Effects of frequent and long-term exercise on neuropsychiatric symptoms in patients with Alzheimer's disease - Secondary analyses of a randomized, controlled trial (FINALEX)

Background: Neuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD) and are associated with admission to institutional care. Current guidelines recommend non-pharmacological interventions as the first-line treatment for NPS. However, high-quality randomized studies focused on NPS are scarce. The objective here was to examine whether a regular and long-term exercise programme either at home or as a group-based exercise at an adult day care centre has beneficial effects on AD patients' NPS or permanent institutionalizations. Design, setting, and participants: A randomized, controlled trial with 210 community-dwelling AD patients. Intervention: Two types of intervention comprising (1) group-based exercise in day care centres (GE) and (2) tailored home-based exercise (HE), both twice a week for 12 months, were compared with (3) a control group (CG) receiving usual community care. Measurements: NPS were measured with the Neuropsychiatric Inventory (NPI) at baseline and 6 months, and depression with the Cornell Scale for Depression in Dementia (CSDD) at baseline and 12 months. Data on institutionalizations were retrieved from central registers. Results: No significant differences between the groups were detected in NPI at 6 months or in CSDD at 12 months when analyses were adjusted for age, sex, baseline Clinical Dementia Rating, and Functional Independence Measure. There was no difference in admissions to permanent institutional care between the groups. Conclusions: Regular, long-term exercise intervention did not decrease NPS in patients with AD. (C) 2017 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.Peer reviewe

Human pluripotent stem cell-derived cells endogenously expressing follicle-stimulating hormone receptors : modeling the function of an inactivating receptor mutation

Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. The actions of human FSH and its receptor (FSHR) and mutations therein have mainly been studied using in vivo models, primary cells, cancer cells and cell lines ectopically expressing the FSHR. To allow studies of endogenous FSHR function in vitro, we differentiated FSHR-expressing cells from human pluripotent stem cells. FSH stimulation of the wild-type (WT), but not the inactivating Finnish founder mutant (A189V) receptor, activated the canonical cyclic adenosine monophosphate (cAMP)-dependent signaling pathway and downstream mediators. To investigate protein-protein interaction partners of FSHR at resting state and upon FSH stimulation, we expressed FSHR in HEK293 cells followed by affinity purification mass spectrometry analyses. We found 19 specific high-confidence interacting proteins for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility. Interestingly, while only WT FSHR interacted with FSH, insulin-like growth factor 1 receptor (IGF1R), for example, interacted with both WT and A189V FSHR upon FSH stimulation. In conclusion, our protocol allows detailed studies of FSH action and disease modeling in human cells endogenously expressing FSHR.Peer reviewe

Human pluripotent stem cell-derived cells endogenously expressing follicle-stimulating hormone receptors : modeling the function of an inactivating receptor mutation

Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. The actions of human FSH and its receptor (FSHR) and mutations therein have mainly been studied using in vivo models, primary cells, cancer cells and cell lines ectopically expressing the FSHR. To allow studies of endogenous FSHR function in vitro, we differentiated FSHR-expressing cells from human pluripotent stem cells. FSH stimulation of the wild-type (WT), but not the inactivating Finnish founder mutant (A189V) receptor, activated the canonical cyclic adenosine monophosphate (cAMP)-dependent signaling pathway and downstream mediators. To investigate protein-protein interaction partners of FSHR at resting state and upon FSH stimulation, we expressed FSHR in HEK293 cells followed by affinity purification mass spectrometry analyses. We found 19 specific high-confidence interacting proteins for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility. Interestingly, while only WT FSHR interacted with FSH, insulin-like growth factor 1 receptor (IGF1R), for example, interacted with both WT and A189V FSHR upon FSH stimulation. In conclusion, our protocol allows detailed studies of FSH action and disease modeling in human cells endogenously expressing FSHR.Peer reviewe

Small ubiquitin-related modifier (SUMO)-1, SUMO-2/3 and SUMOylation are involved with centromeric heterochromatin of chromosomes 9 and 1 and proteins of the synaptonemal complex during meiosis in men

Background: Post-transcriptional modification by SUMOylation is involved in numerous cellular processes including human spermatogenesis. For human male meiosis, we previously showed that the small ubiquitin-related modifier-1 (SUMO-1) protein localizes to chromatin axes in early pachytene spermatocytes, then to kinetochores as meiosis progresses. Here, we delineate possible functional roles based on subcellular localization for SUMO-1 and SUMO-2/3. Methods: Western and immunoprecipitation analyses were conducted on proteins isolated from the testis of two normal adult fertile men. Combinatorial immunofluorescence and chromosome-specific fluorescence in situ hybridization analyses were performed on male meiocytes obtained during testicular biopsy from four patients undergoing testicular sperm extraction for assisted reproduction technologies. Results: The synaptonemal complex (SC) and SC proteins (SCP)-1 and SCP2, but not SCP3, are SUMOylated by SUMO-1 during the pachytene substage. Likewise, two distinct localization patterns for SUMO-1 are identified: a linear pattern co-localized with autosomal SCs and isolated SUMO-1 near the centromeric heterochromatin of chromosomes 9 and 1. In contrast to SUMO-1, which is not detectable prior to pachytene in normal tissue, SUMO-2/3 is identified as early as leptotene and zygotene and in some, but not all, pachytene cells; no linear patterns were detected. Similar to SUMO-1, SUMO-2/3 localizes in two predominant subnuclear patterns: a single, dense signal near the centromere of human chromosome 9 and small, individual foci co-localized with autosomal centromeres. Conclusions: Our data suggest that SUMO-1 may be involved in maintenance and/or protection of the autosomal SC. SUMO-2/3, though expressed similarly, may function separately and independently during pachytene in men

WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome

WDR11 has been implicated in congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), human developmental genetic disorders defined by delayed puberty and infertility. However, WDR11's role in development is poorly understood. Here, we report that WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. Disruption of WDR11 expression in mouse and zebrafish results in phenotypic characteristics associated with defective Hh signalling, accompanied by dysgenesis of ciliated tissues. Wdr11-null mice also exhibit early-onset obesity. We find that WDR11 shuttles from the cilium to the nucleus in response to Hh signalling. WDR11 regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotrophin-releasing hormone production. The CHH/KS-associated human mutations result in loss of function of WDR11. Treatment with the Hh agonist purmorphamine partially rescues the WDR11 haploinsufficiency phenotypes. Our study reveals a novel class of ciliopathy caused by WDR11 mutations and suggests that CHH/KS may be a part of the human ciliopathy spectrum.Peer reviewe

Arthroscopic partial meniscectomy versus placebo surgery for a degenerative meniscus tear : a 2-year follow-up of the randomised controlled trial

Objective To assess if arthroscopic partial meniscectomy (APM) is superior to placebo surgery in the treatment of patients with degenerative tear of the medial meniscus. Methods In this multicentre, randomised, participant-blinded and outcome assessor-blinded, placebo-surgery controlled trial, 146 adults, aged 35-65 years, with knee symptoms consistent with degenerative medial meniscus tear and no knee osteoarthritis were randomised to APM or placebo surgery. The primary outcome was the between-group difference in the change from baseline in the Western Ontario Meniscal Evaluation Tool (WOMET) and Lysholm knee scores and knee pain after exercise at 24 months after surgery. Secondary outcomes included the frequency of unblinding of the treatment-group allocation, participants' satisfaction, impression of change, return to normal activities, the incidence of serious adverse events and the presence of meniscal symptoms in clinical examination. Two subgroup analyses, assessing the outcome on those with mechanical symptoms and those with unstable meniscus tears, were also carried out. Results In the intention-to-treat analysis, there were no significant between-group differences in the mean changes from baseline to 24 months in WOMET score: 27.3 in the APM group as compared with 31.6 in the placebo-surgery group (between-group difference, -4.3; 95% CI, -11.3 to 2.6); Lysholm knee score: 23.1 and 26.3, respectively (-3.2; -8.9 to 2.4) or knee pain after exercise, 3.5 and 3.9, respectively (-0.4; -1.3 to 0.5). There were no statistically significant differences between the two groups in any of the secondary outcomes or within the analysed subgroups. Conclusions In this 2-year follow-up of patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after APM were no better than those after placebo surgery. No evidence could be found to support the prevailing ideas that patients with presence of mechanical symptoms or certain meniscus tear characteristics or those who have failed initial conservative treatment are more likely to benefit from APM.Peer reviewe

Combination chemotherapy for choroidal melanoma: ex vivo sensitivity to treosulfan with gemcitabine or Cytosine arabinoside

Treatment of choroidal melanoma by chemotherapy is usually unsuccessful, with response rates of less than 1% reported for dacarbazine (DTIC)-containing regimens which show 20% or more response rates in skin melanoma. Recently, we reported the activity of several cytotoxic agents against primary choroidal melanoma in an ATP-based tumour chemosensitivity assay (ATP-TCA). In this study, we have used the same method to examine the sensitivity of choroidal melanoma to combinations suggested by our earlier study. Tumour material from 36 enucleated eyes was tested against a battery of single agents and combinations which showed some activity in the previous study. The combination of treosulfan with gemcitabine or cytosine arabinoside showed consistent activity in 70% and 86% of cases, respectively. Paclitaxel was also active, particularly in combination with treosulfan (47%) or mitoxantrone (33%). Addition of paclitaxel to the combination of treosulfan + cytosine analogue added little increased sensitivity. For treosulfan + cytosine arabinoside, further sequence and timing experiments showed that simultaneous administration gave the greatest suppression, with minor loss of inhibition if the cytosine analogue was given 24 h after the treosulfan. Administration of cytosine analogue 24 h before treosulfan produced considerably less inhibition at any concentration. While we have so far been unable to study metastatic tumour from choroidal melanoma patients, the combination of treosulfan with gemcitabine or cytosine arabinoside shows activity ex vivo against primary tumour tissue. Clinical trials are in progress. © 1999 Cancer Research Campaig

Reversible Congenital Hypogonadotropic Hypogonadism in Patients with CHD7, FGFR1 or GNRHR Mutations

Peer reviewe

QTLs for height: results of a full genome scan in Dutch sibling pairs.

Height is a highly heritable, complex trait. At present, the genes responsible for the variation in height have not yet been identified. This paper summarizes the results of previous linkage studies and presents results of an additional linkage analysis. Using data from the Netherlands Twin Register, a sib-pair-based linkage analysis for adult height was conducted. For 513 sib-pairs from 174 families complete genome scans and adult height were available. The strongest evidence for linkage was found for a region on chromosome 6, near markers D6S1053 and D6S1031 (LOD = 2.32). This replicated previous findings in other data sets. LOD scores ranging from 1.53 to 2.04 were found for regions on chromosomes 1, 5, 8, 10, and 18. The region on chromosome 18 (LOD = 1.83) also corresponded with the results of previous studies. Several chromosomal regions are now implied in the variance in height, but further study is needed to draw definite conclusions with regard to the significance of these regions for adult heigh

Role of the Two Component Signal Transduction System CpxAR in Conferring Cefepime and Chloramphenicol Resistance in Klebsiella pneumoniae NTUH-K2044

Background: Klebsiella pneumoniae is a Gram-negative, non-motile, facultative anaerobe belonging to the Enterobacteriaceae family of the c-Proteobacteria class in the phylum Proteobacteria. Multidrug resistant K. pneumoniae have caused major therapeutic problems worldwide due to emergence of extended-spectrum b-lactamase producing strains. Twocomponent systems serve as a basic stimulus-response coupling mechanism to allow organisms to sense and respond to changes in many different environmental conditions including antibiotic stress. Principal Findings: In the present study, we investigated the role of an uncharacterized cpxAR operon in bacterial physiology and antimicrobial resistance by generating isogenic mutant (DcpxAR) deficient in the CpxA/CpxR component derived from the hyper mucoidal K1 strain K. pneumoniae NTUH-K2044. The behaviour of DcpxAR was determined under hostile conditions, reproducing stresses encountered in the gastrointestinal environment and deletion resulted in higher sensitivity to bile, osmotic and acid stresses. The DcpxAR was more susceptible to b-lactams and chloramphenicol than the wild-type strain, and complementation restored the altered phenotypes. The relative change in expression of acrB, acrD, eefB efflux genes were decreased in cpxAR mutant as evidenced by qRT-PCR. Comparison of outer membrane protein profiles indicated a conspicuous difference in the knock out background. Gel shift assays demonstrated direct binding of CpxR KP to promoter region of ompC KP in a concentration dependent manner