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Objective: To compare the incidence of dyslipidemia in people with HIV receiving integrase inhibitors (INSTI) versus boosted protease inhibitors (PI/b) and nonnucleoside reverse transcriptase inhibitors (NNRTI) within RESPOND consortium of prospective cohorts. Methods: Participants were eligible if they were at least 18 years, without dyslipidemia and initiated or switched to a three-drug antiretroviral therapy (ART)-regimen consisting of either INSTI, NNRTI, or PI/b for the first time, between 1 January 2012 and 31 December 2018. Dyslipidemia was defined as random total cholesterol more than 240 mg/dl, HDL less than 35 mg/dl, triglyceride more than 200 mg/dl, or initiation of lipid-lowering therapy. Poisson regression was used to determine the adjusted incidence rate ratios. Follow-up was censored after 3 years or upon ART-regimen discontinuation or last lipid measurement or 31 December 2019, whichever occurred first. Results: Overall, 4577 people with HIV were eligible (INSTI = 66.9%, PI/b = 12.5%, and NNRTI = 20.6%), 1938 (42.3%) of whom were ART-naive. During 1.7 (interquartile range, 0.6 - 3.0) median years of follow-up, 1460 participants developed dyslipidemia [incidence rate: 191.6 per 1000 person-years, 95% confidence interval (CI) 182.0 - 201.7]. Participants taking INSTI had a lower incidence of dyslipidemia compared with those on PI/b (adjusted incidence rate ratio 0.71; CI 0.59 - 0.85), but higher rate compared with those on NNRTI (1.35; CI 1.15 - 1.58). Compared with dolutegravir, the incidence of dyslipidemia was higher with elvitegravir/cobicistat (1.20; CI 1.00 - 1.43) and raltegravir (1.24; CI 1.02 - 1.51), but lower with rilpivirine (0.77; CI 0.63 - 0.94). Conclusion: In this large consortium of heterogeneous cohorts, dyslipidemia was less common with INSTI than with PI/b. Compared with dolutegravir, dyslipidemia was more common with elvitegravir/cobicistat and raltegravir, but less common with rilpivirine.

Following percutaneous exposure to the nerve agent VX, the remaining intact agent within the skin after decontamination is of great concern. Consequently, this leads to prolonged agent release to the blood circulation resulting in sustained intoxication, which may complicate the medical management. The decontamination procedure used should therefore possess the ability for agent removal both on and within the skin. The efficacy of three decontamination procedures was evaluated by measuring VX and the primary degradation product ethyl methyl phosphonic acid (EMPA) penetrated through human skin and the amount remaining within the skin.Decontamination was initiated 5 min post-exposure to VX on human dermatomed skin. Experiments were conducted using anIn control experiments without decontamination, higher amounts of VX were recovered in the deeper layers of skin compared to EMPA, which was primarily located in theEfficient skin decontamination of VX requires skin decontaminants reaching deeper layers of the skin, and that both absorption and degradation properties are important. In addition, the "wash-in" effect by using soapy water may enhance VX release to the blood circulation.

Metal-organic frameworks (MOFs) have shown promising properties for removal of chemical warfare agents, in particular for material decontamination and functionalized fabrics. The MOF-properties could also be beneficial for skin decontamination, especially when exposed to highly toxic and low volatile nerve agents. In such exposures, efficient decontamination is crucial for adequate medical management. In the present study, seven zirconium-based MOFs were evaluated for their ability to degrade VX and subsequently tested in vitro for decontamination of VX on human dermatomed skin. Of the MOFs evaluated, MOF-808 showed the greatest ability to degrade VX in an alkaline buffer with complete degradation of VX within 5 min. PCN-777, Zr-NDC and NU-1000 displayed degradation half-lives of approximately 10 min. When including MOF-808 in a skin friendly carrier with slightly acidic pH, a decreased agent degradation rate was observed, requiring over 24 h to reach complete degradation. In skin decontamination experiments, MOF-808 enhanced the efficacy compared to the carrier alone, essentially by improved agent absorption. Adding MOF-808 to Reactive Skin Decontamination Lotion (RSDL) did not improve the high effectiveness of RSDL alone. The present study showed that including MOF in skin decontamination lotions could be beneficial. Further studies should include optimizing the particulates and formulations.

OBJECTIVE To compare the incidence of hypertension in people living with HIV receiving integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) versus non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (PIs) in the RESPOND consortium of HIV cohorts. METHODS Eligible people with HIV were aged ���18��years who initiated a new three-drug ART regimen for the first time (baseline), did not have hypertension, and had at least two follow-up blood pressure (BP) measurements. Hypertension was defined as two consecutive systolic BP measurements ���140��mmHg and/or diastolic BP ���90��mmHg or initiation of antihypertensives. Multivariable Poisson regression was used to determine adjusted incidence rate ratios (aIRRs) of hypertension, overall and in those who were ART na��ve or experienced at baseline. RESULTS Overall, 4606 people living with HIV were eligible (INSTIs��3164, NNRTIs��807, PIs��635). The median baseline systolic BP, diastolic BP, and age were 120 (interquartile range [IQR] 113-130) mmHg, 78 (70-82) mmHg, and 43 (34-50) years, respectively. Over 8380.4 person-years (median follow-up 1.5 [IQR 1.0-2.7]��years), 1058 (23.0%) participants developed hypertension (incidence rate 126.2/1000 person-years, 95% confidence interval [CI] 118.9-134.1). Participants receiving INSTIs had a higher incidence of hypertension than those receiving NNRTIs (aIRR 1.76; 95% CI 1.47-2.11), whereas the incidence was no different in those receiving PIs (aIRR 1.07; 95% CI 0.89-1.29). The results were similar when the analysis was stratified by ART status at baseline. CONCLUSION Although unmeasured confounding and channelling bias cannot be excluded, INSTIs were associated with a higher incidence of hypertension than were NNRTIs, but rates were similar to those of PIs overall, in ART-na��ve and ART-experienced participants within RESPOND.

Introduction The COVID-19 pandemic has caused large disruptions to healthcare systems. Refocus on COVID-19 related care might have contributed to indirect effects on other healthcare areas. Care focused on acute conditions have been negatively affected although research into the effects on chronic and care intensive patient groups such as patients with dementia diseases is lacking. In this study we evaluated dementia diagnosis trends in Sweden during 2015–2020 according to International Classification of Disease version 10 coding of common dementia diseases. Methods Regional and national statistics in the form of International Classification of Disease version 10 coding, COVID-19 incidence, mortality data, and population census data were collected from the National Institute of Health and Welfare. Logistic regression analysis was performed to identify trends of dementia diagnosis during 2015–2020. Correlation test was performed between COVID-19 incidence, mortality rates, and dementia coding. Results Dementia diagnosis incidence has been declining since 2015 and further decline was noted in many regions in Sweden during 2020. As COVID-19 incidence increased, fewer cases of dementia were diagnosed, a decrease that differentially impacted women and those who were advanced in age. Conclusions Dementia diagnosis incidence in Sweden has been on a decline since 2015. The COVID-19 pandemic caused a further larger decline in dementia diagnosis incidence during 2020. COVID-19 incidence, but not mortality, was associated with decrease in dementia diagnosis incidence. There might be a large number of undiagnosed patients with dementia and healthcare reforms should be enacted to address this. Women and elderly are particularly vulnerable groups.

In mass casualty incidents including hazardous chemical skin exposure, decontamination is the primary intervention to avoid systemic uptake of the toxic compound. The protocol needs to be both simple and efficient to enable a rapid response and avoid delay of patient management. In the present study, decontamination strategies included in the initial operational response were evaluated following human skin exposure in vitro to four different contaminants. Results demonstrated that the efficacy of selected decontamination procedures was highly dependent on the chemical contaminant used. Dry removal of the sulfur mustard simulant methyl salicylate prior to wet decontamination was found beneficial compared to wet decontamination alone. Rapidly initiated wet decontamination was more efficient compared to dry and wet removal of the industrial chemical 2-butoxyethanol and the nerve agent tabun. Following VX-exposure, all wet decontamination procedures resulted in increased agent penetration compared to the control. In conclusion, challenges in establishing simple and efficient decontamination procedures for a broad-spectrum of chemicals have been demonstrated. The impact of including a dry removal step during decontamination was evidently agent specific. Despite the variation in efficacy, immediately initiated dry removal may facilitate patient management until wet decontamination resources are available and to reduce the risk of secondary contamination.

Skin decontamination in cold weather temperatures might be challenging due to the aggravating circumstances. However, no information is available on the efficacy of commonly used procedures in winter conditions. Therefore, the efficacy of the reactive skin decontamination lotion (RSDL) and soapy water decontamination following skin exposure to the nerve agent VX was evaluated at three ambient air temperatures (-5°C, -15°C and room temperature). Experiments were performed in vitro using human dermatomed skin. The ability of RSDL to degrade VX at the three different air temperatures was separately evaluated. The ambient air temperature in experiments without decontamination did not influence the penetration rate of VX through skin. RSDL decontamination was highly efficient in removing VX from skin when performed in all three ambient temperatures, despite the slower agent degradation rate of VX at the lower temperatures. Decontamination with soapy water at RT resulted in an increased skin penetration of VX compared with the control without decontamination; however, in colder temperatures the VX skin penetration was similar to the corresponding control without decontamination. At RT, dry removal prior to washing with soapy water did not improve decontamination of VX compared with washing solely with soapy water. This study demonstrated high efficacy of RSDL decontamination following skin exposure to VX also at cold temperatures. The previously reported 'wash-in' effect of soapy water on VX skin penetration was reduced at cold temperatures. Altogether, this study found a scientific basis to establish guidelines for skin decontamination of chemical casualties at cold weather temperatures.

Predicting risk of zoonotic diseases, i.e., diseases shared by humans and animals, is often complicated by the population ecology of wildlife host(s). We here demonstrate how ecological knowledge of a disease system can be used for early prediction of human risk using Puumala hantavirus (PUUV) in bank voles (Myodes glareolus), which causes Nephropathia epidemica (NE) in humans, as a model system. Bank vole populations at northern latitudes exhibit multiannual fluctuations in density and spatial distribution, a phenomenon that has been studied extensively. Nevertheless, existing studies predict NE incidence only a few months before an outbreak. We used a time series on cyclic bank vole population density (1972–2013), their PUUV infection rates (1979–1986; 2003–2013), and NE incidence in Sweden (1990–2013). Depending on the relationship between vole density and infection prevalence (proportion of infected animals), either overall density of bank voles or the density of infected bank voles may be used to predict seasonal NE incidence. The density and spatial distribution of voles at density minima of a population cycle contribute to the early warning of NE risk later at its cyclic peak. When bank voles remain relatively widespread in the landscape during cyclic minima, PUUV can spread from a high baseline during a cycle, culminating in high prevalence in bank voles and potentially high NE risk during peak densities.

Background Differences in the expression of regulatory T cells (Tregs) have been suggested to explain why some smokers develop COPD and some do not. Upregulation of Tregs in response to smoking would restrain airway inflammation and thus the development of COPD; while the absense of such upregulation would over time lead to chronic inflammation and COPD. We hypothesized that—among COPD patients—the same mechanism would affect rate of decline in lung function; specifically, that a decreased expression of Tregs would be associated with a more rapid decline in FEV1. Methods Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry. Results The proportions of Tregs with regulatory function (FoxP3+/CD4+CD25bright) were significantly lower in COPD subjects with a rapid decline in lung function compared to those with a non-rapid decline (p = 0.019). This result was confirmed in a mixed model regression analysis in which adjustments for inhaled corticosteroid usage, smoking, sex and age were evaluated. No significant difference was found between COPD subjects and smokers or non-smokers with normal lung function. Conclusions COPD subjects with a rapid decline in lung function had lower proportions of T cells with regulatory function in BAL fluid, suggesting that an inability to suppress the inflammatory response following smoking might lead to a more rapid decline in FEV1. Trial registration Clinicaltrials.gov identifier NCT02729220

Background: Handgrip strength measurements are feasible with older adults and a reliable indicator for vitality, physical function, and several risk factors in the ageing process. Interventions with exercise training induce a variety of strength, balance, and endurance improvements. The pooled transfer effects of exercise training on handgrip strength has not been investigated to date. Thus, the objective of this meta-analytical review is to examine the effects of different exercise training on handgrip strength in healthy community-dwelling older adults of 60 years or older. Methods: The literature search was conducted in three databases (PubMed, Web of Science, SPORTDiscus) using the following search terms with Boolean conjunctions: (hand grip* OR grip strength OR grip power) AND (sport* OR train* OR exercis* OR strength OR intervention OR endurance OR resistance OR balance OR aerob*) AND (old* OR elder* OR senior*). Non-randomized and randomized controlled trials with an exercise training and handgrip strength as the outcome parameter were screened. Study quality was independently assessed by two researchers using the PEDro scale. Comparison of handgrip strength between the intervention and control groups was conducted by using the hedges g (including adjustment for small sample sizes), calculating standardized mean differences (SMDs). A random effects inverse-variance model was applied for statistical analysis. Results: Twenty-four trials (mean PEDro score 5.8 ± 0.9) with a total of 3,018 participants (mean age 73.3 ± 6.0 years) were included. Small but significant effects (p < 0.001) on handgrip strength were observed (SMD 0.28, 95% CI 0.13–0.44). Study heterogeneity (I2 56%) and the funnel shape for publication bias analyses were acceptable. Conclusions: Meaningful but small transfer effects of a multitude of different training approaches on handgrip strength occurred in healthy community-dwelling older adults. Handgrip strength cannot clearly be recommended to assess general functional performance for all kinds of exercise programs, whereas task-specific training and multimodal training modes seem to provide an appropriate stimulus to also improve handgrip strength.

The decontamination efficacy of four commercially available skin decontamination products following exposure to the nerve agent VX was evaluated in vitro utilizing a diffusion cell and dermatomed human skin. The products included were Reactive Skin Decontamination Lotion (RSDL), the Swedish decontamination powder 104 (PS104), the absorbent Fuller's Earth and the aqueous solution alldecontMED. In addition, various decontamination procedures were assessed to further investigate important mechanisms involved in the specific products, e.g. decontamination removal from skin, physical removal by sponge swabbing and activation of degradation mechanisms. The efficacy of each decontamination product was evaluated 5 or 30 min after dermal application of VX (neat or diluted to 20% in water). The RSDL-lotion was superior in reducing the penetration of VX through human skin, both when exposed as neat agent and when diluted to 20% in water. Swabbing with the RSDL-sponge during 2 min revealed decreased efficacy compared to applying the RSDL-lotion directly on the skin for 30 min. Decontamination with Fuller's Earth and alldecontMED significantly reduced the penetration of neat concentration of VX through human skin. PS104-powder was insufficient for decontamination of VX at both time-points, independently of the skin contact time of PS104. The PS104-slurry (a mixture of PS104-powder and water), slightly improved the decontamination efficacy. Comparing the time-points for initiated decontamination revealed less penetrated VX for RSDL and Fuller's Earth when decontamination was initiated after 5 min compared to 30 min post-exposure, while alldecontMED displayed similar efficacy at both time-points. Decontamination by washing with water only resulted in a significant reduction of penetrated VX when washing was performed 5 min after exposure, but not when decontamination was delayed to 30 min post-exposure of neat VX. In conclusion, early initiated decontamination with the RSDL-lotion, containing both absorption and degrading properties, allowed to act on skin for 30 min was superior in preventing VX from penetrating human skin. Adding water during decontamination resulted in increased penetration of neat VX, however, water in the decontaminant removal process did not influence the decontamination efficacy. From our study on commercially available decontaminants, it is recommended that future product developments should include both strong absorbents and efficient nerve agent degrading components.

Early initiated decontamination is demonstrated to be crucial to avoid systemic effects of highly toxic and low volatile agents exposed on the skin. Skin decontamination can be performed by simple procedures, such as washing with soap and water, or by using advanced decontamination products containing absorption and agent degradation properties. Reactive Skin Decontamination Lotion (RSDL) has demonstrated high efficacy to remove nerve agents from the skin. However, contrary to the current operational recommendations, experimental studies have shown that prolonged skin contact time of RSDL is important for efficient decontamination of VX. In the present study, several RSDL-protocols were evaluated for the efficacy to remove neat VX from human skin in vitro. The decontamination efficacies of the RSDL-procedures were compared with the efficacy of the simple procedure of washing off the skin with soapy water. The RSDL-protocols containing repeated swabbing with the sponge and a 10 min skin contact time of RSDL-lotion demonstrated the greatest decontamination efficacy of all procedures evaluated. Repeating the protocol 2 h after the initial decontamination step resulted in a transient increased skin penetration of remaining intact agent on skin and was followed by rapidly declined agent penetration rate. Decontamination performed with soapy water significantly increased agent amounts penetrating skin, most likely caused by skin hydration and agent dilution. In conclusion, a slightly extended procedure for RSDL-decontamination showed improved efficacy and is therefore recommended for removal of nerve agents from the skin. In addition, it is of highest importance that skin decontamination of nerve agents should consist of procedures using low water content.

Besides strength and balance, flexibility is an important indicator of health-related physical fitness. Thus, the aim of this two-armed randomized controlled pilot trial was to investigate whether sauna yoga at a moderate temperature (50 &deg, C) beneficially affects flexibility, strength, balance, and quality of life (QOL) in healthy elderly community dwellers. Participants were randomly assigned to an intervention group (INT, n = 11, age: 68.7 &plusmn, 5.9) or control group (CON, n = 12, age: 69.3 &plusmn, 4.9), using the minimization method. Age, physical activity, gender, and the primary outcome flexibility were used as strata for group allocation. Both groups completed similar exercises in the sauna over eight weeks. Only the INT group was exposed to moderate temperatures of 50 &deg, C. Large and statistically significant improvement in favor of the sauna group (INT) was observed for the chair sit-and-reach test (INT: +83%, CON +3%, p = 0.028, nр&sup2, = 0.24). The shoulder and lateral spine flexibility were not relevantly affected. Strength in the lower extremities merely showed a tendency to significant changes (INT: 16%, CON: 3%, p = 0.061, nр&sup2, = 0.181). Additionally, balance abilities, with eyes closed, improved (INT: 187%, CON +58%, p = 0.056, nр&sup2, = 0.189) in favor of the INT group. QOL only improved in favor of the INT for environmental dimension (INT: +7%, CON: 0%, p = 0.034, nр&sup2, = 0.227). These first but preliminary findings indicate that sauna yoga may serve as a promising and feasible means to improve flexibility in elderly people. Strength and balance do not meaningfully benefit from a sauna environment, although strength improved to a slightly higher extent in the sauna group. Future large-scale research is needed to elucidate underlying mechanisms and corroborate these findings

Rodent-borne hantaviruses cause two severe acute diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia, and hantavirus pulmonary syndrome (HPS; also called hantavirus cardiopulmonary syndrome [HCPS]) in the Americas. Puumala virus (PUUV) is the most common causative agent of HFRS in Europe. Current routine diagnostic methods are based on serological analyses and can yield inconclusive results. Hantavirus-infected patients are viremic during the early phase of disease; therefore, detection of viral RNA genomes can be a valuable complement to existing serological methods. However, the high genomic sequence diversity of PUUV has hampered the development of molecular diagnostics, and currently no real-time reverse transcription-quantitative (RT)-PCR assay is available for routine diagnosis of HFRS. Here, we present a novel PUUV RT-PCR assay. The assay was validated for routine diagnosis of HFRS on samples collected in Sweden during the winter season from 2013 to 2014. The assay allowed detection of PUUV RNA in 98.7% of confirmed clinical HFRS samples collected within 8 days after symptomatic onset. In summary, this study shows that real-time RT-PCR can be a reliable alternative to serological tests during the early phase of HFRS.

Unintentional exposure to potent synthetic opioids during law enforcement seizures and rescue operations can potentially result in incapacitating effects or life-threatening respiratory depression. The hazard comes mainly from inhalation exposure, however, the skin contact risk should be considered. In the present study, the skin penetration of fentanyl and the efficacy of different decontamination protocols were evaluated by applying two forms of fentanyl on dermatomed human skin mounted in a diffusion cell. Studies were performed on dry skin or skin moistened by water, sweat or hand sanitizer. The free base of fentanyl displayed greater skin penetration ability than the hydrochloride salt and a higher steady state penetration rate of fentanyl in solution compared to powder on dry skin. Sweaty skin increased the penetration rate, both when applied in solution and as powder. The hand sanitizer increased skin penetration of the free base fentanyl but not the hydrochloride salt. Of the evaluated decontamination procedures, only soapy water demonstrated a general efficacy. In conclusion, the skin contact hazard of fentanyl is highly dependent on the exposure conditions and contamination density. The risk for physiological effects of fentanyl is assessed to occur only at very high exposures on sweaty skin. In such events, skin decontamination using soap and water is estimated to be a sufficient decontamination procedure.

There is a compelling need to understand and assess the toxicity of industrially produced nanoparticles (NPs). In order to appreciate the long-term effects of NPs, sensitive human-based screening tests that comprehensively map the NP properties are needed to detect possible toxic mechanisms. Animal models can only be used in a limited number of test applications and are subject to ethical concerns, and the interpretation of experiments in animals is also distorted by the species differences. Here, we present a novel easy-to-perform highly sensitive whole-blood model using fresh non-anticoagulated human blood, which most justly reflects complex biological cross talks in a human system. As a demonstrator of the tests versatility, we evaluated the toxicity of TiO2 NPs that are widely used in various applications and otherwise considered to have relatively low toxic properties. We show that TiO2 NPs at very low concentrations (50 ng/mL) induce strong activation of the contact system, which in this model elicits thromboinflammation. These data are in line with the finding of components of the contact system in the protein corona of the TiO2 NPs after exposure to blood. The contact system activation may lead to both thrombotic reactions and generation of bradykinin, thereby representing fuel for chronic inflammation in vivo and potentially long-term risk of autoimmunity, arteriosclerosis and cancer. These results support the notion that this novel whole-blood model represents an important contribution to testing of NP toxicity.

An unexpected human outbreak of the mosquitoborne Sindbis virus occurred in a previously nonendemic area of Sweden. At follow-up, 6-8 months after infection, 39% of patients had chronic arthralgia that affected their daily activities. Vectorborne infections may disseminate rapidly into new areas and cause acute and chronic disease.

Background Cytotoxic lymphocytes are increased in the airways of COPD patients. Whether this increase is driven primarily by the disease or by smoking is not clear, nor whether it correlates with the rate of decline in lung function. Methods Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study according to pre-determined criteria; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry. Results In BAL fluid, the proportions of NK, iNKT and NKT-like cells all increased with pack-years. Within the COPD group, NK cells – but not iNKT or NKT-like cells – were significantly elevated also in subjects that had quit smoking. In contrast, current smoking was associated with a marked increase in iNKT and NKT-like cells but not in NK cells. Rate of lung function decline did not significantly affect any of the results. Conclusions In summary, increased proportions of NK cells in BAL fluid were associated with COPD; iNKT and NKT-like cells with current smoking but not with COPD. Interestingly, NK cell percentages did not normalize in COPD subjects that had quit smoking, indicating that these cells might play a role in the continued disease progression seen in COPD even after smoking cessation. Trial registration Clinicaltrials.gov identifier NCT02729220. Electronic supplementary material The online version of this article (10.1186/s12931-018-0940-7) contains supplementary material, which is available to authorized users.

Background and objective The use of psychotropic medication and cardiovascular medication has been associated with an increased risk of falling. However, other frequently prescribed medication classes are still under debate as potential risk factors for falls in the older population. The aim of this systematic review and meta-analysis is to evaluate the associations between fall risk and nonpsychotropic and noncardiovascular medications. Methods and design A systematic review and meta-analysis. A search was conducted in Medline, PsycINFO, and Embase. Key search concepts were “falls,” “aged,” “medication,” and “causality.” Studies were included that investigated nonpsychotropic and noncardiovascular medications as risk factors for falls in participants ≥60 years or participants with a mean age ≥70 years. A meta-analysis was performed using the generic inverse variance method, pooling unadjusted and adjusted odds ratio (OR) estimates separately. Results In a qualitative synthesis, 281 studies were included. The results of meta-analysis using adjusted data were as follows (a pooled OR [95% confidence interval]): analgesics, 1.42 (0.91-2.23); nonsteroidal anti-inflammatory drugs (NSAIDs), 1.09 (0.96-1.23); opioids, 1.60 (1.35-1.91); anti-Parkinson drugs, 1.54 (0.99-2.39); antiepileptics, 1.55 (1.25-1.92); and polypharmacy, 1.75 (1.27-2.41). Most of the meta-analyses resulted in substantial heterogeneity that did not disappear after stratification for population and setting in most cases. In a descriptive synthesis, consistent associations with falls were observed for long-term proton pump inhibitor use and opioid initiation. Laxatives showed inconsistent associations with falls (7/20 studies showing a positive association). Conclusion Opioid and antiepileptic use and polypharmacy were significantly associated with increased risk of falling in the meta-analyses. Long-term use of proton pump inhibitors and opioid initiation might increase the fall risk. Future research is necessary because the causal role of some medication classes as fall-risk-increasing drugs remains unclear, and the existing literature contains significant limitations.

Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. α-Fe

In this study aerosol samples collected in an Asian mega-city (Kabul, Afghanistan) were compared to PM samples collected in a European location with traffic (Umeå, Sweden) and a reference urban dust material (SRM 1649b). The toxicity of each sample towards normal human bronchial epithelial (NHBE) cells and a human bronchial epithelial cell line (BEAS-2B) was tested along with their ability to induce reactive oxygen species (ROS) formation and inflammatory responses. The extracts' morphology and elemental composition was studied by SEM-EDXRF, and filter samples were analyzed for metals and organic compounds. The PM from Kabul contained a larger fraction of fine particles, 19 times more polyaromatic hydrocarbons (PAH) and 37 times more oxygenated PAH (oxy-PAH) compared to samples from Umeå. The PM-samples from Kabul and the reference material (SRM 1649b) induced significantly stronger oxidative stress responses than the samples from Umeå. Furthermore, samples collected in Kabul induced significantly higher secretion of the cytokines IL-6, IL-8 and GM-CSF while SRM1649b induced a cytokine pattern more similar to samples collected in Umeå. Several properties of the particles could potentially explain these differences, including differences in their size distribution and contents of PAH and oxy-PAH, possibly in combination with their relative transition metal contents.

Dermal exposure to low volatile organophosphorus compounds (OPC) may lead to penetration through the skin and uptake in the blood circulation. Skin decontamination of toxic OPCs, such as pesticides and chemical warfare nerve agents, might therefore be crucial for mitigating the systemic toxicity following dermal exposure. Reactive skin decontamination lotion (RSDL) has been shown to reduce toxic effects in animals dermally exposed to the nerve agent VX. In the present study, an in vitro flow-through diffusion cell was utilized to evaluate the efficacy of RSDL for decontamination of VX exposed to human epidermis. In particular, the impact of timing in the initiation of decontamination and agent dilution in water was studied. The impact of the lipophilic properties of VX in the RSDL decontamination was additionally addressed by comparing chemical degradation in RSDL and decontamination efficacy between the VX and the hydrophilic OPC triethyl phosphonoacetate (TEPA). The epidermal membrane was exposed to 20, 75 or 90% OPC diluted in deionized water and the decontamination was initiated 5, 10, 30, 60 or 120min post-exposure. Early decontamination of VX with RSDL, initiated 5-10min after skin exposure, was very effective. Delayed decontamination initiated 30-60min post-exposure was less effective but still the amount of penetrated agent was significantly reduced, while further delayed start of decontamination to 120min resulted in very low efficacy. Comparing RSDL decontamination of VX with that of TEPA showed that the decontamination efficacy at high agent concentrations was higher for VX. The degradation mechanism of VX and TEPA during decontamination was dissected by

We have analyzed the V-gene usage in gamma delta T cells of the human gut and joint by using a new mAb (B18) specific for V gamma 8 of human TCR-gamma delta+ T cells. The B18+ population constituted a minor subset of the gamma delta T cells in peripheral blood (PB) of healthy persons (6 +/- 5%) and only 1 of 35 gamma delta T cell clones analyzed was positive. In contrast, the B18+ subset was a dominant gamma delta T cell population among intraepithelial lymphocytes (IEL) derived from the human intestine (74 +/- 29, p < 0.002), and two of three IEL clones from patients with coeliac disease were B18+. Interestingly, a higher proportion of B18+ gamma delta T cells was found in the synovial fluid of patients with rheumatoid arthritis (RA) (21 +/- 18%, 0.02 < p < 0.05) compared with normal PB. Furthermore, the B18+ subset was more frequent among IL-2-expanded gamma delta T cells (42 +/- 20%) derived from synovial tissue than among IL-2-expanded cells derived from synovial fluid (p < 0.002) and PB from RA patients (p < 0.02) as well as normal PB (p < 0.002). The V-gene usage of 13 gamma delta T cell clones from the synovial fluid of arthritic patients was analyzed. All B18+ clones (n = 7) expressed mRNA for V gamma 8 together with mRNA for V delta 1 (n = 5) or mRNA for V delta 3 (n = 2). None of the B18- clones expressed V gamma 8 (n = 6). We conclude that the gamma delta T cell that expresses V gamma 8, together with mainly V delta 1, is a major gamma delta T cell subset among the IEL of the gut and a highly frequent subset in the synovial tissue of patients with RA. This subset may correspond to the mouse V gamma 7+ IEL, which has a high degree of amino acid sequence homology with the human V gamma 8 protein.

Gallium ions have previously been shown to exhibit antibacterial and antibiofilm properties. In this study, we report differential bactericidal activities of two gallium complexes, gallium desferrioxamine B (Ga-DFOB) and gallium citrate (Ga-Cit). Modeling of gallium speciation in growth medium showed that DFOB and citrate both can prevent precipitation of Ga(OH) 3 , but some precipitation can occur above pH 7 with citrate. Despite this, Ga-Cit 90% inhibitory concentrations (IC 90 ) were lower than those of Ga-DFOB for clinical isolates of Pseudomonas aeruginosa and several reference strains of other bacterial species. Treatment with Ga compounds mitigated damage inflicted on murine J774 macrophage-like cells infected with P. aeruginosa PAO1. Again, Ga-Cit showed more potent mitigation than did Ga-DFOB. Ga was also taken up more efficiently by P. aeruginosa in the form of Ga-Cit than in the form of Ga-DFOB. Neither Ga-Cit nor Ga-DFOB was toxic to several human cell lines tested, and no proinflammatory activity was detected in human lung epithelial cells after exposure in vitro . Metabolomic analysis was used to delineate the effects of Ga-Cit on the bacterial cell. Exposure to Ga resulted in lower concentrations of glutamate, a key metabolite for P. aeruginosa , and of many amino acids, indicating that Ga affects various biosynthesis pathways. An altered protein expression profile in the presence of Ga-Cit suggested that some compensatory mechanisms were activated in the bacterium. Furthermore, the antibacterial effect of Ga was shown to vary depending on the carbon source, which has importance in the context of medical applications of gallium.

Purpose: We aimed at developing simulation software capable of producing images of corneal endothelium close to identical to images captured by clinical specular microscopy with defined morphometrical characteristics. It was further planned to demonstrate the usefulness of the simulator by analysing measurement errors associated with a trained operator using a commercially available semi-automatic algorithm for analysis of simulated images. Methods: Software was developed that allows creation of unique images of the corneal endothelium expressing morphology close to identical with that seen in images of corneal specular microscopy. Several hundred unique images of the corneal endothelium were generated with randomization, spanning a physiological range of endothelial cell density. As an example of the usefulness of the simulator for analysis of measurement errors in corneal specular microscopy, a total of 12 of all the images generated were randomly selected such that the endothelial cell density expressed was evenly distributed over the physiological range of endothelial cell density. The images were transferred to a personal computer. The imagenet-640 software was used to analyse endothelial cell size variation, percentage of hexagonal endothelial cells, and endothelial cell density. Results: The simulator developed allows randomized generation of corneal specular microscopy images with a preset expected average and variation of cell structure. Calculated morphometric information of each cell is stored in the simulator. The image quality can secondarily be varied with a toolbox of filters to approximate a large spectrum of clinically captured images. As an example of the use of the simulator, measurement errors associated with one trained operator using the imagenet-640 software, and focusing on endothelial cell density, were examined. The functional dependence between morphometric information estimated with the imagenet-640 software algorithm and real morphometric information as provided by the simulator was analysed with regression. It was demonstrated that that the estimations of endothelial cell size variation was associated with a scaling error and that the random error was strongly dependent on the operator. Conclusion: The newly developed simulator for randomized generation of morphometrically defined corneal specular microscopy images for the first time makes it possible to estimate a spatial scaling error of an available semi-automatic algorithm and to determine the random measurement error of important morphometric estimates in a defined reference sample of images. It is anticipated that the simulator will be a valuable tool for the generation of a large set of morphometrically well-characterized corneal specular microscopy images that can be used for calibration among research centres, for minimization of random errors and for measurement of quality control. Simulated images will be useful for the development of fully automatic analysis of corneal endothelial cell morphometry.

Background and objective Use of certain medications is recognized as a major and modifiable risk factor for falls. Although the literature on psychotropic drugs is compelling, the literature on cardiovascular drugs as potential fall-risk-increasing drugs is conflicting. The aim of this systematic review and meta-analysis is to provide a comprehensive overview of the associations between cardiovascular medications and fall risk in older adults. Methods Design: A systematic review and meta-analysis. Data sources: Medline, Embase, and PsycINFO. Key search concepts were “fall,” “aged,” “causality,” and “medication.” Studies that investigated cardiovascular medications as risk factors for falls in participants ≥60 years old or participants with a mean age of 70 or older were included. A meta-analysis was performed using the generic inverse variance method, pooling unadjusted and adjusted odds ratios (ORs) separately. Results In total, 131 studies were included in the qualitative synthesis. Meta-analysis using adjusted ORs showed significant results (pooled OR [95% confidence interval]) for loop diuretics, OR 1.36 (1.17, 1.57), and beta-blocking agents, OR 0.88 (0.80, 0.97). Meta-analysis using unadjusted ORs showed significant results for digitalis, OR 1.60 (1.08, 2.36); digoxin, OR 2.06 (1.56, 2.74); and statins, OR 0.80 (0.65, 0.98). Most of the meta-analyses resulted in substantial heterogeneity that mostly did not disappear after stratification for population and setting. In a descriptive synthesis, consistent associations were not observed. Conclusion Loop diuretics were significantly associated with increased fall risk, whereas beta-blockers were significantly associated with decreased fall risk. Digitalis and digoxin may increase the risk of falling, and statins may reduce it. For the majority of cardiovascular medication groups, outcomes were inconsistent. Furthermore, recent studies indicate that specific drug properties, such as selectivity of beta-blockers, may affect fall risk, and drug-disease interaction also may play a role. Thus, studies addressing these issues are warranted to obtain a better understanding of drug-related falls.

Data from longitudinal analyses can be useful in the design and implementation of control strategies., Local transmission of chikungunya, a debilitating mosquito-borne viral disease, was first reported in Singapore in January 2008. After 3 months of absence, locally acquired Chikungunya cases resurfaced in May 2008, causing an outbreak that resulted in a total of 231 cases by September 2008. The circulating viruses were related to East, Central, and South African genotypes that emerged in the Indian Ocean region in 2005. The first local outbreak was due to a wild-type virus (alanine at codon 226 of the envelope 1 gene) and occurred in an area where Aedes aegypti mosquitoes were the primary vector. Strains isolated during subsequent outbreaks showed alanine to valine substitution (A226V) and largely spread in areas predominated by Ae. albopictus mosquitoes. These findings led to a revision of the current vector control strategy in Singapore. This report highlights the use of entomologic and virologic data to assist in the control of chikungunya in disease-endemic areas.

The aim of this study was to determine if a three-day treatment of lower urinary tract infection (UTI) is effective. 215 women with symptoms of lower UTI, seen in general practice, were randomly allocated to a double-blind study and given either amoxycillin 1000 mg twice a day for three days or trimethoprim 90 mg/sulphadiazine 410 mg (co-trimazine) 2 tablets initially, then one tablet twice daily for three days. 157 women (73%) had significant bacteriuria. Therapeutic efficacy was evaluated in 146 patients. One week after treatment had started, 88% of the women in the amoxycillin group and 100% in the co-trimazine group were cured (p less than 0.01). After a follow-up period of four weeks, the cumulative relapse frequencies were 19% and 9% respectively. Adverse reactions were mild in most cases. Two patients, both on co-trimazine, had to discontinue treatment because of nausea and vomiting. Vulvovaginal irritation was more often reported by women treated with amoxycillin (n = 8) than by those treated with co-trimazine (n = 1) (p less than 0.05). It is concluded that a three-day course of amoxycillin or co-trimazine in lower UTI is safe, causes few adverse reactions, is simple to administer and comfortable for the patient. Co-trimazine seems to be more effective than amoxycillin.

The urinary concentrating capacity was estimated with the DDAVP test in 87 patients receiving lithium therapy, which was discontinued in all patients. The test was repeated three and eight weeks after withdrawal of lithium in 75 patients and one year after withdrawal in 27 patients. Of the 87 patients, 52 were also treated with neuroleptics, which treatment was continued throughout the study. Two control groups, consisting of 30 patients receiving only neuroleptics and 30 healthy subjects, were studied on one occasion with the DDAVP test. Lithium-treated patients had significantly lower concentrating capacity and higher serum creatinine than healthy subjects at all examinations. Small but statistically significant correlations were found between urinary osmolality and total dose of lithium, between urinary osmolality and duration of lithium treatment, between the highest serum lithium concentration recorded and urinary osmolality after withdrawal of lithium and between the daily dose of lithium and urinary osmolality, while patients were still on lithium. The concentrating capacity improved significantly during the first two months after withdrawal of lithium, but not later. One year after withdrawal of lithium, 17 of 27 patients still had a concentrating capacity below 800 mOsm/kg. Patients receiving lithium and neuroleptics had lower concentrating capacity than patients treated with lithium alone, and patients treated with neuroleptics alone had lower concentrating capacity than healthy subjects.

Ten patients on long-term lithium therapy and ten on lithium and neuroleptics (combination therapy) were examined with renal biopsy and tests of renal function. Patients on combination therapy had more pronounced histopathological changes and lower concentrating capacity than patients on lithium alone. Patients on combination therapy had received a larger total dose of lithium and had had higher maximum serum lithium levels than patients on lithium alone. Patients with large daily urine volumes had a low concentrating capacity. There was a negative correlation between degree of histopathological lesions and urinary concentrating capacity. Estimation of urinary concentrating capacity seems to be of value for the assessment of renal lesions in lithium treatment.

Background: Volatile monoisocyanates are formed through thermal degradation when products containing polyurethane are heated. Repeated exposure to diisocyanates, such as toluene diisocyanate (TDI) are a well-known cause of occupational asthma. However, although monoisocyanates are abundant in occupational settings, there are few data concerning their ability to provoke immune reactions and asthma. We compared immune reactivity and respiratory disease following single or repeated inhalation exposures to the monoisocyanates methyl isocyanate (MIC) and isocyanic acid (ICA) with the effects of TDI. Methods:Isocyanates were administrated either as single vapor exposures or as repeated intranasal instillations in rats. Adverse health effects were monitored by analyzing airway inflammation, respiratory function and weight gain. Immune reactivity caused by repeated exposures was studied by analysis of isocyanate-specific antibodies and airway infiltration of immune competent cells. Results: Repeated exposures to TDI induced airway infiltration of neutrophils and lymphocytes, while neither MIC nor ICA provoked a detectable inflammatory response. Antibodies against isocyanate-albumin conjugates were detected in serum after both exposures to TDI and MIC, but not to ICA. TDI-exposed rats also displayed IgG antibodies against MIC-albumin conjugates. Even though MIC did not induce airway inflammation, single exposure provoked an increase in airway resistance and repeated exposures caused weight loss similar to that of TDI. Conclusions: Airway exposure to TDI produces an antibody response not only against TDI but also against MIC-protein conjugates. This indicates that immune reactivity against abundant monoisocyanates in occupational environments can occur in individuals pre-sensitized with low abundance but highly sensitizing diisocyanates.

The mechanisms behind airway inflammation in chronic obstructive pulmonary disease (COPD) are still not well understood. Here we investigated lymphocyte subtypes in bronchoalveolar lavage fluid, likely to be involved in the pathogenesis of COPD, as well as exploring the effect of smoking cessation. Differential cell counts and T cell subsets were determined in BAL fluid from nineteen individuals with stable COPD (seven smokers, twelve ex-smokers) compared to twelve age-matched never-smokers and thirteen smoking-matched smokers with normal lung function. COPD-patients had higher percentages of airway CD8(+) T cells compared to never-smokers. An increased population of CD4(+) T cells expressed high levels of CD25 in smokers and COPD patients compared to never-smokers, suggesting the presence of regulatory T cells. As the T cell populations in smokers with normal lung function and COPD-patients were similar, the impact of current smoking in COPD was addressed in a subgroup analysis. Activation of CD8(+) T cells was found regardless of smoking habits. In contrast, the enhanced expression of gamma/delta T cells, was mainly associated with current smoking, whilst the increase in T regulatory cells appeared related to both smoking and COPD. Regardless of smoking habits, CD8(+) T cell activation was found in COPD, supporting the contention that this T cell subset may play a role in the pathogenesis of COPD. As CD8(+) T cells coexist with immunoregulatory CD4(+) T cells in airways of COPD patients, it is likely that both cytotoxic T-cell responses and immunosuppressive mechanisms may be of importance in COPD pathogenesis.

The purpose of this study is to describe predictors for discharge and one-year outcomes of acute-care hospital patients, 75 years of age or over, based on admission status information. We carried out a prospective study of a randomly selected patient population, from one urban acute-care hospital in each of the Nordic countries. 763 persons aged 75+ were randomly selected from acute admissions to the participating hospitals. 749 observations at discharge and 655 observations at one year were used in analyses.Data were collected with the MDS-AC 1.1 instrument within 24 hours of admission, and at day 7 or discharge, whichever came first. Outcome information was collected either by interviewing the patient or from patient records or registers. Discharge and one-year outcome (home, institution, death) were modeled by multinomial logistic regression, with admission status variables as predictors.At discharge, 84% of subjects returned home, 11% went to an institution and 5.6% had died. At one year, 64% were still living at home, 24% had died, and 12% had moved to an institution. For discharge outcome, those having hospital admission due to a new problem or exacerbation of an old one had a higher risk of dying (OR 3.3) than returning home. Moderate to severe cognitive problems predicted death (OR 2.2) and institutionalization (OR 8.6) compared with discharge home. Problems in instrumental activities of daily living predicted death (OR 3.1) and institutionalization (OR 6.0). At one year, those with exacerbation of an old problem (OR 2.1) or with a new or exacerbated existing problem (OR 2.3) had a higher risk of dying than of institutionalization or discharge home. Having some cognitive problems (OR 2.8) or moderate to severe cognitive problems (OR 6.6) predicted institutionalization, but not dying or discharge home. Those with some problems in activities of daily living had a higher risk of both dying (OR 1.7) and of institutional care (OR 2.7). Those with moderate to severe problems in activities of daily living had also a higher risk of institutional care (OR 4.7) compared with those living at home.Evidence predictive of discharge and one-year outcomes in older acute hospital medical care patients seems to be visible from the beginning of the hospital stay. In order to increase the efficient use of health care services and quality of care, systematic standardized and streamlined assessment should be performed during the admission process.

Previous studies have shown that chronic opiates may inhibit cell growth and trigger apoptosis leading to impaired cognitive capabilities in both humans and other mammals. In contrast, growth hormone (GH) has been demonstrated to stimulate cell growth and counteract apoptosis. GH has also been shown to improve learning and memory in both human and rodents. In this work, we demonstrate that GH may reverse opiate-induced apoptosis in cells derived from prenatal mouse hippocampus. Primary hippocampal cell cultures derived from 16-day-old fetal mouse neurons were treated with morphine for 7 days during growth in the absence or presence of recombinant human GH (rhGH). The release of lactate dehydrogenase (LDH) into the culture media and the level of cleaved caspase-3 were measured. Results indicate that morphine (15 μM) decreased the cell content in a concentration-dependent manner and increased LDH release and caspase-3 activity. Thus, fetal mouse neurons treated with morphine showed less viability compared with controls. Interestingly, the addition of rhGH (1 μM) counteracted the morphine-induced effect on the cell density. Furthermore, the hormone attenuated the effects on LHD release and caspase-3 activity elicited by morphine. These results suggest that the hormone is capable of preventing or even repairing morphine-induced damage to hippocampal cells.

Puumala hantavirus (PUUV), naturally harboured and shed by bank voles (Myodes [Clethrionomys] glareolus), is the etiological agent to nephropathia epidemica (NE), a mild haemorrhagic fever with renal syndrome. Both host and virus are found throughout much of the European continent and in northern Sweden NE is the second most prevalent serious febrile viral infection after influenza. The reliability of diagnostics by PCR depends on genetic variability for the detection of viral nucleic acids in unknown samples. In the present study we evaluated the genetic variability of PUUV isolated from bank voles in an area of northern Sweden highly endemic for NE. Genetic variability among bank voles was also investigated to evaluate co-evolutionary patterns. We found that the viral sequence appeared stable across the 80km study region, with the exception of the southernmost sampling site, which differed from its nearest neighbour by 7%, despite a geographical separation of only 10km. The southernmost sampling site demonstrated a higher degree of genetic similarity to PUUV previously isolated 100km south thereof; two locations appear to constitute a separate PUUV phylogenetic branch. In contrast to the viral genome, no phylogenetic variance was observed in the bank vole mtDNA in this study. Previous studies have shown that as a result of terrestrial mammals' postglacial re-colonization routes, bank voles and associated PUUV of a southern and a northern lineage established a dichotomous contact zone across the Scandinavian peninsula approximately 100-150km south of the present study sites. Our observations reveal evolutionary divergence of PUUV that has led to dissimilarities within the restricted geographical scale of the northern host re-colonization route as well. These results suggest either a static situation in which PUUV strains are regionally well adapted, or an ongoing process in which strains of PUUV circulate on a geographical scale not yet reliably described.

Galanin is colocalized with adrenocorticotrophin (ACTH) in the human pituitary and with corticotrophin releasing hormone, arginine, vasopressin, and oxytocin in the hypothalamus. Galanin, vasopressin, and oxytocin influence the secretion of pituitary ACTH. The aim of this study was to investigate if the endogenous stimulation of ACTH release in Addison's disease was reflected in plasma galanin, vasopressin, and oxytocin. ACTH, galanin, vasopressin, and oxytocin were measured in plasma from 14 patients with Addison's disease, one patient with Nelson's syndrome, and 14 healthy controls. Eight patients had elevated plasma ACTH whereas six patients and all controls had ACTH levels within the reference-range. There was no difference in galanin or vasopressin between patients and controls or between samples with low or high ACTH concentrations. In contrast, oxytocin was higher in patients with elevated plasma ACTH compared to patients and controls with normal or low ACTH. No relation was found between galanin or oxytocin and age or sex. A tendency towards lower vasopressin with increasing age was found among the men (p=0.057). The highest ACTH and galanin levels were found in the patient with Nelson's syndrome. In conclusion, increased plasma ACTH was not reflected in elevated plasma galanin or vasopressin. In contrast, elevated ACTH levels were accompanied by higher oxytocin levels.

Puumala virus (PUUV) is the endemic hantavirus in northern Sweden and causes nephropathia epidemica (NE), a milder form of hemorrhagic fever with renal syndrome. There is a need for fast and reliable diagnostics to differentiate the disease from other infections. By aligning virus RNA sequences isolated from 11 different bank voles and one human patient, we designed a real-time reverse transcriptase (RT) PCR method for detection of PUUV RNA. The real-time RT-PCR assay showed linearity from 20 to 2 × 10 6 virus copies with a correlation coefficient above 0.98 to 0.99 for all experiments. The detection threshold for PUUV cDNA was two copies per reaction. A two-step qualitative RT-PCR to detect PUUV RNA showed 100% concordance with the real-time RT-PCR assay. PUUV RNA viremia was detected in 33 of 34 PUUV immunoglobulin M (IgM)-positive patients with typical clinical NE disease from the region of endemicity. One PUUV IgM-negative sample had PUUV RNA, and 4 days later, the patient was IgM positive. Of samples with indeterminate IgM, 43% were PUUV RNA positive. The kinetics of antibody titers and PUUV viremia were studied, and five of six NE patients displayed a decrease in PUUV viremia a few days after disease outbreak coupled with an increase in PUUV IgM and IgG. In one patient with continuously high PUUV RNA levels but low IgM and no IgG response, the infection was lethal. These findings demonstrated that real-time RT-PCR is a useful method for diagnosis of PUUV viremia and for detecting PUUV RNA at early time points, before the appearance of IgM antibodies.

A flow-through diffusion cell was validated for in vitro human epidermal penetration studies of organophosphorus compounds (OPCs) applied by infinite dosing. By testing OPCs with similar molecular weight but different physicochemical properties, it was shown that hydrophilic and lipophilic properties are major determinants for the penetration rate. Lipophilic OPCs displayed maximum cumulative penetration in the 20-75% agent concentration range whereas the hydrophilic OPCs displayed maximum cumulative penetration at 10 or 20% agent concentration. Low penetration was observed for all agents at 1% agent concentration or when applied as neat agents. The impact of the receptor solution composition was evaluated by comparing the penetration using receptor solutions of different ratios of ethanol and water. For diluted OPCs, a high concentration of ethanol in the receptor solution significantly increased the penetration compared to lower concentrations. When OPCs were applied as neat agents, the composition of the receptor solution only affected the penetration for one of four tested compounds. In conclusion, the flow-through diffusion cell was useful for examining the penetration of OPCs through the epidermal membrane. It was also demonstrated that the penetration rates of OPCs are strongly influenced by dilution in water and the receptor fluid composition.

Summary The airway epithelium plays an active role in acute lung inflammation by producing chemotactic factors and by expressing cell adhesion molecules involved in the migration of leucocytes to extravascular spaces. We have reported previously that neutrophil migration to airways can be down-modulated by exogenously administered vitamin E (α-tocopherol). The mechanism for this effect is not well understood, however. The action of α-tocopherol was investigated in human alveolar type II and bronchial epithelial cells stimulated with tumour necrosis factor-α. Treatment of alveolar epithelial cells with α-tocopherol resulted in down-regulated cell surface expression of intercellular adhesion molecule-1 (ICAM-1). On bronchial epithelial cells, both ICAM-1 and vascular adhesion molecule-1 were decreased, leading to diminished adherence of leucocytes to the cells. The production of the neutrophil chemoattractant interleukin-8 was attenuated in both alveolar and bronchial cells. These effects were preceded by reduced activation of the mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinase (ERK1/2) and p38, as well as down-regulation of nuclear factor-κB. Comparing the effects of α-tocopherol with that of specific inhibitors of MAPK and protein kinase C (PKC) revealed that effects appear to be partly independent of PKC inhibition. These results implicate the anti-inflammatory action of α-tocopherol in addition to its anti-oxidant properties.

SIR—Older persons are characterised by age-related changes, multiple diseases, multiple drug use and functional deficits. For optimal care, a holistic approach is needed; however, the health care s ...

Galanin, a neuropeptide, has important effects on hormone secretion from the hypothalamus and pituitary, and may also be involved in important biological processes such as pain, memory, and food intake. Yet, there is limited knowledge about how these processes are reflected by circulating galanin. To study the levels and molecular forms of galanin in the human circulation, plasma was analysed from 27 healthy subjects, 14 women and 13 men, using two extraction methods and a specific radioimmunoassay for human galanin. After extraction on Sep Pak C-18 columns, plasma galanin-like immunoreactivity (galanin-LI) in the healthy men was 6.3 +/- 2.5 pmol/l (mean +/- SD, n = 12), which was higher than in the women, 4.1 +/- 1.5 pmol/l (n = 14, p = 0.010). A small increase in galanin-LI was seen with age in the women (r = 0.54, p < 0.05) but there was no significant difference between pre- and postmenopausal women. Galanin immunoreactivity after Sep Pak and immunoextraction correlated (r = 0.74, p < 0.001) the levels being higher after immunoextraction (p < 0.001). Gel chromatography disclosed heterogeneity of circulating galanin-LI with the majority eluting as homologs with a molecular weight higher than synthetic human galanin. Homologs smaller than galanin were also found. Sep Pak C-18 extraction eliminated the majority of the higher molecular forms. In conclusion, circulating galanin-LI was found to be higher in men and to be present mainly as molecular forms larger than synthetic galanin.

To investigate the efficacy and safety of a daily dose of 10 mg of atorvastatin in patients with chronic kidney disease (CKD) stages 4 and 5 and a glomerular filtration rate of30 ml/min.This was an open, prospective, randomized study. A total of 143 patients were included: 73 were controls and 70 were prescribed 10 mg/day of atorvastatin. As efficacy variables, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels were determined at the start of the study and at 1, 3, 6, 12, 18, 24, 30 and 36 months.The follow-up period was a mean of 20+/-14.4 months (range 1-36 months) for those on atorvastatin versus 22+/-12.7 months (range 0.5-36 months) for the controls. Compared with baseline values, patients treated with atorvastatin had significantly lower concentrations of total cholesterol at Month 36 (5.8 vs 4.4 mmol/l; -23%; p0.001), of LDL cholesterol at Month 36 (3.6 vs 2.2 mmol/l; -35%; p0.001) and of triglycerides at Months 24 (2.5 vs 1.9 mmol/l) and 36 (2.5 vs 1.8 mmol/l). The controls had significantly reduced levels of total cholesterol at Month 36 (p0.21) and of LDL cholesterol at Months 30 and 36. Compared with the controls, the atorvastatin group had lower levels of total cholesterol and LDL cholesterol at Months 1-30. Fifteen patients (21%) stopped taking their medication as they could not tolerate the side-effects, the most frequent complaints being gastrointestinal discomfort and headache.Although the medication caused no severe adverse events, we recommend caution when using atorvastatin for severe CKD patients until further evidence of its safety and efficacy is verified.

There have been no endpoint studies with statins for patients with severe renal failure. The purpose of this prospective, open, randomized, controlled study was to investigate whether atorvastatin (10 mg/day) would alter cardiovascular endpoints and the overall mortality rate of patients with chronic kidney disease stage 4 or 5 (creatinine clearance30 ml/min).The study subjects comprised 143 patients who were randomized either to placebo (controls; n=73; mean age 69.5 years) or to treatment with atorvastatin (n=70; mean age 67.9 years). The patients included were either non-dialysis (n=33), haemodialysis (n=97) or peritoneal dialysis (n=13) patients. Analysis focused on the primary endpoints of all-cause mortality, non-lethal acute myocardial infarction, coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty. Statistical analysis for endpoint data was mainly by intention-to-treat.Primary endpoints occurred in 74% of the subjects. There was no difference in outcome between the control and atorvastatin groups. The 5-year endpoint-free survival rate from study entry was 20%. Atorvastatin was withdrawn in 20% of patients due to unacceptable side-effects. In the atorvastatin group, low-density lipoprotein (LDL) cholesterol was reduced by 35% at 1 month and then sustained. The controls showed a progressive reduction in LDL cholesterol until 36 months.Although atorvastatin reduced total and LDL cholesterol effectively it was not beneficial regarding the long-term outcomes of cardiovascular endpoints or survival. In contrast to other patient groups, patients with severe chronic kidney disease, especially those on dialysis, seem to derive limited benefit from this lower dose of atorvastatin.

Violence towards staff has become an important issue, since it has been reported to be common in various health care settings. This study aimed to describe emotional reactions among staff being exposed to violence in residential community care for the elderly: to investigate consequences from violent incidents and to describe the management of violent incidents. Data were collected by telephone interviews with nursing staff reporting incidents of violence. During the period of investigation, 97 of 848 staff (11.4%) reported that they had been exposed to violence. More than one-third of them reported subsequent wound and bruises from the incident and two of the exposed staff consulted a doctor because of the violent incident. The most frequently reported reactions among the staff were aggression, astonishment, and antipathy against the perpetrating care recipient, as well as insufficiency, powerlessness, insult and fear. A majority of the incidents were judged as intentionally perpetuating from the care recipient. Most of the violent incidents were managed by informal discussions in the working team. A low number of the reported incidents of violence involved formal discussions with nurse managers.

Puumala virus is a member of the hantavirus genus in the Bunyaviridae family, and the major causative agent of haemorrhagic fever with renal syndrome in Europe. This study was conducted with a human Puumala virus isolate (PUUV Umeå/hu), and contains the determination of the first complete PUUV sequence from a human source. When the relationship to other Puumala viruses was analysed, a possible RNA segment exchange between two local strains of PUUV was noticed. Furthermore, the coding regions of PUUV Umeå/hu S- and M-segments were cloned, and a large set of gene products were expressed in mammalian cells. In addition, postulated N- and O-linked glycosylation sites in the two envelope proteins (Gn and Gc) were investigated individually by site-directed mutagenesis followed by gel-shift analysis. Our data demonstrate that N-linked glycosylation occurs at three sites in Gn (N142, N357 and N409), and at one site in Gc (N937). Also, one possible O-glycosylation site was identified in Gc (T985). We conclude that the diversity between different Puumala virus isolates is high, and consequently characterization of local PUUV isolates is important for clinical diagnostic work. Finally, the obtained results concerning the encoded gene products are of great importance for the design of new vaccines.

Patients with arginine-vasopressin (AVP) deficiency have been reported to have a decreased bone mass. The mechanism behind this is not known. In this study, the effects of AVP on primary human osteoblast-like (hOB) cells and SaOS-2 cells were investigated. Cell proliferation was measured by [3H]thymidine incorporation or a commercially available kit (EZ4U), and protein synthesis by [3H]proline incorporation. In addition, the production of interleukin-6 (IL-6) and macrophage colony-stimulating factor (M-CSF) in hOB cells was determined. AVP at 10-100 pmol/l increased cell proliferation in hOB and SaOS-2 cells (p0.05). Protein synthesis increased in SaOS-2 cells incubated with 10-100 pmol/l AVP (p0.01). When hOB and SaOS-2 cells were incubated with AVP together with a vasopressin receptor-1 (V1)-antagonist ([beta-Mercapto-beta,beta-cyclopenta-methylenepropionyl1,O-Me-Tyr2,Arg8]-vasopressin) or a protein kinase C (PKC)-inhibitor (chelerythrine) the increase in cell proliferation in response to AVP was abolished. The production of IL-6 and M-CSF was decreased in hOB-cells incubated with 10 pmol/l AVP (p0.01). In addition, by RT-PCR, we found evidence for expression of mRNA for the vasopressin 1a (V1a)-receptor in hOB cells. In conclusion, AVP stimulated proliferation of hOB- and SaOS-2 cells. We suggest that the effect was mediated through the V1-receptor. Additionally, AVP decreased production of IL-6 and M-CSF from the hOB cells. Moreover, the V1a-receptor seems to be expressed in hOB cells.

To investigate whether delirium in older patients with femoral neck fractures is associated with an increased risk of developing dementia and a higher mortality rate.A 5-year prospective follow-up study.Department of Orthopedic Surgery at the University Hospital in Umeå, Sweden.Seventy-eight nondemented patients aged 65 and older operated on for femoral neck fractures were followed for 5 years.The patients were assessed using the Organic Brain Syndrome (OBS) Scale pre- and postoperatively. Medical and social data were collected from the patients, their caregivers, and medical records, and the survivors were visited and assessed with the OBS Scale and the Mini-Mental State Examination in their homes 5 years after the fracture.Thirty of 78 (38.5%) nondemented patients with a femoral neck fracture developed dementia within a 5-year period. Twenty of 29 (69%) who were delirious postoperatively developed dementia, compared with 10 of 49 (20%) who were not delirious during their hospital stay (P.001). Twenty-one (72.4%) of those with postoperative delirium died within 5 years, compared with 17 of 49 (34.7%) of those who remained lucid postoperatively (P =.001).Delirium in nondemented femoral neck fracture patients is associated with the development of dementia and a higher mortality rate. Patients with preoperative or postoperative delirium should therefore be assessed not only for the etiology of the delirium but also for any underlying organic brain disorder. Questions that remain unanswered are whether postoperative delirium is a marker of undetected dementia and whether postoperative delirium contributes to the development of dementia.

Neonates born after pregnancies complicated by diabetes or intrauterine growth restriction (IUGR) have increased incidence of hypocalcaemia. Furthermore, IUGR is associated with reduced bone mineralization in infancy and osteoporosis in adult life. We tested the hypothesis that placental calcium transport is altered in these pregnancy complications. Transport of calcium into syncytiotrophoblast basal plasma membrane (BM) vesicles was studied by rapid filtration and protein expression of Ca(2+) ATPase by Western blot. In IUGR Ca(2+) ATPase activity was increased by 48 per cent (n=13; P0.05) whereas protein expression was 15 per cent lower (n=13; P0.05) than in controls (n=16). Basal membrane ATP dependent calcium transport was unaltered in gestational diabetes (GDM) but increased by 54 per cent in insulin dependent diabetes (IDDM) compared to controls (P0.05; n =14). Diabetes did not affect Ca(2+) ATPase expression in BM. We have previously shown that the mid-molecular fragment of parathyroid hormone related peptide (PTHrP midmolecule) stimulates BM Ca(2+) ATPase in vitro. PTHrP midmolecule concentrations in umbilical cord plasma were measured using radioimmunoassay. The concentrations in umbilical cord plasma were increased in IUGR, but unaltered in diabetes. In conclusion, placental calcium pump is activated in IUGR and IDDM, which may be secondary to increased foetal calcium demand. We speculate that PTHrP midmolecule may be one mechanism for activating BM Ca(2+) ATPase in IUGR.