Medical management of urolithiasis: Great efforts and limited progress

Objective:To provide a comprehensive review on the existing literature on medical management of urolithiasis.Methods:A thorough literature review was performed using Medline,PubMed/PMC,Embase,and the Cochrane Database of Systematic Reviews up to December 2022 to identify publications on the medical management of urolithiasis.Studies that assessed dietary and pharmacologic management of urolithiasis were reviewed;studies on medical expulsive therapy were not included in this review.Results:Medical management of urolithiasis ranges from the prophylactic management of kidney stone disease to dissolution therapies.While most treatment concepts have been long established,large randomized controlled trials are scarce.Dietary modification and increased fluid intake remain cornerstones in the conservative management of urolithiasis.A major limitation for medical management of urolithiasis is poor patient compliance.Conclusion:Medical management of urolithiasis is more important in patients with recurrent urolithiasis and patients with metabolic abnormalities putting them at higher risk of developing stones.Although medical management can be effective in limiting stone recurrence,medical interventions often fail due to poor compliance.

Silk-based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve

Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits(tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects(typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk-based tNGCs and compared the various features of these improved silk^(+) tNGCs with the tubes without holes(silk^(–) tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk^(+) tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk^(+) group was found compared with autologous nerve transplants and silk^(–), accompanied by improved axon regeneration at the distal coaptation point compared with the silk^(–) tNGCs at 7 weeks postoperatively. In the 15-mm(critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk^(+) tNGCs, but without improved functional recovery at 12 weeks postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimization of the macroscopic holes silk^(+) tNGC approach containing macroscopic holes might result in improved grafting technology suitable for future clinical use.

New perspectives on biology,disease progression,and therapy response of head and neck cancer gained from single cell RNA sequencing and spatial transcriptomics

Head and neck squamous cell carcinoma(HNSCC)is one of the most frequent cancers worldwide.The main risk factors are consumption of tobacco products and alcohol,as well as infection with human papilloma virus.Approved therapeutic options comprise surgery,radiation,chemotherapy,targeted therapy through epidermal growth factor receptor inhibition,and immunotherapy,but outcome has remained unsatisfactory due to recurrence rates of~50%and the frequent occurrence of second primaries.The availability of the human genome sequence at the beginning of the millennium heralded the omics era,in which rapid technological progress has advanced our knowledge of the molecular biology of malignant diseases,including HNSCC,at an unprecedented pace.Initially,microarray-based methods,followed by approaches based on next-generation sequencing,were applied to study the genetics,epigenetics,and gene expression patterns of bulk tumors.More recently,the advent of single-cell RNA sequencing(scRNAseq)and spatial transcriptomics methods has facilitated the investigation of the heterogeneity between and within different cell populations in the tumor microenvironment(e.g.,cancer cells,fibroblasts,immune cells,endothelial cells),led to the discovery of novel cell types,and advanced the discovery of cell-cell communication within tumors.This review provides an overview of scRNAseq,spatial transcriptomics,and the associated bioinformatics methods,and summarizes how their application has promoted our understanding of the emergence,composition,progression,and therapy responsiveness of,and intercellular signaling within,HNSCC.

Transurethral resection of bladder tumor: A systematic review of simulator-based training courses and curricula

Objective:Transurethral resection of bladder tumor is one of the most common everyday urological procedures.This kind of surgery demands a set of skills that need training and experience.In this review,we aimed to investigate the current literature to find out if simulators,phantoms,and other training models could be used as a tool for teaching urologists.Methods:A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement and the recommendations of the European Association of Urology guidelines for conducting systematic reviews.Fifteen out of 932 studies met our inclusion criteria and are presented in the current review.Results:The UroTrainer(Karl Storz GmbH,Tuttlingen,Germany),a virtual reality training simulator,achieved positive feedback and an excellent face and construct validity by the participants.The inspection of bladder mucosa,blood loss,tumor resection,and procedural time was improved after the training,especially for inexperienced urologists and medical students.The construct validity of UroSim®(VirtaMed,Zurich,Switzerland)was established.SIMBLA simulator(Samed GmbH,Dresden,Germany)was found to be a realistic and useful tool by experts and urologists with intermediate experience.The test objective competency model based on SIMBLA simulator could be used for evaluating urologists.The porcine model of the Asian Urological Surgery Training and Education Group also received positive feedback by the participants that tried it.The Simulation and Technology Enhanced Learning Initiative Project had an extraordinary face and content validity,and 60%of participants would like to use the simulators in the future.The 5-day multimodal training curriculum“Boot Camp”in the United Kingdom achieved an increase of the level of confidence of the participants that lasted months after the project.Conclusion:Simulators and courses or curricula based on a simulator training could be a valuable learning tool for any surgeon,and there is no doubt that they should be a part of every urologist's technical education.

Percutaneous antegrade management of large proximal ureteral stones using non-papillary puncture

Objective:To evaluate the feasibility and the safety of medial non-papillary percutaneous nephrolithotomy(npPCNL)for the management of large proximal ureteral stones.Methods:We evaluated prospectively collected data of 37 patients with large proximal ureteral stones more than 1.5 cm in diameter treated by prone npPCNL.Depending on stone size,in-toto stone removal or lithotripsy using the Lithoclast®Trilogy(EMS Medical,Nyon,Switzerland)was performed.Perioperative parameters including operative time(from start of puncture to the skin suturing),stone extraction time(from the first insertion of the nephroscope to the extraction of all stone fragments),and the stone-free rate were evaluated.Results:Twenty-one males and 16 females underwent npPCNL for the management of large upper ureteral calculi.The median age and stone size of treated patients were 58(interquartile range[IQR]:51-69)years and 19.3(IQR:18.0-22.0)mm,respectively.The median operative time and stone extraction time were 25(IQR:21-29)min and 8(IQR:7-10)min,respectively.One case(2.7%)of postoperative bleeding and two cases(5.4%)of prolonged fever were managed conservatively.The stone-free rate at a 1-month follow-up was 94.6%.Conclusion:The npPCNL provides a straight route to the ureteropelvic junction and proximal ureter.Approaching from a dilated portion of the ureter under low irrigation pressure with larger diameter instruments results in effective and safe stone extraction within a few minutes.

Long-term follow-up of intravesical abobotulinumtoxinA (Dysport®) injections in women with idiopathic detrusor overactivity

Objective:Only a few numbers of studies have been published on the use of abobotulinumtoxinA(Dysport®)in idiopathic detrusor overactivity(IDO).This study reported the long-term follow-up of women with IDO who were treated with intravesical Dysport®injections.Methods:Two hundred and thirty-six patients with IDO who had failed first-line conservative and antimuscarinic therapy received 500-900 units of Dysport®between April 2014 and July 2015.All patients were followed up for 5 years after their initial injection and interviewed on the phone.Results:A total of 236 women with IDO aged from 18 years to 84 years(mean±standard deviation:49.6±15.9 years)were included in our study.The median follow-up time for patients was 36.5(range:10-70)months,and the median recovery time after injection was 18.5(range:0-70)months.A total of 83(35.2%)patients stated that they had subjective improvement of their symptoms whereas 84(35.6%)patients did not report any improvement in symptoms.The initial International Consultation on Incontinence Questionnaire Overactive Bladder mean score was 6.9(standard deviation 3.4).There was a positive association between the median recovery time and the components of the International Consultation on Incontinence Questionnaire Overactive Bladder questionnaire.Conclusion:In a sub-population of overactive bladder patients with IDO who have failed first-line therapy,a single intravesical Dysport®injection can resolve patient symptoms completely or reduce the symptoms to an acceptable level that can be controlled with antimuscarinics or re-injection on demands.

Calcium channels caught in peripheral glia’s tug-of-war on axon regeneration in Drosophila

Neural damage or degeneration is at the crux of many diseases,and treatment of these diseases will require the development of therapeutics to enhance and guide neural regeneration.Both intrinsic and extrinsic factors dictate a neuron’s ability to regenerate,and the combination of these factors results in the great regenerative capacity of the peripheral nervous system(PNS)and the poor regenerative capacity of the central nervous system(CNS)following injury.At the core of a neuron’s function is its ability to relay electrochemical signals,and a neuron’s excitability is a key factor in its ability to regenerate.Recent works have focused on the changes in neuronal electrophysiological properties,firing patterns,and ion flux after injury,which differentially activate signaling pathways at the core of regeneration.The role of glia in neuron regeneration has long been studied.

A systematic review of cytoreductive prostatectomy outcomes and complications in oligometastatic disease

Objective: To analyze outcomes and complications of cytoreductive prostatectomy (CRP) for oligometastatic prostate cancer (PCa) in order to elucidate its role in this space.Methods: We performed a systematic literature search using three databases (Medline, Scopus, and Web of Science). The primary endpoints were oncologic outcomes. The secondary endpoints were complication rates and functional results.Results: In all studies, overall survival was better or at least comparable variable in the groups with CRP compared to no local treatment. The greatest benefit from CRP in 5-year overall survival in one study was 67.4% for CRP versus 22.5% for no local treatment. Cancer-specific survival (CSS) showed the same trend. Several authors found significant benefits from CSS in the CRP group: from 79% vs. 46% to 100% vs. 61%. CRP was a predictor of better CSS (hazard ratio 0.264, p=0.004). Positive surgical margin rates differed widely from 28.6% to 100.0%. Urinary continence in CRP versus RP for localized PCa was significantly lower (57.4% vs. 90.8%, p<0.0001). Severe incontinence occurred seldom (2.5%-18.6%). Total complication rates after CRP differed widely, from 7.0% to 43.6%. Rates of grades 1 and 2 events prevailed. Patients on ADT alone also showed a considerable number of complications varying from 5.9% to 57.7%.Conclusion: CRP improves medium-term cancer control in patients with oligometastatic PCa. The morbidity and complication rates of this surgery are comparable with other approaches, but postoperative incontinence rate is higher compared with RP for localized disease.

Importance of communication in medical practice and medical education:An emphasis on empathy and attitudes and their possible influences

BACKGROUND Healthcare professionals need to be prepared to promote healthy lifestyles and care for patients.By focusing on what students should be able to perform one day as clinicians,we can bridge the gap between mere theoretical knowledge and its practical application.Gender aspects in clinical medicine also have to be considered when speaking of personalized medicine and learning curricula.AIM To determine sets of intellectual,personal,social,and emotional abilities that comprise core qualifications in medicine for performing well in anamnesis-taking,in order to identify training needs.METHODS An analysis of training clinicians’conceptions with respect to optimal medical history taking was performed.The chosen study design also aimed to assess gender effects.Structured interviews with supervising clinicians were carried out in a descriptive study at the Medical University of Vienna.Results were analyzed by conducting a qualitative computer-assisted content analysis of the interviews.Inductive category formation was applied.The main questions posed to the supervisors dealt with(1)Observed competencies of students in medical history taking;and(2)The supervisor’s own conceptions of"ideal medical history taking".RESULTS A total of 33 training clinicians(n=33),engaged in supervising medical students according to the MedUni Vienna’s curriculum standards,agreed to be enrolled in the study and met inclusion criteria.The qualitative content analysis revealed the following themes relevant to taking an anamnesis:(1)Knowledge;(2)Soft skills(relationship-building abilities,trust,and attitude);(3)Methodical skills(structuring,precision,and completeness of information gathering);and(4)Environmental/contextual factors(language barrier,time pressure,interruptions).Overall,health care professionals consider empathy and attitude as critical features concerning the quality of medical history taking.When looking at physicians’theoretical conceptions,more general practitioners and psychiatrists mentioned attitude and empathy in the context of"ideal medical history taking",with a higher percentage of females.With respect to observations of students’history taking,a positive impact from attitude and empathy was mainly described by male health care professionals,whereas no predominance of specialty was found.Representatives of general medicine and internal medicine,when observing medical students,more often emphasized a negative impact on history taking when students lacked attitude or showed non-empathetic behavior;no gender-specific difference was detected for this finding.CONCLUSION The analysis reveals that for clinicians engaged in medical student education,only a combination of skills,including adequate knowledge and methodical implementations,is supposed to guarantee acceptable performance.This study’s findings support the importance of concepts like relationship building,attitude,and empathy.However,there may be contextual factors in play as well,and transference of theoretical concepts into the clinical setting might prove challenging.

Artificial Intelligence and the Sustainable Development Goals: An Exploratory Study in the Context of the Society Domain

Artificial Intelligence (AI) experienced significant advancements in recent years, and its potential power is already recognized across various industries. Yet, the rise of AI has led to a growing concern about its impact on meeting the Sustainable Development Goals (SDGs). The aim of this paper was to evaluate contributions and the potential influence of AI to sustainable development in the society domain. Furthermore, the study analyzed GPT-3 responses, as one of the largest language models developed by OpenAI, descriptively. We conducted a set of queries on the SDGs to gather information on GPT-3’s perceptions of AI impact on sustainable development. Analysis of GPT-3’s contribution potential towards the SDGs showcased its broad range of capabilities for contributing to the SDGs in areas such as education, health, and communication. The study findings provide valuable insights into the contributions of AI to sustainable development in the society domain and highlight the importance of proper regulations to promote the responsible use of AI for sustainable development. We highlighted the potential for improvement in neural language processing skills of GPT-3 by avoiding imitating weak human writing styles with more mistakes in longer texts.

Changes of protein expression during tumorosphere formation of small cell lung cancer circulating tumor cells

Small cell lung cancer(SCLC)is frequently disseminated and has a dismal prognosis with survival times of approximately two years.This cancer responds well to initial chemotherapy but recurs within a short time as a globally chemoresistant tumor.Circulating tumor cells(CTCs)are held responsible for metastasis,the extremely high numbers of these cells in advanced SCLC allowed us to establish several permanent CTC cell lines.These CTCs are distinguished by the spontaneous formation of large spheroids,termed tumorospheres,in regular tissue culture.These contain quiescent and hypoxic cells in their interior and are associated with high chemoresistance compared to single cell cultures.Nine CTC lines were compared for their expression of 84 proteins associated with cancer either as single cells or in the form of tumorospheres in Western blot arrays.With the exception of the UHGc5 line,all other CTC lines express EpCAM and lack a complete EpCAM-negative,vimentin-positive epithelial-mesenchymal transition(EMT)phenotype.Upon formation of tumorospheres the expression of EpCAM,that mediates cell-cell adhesion is markedly upregulated.Proteins such as E-Cadherin,p27 KIP1,Progranulin,BXclx,Galectin-3,and Survivin showed variable changes for the distinct CTC cell lines.In conclusion,EpCAM presents the most critical marker for individual SCLC CTCs and the assembly of highly chemoresistant tumorospheres.

Characteristic metabolic and microbial profiles in acute ischemic stroke patients with phlegm-heat pattern

Objective:To explore the characteristics of plasma metabolites,feces gut microbiota and the crosstalk between gut microbiota and host metabolism in patients with acute ischemic stroke and phlegm-heat pattern(AIS-PHP).Methods:The metabolic and microbiome profiles of 20 AIS-PHP patients and 20 healthy controls(HCs)were analyzed using liquid chromatography-tandem mass spectrometry(LC-MS/MS)-based metabolomics and 16s rDNA sequencing,respectively.The covariation between LC-MS/MS-based metabolite data and 16s rDNA sequence data was presented.Results:Distinct alterations in the plasma metabolic phenotype of AIS-PHP patients were found,in which 16 metabolites differed significantly between the AIS-PHP patients and the HCs.These metabolites represented 17 different metabolic pathways,including amino acid metabolism,lipid metabolism,and nucleotide metabolism.Additionally,significant alterations of gut microbiota composition and taxon were revealed at the phylum level between the AIS-PHP patients and the HCs.In AIS-PHP,Bacteroidetes,Firmicutes,and Proteobacteria dominated.Moreover,some microbes that differed between the 2 groups manifested a sole association with certain metabolites,such as the connection between Bacteroides and inosine and between Lachnospiraceae_unclassified and hypoxanthine.Conclusion:The present study preliminarily investigated the metabolomic and gut microbiome characteristics of AIS-PHP patient indicators.The link between metabolic and microbial dysbiosis in AIS-PHP sheds new light on the function of gut microbiota and associated metabolomics in the pathogenesis of the disease.

Diagnostic value ultrasound signs of stones less than or equal to 10 mm and clinicoradiological variants of ureteric colic

Objective:To determine the diagnostic value of ultrasound signs of urinary stones less than or equal to 10 mm and to determine clinico-radiological variants of ureteric colic.Methods:A total of 455 ultrasound investigations were performed in patients referring to emergency department with urolithiasis and symptoms suspected of ureteric colic between January 2021 and May 2021.In addition to microscopic evaluation of urine sediment to detect different crystals and non-contrast spiral computed tomography to detect stones,B-mode and color Doppler sonography was performed to assess the presence of acoustic shadow(AS)and twinkle artifacts(TA)as possible signs of stone(s)in ureter.Results:While the sensitivity and specificity of AS and TA were higher than 90%in patients with stones greater than 5 mm;positive prognostic values of these parameters were found to be extremely low for stones with sizes of 1-3 mm with specificity and sensitivity values not exceeding 53%.The sensitivity and specificity of AS and TA in the upper and lower ureters were higher for stones greater than or equal to 5 than for compared to those less than 5 mm.At the same time,the diagnostic values of TA and AS for middle ureter stones were very limited.The most prevalent clinico-radiological variants of ureteric colic were types I,III,and V being observed in 39%,28% and 21% cases,respectively.Conclusion:Our results demonstrate that TA and AS parameters seem to have a very low sensitivity and specificity in the diagnosis of urinary stones less than 5 mm.The diagnostic value of TA and AS increase significantly in stones greater than or equal to 5 mm.Therefore,clinicians need to be very careful for overestimating the diagnostic values of TA and AS for stones less than 5 mm and non-contrast spiral computed tomography must be the method of choice for patients presenting to emergency department with ureteric colic.

Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma

BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI.Deaths are reported in<5%of patients treated with ICI.There are,however,no reliable markers to predict the onset and severity of IrAEs.We tested the association between neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR)at baseline with development of clinically significant IrAEs(grade≥2)in hepatocellular carcinoma(HCC)patients treated with ICI.AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs(grade≥2)in HCC patients treated with ICI.METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers.NLR=absolute neutrophil count/absolute lymphocyte count(ALC)and PLR=platelet count/ALC.Cutoff of 5 was used for NLR and 300 for PLR based on literature.We also tested the association between RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States(67%),Asia(14%)and Europe(19%).Most patients received Nivolumab(n=255,71%).One hundred sixty-seven(46%)patients developed at least one IrAE,highest grade 1 in 80(48%),grade≥2 in 87(52%)patients.In a univariable regression model PLR>300 was significantly associated with a lower incidence of grade≥2 IrAEs(OR=0.40;P=0.044).Similarly,a trend was observed between NLR>5 and lower incidence of grade≥2 IrAEs(OR=0.58;P=0.097).Multivariate analyses confirmed PLR>300 as an independent predictive marker of grade≥2 IrAEs(OR=0.26;P=0.011),in addition to treatment with programmed cell death ligand 1(PD-1)/cytotoxic T lymphocyte-associated protein-4(OR=2.57;P=0.037)and PD-1/tyrosine kinase inhibitor(OR=3.39;P=0.01)combinations.Antibiotic use was not associated with IrAE incidence(OR=1.02;P=0.954).Patients treated with steroids had a>2-fold higher incidence of grade≥2 IrAEs(OR=2.74;P<0.001),although 74%were prescribed steroids for the treatment of IrAEs.CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs,lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI.This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Targeting KRAS in pancreatic cancer

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies.The Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and constitutes an attractive target for therapy.However,the most common KRAS mutations in PDAC are G12D(44%),G12V(34%)and G12R(20%)that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer.KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3%of PDAC.Recently,the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development.The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor(GEF)Son of Sevenless 1 that drives KRAS.These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

Immunomodulatory properties of dental tissue-derived mesenchymal stem cells: Implication in disease and tissue regeneration

Mesenchymal stem cells(MSCs)are considered as an attractive tool for tissue regeneration and possess a strong immunomodulatory ability.Dental tissuederived MSCs can be isolated from different sources,such as the dental pulp,periodontal ligament,deciduous teeth,apical papilla,dental follicles and gingiva.According to numerous in vitro studies,the effect of dental MSCs on immune cells might depend on several factors,such as the experimental setting,MSC tissue source and type of immune cell preparation.Most studies have shown that the immunomodulatory activity of dental MSCs is strongly upregulated by activated immune cells.MSCs exert mostly immunosuppressive effects,leading to the dampening of immune cell activation.Thus,the reciprocal interaction between dental MSCs and immune cells represents an elegant mechanism that potentially contributes to tissue homeostasis and inflammatory disease progression.Although the immunomodulatory potential of dental MSCs has been extensively investigated in vitro,its role in vivo remains obscure.A few studies have reported that the MSCs isolated from inflamed dental tissues have a compromised immunomodulatory ability.Moreover,the expression of some immunomodulatory proteins is enhanced in periodontal disease and even shows some correlation with disease severity.MSC-based immunomodulation may play an essential role in the regeneration of different dental tissues.Therefore,immunomodulation-based strategies may be a very promising tool in regenerative dentistry.

Molecular biology of high-grade gliomas: what should the clinician know?

The current World Health Organization classification system of primary brain tumors is solely based on morphologic criteria. However, there is accumulating evidence that tumors with similar histology have distinct molecular signatures that significantly impact treatment response and survival. Recent practice-changing clinical trials have defined a role for routine assessment of O-6-methylguanine-DNA methyltransferase(MGMT) promoter methylation in glioblastoma patients, especially in the elderly, and 1p and 19q codeletions in patients with anaplastic glial tumors. Recently discovered molecular alterations including mutations in IDH-1/2, epidermal growth factor receptor(EGFR), and BRAF also have the potential to become targets for future drug development. This article aims to summarize current knowledge on the molecular biology of high-grade gliomas relevant to daily practice.

Assessment of bone turnover and bone quality in type 2 diabetic bone disease： current concepts and future directions

Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due to altered bone properties in diabetes. Circulating biochemical markers of bone turnover have been found to be decreased in type 2 diabetes （T2D） and may be predictive of fractures independently of bone mineral density （BMD）. Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Bone imaging technologies, including trabecular bone score （TBS） and quantitative CT testing have revealed differences in diabetic bone as compared to non-diabetic individuals. Specifically, high resolution peripheral quantitative CT （HRpQCT） imaging has demonstrated increased cortical porosity in diabetic postmenopausal women. Other factors such as bone marrow fat saturation and advanced glycation endproduct （AGE） accumulation might also relate to bone cell function and fracture risk in diabetes. These data have increased our understanding of how T2D adversely impacts both bone metabolism and fracture risk.

Identification of CD13,CD107a,and CD164 as novel basophil-activation markers and dissection of two response patterns in time kinetics of IgE-de-pendent upregulation

Using two-colour flow cytometry >200 antibodies submitted to the 8th International Workshop of Human Leukocyte Differentiation Antigens (HLDA8) have been analyzed for their reactivity with resting and activated CD203c+ basophils. Four antibodies either non-reactive or weakly reactive with resting basophils exhibited an increased reactivity with basophils activated by anti-IgE-mediated cross-linking of the high affinity IgE receptor (FcεRI). These include antibod- ies against CD164 (WS-80160, clone N6B6 and WS-80162, clone 67D2), as well as two reagents with previously unknown specificities that were identified as CD13 (WS-80274, clone A8) and CD107a (WS-80280, clone E63-880). The activation patterns followed either the “CD203c-like” or “CD63-like” activation profile. The CD203c profile is characterized by a rapid and significant upregulation (of CD13, CD164, and CD203c), reaching maximum levels after 5- 15 min of stimulation. The phosphoinositide-3-kinase (PI3K)-specific inhibitor wortmannin inhibited the upregulation of these markers whereas 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced a rapid and FcεRI-independent upregulation within 1-2 min. In the CD63 profile, maximum upregulation (of CD63 and CD107a) was detected only after 20-40 min, and upregulation by TPA reached maximum levels after 60 min. In summary, our data identify CD13, CD107a, and CD164 as novel basophil-activation antigens. Based on time kinetics of upregulation, we hypothesize that molecules of the “CD203c group” and the “CD63 group” are linked to two different mechanisms of basophil activation.

Clinical algorithms for the prevention of variceal bleeding and rebleeding in patients with liver cirrhosis

Portal hypertension(PH),a common complication of liver cirrhosis,results in development of esophageal varices.When esophageal varices rupture,they cause significant upper gastrointestinal bleeding with mortality rates up to 20%despite state-of-the-art treatment.Thus,prophylactic measures are of utmost importance to improve outcomes of patients with PH.Several high-quality studies have demonstrated that non-selective beta blockers(NSBBs)or endoscopic band ligation(EBL)are effective for primary prophylaxis of variceal bleeding.In secondary prophylaxis,a combination of NSBB+EBL should be routinely used.Once esophageal varices develop and variceal bleeding occurs,standardized treatment algorithms should be followed to minimize bleeding-associated mortality.Special attention should be paid to avoidance of overtransfusion,early initiation of vasoconstrictive therapy,prophylactic antibiotics and early endoscopic therapy.Pre-emptive transjugular intrahepatic portosystemic shunt should be used in all Child C10-C13 patients experiencing variceal bleeding,and potentially in Child B patients with active bleeding at endoscopy.The use of carvedilol,safety of NSBBs in advanced cirrhosis(i.e.with refractory ascites)and assessment of hepatic venous pressure gradient response to NSBB is discussed.In the present review,we give an overview on the rationale behind the latest guidelines and summarize key papers that have led to significant advances in the field.