Background:The German Military Medical Service contributed to the medical screening of unaccompanied minor refugees(UMRs)coming to Germany in 2014 and 2015.In this study,a broad range of diagnostic procedures was appl...Background:The German Military Medical Service contributed to the medical screening of unaccompanied minor refugees(UMRs)coming to Germany in 2014 and 2015.In this study,a broad range of diagnostic procedures was applied to identify microorganisms with clinical or public health significance.Previously,those tests had only been used to screen soldiers returning from tropical deployments.This instance is the first time the approach has been studied in a humanitarian context.Methods:The offered screenings included blood cell counts,hepatitis B serology and microscopy of the stool to look for protozoa and worm eggs as well as PCR from stool samples targeting pathogenic bacteria,protozoa and helminths.If individuals refused certain assessments,their decision to do so was accepted.A total of 219 apparently healthy male UMRs coming from Afghanistan,Egypt,Somalia,Eritrea,Syria,Ghana,Guinea,Iran,Algeria,Iraq,Benin,Gambia,Libya,Morocco,Pakistan,and Palestine were assessed.All UMRs who were examined at the study department were included in the assessment.Results:We detected decreasing frequencies of pathogens that included diarrhoea-associated bacteria[Campylobacter(C.)jejuni,enteropathogenic Escherichia(E.)coli(EPEC),enterotoxic E.coli(ETEC),enteroaggregative E.coli(EAEC),enteroinvasive E.coli(EIEC)/Shigella spp.),Giardia(G.)duodenalis,helminths(comprising Schistosoma spp.,Hymenolepis(H.)nana,Strongyloides(S.)stercoralis]as well as hepatitis B virus.Pathogenic microorganisms dominated the samples by far.While G.duodenalis was detected in 11.4%of the assessed UMRs,the incidence of newly identified cases in the German population was 4.5 cases per 100,000 inhabitants.Conclusion:We conclude that the applied in-house PCR screening systems,which have proven to be useful for screening military returnees from tropical deployments,can also be used for health assessment of immigrants from the respective sites.Apparently healthy UMRs may be enterically colonized with a broad variety of pathogenic and apathogenic microorganisms.Increased colonization rates,as shown for G.duodenalis,can pose a hygiene problem in centralized homes for asylum seekers.展开更多
Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell types.While we and others have previously demonstrated that the expression of Piezo1 in osteo...Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell types.While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage.Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)development.Mice with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate postnatally.Moreover,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth plates.While skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age.Likewise,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage degeneration.Importantly,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) mice.We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes.Finally,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes.Collectively,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.展开更多
Objective:In this study,we investigated the concept of empowerment in chronic wound care and propose to facilitate patient control by making use of degrees of freedom(DOF):that is,shaping of everyday wound care tasks ...Objective:In this study,we investigated the concept of empowerment in chronic wound care and propose to facilitate patient control by making use of degrees of freedom(DOF):that is,shaping of everyday wound care tasks initiated by patients and based on their wishes,mostly in terms of patients executing treatment steps,requesting or directing health care professionals to under take changes,or modifications of internal states.Methods:As a first step,we conducted a systematic literature search,followed by an inductive form of qualitative content analysis,which resulted in the identification of 5 dimensions as main elements of empowerment:education and shared decision making,adherence to self-care behaviors,responsibility and control,general call for empowerment,and DOF.However,the latter are noticeably absent in the literature.To investigate patients'freedom in shaping the wound care process,we conducted a second literature search.Results:A number of possibilities for patients to influence the wound care process could be identified,but experimental or clinical evidence about their effects is missing,their variety is limited,and they are only inadequately described.Conclusions:However,DOF should be an indispensable aspect of genuine empowerment,since they allow patients to occupy the role of the agent in the treatment process and give rise to the subjective experience of feeling empowered.Thus,in the third part,we develop a research proposal on how to investigate and include DOF in the clinical practice of wound care.Finally,limitations about implementations are discussed(e.g.,patients being reluctant to overcome their passive role,resulting in frustration for health care professionals).展开更多
In the last decades,the role of the prion protein(PrP) in neurodegenerative diseases has been intensively investigated,initially in prion diseases of humans(e.g., Creutzfeldt-J akob disease) and animals(e.g.,scrapie i...In the last decades,the role of the prion protein(PrP) in neurodegenerative diseases has been intensively investigated,initially in prion diseases of humans(e.g., Creutzfeldt-J akob disease) and animals(e.g.,scrapie in sheep,chronic wasting disease in deer and elk,or "mad cow disease" in cattle).Templated misfolding of physiological cellular prion protein(PrPC) into an aggregation-prone isoform(termed PrP "Scrapie"(PrPSc)),self-re plication and spreading of the latter inside the brain and to peripheral tissues,and the associated formation of infectious proteopathic seeds(termed "prions")are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies.Late r,key roles of the correctly folded PrPCwere identified in more common human brain diseases(such as Alzheimer s disease or Parkinson’s disease) associated with the misfolding and/or accumulation of other proteins(such as amyloid-β,tau or α-synuclein,respectively).PrPChas also been linked with n euro protective and regenerative functions,for instance in hypoxic/ischemic conditions such as stroke.However,despite a mixed "bouquet" of suggested functions,our understanding of pathological and,especially,physiological roles played by PrPCin the brain and beyond is ce rtainly incomplete.Interactions with various other proteins at the cell surfa ce or within intracellular compartments may account for the functional diversity linked with PrPC.Moreover,conserved endogenous proteolytic processing of PrPCgenerates seve ral defined PrPCfragments,possibly holding intrinsic functions in physiological and pathological conditions,thus making the "true and complete biology" of this protein more complicated to be elucidated.Here,we focus on one of those released PrPCfragments,namely shed PrP(sPrP),generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surfa ce.Similar to other soluble PrP fragments(such as the N1 fragment representing PrP’s released N-terminal tail upon the major α-cleavage event)or expe rimentally employed recombinant PrP,sPrP is being suggested to act n euro protective in Alzheimer’s disease and other protein misfolding diseases.Seve ral lines of evidence on extracellular PrPC(fragments) suggest that induction of PrPCrelease co uld be a future therapeutic option in various brain disorders.Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM 10,based on ligands binding to cell surface PrPC,may further set the stage for research into this direction.展开更多
Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life.Here,we summarize emerging links between the most common ...Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life.Here,we summarize emerging links between the most common late life neurodegenerative disease,Alzheimer’s disease,and the most common early life neurodegenerative diseases,neuronal ceroid lipofuscinoses.Genetic studies reported an overlap of clinically diagnosed Alzheimer’s disease and mutations in genes known to cause neuronal ceroid lipofuscinoses.Accumulating data strongly suggest dysfunction of intracellular trafficking mechanisms and the autophagy-endolysosome system in both types of neurodegenerative disorders.This suggests shared cytopathological processes underlying these different types of neurodegenerative diseases.A better understanding of the common mechanisms underlying the different diseases is important as this might lead to the identification of novel targets for therapeutic concepts,the transfer of therapeutic strategies from one disease to the other and therapeutic approaches tailored to patients with specific mutations.Here,we review dysfunctions of the endolysosomal autophagy pathway in Alzheimer’s disease and neuronal ceroid lipofuscinoses and summarize emerging etiologic and genetic overlaps.展开更多
Neuronal ceroid lipofuscinosis(NCL),also known as Batten disease,is the umbrella term for a group of neurodegenerative lysosomal storage disorders with onset mainly in childhood.The total 13 genetically distinct NCLs ...Neuronal ceroid lipofuscinosis(NCL),also known as Batten disease,is the umbrella term for a group of neurodegenerative lysosomal storage disorders with onset mainly in childhood.The total 13 genetically distinct NCLs are caused by mutations in genes encoding soluble or transmembrane proteins,and have been classified according to the affected gene into CLN1 to CLN8 and CLN10 to CLN14.Intracellular accumulation of autofluorescent storage material due to lysosomal dysfunction is a hallmark of all NCLs.展开更多
BACKGROUND Periodontitis has been associated with various liver diseases.However,the relevance of periodontitis in the progression of decompensated cirrhosis remains inconclusive.In particular,it is unclear whether th...BACKGROUND Periodontitis has been associated with various liver diseases.However,the relevance of periodontitis in the progression of decompensated cirrhosis remains inconclusive.In particular,it is unclear whether the common periodontitis pathogens,Porphyromonas gingivalis(P.gingivalis)and Actinobacillus actinomycetemcomitans(A.actinomycetemcomitans),can be detected not only in the oral mucosa but also in ascites and stool.AIM To investigate the significance of periodontitis,P.gingivalis,and A.actinomycetemcomitans in cirrhosis patients with ascitic decompensation.METHODS This prospective study was conducted at the University Hospital Hamburg Eppendorf,a tertiary center in Northern Germany.A cohort of 27 patients with ascitic decompensated liver cirrhosis underwent dental examinations to assess the association between periodontitis and various clinical parameters of cirrhosis,as well as patient outcomes.PCR was used to test gingival samples,ascites,and stool for the presence of P.gingivalis and A.actinomycetemcomitans.Gingival samples were collected by probing the deepest gum pocket of a sextant and wiping them on a cotton swab.RESULTS Periodontitis was diagnosed in 22 out of 27(82%)ascite patients,which is significantly more common than in a control cohort of 100 unselected patients(59%,P=0.04).P.gingivalis was detected in the gingiva of six patients,and one of them also had P.gingivalis in their stool.However,P.gingivalis was not found in the ascites of any patient.Five out of six patients with P.gingivalis had periodontitis(83%).A.actinomycetemcomitans was not detected in any sample.Patients without periodontitis had a significantly higher mortality rate compared to those with periodontitis,and survival(Kaplan-Meier analysis)was longer in patients with periodontitis(P=0.02).Transplantfree survival was also more common in patients with periodontitis compared to those without(63%vs 0%,P=0.02).CONCLUSION Decompensated cirrhotic patients frequently suffer from periodontitis.However,there was no evidence of the translocation of P.gingivalis or A.actinomycetemcomitans into ascites.The survival of cirrhotic patients with periodontitis was not reduced.展开更多
Acute hepatic failure due to hepatitis B virus(HBV)can occur both during primary infection as well as after reactivation of chronic infection.Guidelines recommend considering antiviral therapy in both situations,altho...Acute hepatic failure due to hepatitis B virus(HBV)can occur both during primary infection as well as after reactivation of chronic infection.Guidelines recommend considering antiviral therapy in both situations,although evidence supporting this recommendation is weak.Since HBV is not directly cytopathic,the mechanism leading to fulminant hepatitis B is thought to be primarily immunemediated.Therefore,immunosuppression combined with antiviral therapy might be a preferred therapeutic intervention in acute liver failure in hepatitis B.Here wereport our favourable experience in three hepatitis B patients with fulminant hepatic failure who were treated by combining high-dose steroid therapy with standard antiviral treatment,which resulted in a rapid improvement of clinical and liver parameters.展开更多
Associating liver partition and portal vein ligation for staged hepatectomy(ALPPS) is a novel approach in liver surgery that allows for extensive resection of liver parenchyma by inducing a rapid hypertrophy of the fu...Associating liver partition and portal vein ligation for staged hepatectomy(ALPPS) is a novel approach in liver surgery that allows for extensive resection of liver parenchyma by inducing a rapid hypertrophy of the future remnant liver. However,recent reports indicate that not all patients eligible for ALPPS will benefit from this procedure. Therefore,careful patient selection will be necessary to fully exploit possible benefits of ALPPS. Here,we provide a comprehensive overview of the technical evolution of ALPPS with a special emphasis on safety and oncologic efficacy. Furthermore,we review the contemporary literature regarding indication and benefits,but also limitations of ALPPS.展开更多
Aim： To test the hypothesis that sildenafil （50 mg nightly for one year） can improve spontaneous erectile function （EF） in men with mild-to-moderate arteriogenic erectile dysfunction （ED） responsive to erectoge...Aim： To test the hypothesis that sildenafil （50 mg nightly for one year） can improve spontaneous erectile function （EF） in men with mild-to-moderate arteriogenic erectile dysfunction （ED） responsive to erectogenic treatment. Methods： In a prospective open-label trial, 112 men with ED were randomized to sildenafil 50 mg nightly or sildenafil 50 or 100 mg as needed for 12 months, followed by one-month and 6-month non-medicated periods. Non-randomized, non-medicated men with ED were also assessed. The EF domain of the International Index of Erectile Function （IIEF EF） and the peak systolic velocity （PSV） of penile cavernous arteries were used to measure the efficacy. Results： After sildenafil treatment and a subsequent non-medicated month, IIEF EF was normal in 29 of 48 （60.4%, 95% confidence interval [CI]： 45.3-74.2%） of the nightly group vs. 4 of 49 （8.2%, 95% CI： 2.3-19.6%） of the as-needed group. PSV improved by 11.2 cm/s （95% CI： 4.7-21.4; P = 0.012） in the nightly group but only by 3.4 cm/s （-5.1- 14.7; P = 0.435） in the as-needed group. IIEF EF normalized in 1 of 18 （5.6%, 95% CI： 0.1-27.3%） non-medicated men and the PSV declined slightly. Six months after treatment, the IIEF EF remained normal and PSV was stabilized in most （28/29, 97%） nightly group men who had initially normalized. Conclusion： Sildenafil nightly for one year resulted in ED regression that persisted well beyond the end of treatment, so that spontaneous EF was characterized as normal on the IIEF in most men. The results from this open-label, randomized trial warrant verification under double-blind, placebo-controlled conditions.展开更多
Iatrogenic ureteral injuries and strictures are relatively common complication of pelvic surgery and radiation treatment.Left untreated they are associated with severe shortand long-term complications such as urinoma,...Iatrogenic ureteral injuries and strictures are relatively common complication of pelvic surgery and radiation treatment.Left untreated they are associated with severe shortand long-term complications such as urinoma,septic state,renal failure,and loss of a renal unit.Treatment depends on timing of diagnosis,as well as extent of injury,and ranges from simple endoscopic management to complex surgical reconstruction under usage of pedicled grafts.While recent advances in ureteral tissue engineering are promising the topic is still underreported.Historically a domain of open surgery,laparoscopic and robotic-assisted approaches have proven their feasibility in small case series,and are increasingly being utilized as means of reconstructive surgery.This review aims to give an outline of incidence and treatment of ureteral injuries and strictures in light of the latest advances.展开更多
Due to a lack of substantial improvement in the outcome of patients suffering from oral squamous cell carcinoma(OSCC) during the past decades, current staging methods need to be revised. This disease is associated wit...Due to a lack of substantial improvement in the outcome of patients suffering from oral squamous cell carcinoma(OSCC) during the past decades, current staging methods need to be revised. This disease is associated with poor survival rates despite considerable advances in diagnosis and treatment. The early detection of metastases is an important indicator of survival, prognosis and relapse. Therefore, a better understanding of the mechanisms underlying metastasis is crucial. Exploring alternative measures apart from common procedures is needed to identify new prognostic markers. Similar to previous findings predominantly for other solid tumours, recently published studies demonstrate that circulating tumour cells(CTCs) and disseminated tumour cells(DTCs) might serve as prognostic markers and could supplement routine staging in OSCC. Thus, the detection of CTCs/DTCs is a promising tool todetermine the individual need for therapeutic intervention. Encouraging results and new approaches point to the future use of targeted therapies for OSCC, an exceedingly heterogeneous subgroup of head and neck cancer. This review focuses on summarising technologies currently used to detect CTCs/DTCs. The translational relevance for OSCC is highlighted. The inherent challenges in detecting CTCs/DTCs will be emphasised.展开更多
AIM： Microcirculatory dysfunction and free oxygen radicals are important factors in the pathogenesis of severe acute pancreatitis. Additional oxygen delivery might enhance lipid peroxidation but may also improve panc...AIM： Microcirculatory dysfunction and free oxygen radicals are important factors in the pathogenesis of severe acute pancreatitis. Additional oxygen delivery might enhance lipid peroxidation but may also improve pancreatic microcirculation. This study assesses the effect of free cellular bovine hemoglobin on the formation of oxygen radicals and microcirculation in a rodent model of severe acute pancreatitis. METHODS： Fifteen minutes after induction of acute pancreatitis Wistar rats received either 0.8 mL bovine hemoglobin （HBOC-200）, hydroxyethyl starch （HES） or 2.4 mL of normal saline to ensure normovolemic substitution. After 6 h of examination the pancreas was excised and rapidly processed for indirect measurement of lipid peroxidation products malondialdehyde （MDA） and reduced glutathione （GSH） in pancreatic tissue. RESULTS： The single application of HBOC-200 improved pancreatic microcirculation and reduced histopathological tissue damage significantly. Tissue concentration of MDA did not differ between the groups. Also no differences in GSH levels were detected.CONCLUSION： Though the single application of HBOC-200 and HES improve pancreatic microcirculation, no differences in lipid peroxidation products were detected. The beneficial effect of additional oxygen supply （HBOC-200） does not lead to enhanced lipid peroxidation.展开更多
In contrast to other tumor types, immunotherapy has not yet become a relevant part of the treatment landscape of unselected colorectal cancer. Beside the small subgroup of deficient mismatch repair or microsatellite i...In contrast to other tumor types, immunotherapy has not yet become a relevant part of the treatment landscape of unselected colorectal cancer. Beside the small subgroup of deficient mismatch repair or microsatellite instable tumors (about 5%) as a surrogate for high mutational burden and subsequently high neoantigen load and immunogenicity, inhibitors of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and/or cytotoxic T lymphocyte-associated antigen-4 were not or only modestly effective in metastatic colorectal cancer. Thus, a variety of combination approaches with chemotherapy, targeted therapy, toll-like receptor agonists, local ablation or oncolytic viruses is currently being evaluated in different disease settings. Despite several encouraging single arm data already presented or published, available randomized data are unimpressive. Adding PD-1/PD-L1 inhibitors to fluoropyrimidines and bevacizumab maintenance showed no beneficial impact on delaying progression. In refractory disease, the combination of PD-1/PD-L1 and MEK inhibitor was not different from regorafenib, whereas a PD-1/PD-L1 and cytotoxic T lymphocyteassociated antigen-4 inhibitor combination demonstrated better overall survival compared to supportive care alone. Clinical trials in all disease settings applying different combination approaches are ongoing and may define the role of immunotherapy in colorectal cancer.展开更多
Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic stu...Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1(Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and bone mass.Mice lacking Lrp1 specifically in the osteoblast lineage displayed normal osteoblast function but severe osteoporosis due to highly increased osteoclast numbers and bone resorption. Osteoblast Lrp1 limited receptor activator of NF-κB ligand(RANKL) expression in vivo and in vitro through attenuation of platelet-derived growth factor(PDGF-BB) signaling. In co-culture, Lrp1-deficient osteoblasts stimulated osteoclastogenesis in a PDGFRβ-dependent manner and in vivo treatment with the PDGFR tyrosine kinase inhibitor imatinib mesylate limited RANKL production and led to complete remission of the osteoporotic phenotype. These results identify osteoblast Lrp1 as a key regulator of osteoblast-to-osteoclast communication and bone mass through a PDGF–RANKL signaling axis in osteoblasts and open perspectives to further explore the potential of PDGF signaling inhibitors in counteracting bone loss as well as to evaluate the importance of functional LRP1 gene variants in the control of bone mass in humans.展开更多
Osteoporosis is a systemic bone disease that affects more than 200 million people worldwide and is caused by the disruption of the equilibrium between osteoclastic bone resorption and osteoblastic bone formation. Sphi...Osteoporosis is a systemic bone disease that affects more than 200 million people worldwide and is caused by the disruption of the equilibrium between osteoclastic bone resorption and osteoblastic bone formation. Sphingosine-1-phosphate(S1 P) is a natural,bioactive sphingolipid that has been shown to play a major role in cardiovascular and immunological pathologies by regulating biological and cellular processes, including migration, differentiation, proliferation and survival. Recent studies also suggest a central role for S1 P in bone diseases, including osteoporosis;however, the effects of S1 P, particularly in bone metabolism, remain to be further elucidated. In this review, we summarize the available literature on the role of S1 P in bone metabolism with a focus on osteoporosis. On the cellular level, S1 P acts as an osteoclast-osteoblast coupling factor to promote osteoblast proliferation and bone formation. Moreover, the recruitment of osteoclast precursors to resorption sites is regulated by the interplay of S1 P gradients and S1 P receptor expression. From a clinical perspective, increasing evidence suggests that systemically elevated S1 P blood levels may serve as an independent risk factor for osteoporosis-related fractures. Taken together, S1 P signaling is a potential therapeutic target and may serve as a novel biomarker in patients with systemic bone disease.展开更多
AIM To identify predictive factors associated with long-term patient and graft survival(> 15 years) in liver transplant recipients.METHODS Medical charts of all de novo adult liver transplant recipients(n = 140) wh...AIM To identify predictive factors associated with long-term patient and graft survival(> 15 years) in liver transplant recipients.METHODS Medical charts of all de novo adult liver transplant recipients(n = 140) who were transplanted in Hamburg between 1997 and 1999 were retrospectively reviewed.In total,155 transplantations were identified in this time period(15 re-transplantations).Twenty-six orthotopic liver transplant(OLT) recipients were early lost to followup due to moving to other places within 1 year after transplantation.All remaining 114 patients were included in the analysis.The following recipient factors were analysed:Age,sex,underlying liver disease,pre-OLT body mass index(BMI),and levels of alanine aminotransferase(ALT),bilirubin,creatinine and gammaglutamyltransferase(gamma-GT),as well as warm and cold ischemia times.Furthermore,the following donor factors were assessed:Age,BMI,cold ischemia time and warm ischemia time.All surviving patients were followed until December 2014.We divided patients into groups according to their underlying diagnosis:(1) hepatocellularcarcinoma(n = 5,4%);(2) alcohol toxic liver disease(n = 25,22.0%);(3) primary sclerosing cholangitis(n = 6,5%);(4) autoimmune liver diseases(n = 7,6%);(5) hepatitis C virus cirrhosis(n = 15,13%);(6) hepatitis B virus cirrhosis(n = 21,19%);and(7) other(n = 35,31%).The group "other" included rare diagnoses,such as acute liver failure,unknown liver failure,stenosis and thrombosis of the arteria hepatica,polycystic liver disease,Morbus Osler and Caroli disease.RESULTS The majority of patients were male(n = 70,61%).Age and BMI at the time point of transplantation ranged from 16 years to 69 years(median:53 years) and from 15 kg/m^2 to 33 kg/m^2(median:24),respectively.Sixty-six OLT recipients(58%) experienced a follow-up of 15 years after transplantation.Recipient's age(P = 0.009) and BMI(P = 0.029) were identified as risk factors for death by χ~2-test.Kaplan-Meier analysis confirmed BMI or age above the median as predictors of decreased long-term survival(P = 0.008 and P = 0.020).Hepatitis B as underlying disease showed a trend for improved long-term survival(P = 0.049,χ~2-test,P = 0.055;Kaplan-Meier analysis,Log rank).Pre-transplant bilirubin,creatinine,ALT and gamma-GT levels were not associated with survival in these patients of the pre-era of the model of end stage liver disease.CONCLUSION The recipients' age and BMI were predictors of longterm survival after OLT,as well as hepatitis B as underlying disease.In contrast,donors' age and BMI were not associated with decreased survival.These findings indicate that recipient factors especially have a high impact on long-term outcome after liver transplantation.展开更多
AIM: To elucidate the question of whether the ocular trauma score(OTS) and the zones of injury could be used as a predictive model of traumatic and post traumatic retinal detachment(RD) in patients with open globe inj...AIM: To elucidate the question of whether the ocular trauma score(OTS) and the zones of injury could be used as a predictive model of traumatic and post traumatic retinal detachment(RD) in patients with open globe injury(OGI).METHODS: A retrospective observational chart analysis of OGI patients was performed. The collected variables consisted of age, date, gender, time of injury, time until repair, mechanism of injury, zone of injury, injury associated vitreous hemorrhage, trauma associated RD, post traumatic RD, aphakia at injury, periocular trauma and OTS in cases of OGI. RESULTS: Totally 102 patients with traumatic OGI with a minimum of 12 mo follow-up and a median age at of 48.6 y(range: 3-104 y) were identified. Final best corrected visual acuity(BCVA) was independent from the time of repair, yet a statistically significant difference was present between the final BCVA and the zone of injury. Severe trauma presenting with an OTS score Ⅰ(P<0.0001) or Ⅱ(P<0.0001) revealed a significantly worse BCVA at last follow up when compared to the cohort with an OTS score >Ⅲ. OGI associated RD was observed in 36/102 patients(35.3%), whereas post traumatic RD(defined as RD following 14 d after OGI) occurred in 37 patients(36.3%). OGI associated RD did not correlate with the OTS and the zone of injury(P=0.193), yet post traumatic RD correlated significantly with zone Ⅲ injuries(P=0.013). CONCLUSION: The study shows a significant association between lower OTS score and zone Ⅲ injury with lower final BCVA and a higher number of surgeries, but only zone Ⅲ could be significantly associated with a higher rate of RD.展开更多
AIM: To determine the diagnostic accuracy and radiation dose of conventional radiography and multidetector computed tomography(MDCT) in suspected scaphoid fractures.METHODS: One hundred twenty-four consecutive patient...AIM: To determine the diagnostic accuracy and radiation dose of conventional radiography and multidetector computed tomography(MDCT) in suspected scaphoid fractures.METHODS: One hundred twenty-four consecutive patients were enrolled in our study who had suffered from a wrist trauma and showed typical clinical symptoms suspicious of an acute scaphoid fracture. All patients had initially undergone conventional radiography. Subsequent MDCT was performed within 10 d because of persisting clinical symptoms. Using the MDCT data as the reference standard, a fourfold table was used to classify the test results. The effective dose and impaired energy were assessed in order to compare the radiation burden of the two techniques. The Wilcoxon test was performed to compare the two diagnostic modalities.RESULTS: Conventional radiography showed 34 acute fractures of the scaphoid in 124 patients(42.2%). Subsequent MDCT revealed a total of 42 scaphoid fractures. The sensitivity of conventional radiography for scaphoid fracture detection was 42.8% and its specificity was 80% resulting in an overall accuracy of 59.6%. Conventional radiography was significantly inferior to MDCT(P < 0.01) concerning scaphoidfracture detection. The mean effective dose of MDCT was 0.1 m Sv compared to 0.002 m Sv of conventional radiography.CONCLUSION: Conventional radiography is insufficient for accurate scaphoid fracture detection. Regarding the almost negligible effective dose, MDCT should serve as the first imaging modality in wrist trauma.展开更多
AIM: To propose an allocation system of patients with liver cirrhosis to intensive care unit(ICU), and developed a decision tool for clinical practice. METHODS: A systematic review of the literature was performed in P...AIM: To propose an allocation system of patients with liver cirrhosis to intensive care unit(ICU), and developed a decision tool for clinical practice. METHODS: A systematic review of the literature was performed in Pub Med, MEDLINE and EMBASE databases. The search includes studies on hospitalized patients with cirrhosis and organ failure, or acute on chronic liver failure and/or intensive care therapy. RESULTS: The initial search identified 660 potentially relevant articles. Ultimately, five articles were selected; two cohort studies and three reviews were found eligible. The literature on this topic is scarce and no studies specifically address allocation of patients with liver cirrhosis to ICU. Throughout the literature, there is consensus that selection criteria for ICU admission should be developed and validated for this group of patients and multidisciplinary approach is mandatory. Based on current available data we developed an algorithm, to determine if a patient is candidate to intensive care if needed, based on three scoring systems: premorbid Child-Pugh Score, Model of End stage Liver Disease score and the liver specific Sequential Organ Failure Assessment score.CONCLUSION: There are no established systems for allocation of patients with liver cirrhosis to the ICU and no evidence-based recommendations can be made.展开更多
文摘Background:The German Military Medical Service contributed to the medical screening of unaccompanied minor refugees(UMRs)coming to Germany in 2014 and 2015.In this study,a broad range of diagnostic procedures was applied to identify microorganisms with clinical or public health significance.Previously,those tests had only been used to screen soldiers returning from tropical deployments.This instance is the first time the approach has been studied in a humanitarian context.Methods:The offered screenings included blood cell counts,hepatitis B serology and microscopy of the stool to look for protozoa and worm eggs as well as PCR from stool samples targeting pathogenic bacteria,protozoa and helminths.If individuals refused certain assessments,their decision to do so was accepted.A total of 219 apparently healthy male UMRs coming from Afghanistan,Egypt,Somalia,Eritrea,Syria,Ghana,Guinea,Iran,Algeria,Iraq,Benin,Gambia,Libya,Morocco,Pakistan,and Palestine were assessed.All UMRs who were examined at the study department were included in the assessment.Results:We detected decreasing frequencies of pathogens that included diarrhoea-associated bacteria[Campylobacter(C.)jejuni,enteropathogenic Escherichia(E.)coli(EPEC),enterotoxic E.coli(ETEC),enteroaggregative E.coli(EAEC),enteroinvasive E.coli(EIEC)/Shigella spp.),Giardia(G.)duodenalis,helminths(comprising Schistosoma spp.,Hymenolepis(H.)nana,Strongyloides(S.)stercoralis]as well as hepatitis B virus.Pathogenic microorganisms dominated the samples by far.While G.duodenalis was detected in 11.4%of the assessed UMRs,the incidence of newly identified cases in the German population was 4.5 cases per 100,000 inhabitants.Conclusion:We conclude that the applied in-house PCR screening systems,which have proven to be useful for screening military returnees from tropical deployments,can also be used for health assessment of immigrants from the respective sites.Apparently healthy UMRs may be enterically colonized with a broad variety of pathogenic and apathogenic microorganisms.Increased colonization rates,as shown for G.duodenalis,can pose a hygiene problem in centralized homes for asylum seekers.
基金supported by the German Research Foundation(SCHI 504/19-1(to TS)and IG 18/22-1(to AI))the Else Kröner-Fresenius foundation under grant no.2021_EKEA.23(to TR)financial support from the Open Access Publication Fund of UKE–Universitatsklinikum Hamburg-Eppendorf and DFG–German Research Foundation.
文摘Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell types.While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage.Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)development.Mice with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate postnatally.Moreover,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth plates.While skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age.Likewise,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage degeneration.Importantly,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) mice.We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes.Finally,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes.Collectively,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.
基金supported by Dr.Ausbüttel&Co.Gmb H,the University of Witten/Herdecke。
文摘Objective:In this study,we investigated the concept of empowerment in chronic wound care and propose to facilitate patient control by making use of degrees of freedom(DOF):that is,shaping of everyday wound care tasks initiated by patients and based on their wishes,mostly in terms of patients executing treatment steps,requesting or directing health care professionals to under take changes,or modifications of internal states.Methods:As a first step,we conducted a systematic literature search,followed by an inductive form of qualitative content analysis,which resulted in the identification of 5 dimensions as main elements of empowerment:education and shared decision making,adherence to self-care behaviors,responsibility and control,general call for empowerment,and DOF.However,the latter are noticeably absent in the literature.To investigate patients'freedom in shaping the wound care process,we conducted a second literature search.Results:A number of possibilities for patients to influence the wound care process could be identified,but experimental or clinical evidence about their effects is missing,their variety is limited,and they are only inadequately described.Conclusions:However,DOF should be an indispensable aspect of genuine empowerment,since they allow patients to occupy the role of the agent in the treatment process and give rise to the subjective experience of feeling empowered.Thus,in the third part,we develop a research proposal on how to investigate and include DOF in the clinical practice of wound care.Finally,limitations about implementations are discussed(e.g.,patients being reluctant to overcome their passive role,resulting in frustration for health care professionals).
基金supported by funding from the Creutzfeldt-Jakob Disease FoundationInc.(USA)+4 种基金the Alzheimer Forschung Initiative (AFI e.V.,Germany)the Werner-Otto-Stiftung (Hamburg,Germany)(all to HCA)the China Scholarship Council (to FS)European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie Grant Agreement N°101030402 (to AMA)Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Center (CRC) 877"Proteolysis as a regulatory event in pathophysiology"(to MG)。
文摘In the last decades,the role of the prion protein(PrP) in neurodegenerative diseases has been intensively investigated,initially in prion diseases of humans(e.g., Creutzfeldt-J akob disease) and animals(e.g.,scrapie in sheep,chronic wasting disease in deer and elk,or "mad cow disease" in cattle).Templated misfolding of physiological cellular prion protein(PrPC) into an aggregation-prone isoform(termed PrP "Scrapie"(PrPSc)),self-re plication and spreading of the latter inside the brain and to peripheral tissues,and the associated formation of infectious proteopathic seeds(termed "prions")are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies.Late r,key roles of the correctly folded PrPCwere identified in more common human brain diseases(such as Alzheimer s disease or Parkinson’s disease) associated with the misfolding and/or accumulation of other proteins(such as amyloid-β,tau or α-synuclein,respectively).PrPChas also been linked with n euro protective and regenerative functions,for instance in hypoxic/ischemic conditions such as stroke.However,despite a mixed "bouquet" of suggested functions,our understanding of pathological and,especially,physiological roles played by PrPCin the brain and beyond is ce rtainly incomplete.Interactions with various other proteins at the cell surfa ce or within intracellular compartments may account for the functional diversity linked with PrPC.Moreover,conserved endogenous proteolytic processing of PrPCgenerates seve ral defined PrPCfragments,possibly holding intrinsic functions in physiological and pathological conditions,thus making the "true and complete biology" of this protein more complicated to be elucidated.Here,we focus on one of those released PrPCfragments,namely shed PrP(sPrP),generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surfa ce.Similar to other soluble PrP fragments(such as the N1 fragment representing PrP’s released N-terminal tail upon the major α-cleavage event)or expe rimentally employed recombinant PrP,sPrP is being suggested to act n euro protective in Alzheimer’s disease and other protein misfolding diseases.Seve ral lines of evidence on extracellular PrPC(fragments) suggest that induction of PrPCrelease co uld be a future therapeutic option in various brain disorders.Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM 10,based on ligands binding to cell surface PrPC,may further set the stage for research into this direction.
基金supported by the Deutsche Forschungsgemeinschaft(DFG,425373668,HE 3220/4-1)(to GH).
文摘Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life.Here,we summarize emerging links between the most common late life neurodegenerative disease,Alzheimer’s disease,and the most common early life neurodegenerative diseases,neuronal ceroid lipofuscinoses.Genetic studies reported an overlap of clinically diagnosed Alzheimer’s disease and mutations in genes known to cause neuronal ceroid lipofuscinoses.Accumulating data strongly suggest dysfunction of intracellular trafficking mechanisms and the autophagy-endolysosome system in both types of neurodegenerative disorders.This suggests shared cytopathological processes underlying these different types of neurodegenerative diseases.A better understanding of the common mechanisms underlying the different diseases is important as this might lead to the identification of novel targets for therapeutic concepts,the transfer of therapeutic strategies from one disease to the other and therapeutic approaches tailored to patients with specific mutations.Here,we review dysfunctions of the endolysosomal autophagy pathway in Alzheimer’s disease and neuronal ceroid lipofuscinoses and summarize emerging etiologic and genetic overlaps.
基金supported by the“Stiftung zur F?rderung der Universit?tsmedizin Hamburg”the“Ernst and Berta Grimmke Stiftung”(to UB)。
文摘Neuronal ceroid lipofuscinosis(NCL),also known as Batten disease,is the umbrella term for a group of neurodegenerative lysosomal storage disorders with onset mainly in childhood.The total 13 genetically distinct NCLs are caused by mutations in genes encoding soluble or transmembrane proteins,and have been classified according to the affected gene into CLN1 to CLN8 and CLN10 to CLN14.Intracellular accumulation of autofluorescent storage material due to lysosomal dysfunction is a hallmark of all NCLs.
文摘BACKGROUND Periodontitis has been associated with various liver diseases.However,the relevance of periodontitis in the progression of decompensated cirrhosis remains inconclusive.In particular,it is unclear whether the common periodontitis pathogens,Porphyromonas gingivalis(P.gingivalis)and Actinobacillus actinomycetemcomitans(A.actinomycetemcomitans),can be detected not only in the oral mucosa but also in ascites and stool.AIM To investigate the significance of periodontitis,P.gingivalis,and A.actinomycetemcomitans in cirrhosis patients with ascitic decompensation.METHODS This prospective study was conducted at the University Hospital Hamburg Eppendorf,a tertiary center in Northern Germany.A cohort of 27 patients with ascitic decompensated liver cirrhosis underwent dental examinations to assess the association between periodontitis and various clinical parameters of cirrhosis,as well as patient outcomes.PCR was used to test gingival samples,ascites,and stool for the presence of P.gingivalis and A.actinomycetemcomitans.Gingival samples were collected by probing the deepest gum pocket of a sextant and wiping them on a cotton swab.RESULTS Periodontitis was diagnosed in 22 out of 27(82%)ascite patients,which is significantly more common than in a control cohort of 100 unselected patients(59%,P=0.04).P.gingivalis was detected in the gingiva of six patients,and one of them also had P.gingivalis in their stool.However,P.gingivalis was not found in the ascites of any patient.Five out of six patients with P.gingivalis had periodontitis(83%).A.actinomycetemcomitans was not detected in any sample.Patients without periodontitis had a significantly higher mortality rate compared to those with periodontitis,and survival(Kaplan-Meier analysis)was longer in patients with periodontitis(P=0.02).Transplantfree survival was also more common in patients with periodontitis compared to those without(63%vs 0%,P=0.02).CONCLUSION Decompensated cirrhotic patients frequently suffer from periodontitis.However,there was no evidence of the translocation of P.gingivalis or A.actinomycetemcomitans into ascites.The survival of cirrhotic patients with periodontitis was not reduced.
文摘Acute hepatic failure due to hepatitis B virus(HBV)can occur both during primary infection as well as after reactivation of chronic infection.Guidelines recommend considering antiviral therapy in both situations,although evidence supporting this recommendation is weak.Since HBV is not directly cytopathic,the mechanism leading to fulminant hepatitis B is thought to be primarily immunemediated.Therefore,immunosuppression combined with antiviral therapy might be a preferred therapeutic intervention in acute liver failure in hepatitis B.Here wereport our favourable experience in three hepatitis B patients with fulminant hepatic failure who were treated by combining high-dose steroid therapy with standard antiviral treatment,which resulted in a rapid improvement of clinical and liver parameters.
文摘Associating liver partition and portal vein ligation for staged hepatectomy(ALPPS) is a novel approach in liver surgery that allows for extensive resection of liver parenchyma by inducing a rapid hypertrophy of the future remnant liver. However,recent reports indicate that not all patients eligible for ALPPS will benefit from this procedure. Therefore,careful patient selection will be necessary to fully exploit possible benefits of ALPPS. Here,we provide a comprehensive overview of the technical evolution of ALPPS with a special emphasis on safety and oncologic efficacy. Furthermore,we review the contemporary literature regarding indication and benefits,but also limitations of ALPPS.
文摘Aim： To test the hypothesis that sildenafil （50 mg nightly for one year） can improve spontaneous erectile function （EF） in men with mild-to-moderate arteriogenic erectile dysfunction （ED） responsive to erectogenic treatment. Methods： In a prospective open-label trial, 112 men with ED were randomized to sildenafil 50 mg nightly or sildenafil 50 or 100 mg as needed for 12 months, followed by one-month and 6-month non-medicated periods. Non-randomized, non-medicated men with ED were also assessed. The EF domain of the International Index of Erectile Function （IIEF EF） and the peak systolic velocity （PSV） of penile cavernous arteries were used to measure the efficacy. Results： After sildenafil treatment and a subsequent non-medicated month, IIEF EF was normal in 29 of 48 （60.4%, 95% confidence interval [CI]： 45.3-74.2%） of the nightly group vs. 4 of 49 （8.2%, 95% CI： 2.3-19.6%） of the as-needed group. PSV improved by 11.2 cm/s （95% CI： 4.7-21.4; P = 0.012） in the nightly group but only by 3.4 cm/s （-5.1- 14.7; P = 0.435） in the as-needed group. IIEF EF normalized in 1 of 18 （5.6%, 95% CI： 0.1-27.3%） non-medicated men and the PSV declined slightly. Six months after treatment, the IIEF EF remained normal and PSV was stabilized in most （28/29, 97%） nightly group men who had initially normalized. Conclusion： Sildenafil nightly for one year resulted in ED regression that persisted well beyond the end of treatment, so that spontaneous EF was characterized as normal on the IIEF in most men. The results from this open-label, randomized trial warrant verification under double-blind, placebo-controlled conditions.
文摘Iatrogenic ureteral injuries and strictures are relatively common complication of pelvic surgery and radiation treatment.Left untreated they are associated with severe shortand long-term complications such as urinoma,septic state,renal failure,and loss of a renal unit.Treatment depends on timing of diagnosis,as well as extent of injury,and ranges from simple endoscopic management to complex surgical reconstruction under usage of pedicled grafts.While recent advances in ureteral tissue engineering are promising the topic is still underreported.Historically a domain of open surgery,laparoscopic and robotic-assisted approaches have proven their feasibility in small case series,and are increasingly being utilized as means of reconstructive surgery.This review aims to give an outline of incidence and treatment of ureteral injuries and strictures in light of the latest advances.
基金Supported by Hamburger Stiftung zur Forderung der KrebsbekampfungNo.188 to Grobe A and Riethdorf SERC Advanced Investigator Grant "DISSECT"(Pantel K),No.269081.
文摘Due to a lack of substantial improvement in the outcome of patients suffering from oral squamous cell carcinoma(OSCC) during the past decades, current staging methods need to be revised. This disease is associated with poor survival rates despite considerable advances in diagnosis and treatment. The early detection of metastases is an important indicator of survival, prognosis and relapse. Therefore, a better understanding of the mechanisms underlying metastasis is crucial. Exploring alternative measures apart from common procedures is needed to identify new prognostic markers. Similar to previous findings predominantly for other solid tumours, recently published studies demonstrate that circulating tumour cells(CTCs) and disseminated tumour cells(DTCs) might serve as prognostic markers and could supplement routine staging in OSCC. Thus, the detection of CTCs/DTCs is a promising tool todetermine the individual need for therapeutic intervention. Encouraging results and new approaches point to the future use of targeted therapies for OSCC, an exceedingly heterogeneous subgroup of head and neck cancer. This review focuses on summarising technologies currently used to detect CTCs/DTCs. The translational relevance for OSCC is highlighted. The inherent challenges in detecting CTCs/DTCs will be emphasised.
文摘AIM： Microcirculatory dysfunction and free oxygen radicals are important factors in the pathogenesis of severe acute pancreatitis. Additional oxygen delivery might enhance lipid peroxidation but may also improve pancreatic microcirculation. This study assesses the effect of free cellular bovine hemoglobin on the formation of oxygen radicals and microcirculation in a rodent model of severe acute pancreatitis. METHODS： Fifteen minutes after induction of acute pancreatitis Wistar rats received either 0.8 mL bovine hemoglobin （HBOC-200）, hydroxyethyl starch （HES） or 2.4 mL of normal saline to ensure normovolemic substitution. After 6 h of examination the pancreas was excised and rapidly processed for indirect measurement of lipid peroxidation products malondialdehyde （MDA） and reduced glutathione （GSH） in pancreatic tissue. RESULTS： The single application of HBOC-200 improved pancreatic microcirculation and reduced histopathological tissue damage significantly. Tissue concentration of MDA did not differ between the groups. Also no differences in GSH levels were detected.CONCLUSION： Though the single application of HBOC-200 and HES improve pancreatic microcirculation, no differences in lipid peroxidation products were detected. The beneficial effect of additional oxygen supply （HBOC-200） does not lead to enhanced lipid peroxidation.
文摘In contrast to other tumor types, immunotherapy has not yet become a relevant part of the treatment landscape of unselected colorectal cancer. Beside the small subgroup of deficient mismatch repair or microsatellite instable tumors (about 5%) as a surrogate for high mutational burden and subsequently high neoantigen load and immunogenicity, inhibitors of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and/or cytotoxic T lymphocyte-associated antigen-4 were not or only modestly effective in metastatic colorectal cancer. Thus, a variety of combination approaches with chemotherapy, targeted therapy, toll-like receptor agonists, local ablation or oncolytic viruses is currently being evaluated in different disease settings. Despite several encouraging single arm data already presented or published, available randomized data are unimpressive. Adding PD-1/PD-L1 inhibitors to fluoropyrimidines and bevacizumab maintenance showed no beneficial impact on delaying progression. In refractory disease, the combination of PD-1/PD-L1 and MEK inhibitor was not different from regorafenib, whereas a PD-1/PD-L1 and cytotoxic T lymphocyteassociated antigen-4 inhibitor combination demonstrated better overall survival compared to supportive care alone. Clinical trials in all disease settings applying different combination approaches are ongoing and may define the role of immunotherapy in colorectal cancer.
基金supported by Deutsche Forschungsgemeinschaft grants to A.N. (Ni637/2-3), J.Hee. (GRK1459), to J.P.T. (Tu220/6-1, 6-2, Collaborative Research Centre 1149 ‘Trauma’ (INST 40/492-1)) as well as to M.A. and T.S. (AM103/15-2 and Schi504/5-2 within the FOR793)the Bundesministerium für Bildung und Forschung projects A Network on Clinics and Pathophysiology of Osteophytes and Ancylosis, Metabolic Impact on Joint and Bone Diseases (ANCYLOSS 01EC1002B, METARTHROS) to A.N.+4 种基金Tailored Magnetic Nanoparticles for Cancer Targeting project (TOMCAT 01EZ0824) to M.H.supported by NIH grant R37-HL63762the Ted Nash Longlife Foundationthe Bright Focus Foundationthe Consortium for Frontotemporal Dementia Research
文摘Skeletal health relies on architectural integrity and sufficient bone mass, which are maintained through a tightly regulated equilibrium of bone resorption by osteoclasts and bone formation by osteoblasts. Genetic studies have linked the gene coding for low-density lipoprotein receptor-related protein1(Lrp1) to bone traits but whether these associations are based on a causal molecular relationship is unknown. Here, we show that Lrp1 in osteoblasts is a novel regulator of osteoclast activity and bone mass.Mice lacking Lrp1 specifically in the osteoblast lineage displayed normal osteoblast function but severe osteoporosis due to highly increased osteoclast numbers and bone resorption. Osteoblast Lrp1 limited receptor activator of NF-κB ligand(RANKL) expression in vivo and in vitro through attenuation of platelet-derived growth factor(PDGF-BB) signaling. In co-culture, Lrp1-deficient osteoblasts stimulated osteoclastogenesis in a PDGFRβ-dependent manner and in vivo treatment with the PDGFR tyrosine kinase inhibitor imatinib mesylate limited RANKL production and led to complete remission of the osteoporotic phenotype. These results identify osteoblast Lrp1 as a key regulator of osteoblast-to-osteoclast communication and bone mass through a PDGF–RANKL signaling axis in osteoblasts and open perspectives to further explore the potential of PDGF signaling inhibitors in counteracting bone loss as well as to evaluate the importance of functional LRP1 gene variants in the control of bone mass in humans.
基金funded by grants to JK by the Else-Kr?ner-Fresenius-Stiftung (EKFS 2017_A22)by grants to JK from the Berlin Institute of Health
文摘Osteoporosis is a systemic bone disease that affects more than 200 million people worldwide and is caused by the disruption of the equilibrium between osteoclastic bone resorption and osteoblastic bone formation. Sphingosine-1-phosphate(S1 P) is a natural,bioactive sphingolipid that has been shown to play a major role in cardiovascular and immunological pathologies by regulating biological and cellular processes, including migration, differentiation, proliferation and survival. Recent studies also suggest a central role for S1 P in bone diseases, including osteoporosis;however, the effects of S1 P, particularly in bone metabolism, remain to be further elucidated. In this review, we summarize the available literature on the role of S1 P in bone metabolism with a focus on osteoporosis. On the cellular level, S1 P acts as an osteoclast-osteoblast coupling factor to promote osteoblast proliferation and bone formation. Moreover, the recruitment of osteoclast precursors to resorption sites is regulated by the interplay of S1 P gradients and S1 P receptor expression. From a clinical perspective, increasing evidence suggests that systemically elevated S1 P blood levels may serve as an independent risk factor for osteoporosis-related fractures. Taken together, S1 P signaling is a potential therapeutic target and may serve as a novel biomarker in patients with systemic bone disease.
文摘AIM To identify predictive factors associated with long-term patient and graft survival(> 15 years) in liver transplant recipients.METHODS Medical charts of all de novo adult liver transplant recipients(n = 140) who were transplanted in Hamburg between 1997 and 1999 were retrospectively reviewed.In total,155 transplantations were identified in this time period(15 re-transplantations).Twenty-six orthotopic liver transplant(OLT) recipients were early lost to followup due to moving to other places within 1 year after transplantation.All remaining 114 patients were included in the analysis.The following recipient factors were analysed:Age,sex,underlying liver disease,pre-OLT body mass index(BMI),and levels of alanine aminotransferase(ALT),bilirubin,creatinine and gammaglutamyltransferase(gamma-GT),as well as warm and cold ischemia times.Furthermore,the following donor factors were assessed:Age,BMI,cold ischemia time and warm ischemia time.All surviving patients were followed until December 2014.We divided patients into groups according to their underlying diagnosis:(1) hepatocellularcarcinoma(n = 5,4%);(2) alcohol toxic liver disease(n = 25,22.0%);(3) primary sclerosing cholangitis(n = 6,5%);(4) autoimmune liver diseases(n = 7,6%);(5) hepatitis C virus cirrhosis(n = 15,13%);(6) hepatitis B virus cirrhosis(n = 21,19%);and(7) other(n = 35,31%).The group "other" included rare diagnoses,such as acute liver failure,unknown liver failure,stenosis and thrombosis of the arteria hepatica,polycystic liver disease,Morbus Osler and Caroli disease.RESULTS The majority of patients were male(n = 70,61%).Age and BMI at the time point of transplantation ranged from 16 years to 69 years(median:53 years) and from 15 kg/m^2 to 33 kg/m^2(median:24),respectively.Sixty-six OLT recipients(58%) experienced a follow-up of 15 years after transplantation.Recipient's age(P = 0.009) and BMI(P = 0.029) were identified as risk factors for death by χ~2-test.Kaplan-Meier analysis confirmed BMI or age above the median as predictors of decreased long-term survival(P = 0.008 and P = 0.020).Hepatitis B as underlying disease showed a trend for improved long-term survival(P = 0.049,χ~2-test,P = 0.055;Kaplan-Meier analysis,Log rank).Pre-transplant bilirubin,creatinine,ALT and gamma-GT levels were not associated with survival in these patients of the pre-era of the model of end stage liver disease.CONCLUSION The recipients' age and BMI were predictors of longterm survival after OLT,as well as hepatitis B as underlying disease.In contrast,donors' age and BMI were not associated with decreased survival.These findings indicate that recipient factors especially have a high impact on long-term outcome after liver transplantation.
文摘AIM: To elucidate the question of whether the ocular trauma score(OTS) and the zones of injury could be used as a predictive model of traumatic and post traumatic retinal detachment(RD) in patients with open globe injury(OGI).METHODS: A retrospective observational chart analysis of OGI patients was performed. The collected variables consisted of age, date, gender, time of injury, time until repair, mechanism of injury, zone of injury, injury associated vitreous hemorrhage, trauma associated RD, post traumatic RD, aphakia at injury, periocular trauma and OTS in cases of OGI. RESULTS: Totally 102 patients with traumatic OGI with a minimum of 12 mo follow-up and a median age at of 48.6 y(range: 3-104 y) were identified. Final best corrected visual acuity(BCVA) was independent from the time of repair, yet a statistically significant difference was present between the final BCVA and the zone of injury. Severe trauma presenting with an OTS score Ⅰ(P<0.0001) or Ⅱ(P<0.0001) revealed a significantly worse BCVA at last follow up when compared to the cohort with an OTS score >Ⅲ. OGI associated RD was observed in 36/102 patients(35.3%), whereas post traumatic RD(defined as RD following 14 d after OGI) occurred in 37 patients(36.3%). OGI associated RD did not correlate with the OTS and the zone of injury(P=0.193), yet post traumatic RD correlated significantly with zone Ⅲ injuries(P=0.013). CONCLUSION: The study shows a significant association between lower OTS score and zone Ⅲ injury with lower final BCVA and a higher number of surgeries, but only zone Ⅲ could be significantly associated with a higher rate of RD.
文摘AIM: To determine the diagnostic accuracy and radiation dose of conventional radiography and multidetector computed tomography(MDCT) in suspected scaphoid fractures.METHODS: One hundred twenty-four consecutive patients were enrolled in our study who had suffered from a wrist trauma and showed typical clinical symptoms suspicious of an acute scaphoid fracture. All patients had initially undergone conventional radiography. Subsequent MDCT was performed within 10 d because of persisting clinical symptoms. Using the MDCT data as the reference standard, a fourfold table was used to classify the test results. The effective dose and impaired energy were assessed in order to compare the radiation burden of the two techniques. The Wilcoxon test was performed to compare the two diagnostic modalities.RESULTS: Conventional radiography showed 34 acute fractures of the scaphoid in 124 patients(42.2%). Subsequent MDCT revealed a total of 42 scaphoid fractures. The sensitivity of conventional radiography for scaphoid fracture detection was 42.8% and its specificity was 80% resulting in an overall accuracy of 59.6%. Conventional radiography was significantly inferior to MDCT(P < 0.01) concerning scaphoidfracture detection. The mean effective dose of MDCT was 0.1 m Sv compared to 0.002 m Sv of conventional radiography.CONCLUSION: Conventional radiography is insufficient for accurate scaphoid fracture detection. Regarding the almost negligible effective dose, MDCT should serve as the first imaging modality in wrist trauma.
文摘AIM: To propose an allocation system of patients with liver cirrhosis to intensive care unit(ICU), and developed a decision tool for clinical practice. METHODS: A systematic review of the literature was performed in Pub Med, MEDLINE and EMBASE databases. The search includes studies on hospitalized patients with cirrhosis and organ failure, or acute on chronic liver failure and/or intensive care therapy. RESULTS: The initial search identified 660 potentially relevant articles. Ultimately, five articles were selected; two cohort studies and three reviews were found eligible. The literature on this topic is scarce and no studies specifically address allocation of patients with liver cirrhosis to ICU. Throughout the literature, there is consensus that selection criteria for ICU admission should be developed and validated for this group of patients and multidisciplinary approach is mandatory. Based on current available data we developed an algorithm, to determine if a patient is candidate to intensive care if needed, based on three scoring systems: premorbid Child-Pugh Score, Model of End stage Liver Disease score and the liver specific Sequential Organ Failure Assessment score.CONCLUSION: There are no established systems for allocation of patients with liver cirrhosis to the ICU and no evidence-based recommendations can be made.
