Acute worsening of microvascular complications of diabetes mellitus during rapid glycemic control:The pathobiology and therapeutic implications

While chronic hyperglycaemia resulting from poorly controlled diabetes mellitus(DM)is a well-known precursor to complications such as diabetic retinopathy,neuropathy(including autonomic neuropathy),and nephropathy,a paradoxical intensification of these complications can rarely occur with aggressive glycemic management resulting in a rapid reduction of glycated haemoglobin.Although,acute onset or worsening of retinopathy and treatment induced neuropathy of diabetes are more common among these complications,rarely other problems such as albuminuria,diabetic kidney disease,Charcot’s neuroarthropathy,gastroparesis,and urinary bladder dysfunction are also encountered.The World Journal of Diabetes recently published a rare case of all these complications,occurring in a young type 1 diabetic female intensely managed during pregnancy,as a case report by Huret et al.It is essential to have a comprehensive understanding of the pathobiology,prevalence,predisposing factors,and management strategies for acute onset,or worsening of microvascular complications when rapid glycemic control is achieved,which serves to alleviate patient morbidity,enhance disease management compliance,and possibly to avoid medico-legal issues around this rare clinical problem.This editorial delves into the dynamics surrounding the acute exacerbation of microvascular complications in poorly controlled DM during rapid glycaemic control.

Genetic screening of liver cancer:State of the art

Liver cancer,primarily hepatocellular carcinoma,remains a global health challenge with rising incidence and limited therapeutic options.Genetic factors play a pivotal role in the development and progression of liver cancer.This state-of-the-art paper provides a comprehensive review of the current landscape of genetic screening strategies for liver cancer.We discuss the genetic underpinnings of liver cancer,emphasizing the critical role of risk-associated genetic variants,somatic mutations,and epigenetic alterations.We also explore the intricate interplay between environmental factors and genetics,highlighting how genetic screening can aid in risk stratification and early detection via using liquid biopsy,and advancements in high-throughput sequencing technologies.By synthesizing the latest research findings,we aim to provide a comprehensive overview of the state-of-the-art genetic screening methods for liver cancer,shedding light on their potential to revolutionize early detection,risk assessment,and targeted therapies in the fight against this devastating disease.

Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus:A real-world experience

BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are a class of drugs with modest antidiabetic efficacy,weight loss effect,and cardiovascular benefits as proven by multiple randomised controlled trials(RCTs).However,real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse.AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data.METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs(dapagliflozin,canagliflozin,and empagliflozin)used for treating patients with type 2 diabetes mellitus.Data on the reduction of glycated hemoglobin(HbA1c),body weight,blood pressure(BP),urine albumin creatinine ratio(ACR),and adverse effects were recorded retrospectively.RESULTS Data from 467 patients with a median age of 64(14.8)years,294(62.96%)males and 375(80.5%)Caucasians were analysed.Median diabetes duration was 16.0(9.0)years,and the duration of SGLT-2i use was 3.6(2.1)years.SGLT-2i molecules used were dapagliflozin 10 mg(n=227;48.6%),canagliflozin 300 mg(n=160;34.3%),and empagliflozin 25 mg(n=80;17.1).Baseline median(interquartile range)HbA1c in mmol/mol were:dapagliflozin-78.0(25.3),canagliflozin-80.0(25.5),and empagliflozin-75.0(23.5)respectively.The respective median HbA1c reduction at 12 months and the latest review(just prior to the study)were:66.5(22.8)&69.0(24.0),67.0(16.3)&66.0(28.0),and 67.0(22.5)&66.5(25.8)respectively(P<0.001 for all comparisons from baseline).Significant improvements in body weight(in kilograms)from baseline to study end were noticed with dapagliflozin-101(29.5)to 92.2(25.6),and canagliflozin 100(28.3)to 95.3(27.5)only.Significant reductions in median systolic and diastolic BP,from 144(21)mmHg to 139(23)mmHg;(P=0.015),and from 82(16)mmHg to 78(19)mmHg;(P<0.001)respectively were also observed.A significant reduction of microalbuminuria was observed with canagliflozin only[ACR 14.6(42.6)at baseline to 8.9(23.7)at the study end;P=0.043].Adverse effects of SGLT-2i were as follows:genital thrush and urinary infection-20(8.8%)&17(7.5%)with dapagliflozin;9(5.6%)&5(3.13%)with canagliflozin;and 4(5%)&4(5%)with empagliflozin.Diabetic ketoacidosis was observed in 4(1.8%)with dapagliflozin and 1(0.63%)with canagliflozin.CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c,body weight,and better than those reported in RCTs,with low side effect profiles.A review of large-scale real-world data is needed to inform better clinical practice decision making.

Prolonged intermittent theta burst stimulation restores the balance between A_(2A)R-and A_(1)R-mediated adenosine signaling in the 6-hydroxidopamine model of Parkinson's disease

An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.

A review of mechanism of action of outdoor exposure in preventing myopia incidence and progression

Various studies have suggested several environmental,pharmacological,medical,and optical interventions and some are in use but their efficacy in myopia control may be transient,and the cellular,molecular,and biochemical mechanisms involved unclear.Daylight exposure is currently regarded as an effective and enduring strategy in the control of myopia development and progression.However,the mechanism behind the effect of outdoor exposure and its association with genetic predisposition and other relatively more significant environmental factors on myopia is still a conundrum.This review focuses on survey-based and intervention-based studies carried out to propose a mechanism that accounts for myopia development and important for its control.

Periodontitis:An often-neglected complication of diabetes

The bidirectional association between type 2 diabetes mellitus(T2DM)and periodontitis is now well established,resulting in periodontal disease being considered as the 6th major complication of diabetes mellitus(DM)after cardiovascular disease,eye disease,neuropathy,nephropathy,and peripheral vascular disease.DM can worsen the virulence and invasiveness of pathogenic oral microbial flora aggravating the local inflammation and infection in those with periodontal disease.On the other hand,the chemical and immunological mediators released into the circulation as part of periodontal inflammation worsen the systemic insulin resistance with worsening of T2DM.Periodontitis if undiagnosed or left untreated can also result in eventual tooth loss.A study by Xu et al in the World Journal of Diabetes examined the predictive factors associated with periodontitis in Chinese patients with T2DM.The prevalence of periodontitis was found to be 75.7%in this study.Based on logistic regression analysis,the predictive factors for higher risk were low tooth brushing frequency[odds ratio(OR)=4.3],high triglycerides(TG;OR=3.31),high total cholesterol(TC;OR=2.87),higher glycated hemoglobin(HbA1c;OR=2.55),and higher age(OR=1.05)while higher education level was protective(OR=0.53).However,the most influential variables were HbA1c followed by age,TC,TG,low education level,brushing frequency,and sex on the random forest model(this model showed higher sensitivity for predicting the risk).A good understanding of the predictors for periodontitis in T2DM patients is important in prevention,early detection of susceptible patients,and intervention to improve periodontal health and enable long-term glycaemic control as observed by Xu et al.

Alterations of protein homeostasis in Alzheimer's disease:beyond Procrustean bed of endoplasmic reticulum stress and unfolded protein response

Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evident in postmortem AD brains,include a massive loss of the grey matter in the neocortex,extracellular deposition of amyloid-β(Aβ)in the form of senile plaques and cerebrovascular amyloid angiopathy,and intra-neuronal accumulation of neurofibrillary tangles,formed by hyper-phosphorylated tau protein.

Rising tide: The global surge of type 2 diabetes in children and adolescents demands action now

Childhood-onset obesity has emerged as a major public healthcare challenge across the globe,fueled by an obesogenic environment and influenced by both genetic and epigenetic predispositions.This has led to an exponential rise in the incidence of type 2 diabetes mellitus in children and adolescents.The looming wave of diabetes-related complications in early adulthood is anticipated to strain the healthcare budgets in most countries.Unless there is a collective global effort to curb the devastation caused by the situation,the impact is poised to be pro-found.A multifaceted research effort,governmental legislation,and effective social action are crucial in attaining this goal.This article delves into the current epidemiological landscape,explores evidence concerning potential risks and consequences,delves into the pathobiology of childhood obesity,and discusses the latest evidence-based management strategies for diabesity.

Flat-footed Females and Missing Males:A New Genus and Species of Pleciofungivoridae(Diptera:Bibionomorpha)Represents the First Record of the Family from Mid-Cretaceous Kachin Amber

A new genus and species,Cretopleciofungivora simpsoni gen.et sp.nov.,from the extinct family Pleciofungivoridae(Diptera:Bibionomorpha),is discovered in mid-Cretaceous Kachin amber.Previously,this family was known only from imprints in sedimentary rocks of the Jurassic and the Lower Cretaceous.Discovery of a representative of Pleciofungivoridae in Kachin amber confirms the presence of the family in the Upper Cretaceous.The new species has a unique structure of fore tarsus,with lobed and extended tarsal segments Ⅱ to Ⅳ,a feature hitherto known only in a few species of extant Sciaroidea.Although not particularly rare,the new species is currently known only from female specimens.Possible reasons for this phenomenon,very unusual in Sciaroidea,are briefly discussed,including parthenogenesis as a potentially plausible hypothesis.

Decline and fall of aging astrocytes:the human perspective

“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.

Carbonic anhydrase 2 mediates anti-obesity effects of black tea as thermogenic activator

Obesity is a metabolic disorder due to over-accumulation of adipose tissue and ultimately becomes a“disease”.Brown adipose tissue(BAT)thermogenesis and white adipose tissue(WAT)browning emerge as a potential strategy of anti-obesity by dissipating energy as heat.However,drugs based on adipose tissue thermogenesis have not been successfully approved yet.In current study,we found that black tea extract(BTE)obtained by patentauthorized manufacturing process prevented body weight gain as novel thermogenic activator with reduction of adiposity,improvement of adipose distribution,and glucose metabolism improvement in diet-induced obesity mice.Mechanismly,anti-obesity effect of BTE depends on promoting BAT thermogenesis and WAT browning with upregulation of uncoupling protein 1(UCP1),especially visceral adipose tissue(VAT)with browning resistance.Specifically,utilizing in silico approach of network pharmacology and molecular docking,we identified carbonic anhydrase 2(CA2)in nitrogen metabolism as anti-obesity target of BTE and further elucidated that protein kinase B(AKT)signaling pathway linked CA2 and UCP1.Meanwhile gut microbiota regulation may prompt the CA2-dependent thermogenesis activation.Our findings demonstrated anti-obesity effect of BTE as thermogenic activator through CA2-mediated BAT thermogenesis and WAT browning via CA2-AKT-UCP1 signaling pathway,which could be developed as promising anti-obesity agent with good safety and efficacy.

Autoantibodies related to ataxia and other central nervous system manifestations of gluten enteropathy

Gluten ataxia and other central nervous system disorders could be linked to gluten enteropathy and related autoantibodies.In this narrative review,we focus on the various neuro-logical manifestations in patients with gluten sensitivity/celiac disease,immunological and autoimmune mechanisms of ataxia in connection to gluten sensitivity and the autoantibodies that could be used as a biomarker for diagnosing and following.We focused on the anti-gliadin antibodies,antibodies to different isoforms of tissue transglutaminase(TG)(anti-TG2,3,and 6 antibodies),anti-glycine receptor antibodies,anti-glutamine acid decarboxylase antibodies,anti-deamidated gliadin peptides antibodies,etc.Most studies found a higher prevalence of these antibodies in patients with gluten sensitivity and neurological dysfunction,presented as different neurological disorders.We also discuss the role of a gluten-free diet on the clinical improvement of patients and also on imaging of these disorders.

Molecular phylogeny and taxonomy of Phlomoides(Lamiaceae subfamily Lamioideae)in China:Insights from molecular and morphological data

Phlomoides,with 150-170 species,is the second largest and perhaps most taxonomically challenging genus within the subfamily Lamioideae(Lamiaceae).With about 60 species,China is one of three major biodiversity centers of Phlomoides.Although some Phlomoides species from China have been included in previous molecular phylogenetic studies,a robust and broad phylogeny of this lineage has yet to be completed.Moreover,given the myriad new additions to the genus,the existing infrageneric classification needs to be evaluated and revised.Here,we combine molecular and morphological data to investigate relationships within Phlomoides,with a focus on Chinese species.We observed that plastid DNA sequences can resolve relationships within Phlomoides better than nuclear ribosomal internal and external transcribed spacer regions(nrITS and nrETS).Molecular phylogenetic analyses confirm the monophyly of Phlomoides,but most previously defined infrageneric groups are not monophyletic.In addition,morphological analysis demonstrates the significant taxonomic value of eight characters to the genus.Based on our molecular phylogenetic analyses and morphological data,we establish a novel section Notochaete within Phlomoides,and propose three new combinations as well as three new synonyms.This study presents the first molecular phylogenetic analyses of Phlomoides in which taxa representative of the entire genus are included,and highlights the phylogenetic and taxonomic value of several morphological characters from species of Phlomoides from China.Our study suggests that a taxonomic revision and reclassification for the entire genus is necessary in the future.

Controversies regarding transplantation of mesenchymal stem cells

Mesenchymal stem cells(MSCs)have tantalized regenerative medicine with their therapeutic potential,yet a cloud of controversies looms over their clinical tran-splantation.This comprehensive review navigates the intricate landscape of MSC controversies,drawing upon 15 years of clinical experience and research.We delve into the fundamental properties of MSCs,exploring their unique immuno-modulatory capabilities and surface markers.The heart of our inquiry lies in the controversial applications of MSC transplantation,including the perennial debate between autologous and allogeneic sources,concerns about efficacy,and lingering safety apprehensions.Moreover,we unravel the enigmatic mechanisms surro-unding MSC transplantation,such as homing,integration,and the delicate balance between differentiation and paracrine effects.We also assess the current status of clinical trials and the ever-evolving regulatory landscape.As we peer into the future,we examine emerging trends,envisioning personalized medicine and innovative delivery methods.Our review provides a balanced and informed perspective on the controversies,offering readers a clear understanding of the complexities,challenges,and potential solutions in MSC transplantation.

Semaglutide for the management of diabesity:The real-world experience

BACKGROUND Diabesity(diabetes as a consequence of obesity)has emerged as a huge healthcare challenge across the globe due to the obesity pandemic.Judicious use of antidiabetic medications including semaglutide is important for optimal management of diabesity as proven by multiple randomized controlled trials.However,more real-world data is needed to further improve the clinical practice.AIM To study the real-world benefits and side effects of using semaglutide to manage patients with diabesity.METHODS We evaluated the efficacy and safety of semaglutide use in managing patients with diabesity in a large academic hospital in the United States.Several parameters were analyzed including demographic information,the data on improvement of glycated hemoglobin(HbA1c),body weight reduction and insulin dose adjustments at 6 and 12 months,as well as at the latest follow up period.The data was obtained from the electronic patient records between January 2019 to May 2023.RESULTS 106 patients(56 males)with type 2 diabetes mellitus(T2DM),mean age 60.8±11.2 years,mean durations of T2DM 12.4±7.2 years and mean semaglutide treatment for 2.6±1.1 years were included.Semaglutide treatment was associated with significant improvement in diabesity outcomes such as mean weight reductions from baseline 110.4±24.6 kg to 99.9±24.9 kg at 12 months and 96.8±22.9 kg at latest follow up and HbA1c improvement from baseline of 82±21 mmol/mol to 67±20 at 12 months and 71±23 mmol/mol at the latest follow up.An insulin dose reduction from mean baseline of 95±74 units to 76.5±56.2 units was also observed at the latest follow up.Side effects were mild and mainly gastrointestinal like bloating and nausea improving with prolonged use of semaglutide.CONCLUSION Semaglutide treatment is associated with significant improvement in diabesity outcomes such as reduction in body weight,HbA1c and insulin doses without major adverse effects.Reviews of largescale real-world data are expected to inform better clinical practice decision making to improve the care of patients with diabesity.

Management of male obesity-related secondary hypogonadism:A clinical update

The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism(MOSH)with emerging evidence on the role of testosterone therapy.We aim to provide an updated and practical approach towards its management.We did a comprehensive literature search across MEDLINE(via PubMed),Scopus,and Google Scholar databases using the keywords“MOSH”OR“Obesity-related hypogonadism”OR“Testosterone replacement therapy”OR“Selective estrogen receptor modulator”OR“SERM”OR“Guidelines on male hypogonadism”as well as a manual search of references within the articles.A narrative review based on available evidence,recommendations and their practical implications was done.Although weight loss is the ideal therapeutic strategy for patients with MOSH,achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice.Therefore,androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity.However,there is conflicting evidence for the appropriate use of testosterone replacement therapy(TRT),and it can also be associated with complications.This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH.Before starting testosterone replacement in functional hypogonadism of obesity,it would be desirable to initiate lifestyle modification to ensure weight reduction.TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients.Balancing the risks and benefits of TRT should be considered in every patient before and during longterm management.

Mechanisms and treatment strategies of demyelinating and dysmyelinating Charcot-Marie-Tooth disease

Schwann cells,the myelinating glia of the peripheral nervous system,wrap axons multiple times to build their myelin sheath.Myelin is of paramount importance for axonal integrity and fast axon potential propagation.However,myelin is lacking or dysfunctional in several neuropathies including demyelinating and dysmyelinating Charcot-M arie-To oth disease.Charcot-Marie-To oth disease represents the most prevalent inherited neuropathy in humans and is classified either as axonal,demyelinating or dysmyelinating,or as intermediate.The demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease constitute the majority of the disease cases and are most frequently due to mutations in the three following myelin genes:peripheral myelin protein 22,myelin protein ze ro and gap junction beta 1(coding for Connexin 32) causing Charcot-M arie-Tooth disease type 1A,Charcot-Marie-Tooth disease type 1B,and X-linked Charcot-M arie-Tooth disease type 1,respectively.The resulting perturbation of myelin structure and function leads to axonal demyelination or dysmyelination and causes severe disabilities in affected patients.No treatment to cure or slow down the disease progression is currently available on the market,howeve r,scientific discoveries led to a better understanding of the pathomechanisms of the disease and to potential treatment strategies.In this review,we describe the features and molecular mechanisms of the three main demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease,the rodent models used in research,and the emerging therapeutic approaches to cure or counteract the progression of the disease.

Management of diabesity:Current concepts

The global prevalence of obesity is increasing rapidly with an exponential rise in incidence of type 2 diabetes mellitus in recent years.‘Diabesity’,the term coined to show the strong interlink between obesity and diabetes,is the direct cons-equence of the obesity pandemic,and poses significant challenges in the management of the disease.Without addressing the clinical and mechanistic complications of obesity such as metabolic-associated fatty liver disease and obstructive sleep apnoea,a rational management algorithm for diabesity cannot be developed.Several classes of anti-diabetic medications including insulins,sulphonylureas,thiazolidinediones and meglitinides are associated with the risk of weight gain and may potentially worsen diabesity.Therefore,appropriate selection of antidiabetic drug regimen is crucial in the medical management of diabesity.The role of non-pharmacological measures such as dietary adjustments,exercise interventions and bariatric procedures should also be emphasised.Unfortunately,the importance of appropriate and optimal management of diabesity is often overlooked by medical professionals when achieving adequate glycemic control which results in inappropriate management of the disease and its complications.This review provides a narrative clinical update on the evidence behind the management of diabesity.

Management of metabolic-associated fatty liver disease: The diabetology perspective

The metabolic syndrome as a consequence of the obesity pandemic resulted in a substantial increase in the prevalence of metabolic-associated fatty live disease(MAFLD)and type 2 diabetes mellitus(T2DM).Because of the similarity in pathobiology shared between T2DM and MAFLD,both disorders coexist in many patients and may potentiate the disease-related outcomes with rapid progression and increased complications of the individual diseases.In fact,awareness about this coexistence and the risk of complications are often overlooked by both hepatologists and diabetologists.Management of these individual disorders in a patient should be addressed wholistically using an appropriate multidisciplinary team approach involving both the specialists and,when necessary,liaising with dieticians and surgeons.This comprehensive review is to compile the current evidence from a diabetologist's perspective on MAFLD and T2DM and to suggest optimal management strategies.

Pointing fingers at blood contact:mechanisms of subventricular zone neural stem cell differentiation

The limited ability of the central nervous system(CNS)to regenerate in adult mammals after injury or disease is a significant problem.Intriguingly,neural stem/progenitor cells(NSPCs)offer great promise for regenerating the CNS.Endogenous or transplanted NSPCs contribute to repair processes,but their differentiation and function are abnormal in CNS injury and disease.The main reasons for these abnormalities are changes in the extracellular environment in the injured CNS that affect signaling pathways and transcriptional regulation in NSPCs.