Multiple sclerosis drug repurposing for neuroregeneration

Multiple sclerosis(MS)is an autoimmune disorder of the central nervous system(CNS)and is primarily characterized by immune cell infiltration leading to relapses followed by remission phases and a disease course turning progressive over time with neurodegenerative processes taking over(Amin and Hersh,2023).Of note,beyond relapse-associated worsening early in disease progression independent of relapse activity may arise independently of relapse activity and can occur in all phenotypes.Autoimmune-mediated damage of myelin sheaths and the subsequent loss of mature oligodendrocytes are resulting in impaired axonal integrity,neurodegeneration and accounts for irreversible neuronal damage(Kuhlmann et al.,2023).The current landscape of available disease-modifying therapies comprises mainly immunomodulatory drugs that effectively diminish relapses and slow down progression at the onset form of the disease,namely relapsing MS(RMS).In this regard,a number of drugs have been approved as disease-modifying therapies for MS by US Food and Drug Administration and European Medicines Agencies(Box 1).

Hyperinsulinemic hypoglycemia due to adult nesidioblastosis in insulin-dependent diabetes

In neonates, persistent hyperinsulinemic hypoglycemia (PHH) is associated with nesidioblastosis. In adults, PHH is usually caused by solitary benign insulinomas. We report on an adult patient who suffered from insulin-de- pendent diabetes mellitus, and subsequently developed PHH caused by diffuse nesidioblastosis. Mutations of the MEN1 and Mody 2/3 genes were ruled out. Preoperative diagnostic procedures, the histopathological criteria and the surgical treatment options of adult nesidioblastosis are discussed. So far only one similar case of adult nesidioblastosis subsequent to diabetes mellitus Ⅱ has been reported in the literature. In case of conversion of diabetes into hyperinsulinemic hypoglycemia syndrome, nesidioblastosis in addition to insulinoma should be con- sidered.

Complications and treatment of migrated biliary endoprostheses:A review of the literature

Endoscopic biliary stent insertion is a well-established procedure. It is especially successful in treating postoperative biliary leaks, and may prevent surgical intervention. A routine change of endoprostheses after 3 mo is a common practice but this can be prolonged to 6 too. We reported a colonic perforation due to biliary stent dislocation and migration to the rectosigmoid colon, and reviewed the literature.

From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancerrelated genes.Several therapeutic strategies targeting oncogenic KRAS(KRASonc) signaling pathways have been suggested,including the inhibition of synthetic lethal interactions, direct inhibition of KRASonc itself, blockade of downstream KRASonc effectors, prevention of post-translational KRASonc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways,targeted RNA replacement, and oncogene-induced senescence.Despite intensive and continuous efforts, KRASonc remains an elusive target for cancer therapy.To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date.An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRASonc-signaling targeted therapeutics.

The treatment of Parkinson's disease with deep brain stimulation: current issues

Deep brain stimulation has become a well-established symptomatic treatment for Parkinson＇s disease during the last 25 years. Besides improving motor symptoms and long-term motor complications, positive effects on patients＇ mobility, activities of daily living, emotional well-being and health-related quality of life have been recognized. Apart from that, numerous clinical trials analyzed effects on non-motor symptoms and side effects of deep brain stimulation. Several technical issues and stimulation paradigms have been and are still being developed to optimize the therapeutic effects, minimize the side effects and facilitate handling. This review summarizes current therapeutic issues, i.e., patient and target selection, surgical procedure and programming paradigms. In addition it focuses on neuropsychological effects and side effects of deep brain stimulation.

Effects of age and sex on clinical high-risk for psychosis in the community

BACKGROUND Recent reports of both heightened prevalence rates and limited clinical relevance of clinical high-risk(CHR)criteria and their relevant symptoms in children and adolescents indicate an important role of neurodevelopment in the early detection of psychoses.Furthermore,sex effects in CHR symptoms have been reported,though studies were inconclusive.As sex also impacts on neurodevelopment,we expected that sex might have an additional contribution to age in the prevalence and clinical relevance of CHR symptoms and criteria.AIM To investigate age and sex effects on CHR criteria and symptoms and their association with psychosocial impairment and mental disorder.METHODS In this cross-sectional cohort study,n=29168-to 40-year-olds,randomly drawn from the population register of the Swiss canton Bern,were assessed in semistructured interviews by phone or face-to-face for CHR symptoms and criteria using the Structured Interview for Psychosis-Risk Syndromes and the Schizophrenia Proneness Instrument in its child and youth,and adult version,respectively.Furthermore,social and occupational functioning and DSM-IV axis I disorders were assessed.Simple and interaction effects of age and sex on CHR symptoms and criteria,and interaction effects of age,sex,and CHR symptoms and criteria on presentation of functional impairment and of non-psychotic disorder were investigated using logistic regression analyses.RESULTS Altogether,542(18.6%)participants reported any CHR symptom;of these,261(9.0%)participants reported any one of the 11 criteria relevant cognitive and perceptual basic symptoms,and 381(13.1%)any one of the five attenuated or transient psychotic symptoms(attenuated psychotic symptoms/brief intermittent psychotic symptoms).Fewer participants met any one of the CHR criteria(n=82,2.8%)or any one of the three recently recommended CHR criteria(n=38,1.3%).Both age and sex were significantly(P<0.05)associated with CHR symptoms and criteria,mostly by younger age and female sex.Though slightly differing between symptom groups,age thresholds were detected around the turn from adolescence to adulthood;they were highest for cognitive basic symptoms and CHR criteria.With the exception of the infrequent speech disorganization attenuated psychotic symptom,the interaction of age with CHR symptoms and criteria predicted functional impairment;whereas,independent of each other,sex and CHR symptoms mostly predicted mental disorders.CONCLUSION Age and sex differentially impact on CHR symptoms and criteria;these differences may support better understanding of causal pathways.Thus,future CHR studies should consider effects of sex and age.

Immunomodulatory activity of a lupane triterpenoid ester isolated from the eastern Nigeria mistletoe,Loranthus micranthus(Linn)

Objective:To provide further evidence for the ethnomedicinal use of the Eastern Nigeria mistletoe,Loranthus micranthus(L.micranthus),as an immunostimulant.Methods:Solvent fractions from the crude extract of the mistletoe plant was obtained and screened by the cell mediated delayed type hypersensitivity reaction(DTHR) model in mice.Then the immunomodulatory potentials of a major lupane triterpenoid ester isolated from an active hexane fraction of the Eastern Nigeria mistletoe was investigated.Three lupeol-based triterpenoid esters: 7β15α-dihydroxyl-lup-20(29)-ene-3β-palmitate(Ⅰ),7β,15α-dihydroxyl-lup-20(29)- ene-3β-stearate(Ⅱ) and 7β,15α-dihydroxyl-lup-20(29)-ene-3β-decadecanoate(Ⅲ) were isolated from the plant leaves epiphyting on a local kola nut tree and were characterized. Compound 1 was subjected to cell proliferation studies using C57H1/6 splenocvtes at three dose levels(5.25 and 100μg/mL) in presence of controls.Furthermore,the effect of this compound on IL-8 receptor expression was evaluated at three doses(1,5 and 10μg/mL) using the real time polymerase chain reaction assay.Results:This triterpenoid ester produced some enhancement of the splenocytes at the tested doses but at doses higher than 5μg/mL caused inhibition of the IL-8 receptor expression.Conclusions:The present findings support the ethnomedicinal use of the Eastern Nigeria Mistletoe in the management of diseases affecting the immune system.The trilerpenoid(s) have some immunomodulatory abilities on splenocytes and IL-8 receptors and may partly account lor the overall immunomodulatory activity of this plant.

COHERENT ANTI-STOKES RAMAN SCATTERING MICROSCOPY TO MONITOR DRUG DISSOLUTION IN DIFFERENT ORAL PHARMACEUTICAL TABLETS

Coherent anti-Stokes Raman scattering(CARS)microscopy is used to visualize the release of a model drug(theophylline)from a lipid(tripalmitin)based tablet during dissolution.The effects of transformation and dissolution of the drug are imaged in real time.This study reveals that the manufacturing process causes significant differences in the release process:tablets prepared from powder show formation of theophylline monohydrate on the surface which prevents a controlled drug release,whereas solid lipid extrudates did not show formation of monohydrate.This visualization technique can aid future tablet design.

Intrahepatic cholestasis without jaundice

BACKGROUND:Cholangiocarcinoma(CC),the most common biliary tract malignancy,is frequently seen in advanced unresectable stages and is typically localized extrahepatically.Early diagnosis is unusual because of nonspecific symptoms.Painless jaundice is usually the first sign of tumor. METHOD:We present a patient with a CC(Klatskin tumor) with a complete biliary drainage by an aberrant bile duct without jaundice. RESULTS:A 67-year-old woman presented with persisting elevation of liver parameters.Diagnostic tests showed a Klatskin tumor typeⅡ.A curative right hepatic trisegmentectomy was performed after liver volume augmentation by preoperative vein embolization. CONCLUSIONS:A direct drainage of the right posterior bile duct into the common bile duct as an aberrant hepatic duct is a rare variation and is present in less than 5%of the population.In case of persistently perturbed liver function tests,an aberrant bile duct can cover up severe intrahepatic cholestasis and even obscure the diagnosis of a Klatskin tumor.Up to now it has not been described in the literature.

Restoration of the joint geometry and outcome after stemless TESS shoulder arthroplasty

AIM To evaluate the joint geometry and the clinical outcome of stemless, anatomical shoulder arthroplasty with the TESS system.METHODS Twenty-one shoulders with a mean follow-up 18 of months were included. On scaled digital radiographs the premorbid center of rotation(CoR) was assessed and compared to the CoR of the prosthesis by using the MediC AD~? software. Additionally, the pre-and post-operative geometry of the CoR was assessed in relation to the glenoid, the acromion as well as to the proximal humerus. Radiological changes, such as radiolucencies, were also assessed. Clinical outcome was assessed with the Constant and DASH score. RESULTS Both, the Constant and DASH scores improved signifi-cantly from 11% to 75% and from 70 to 30 points, P < 0.01 respectively. There were no significant differences regarding age, etiology, cemented or metal-backed glenoids, etc.(P > 0.05). The pre-and postoperative humeral offset, the lateral glenohumeral offset, the height of the CoR, the acromiohumeral distance as well as neckshaft angle showed no significant changes(P > 0.05). The mean deviation of the CoR of the prosthesis from the anatomic center was 1.0 ± 2.8 mm. Three cases showed a medial deviation of more than 3 mm. These deviations of 5.1, 5.7 and 7.6 mm and were caused by an inaccurate humeral neck cut. These 3 patients showed a relatively poor outcome scoring.CONCLUSION TESS arthroplasty allows an anatomical joint reconstruction with a very good outcome. Outliers described in this study sensitize the surgeon for an accurate humeral neck cut.

Testicular germ cell tumors

Optimal quality of cancer care is crucial for best outcomes.This is especially true for patients suffering from testicular germ cell tumors.These patients are very young,sometimes adolescent,usually healthy and cure rates independent of stage of the disease in industrialized countries approach 97%.With these figures,testicular germ cell tumors present a role model for a curable cancer.The life expectancy of patients in early stages with local treatment followed by active surveillance is not limited compared to the general population.In patients with metastatic disease tumor recurrences do not impact on the life expectancy either since most of the recurrences are curable as well.However,in metastatic patients,the long-term sequelae of the initial systemic treatment like secondary malignancies and life-threatening long-term toxicities due to cisplatin meanwhile represent the most frequent causes of death 30 and more years after end of treatment.

Clinical high-risk criteria of psychosis in 8–17-year-old community subjects and inpatients not suspected of developing psychosis

BACKGROUND In children and adolescents compared to adults,clinical high-risk of psychosis(CHR)criteria and symptoms are more prevalent but less psychosis-predictive and less clinically relevant.Based on high rates of non-converters to psychosis,especially in children and adolescents,it was suggested that CHR criteria were:(1)Pluripotential;(2)A transdiagnostic risk factor;and(3)Simply a severity marker of mental disorders rather than specifically psychosis-predictive.If any of these three alternative explanatory models were true,their prevalence should differ between persons with and without mental disorders,and their severity should be associated with functional impairment as a measure of severity.AIM To compare the prevalence and severity of CHR criteria/symptoms in children and adolescents of the community and inpatients.METHODS In the mainly cross-sectional examinations,8–17-year-old community subjects(n=233)randomly chosen from the population register of the Swiss Canton Bern,and inpatients(n=306)with primary diagnosis of attention-deficit/hyperactivity disorder(n=86),eating disorder(n=97),anxiety including obsessive–compulsive disorder(n=94),or autism spectrum disorder(n=29),not clinically suspected to develop psychosis,were examined for CHR symptoms/criteria.Positive items of the Structured Interview for Psychosis-Risk Syndromes(SIPS)were used to assess the symptomatic ultra-high-risk criteria,and the Schizophrenia Proneness Instrument,Child and Youth version(SPI-CY)was used to assess the 14 basic symptoms relevant to basic symptom criteria.We examined group differences in frequency and severity of CHR symptoms/criteria usingχ^(2) tests and nonparametric tests with Cramer’s V and Rosenthal’s r as effect sizes,and their association with functioning using correlation analyses.RESULTS The 7.3%prevalence rate of CHR criteria in community subjects did not differ significantly from the 9.5%rate in inpatients.Frequency and severity of CHR criteria never differed between the community and the four inpatient groups,while the frequency and severity of CHR symptoms differed only minimally.Group differences were found in only four CHR symptoms:suspiciousness/persecutory ideas of the SIPS[χ2(4)=9.425;P=0.051,Cramer’s V=0.132;and Z=-4.281,P<0.001;Rosenthal’s r=0.184],and thought pressure[χ^(2)(4)=11.019;P=0.026,Cramer’s V=0.143;and Z=-2.639,P=0.008;Rosenthal’s r=0.114],derealization[χ2(4)=32.380;P<0.001,Cramer’s V=0.245;and Z=-3.924,P<0.001;Rosenthal’s r=0.169]and visual perception disturbances[χ^(2)(4)=10.652;P=0.031,Cramer’s V=0.141;and Z=-2.822,P=0.005;Rosenthal’s r=0.122]of the SPI-CY.These were consistent with a transdiagnostic risk factor or dimension,i.e.,displayed higher frequency and severity in inpatients,in particular in those with eating,anxiety/obsessive–compulsive and autism spectrum disorders.Low functioning,however,was at most weakly related to the severity of CHR criteria/symptoms,with the highest correlation yielded for suspiciousness/persecutory ideas(Kendall’s tau=-0.172,P<0.001).CONCLUSION The lack of systematic differences between inpatients and community subjects does not support suggestions that CHR criteria/symptoms are pluripotential or transdiagnostic syndromes,or merely markers of symptom severity.

伴甲状旁腺功能亢进的疱疹样脓疱病

Impetigo herpetiformis, first described by Hebra, is a rare pustular disorder that primarily affects pregnant women and it is often complicated by an increased risk of spontaneous abortion. A commonly associated hypocalcemia often appears with hypoparathyroidism. Here we report a case of complicated impetigo herpetiformis without hypocalcemia paired with a compensatory hyperparathyroidism.

动脉瘤性蛛网膜下腔出血患者的重症监护处理：神经危重症监护学会多学科共识会议的推荐意见

蛛网膜下腔出血（subarachnoidhemorrhage，SAH）是一种可对中枢神经系统造成毁灭性打击并对其他多个器官产生显著影响的急性脑血管病。SAH患者被常规收入重症监护病房并由多学科团队进行治疗。由于高质量研究证据的缺乏，使得治疗方法各异，可供选择的指导意见不多。现有的指南主要强调危险因素、预防、自然史以及再出血的预防，很少涉及SAH患者的重症监护问题。美国神经危重症监护学会组织了一次国际性多学科共识会议来探讨SAH的重症监护处理。根据发表的文章和研究领域，此次会议召集了来自欧洲和北美地区的神经重症监护科、神经外科、神经内科、介入神经放射科和神经麻醉科方面的专家。根据临床经验和制定实践指南方面的经验，选择4名经验丰富的神经重症监护专家组成评判委员会。应用推荐分级的评估、制定与评价（GradesofRecommendationsAssessment，DevelopmentandEvaluation，GRADE）系统进行文献回顾，结合参会者的经验、评判委员会的审评以及文献讨论产生推荐意见。应用GRADE系统制定推荐意见，其制定原则不仅强调研究资料的质量，而且还重视利弊权衡与实践转化。对SAH患者日常处理过程中面临的所有问题均提供指导和推荐意见，即使缺乏高质量的证据。

Targeting Plant Ethylene Responses by Controlling Essential Protein-Protein Interactions in the Ethylene Pathway

The gaseous plant hormone ethylene regulates many processes of high agronomic relevance throughout the life span of plants. A central element in ethylene signaling is the endoplasmic reticulum （ER）-Iocalized membrane protein ETHYLENE INSENSITIVE2 （EIN2）. Recent studies indicate that in response to ethylene, the extra-membranous C-terminal end of EIN2 is proteolytically processed and translocated from the ER to the nucleus. Here, we report that the conserved nuclear localization signal （NLS） mediating nuclear import of the EIN2 C-terminus provides an important domain for complex formation with ethylene receptor ETHYLENE RESPONSE1 （ETR1）. EIN2 lacking the NLS domain shows strongly reduced affinity for the receptor. Interaction of EIN2 and ETR1 is also blocked by a synthetic peptide of the NLS motif. The corre- sponding peptide substantially reduces ethylene responses in planta. Our results uncover a novel mecha- nism and type of inhibitor interfering with ethylene signal transduction and ethylene responses in plants. Disruption of essential protein-protein interactions in the ethylene signaling pathway as shown in our study for the EIN2-ETR1 complex has the potential to guide the development of innovative ethylene antagonists for modern agriculture and horticulture.

The CLE40 and CRN/CLV2 Signaling Pathways Antagonistically Control Root Meristem Growth in Arabidopsis

Differentiation processes in the primary root meristem are controlled by several signaling pathways that are regulated by phytohormones or by secreted peptides. Long-term maintenance of an active root meristem requires that the generation of new stem cells and the loss of these from the meristem due to differentiation are precisely coordinated. Via phenotypic and large-scale transcriptome analyses of mutants, we show that the signaling peptide CLE40 and the recep- tor proteins CLV2 and CRN act in two genetically separable pathways that antagonistically regulate cell differentiation in the proximal root meristem. CLE40 inhibits cell differentiation throughout the primary root meristem by controlling genes with roles in abscisic acid, auxin, and cytokinin signaling. CRN and CLV2 jointly control target genes that promote cell differentiation specifically in the transition zone of the proximal root meristem. While CRN and CLV2 are not acting in the CLE40 signaling pathway under normal growth conditions, both proteins are required when the levels of CLE40 or related CLE peptides increase. We show here that two antagonistically acting pathways controlling root meristem differentiation can be activated by the same peptide in a dosage-dependent manner.

Hemispheric Specialization of the Primate Inferior Parietal Lobule

Hemispheric asymmetries can be seen as one of the evolutionary adaptations that allowed the human brain to muster more complex cognitive processes than other primates.In this vein,the study published by Cheng et al.[1]presents a pivotal investigation of both the regional and connectional asymmetries within the inferior parietal lobule(IPL)in human,chimpanzee,and macaque.By investigating 4 sub-divisions of the IPL across the three species,Cheng and colleagues showed that the macroanatomical and connectional architecture of the IPL became more asymmetric throughout the primate lineage.While macaques show little to no structural asymmetries,chimpanzees display a more asymmetric architecture but with both leftward and rightward asymmetries in various connections.In contrast,the human IPL displayed the highest number of asymmetries among the three species with a clear tendency towards more lateralization.This evolutionary trend towards a more lateralized organization of the IPL may have accompanied an improved command of tool-use,stronger forelimb asymmetries,and the increasing complexity of communicative behavior.