Abstract Growth/differentiation factor-15 (Gdf-15) is a member of the TGF-β superfamily and a pleiotropic, widely distributed cytokine, which has been shown to play roles in various pathologies, ...including inflammation. Analysis of Gdf-15 −/− mice has revealed that it serves the postnatal maintenance of spinal cord motor neurons and sensory neurons. In a previous study, exogenous Gdf-15 rescued 6-hydroxydopamine (6-OHDA) lesioned Gdf-15 +/+ nigrostriatal dopaminergic (DAergic) neurons in vitro and in vivo. Whether endogenous Gdf-15 serves the physiological maintenance of nigrostriatal DAergic neurons in health and disease is not known and was addressed in the present study. Stereotactic injection of 6-OHDA into the medial forebrain bundle (MFB) led to a significant decline in the numbers of DAergic neurons in both Gdf-15 +/+ and Gdf-15 −/− mice over a time-period of 14 days. However, this decrease was exacerbated in the Gdf-15 −/− mice, with only 5.5% surviving neurons as compared to 24% in the Gdf-15 +/+ mice. Furthermore, the microglial response to the 6-OHDA lesion was reduced in Gdf-15 −/− mice, with significantly lower numbers of total and activated microglia and a differential cytokine expression as compared to the Gdf-15 +/+ mice. Using in vitro models, we could demonstrate the importance of endogenous Gdf-15 in promoting DAergic neuron survival thus highlighting its relevance in a direct neurotrophic supportive role. Taken together, these results indicate the importance of Gdf-15 in promoting survival of DAergic neurons and regulating the inflammatory response post 6-OHDA lesion.
Falls are a leading cause of injury-related deaths and hospitalizations among Canadians. Falls risk has been reported to be increased in individuals who are older and with certain health conditions. ...It is unclear whether rurality is a risk factor for falls. This study aimed to investigate: 1) fall profiles by age group e.g., 45 to 54 years, 55 to 64 years, 65 to 74 years, 75 to 85 years; and 2) falls profiles of individuals, by age group, living in rural versus urban areas of Canada. Data (N = 51,338) from the Canadian Longitudinal Study on Aging was used to examine the relationship between falls and age, rurality, chronic conditions, need for medical attention, and fall characteristics (manner, location, injury). Self-reported falls within a twelve-month period occurred in only 4.8% (single fall) and 0.8% (multiple falls) of adults. Falls were not related to rural residence or age, but those with memory impairment, multiple sclerosis, as well as other chronic conditions such as mood disorder, anxiety disorder, and hyperthyroidism not often thought to be associated with falls, were also more likely to fall. Older individuals were more likely to fall indoors or fall while standing or walking. In contrast, middle-aged individuals were more likely to fall outdoors or while exercising. Type of injury was not associated with age, but older individuals were more likely to report hospitalization after a fall. This study shows that falls occur with a similar frequency in individuals regardless of age or urban/rural residence. Age was associated with fall location and activity. A more universally applicable multi-facted approach, rather than one solely based on older age considerations, to screening, primary prevention and management may reduce the personal, social, and economic burden of falls and fall-related injuries.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aspergillus fumigatus is the leading cause of invasive aspergillosis. Adequate treatment is complicated by an increase in azole resistance. Here, the incidence of voriconazole, posaconazole and ...itraconazole resistance in clinical isolates from high-risk patients from either the haematology ward or the ICU of the University Medical Center Utrecht in the period 2011-13 is analysed. Putative clonality of resistant strains was tested through cyp51A and microsatellite typing.
Primary A. fumigatus isolates from 105 patients were collected by an unbiased routine diagnostic-driven approach and phenotypically tested for azole susceptibility. Of the 105 isolates, 5 were from patients with a proven invasive A. fumigatus infection, 48 were from patients with a probable invasive A. fumigatus infection and 52 were from patients with non-invasive infections. Real-time PCR and cyp51A gene and strain typing were performed.
Twenty-one out of 105 (20.0%) isolates were resistant to at least one of the three clinical azoles and 17/105 (16.2%) isolates were resistant (MIC >2 mg/L) to voriconazole, the empirical drug of choice for treatment of aspergillosis. There was a striking difference in the prevalence of triazole resistance, with 15.9% resistant isolates (25.0% in proven/probable patients) in the haematology population and 4.5% (10% in proven/probable) in the ICU. While the majority of isolates with elevated MICs of voriconazole were cyp51A related (17/23), both microsatellite and cyp51A sequence typing argue against clonal spread of resistant strains.
This study reveals a high incidence of voriconazole resistance (16.2%) in A. fumigatus in high-risk patients. Our data stress the need for laboratory detection of azole resistance prior to treatment.
Summary Compliance with hand hygiene is widely recognized as the most important factor in preventing transmission of infection to patients in health care settings. However, there is no standardized ...method for measuring compliance. The three major methods used are direct observation, self-report and indirect measurement of hand hygiene product usage. This review discusses the methods of compliance monitoring and the advantages and drawbacks of each.
Systemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever ...syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries.
Data of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients.
Clinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria.
Patients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.
Hydrological observatories bear a lot of resemblance to the more traditional research catchment concept, but tend to differ in providing more long-term facilities that transcend the lifetime of ...individual projects, are more strongly geared towards performing interdisciplinary research, and are often designed as networks to assist in performing collaborative science. This paper illustrates how the experimental and monitoring set-up of an observatory, the 66 ha Hydrological Open Air Laboratory (HOAL) in Petzenkirchen, Lower Austria, has been established in a way that allows meaningful hypothesis testing. The overarching science questions guided site selection, identification of dissertation topics and the base monitoring. The specific hypotheses guided the dedicated monitoring and sampling, individual experiments, and repeated experiments with controlled boundary conditions. The purpose of the HOAL is to advance the understanding of water-related flow and transport processes involving sediments, nutrients and microbes in small catchments. The HOAL catchment is ideally suited for this purpose, because it features a range of different runoff generation processes (surface runoff, springs, tile drains, wetlands), the nutrient inputs are known, and it is convenient from a logistic point of view as all instruments can be connected to the power grid and a high-speed glassfibre local area network (LAN). The multitude of runoff generation mechanisms in the catchment provides a genuine laboratory where hypotheses of flow and transport can be tested, either by controlled experiments or by contrasting sub-regions of different characteristics. This diversity also ensures that the HOAL is representative of a range of catchments around the world, and the specific process findings from the HOAL are applicable to a variety of agricultural catchment settings. The HOAL is operated jointly by the Vienna University of Technology and the Federal Agency for Water Management and takes advantage of the Vienna Doctoral Programme on Water Resource Systems funded by the Austrian Science Funds. The paper presents the science strategy of the set-up of the observatory, discusses the implementation of the HOAL, gives examples of the hypothesis testing and summarises the lessons learned. The paper concludes with an outlook on future developments.
Drug‐drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral ...androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P‐glycoprotein P‐gp probe substrate) and rosuvastatin (breast cancer resistance protein BCRP probe substrate) in men with metastatic castration‐resistant prostate cancer (mCRPC). This was a phase I, open‐label, fixed‐sequence, crossover study (NCT04094519). Eligible men with mCRPC received a single dose of transporter probe cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin plus enzalutamide placebo‐to‐match on day 1. On day 8, patients started 160 mg enzalutamide once daily through day 71. On day 64, patients also received a single dose of the cocktail. The primary end points were digoxin and rosuvastatin plasma maximum concentration (Cmax), area under the concentration‐time curve from the time of dosing to the last measurable concentration (AUClast), and AUC from the time of dosing extrapolated to time infinity (AUCinf). Secondary end points were enzalutamide and N‐desmethyl enzalutamide (metabolite) plasma Cmax, AUC during a dosing interval, where tau is the length of the dosing interval (AUCtau), and concentration immediately prior to dosing at multiple dosing (Ctrough). When administered with enzalutamide, there was a 17% increase in Cmax, 29% increase in AUClast, and 33% increase in AUCinf of plasma digoxin compared to digoxin alone, indicating that enzalutamide is a “mild” inhibitor of P‐gp. No PK interaction was observed between enzalutamide and rosuvastatin (BCRP probe substrate). The PK of enzalutamide and N‐desmethyl enzalutamide were in agreement with previously reported data. The potential for transporter‐mediated DDI between enzalutamide and digoxin and rosuvastatin is low in men with prostate cancer. Therefore, concomitant administration of enzalutamide with medications that are substrates for P‐gp and BCRP does not require dose adjustment in this patient population.
Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has ...been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting.
In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) ( https://aid-register.de ). Data for this retrospective TCZ study were documented by 13 centers.
From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1-18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%.
Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%.
The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).
Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant ...therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride (dut) and leuprolide (enza/dut/luteinizing hormone-releasing hormone analogues LHRHa).
Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enzalutamide or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of PSA and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa.
In the enzalutamide arm, none of the 25 patients achieved pCR or MRD. In the enza/dut/LHRHa arm, one of 23 patients (4.3%) achieved pCR and 3 of 23 (13.0%) achieved MRD. Median RCB was higher in the enzalutamide arm than in the enza/dut/LHRHa arm (0.41 cm
vs. 0.06 cm
, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported.
Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable with historical controls. Evidence of continued AR activity in residual tumor suggests that AR signaling may contribute to survival. Strategies to more effectively ablate AR activity are warranted to determine whether more substantial antitumor effects are observed.
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