delay in the initiation of treatment, resulting in accumulative morbidity. Thus, there is a dire necessity to create more awareness. Furthermore, additional multiple large-scale trials are needed to evaluate the long-term safety and efficacy of velmanase alfa.

Association of Interferon Alpha Receptor 1 with sustained virological response in hepatitis C and B co-infected patients.

OBJECTIVE: To determine the association of interferon alpha receptor-1 with success rate of interferon therapy in patients co-infected with hepatitis C virus and hepatitis B virus. METHODS: The study was conducted at the Army Medical College, Rawalpindi, Pakistan, from December 2013 to November 2014, and comprised patients with hepatitis C and hepatitis B co-infection. The patients were treated with pegylated-interferon-2b plus ribavirin therapy for six months. With respect to interferon therapy, patients with undetectable hepatitis C virus-ribonucleic acid along with normal alanine aminotransferase were considered responders and patients with detectable hepatitis C virus-ribonucleic acid at week 48 were considered as non-responders. SPSS 20 was used for data analysis. RESULTS: Of the 86 patients, there were 50(58%) males and 36(42%) females. The presence of high pre-treatment interferon alpha receptors 1-messenger ribonucleic acid in peripheral blood mononuclear cells was significantly associated with sustained virological response (85.7% vs. 64.7%, P = 0.031). Multiple regression analysis showed that females (p < 0.001), lower hepatitis C virus-ribonucleic acid levels (p < 0.001) and lower hepatitis B virus-deoxyribonucleic acid levels (p < 0.001) were associated with expression level of interferon alpha receptors 1 in the co-infected patients. CONCLUSIONS: Interferon alpha receptors 1-messenger ribonucleic acid may be useful for predicting response to interferon plus ribavirin therapy in hepatitis C virus/ hepatitis B virus co-infected patients who were females with lower hepatitis C virus-ribonucleic acid and hepatitis B virus-deoxyribonucleic acid levels.

Early Onset Diabetes - Genetic And Hormonal Analysis In Pakistani Population.

BACKGROUND: Mitochondrial DNA mutation and hormonal imbalance is involved in the pathogenesis of early onset diabetes but data is lacking in Pakistani population. The study was planned to delineate the clinical presentation of early onset diabetes with possible hormonal and genetic etiological factors and aascertain the possible etiological role of insulin and glucagon in these patients either on oral hypoglycaemic or subcutaneous insulin therapy. METHODS: Retrospective, analytical case control study with conventional sampling technique carried at Centre for Research in Experimental and Applied Medicine (CREAM) affiliated with the department of Biochemistry and Molecular Biology, Army Medical College Rawalpindi from Dec 2006 to July 2011. Study included the patients (20-35 years of age) with early onset diabetes on oral hypoglycemic (n=240), insulin therapy (n=280), and compared with non-diabetic healthy controls (n=150). A fragment surrounding tRNALeu (UUR) gene was amplified by AmpliTaq from mtDNA which was extracted from peripheral blood leucocytes. Then it was subjected to restriction endonucleases, ApaI for A3242G mutation and HaeIII for G3316A mutation detection. Plasma glucose, glycosylated Hb, osmolality, insulin and glucagon levels along with ABGs analysis was also done. RESULTS: Non diabetic controls comprised of 51% males and 49% females, diabetics on oral hypoglycemic 60% males and 40 % females and on insulin therapy 54% males and 46% females. Insulin dependent diabetics had statistically significant hyperglucagonemia, acidemia and bicarbonate deficit. MtDNA A3242G and G3316A mutations were not detected. CONCLUSIONS: relative hyperglucagonemia and acidemia in Insulin dependent diabetics was a potent threat leading to DKA. The absence of two mtDNA mutations in ND1 gene rules out the possibility of involvement of these mutations in early onset diabetes in Pakistani population.

Significance of glycaemic control in type 1 diabetes.

BACKGROUND: Diabetes mellitus is accompanied with drastic hormonal and metabolic alterations. In uncontrolled diabetes, these disturbances worsen the condition leading to development of life threatening complications. Present study was planned to compare hormonal and metabolic disturbances in controlled and uncontrolled type 1 diabetes (T1D). METHODS: This retrospective, analytical case control study was carried out from Jan 2004 to July 2007. Sample size was 60, divided into 3 groups: Non-diabetic control (group A), controlled TID (group B) and uncontrolled TID (group C). RESULTS: Uncontrolled type 1 diabetics when compared with control group, presented with significant hyperglycaemia (p < 0.001), hypoinsulinemia (p < 0.001), hyperglucagonemia (p < 0.01), raised BMI (p < 0.05), hyponatremia (p < 0.01), hyperkalemia (p < 0.01), acidemia (p < 0.05), high arterial Pco2 (p < 0.05), low plasma HCO3- (p < 0.05), raised plasma triglyceride, LDL Cholesterol and total cholesterol level (p < 0.01) but low HDL cholesterol (p < 0.05). On similar comparison controlled type I diabetics showed significant hyperglycaemia (p < 0.001 ) and hypoinsulinemia (p < 0.05). CONCLUSION: Regular assessment, monitoring and control of T1D has positive impact in preventing development of diabetic dyslipidemia and other hormonal and metabolic derangements which, if left uncontrolled can lead to life threatening diabetic complications.

Insulin and glucagon ratio in the patho-physiology of diabetic ketoacidosis and hyperosmolar hyperglycemic non-ketotic diabetes.

OBJECTIVE: To assess the role of insulin / glucagon ratio in pathophysiology of diabetic ketoacidosis and hyperosmolar hyperglycemic non-ketotic diabetes. DESIGN: Case control, analytical study. PLACE AND DURATION OF STUDY: Military Hospital, Rawalpindi from September 2003 to August 2004. PATIENTS AND METHODS: The study included 7 patients with diabetic ketoacidosis, 3 patients with hyperosmolar hyperglycemic non-ketotic diabetes, 8 patients with uncontrolled type 1 diabetes mellitus and 12 patients with uncontrolled type 2 diabetes mellitus. Twenty non-diabetic persons having blood glucose level less than 6 mmol/L were selected as control group. Patient s detailed history was taken and general physical examination was done. Plasma samples of all the patients and control subjects were assayed for plasma glucose, glycosylated hemoglobin, plasma insulin and glucagon levels. Presence or absence of ketone bodies in urine was also determined. RESULTS: Seven patients with diabetic ketoacidosis, 3 females and 4 males, were found to be hyperglycemic ( p<0.001 ), hypoinsulinemic ( p < 0.05) and hyperglucagonemic ( p < 0.001 ) as compared to control group. Three patients with hyperosmolar hyperglycemic non-ketotic diabetes, 1 male and 2 females, were hyperglycemic ( p < 0.001 ). Eight patients with uncontrolled type I diabetes mellitus, 6 males and 2 females, were having hyperglycemia (p< 0.001) along with hyperglucagonemia (p < 0.001). Twelve patients with uncontrolled type 2 diabetes mellitus, 6 males and 6 females, were found to be hyperglycemic ( p < 0.001 ) and hyperinsulinemic (p < 0.001) as compared to control group. The insulin / glucagon ratio was found to be 1 : 0.9 in diabetic ketoacidosis, 1: 0.15 in hyperosmolar hyperglycemic non-ketotic diabetes, 1: 0.24 in type 1 diabetics, 1: 0.08 in type 2 diabetics, and 1: 0.1 in the control group. CONCLUSION: It was concluded that if insulin / glucagon ratio in type 2 diabetics reduces to 1: 0.9 then these patients may develop ketoacidosis instead of hyperosmolar hyperglycemic non ketotic diabetes. Hence, it is the balance and interplay of insulin and glucagon which predicts the type of acute hyperglycemic emergencies (diabetic ketoacidosis and hyperosmolar hyperglycemic non-ketotic diabetes ) being observed in diabetic patients and not the type of diabetes mellitus.