Clofazimine Inhalation Suspension Demonstrates Promising Toxicokinetics in Canines for Treating Pulmonary Nontuberculous Mycobacteria Infection.

Pulmonary nontuberculous mycobacteria (NTM) infection is recognized as a major global health concern due to its rising prevalence worldwide. As an opportunistic pathogen with increasing antibiotics resistance, prolonged systemic dosing with multiple antibiotics remains the primary treatment paradigm. These prolonged treatments, administered predominantly by oral or parenteral routes, often lead to systemic toxicity. A novel inhaled formulation of clofazimine may finally resolve issues of toxicity, thereby providing for improved NTM therapy. Clofazimine inhalation suspension was evaluated in canines to determine toxicity over 28 days of once-a-day dosing. The good laboratory practice (GLP) repeat dosing study evaluated low, mid, and high dosing (2.72 mg/kg and 2.95 mg/kg; 5.45 mg/kg and 5.91 mg/kg; and 10.87 mg/kg and 10.07 mg/kg, average male versus female dosing) of nebulized clofazimine over 30, 60, and 120 min using a jet nebulizer. Toxicokinetic analyses were performed on study days 29, 56, and 84. All three dose levels showed significant residual drug in lung tissue, demonstrating impressive lung loading and long lung residence. Drug concentrations in the lung remained well above the average NTM MIC at all time points, with measurable clofazimine levels at 28 and 56 days postdosing. In contrast, plasma levels of clofazimine were consistently measurable only through 14 days postdosing, with measurements below the limit of quantitation at 56 days postdosing. Clofazimine inhalation suspension may provide an effective therapy for the treatment of NTM infections through direct delivery of antibiotic to the lungs, overcoming the systemic toxicity seen in oral clofazimine treatment for NTM.

Fast In Situ Observation of Atomic Feshbach Resonances by Photoassociative Ionization.

We propose and experimentally investigate a scheme for observing Feshbach resonances in atomic quantum gases in situ and with a high temporal resolution of several tens of nanoseconds. The method is based on the detection of molecular ions, which are optically generated from atom pairs at small interatomic distances. As a test system we use a standard rubidium gas (^{87}Rb) with well known magnetically tunable Feshbach resonances. The fast speed and the high sensitivity of our detection scheme allows us to observe a complete Feshbach resonance within one millisecond and without destroying the gas.

Comparative disposition of dimethylaminoethanol and choline in rats and mice following oral or intravenous administration.

Dimethylaminoethanol (DMAE) and its salts have been used to treat numerous disorders in humans and hence safety of its use is a concern. DMAE is a close structural analog of choline, an essential nutrient. Exposure to DMAE may affect choline uptake and synthesis. The current investigation characterizes: 1) the absorption, distribution, metabolism, and excretion (ADME) of DMAE in Wistar Han rats and B6C3F1 mice following a single gavage or intravenous (IV) administration of 10, 100 or 500 mg/kg [14C]DMAE, and 2) the ADME of [14C]choline (160 mg/kg) and the effect on its disposition following pre-treatment with DMAE (100 or 500 mg/kg). In both rats and mice, following gavage administration, DMAE was excreted in urine (16-69%) and as exhaled CO2 (3-22%). The tissue retention was moderate (21-44%); however, the brain concentrations were low and there was no accumulation. Serum choline levels were not elevated following administration of DMAE. The DMAE metabolites in urine were DMAE N-oxide and N,N-dimethylglycine; the carcinogen, N-N-dimethylnitrosamine, was not detected. The pattern of disposition of [14C]choline following gavage administration was similar to that of [14C]DMAE. Prior treatment with DMAE had minimal effects on choline disposition. The pattern of disposition of [14C]DMAE and [14C]choline following IV administration was similar to gavage administration. There were minimal dose-, sex- or species-related effects following gavage or IV administration of [14C]DMAE or [14C]choline. Data from the current study did not support previous reports that: 1) DMAE alters choline uptake and distribution, or 2) that DMAE is converted into choline in vivo.

Does Visual Impairment Affect Social Ties in Late Life? Findings of a Multicenter Prospective Cohort Study in Germany.

OBJECTIVE: To investigate how visual impairment affects social ties in late life longitudinally. DESIGN: Population-based prospective cohort study. SETTING: Individuals in old age were recruited via general practitioners' offices (at six study centers) in Germany. They were interviewed every 18 months. PARTICIPANTS: Individuals aged 75 years and above at baseline. Follow-up wave 2 (36 months after baseline, n=2,443) and wave 4 (72 months after baseline, n=1,618) were used for the analyses presented here. MEASUREMENTS: Social ties were assessed using the 14-item form of the questionnaire for social support (F-SozU K-14). Visual impairment was self-rated on a three level Likert scale (no impairment, mild visual impairment, or severe/profound visual impairment). RESULTS: Adjusting for sociodemographic factors, hearing impairment and comorbidity, fixed effects regressions revealed that the onset of mild visual impairment decreased the social support score, in particular the emotional support score. Additionally, the onset of mild hearing impairment decreased the social support score in men. Moreover, increasing age decreased the social support score in the total sample and in both sexes. Loss of spouse and increasing comorbidity did not affect the social support score. CONCLUSION: Our results highlight the importance of visual impairment for social ties in late life. Consequently, appropriate strategies in order to delay visual impairment might help to maintain social ties in old age.

Ultrafast Mid-Infrared Nanoscopy of Strained Vanadium Dioxide Nanobeams.

Long regarded as a model system for studying insulator-to-metal phase transitions, the correlated electron material vanadium dioxide (VO2) is now finding novel uses in device applications. Two of its most appealing aspects are its accessible transition temperature (∼341 K) and its rich phase diagram. Strain can be used to selectively stabilize different VO2 insulating phases by tuning the competition between electron and lattice degrees of freedom. It can even break the mesoscopic spatial symmetry of the transition, leading to a quasiperiodic ordering of insulating and metallic nanodomains. Nanostructuring of strained VO2 could potentially yield unique components for future devices. However, the most spectacular property of VO2--its ultrafast transition--has not yet been studied on the length scale of its phase heterogeneity. Here, we use ultrafast near-field microscopy in the mid-infrared to study individual, strained VO2 nanobeams on the 10 nm scale. We reveal a previously unseen correlation between the local steady-state switching susceptibility and the local ultrafast response to below-threshold photoexcitation. These results suggest that it may be possible to tailor the local photoresponse of VO2 using strain and thereby realize new types of ultrafast nano-optical devices.

Efimov Resonance and Three-Body Parameter in a Lithium-Rubidium Mixture.

We study collisional heating in a cold ^{7}Li-^{87}Rb mixture near a broad Feshbach resonance at 661 G. At the high field slope of the resonance, we find an enhanced three-body recombination rate that we interpret as a heteronuclear Efimov resonance. With improved Feshbach spectroscopy of two further resonances, a model for the molecular potentials has been developed that now consistently explains all known Feshbach resonances of the various Li-Rb isotope mixtures. The model is used to determine the scattering length of the observed Efimov state. Its value of -1870a_{0} Bohr radii supports the currently discussed assumption of universality of the three-body parameter also in heteronuclear mixtures.

The National Environmental Respiratory Center (NERC) experiment in multi-pollutant air quality health research: IV. Vascular effects of repeated inhalation exposure to a mixture of five inorganic gases.

An experiment was conducted to test the hypothesis that a mixture of five inorganic gases could reproduce certain central vascular effects of repeated inhalation exposure of apolipoprotein E-deficient mice to diesel or gasoline engine exhaust. The hypothesis resulted from preceding multiple additive regression tree (MART) analysis of a composition-concentration-response database of mice exposed by inhalation to the exhausts and other complex mixtures. The five gases were the predictors most important to MART models best fitting the vascular responses. Mice on high-fat diet were exposed 6 h/d, 7 d/week for 50 d to clean air or a mixture containing 30.6 ppm CO, 20.5 ppm NO, 1.4 ppm NO2, 0.5 ppm SO2, and 2.0 ppm NH3 in air. The gas concentrations were below the maxima in the preceding studies but in the range of those in exhaust exposure levels that caused significant effects. Five indicators of stress and pro-atherosclerotic responses were measured in aortic tissue. The exposure increased all five response indicators, with the magnitude of effect and statistical significance varying among the indicators and depending on inclusion or exclusion of an apparent outlying control. With the outlier excluded, three responses approximated predicted values and two fell below predictions. The results generally supported evidence that the five gases drove the effects of exhaust, and thus supported the potential of the MART approach for identifying putative causal components of complex mixtures.

[Epidemics and pandemics in general practice. What can we learn from the swine flu (H1N1) and EHEC outbreak?]. / Epidemien und Pandemien in der hausärztlichen Praxis. Was können wir aus dem Schweinegrippe (H1N1)- und EHEC-Ausbruch lernen?

BACKGROUND: As primary care givers with a coordinating function, general practitioners (GP) play a key role in dealing with epidemics and pandemics. As of yet, there are no studies in Germany describing the difficulties experienced by GPs in patient care during epidemics/pandemics. OBJECTIVES: This study aimed at identifying the problem areas in GPs' patient care during the H1N1 and EHEC (enterohemorrhagic strain of Escherichia coli) outbreaks. With this information, recommendations for guaranteeing proper patient care during future epidemics/pandemics can be derived. MATERIALS AND METHODS: In all, 12 qualitative, semi-structured, open guideline interviews with GPs in Hamburg and Lübeck were conducted, transcribed, and evaluated with qualitative content analysis. RESULTS: Five areas in ambulatory patient care were identified in which changes are needed from the primary care perspective: provision of information for GPs, workload, financing of epidemic-related measures, organization of the practices, care of those taken ill. CONCLUSIONS: The workload of GPs in particular can and should be reduced through successful, centralized information distribution during epidemics/pandemics. The GP's function as a coordinator should be supported and consolidated, in order to relieve the in-patient sector in cases of an epidemic/pandemic. Secured financing of epidemic-associated measures can help ensure patient care.

A hierarchy of predictors for dementia-free survival in old-age: results of the AgeCoDe study.

OBJECTIVE: Progression from cognitive impairment (CI) to dementia is predicted by several factors, but their relative importance and interaction are unclear. METHOD: We investigated numerous such factors in the AgeCoDe study, a longitudinal study of general practice patients aged 75+. We used recursive partitioning analysis (RPA) to identify hierarchical patterns of baseline covariates that predicted dementia-free survival. RESULTS: Among 784 non-demented patients with CI, 157 (20.0%) developed dementia over a follow-up interval of 4.5 years. RPA showed that more severe cognitive compromise, revealed by a Mini-Mental State Examination (MMSE) score < 27.47, was the strongest predictor of imminent dementia. Dementia-free survival time was shortest (mean 2.4 years) in such low-scoring patients who also had impaired instrumental activities of daily living (iADL) and subjective memory impairment with related worry (SMI-w). Patients with identical characteristics but without SMI-w had an estimated mean dementia-free survival time of 3.8 years, which was still shorter than in patients who had subthreshold MMSE scores but intact iADL (4.2-5.2 years). CONCLUSION: Hierarchical patterns of readily available covariates can predict dementia-free survival in older general practice patients with CI. Although less widely appreciated than other variables, iADL impairment appears to be an especially noteworthy predictor of progression to dementia.

Rapid-scan acousto-optical delay line with 34 kHz scan rate and 15 as precision.

An optical fast scan delay exploiting the near-collinear interaction between a train of ultrashort optical pulses and an acoustic wave propagating in a birefringent crystal is introduced. In combination with a femtosecond Er:fiber laser, the scheme is shown to delay few femtosecond pulses by up to 6 ps with a precision of 15 as. A resolution of 5 fs is obtained for a single sweep at a repetition rate of 34 kHz. This value can be improved to 39 as for multiple scans at a total rate of 0.3 kHz.

Age of major depression onset, depressive symptoms, and risk for subsequent dementia: results of the German study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe).

BACKGROUND: Whether late-onset depression is a risk factor for or a prodrome of dementia remains unclear. We investigated the impact of depressive symptoms and early- v. late-onset depression on subsequent dementia in a cohort of elderly general-practitioner patients (n = 2663, mean age = 81.2 years). METHOD: Risk for subsequent dementia was estimated over three follow-ups (each 18 months apart) depending on history of depression, particularly age of depression onset, and current depressive symptoms using proportional hazard models. We also examined the additive prediction of incident dementia by depression beyond cognitive impairment. RESULTS: An increase of dementia risk for higher age cut-offs of late-onset depression was found. In analyses controlling for age, sex, education, and apolipoprotein E4 genotype, we found that very late-onset depression (aged ≥ 70 years) and current depressive symptoms separately predicted all-cause dementia. Combined very late-onset depression with current depressive symptoms was specifically predictive for later Alzheimer's disease (AD; adjusted hazard ratio 5.48, 95% confidence interval 2.41-12.46, p < 0.001). This association was still significant after controlling for cognitive measures, but further analyses suggested that it was mediated by subjective memory impairment with worries. CONCLUSIONS: Depression might be a prodrome of AD but not of dementia of other aetiology as very late-onset depression in combination with current depressive symptoms, possibly emerging as a consequence of subjectively perceived worrisome cognitive deterioration, was most predictive. As depression parameters and subjective memory impairment predicted AD independently of objective cognition, clinicians should take this into account.

[Improvements in survival in patients with heart failure]. / Überlebensfortschritte bei Patienten mit Herzinsuffizienz.

The aim of this study is to describe improvements in survival of patients with heart failure. In addition, factors that may have contributed to these improvements are discussed. The extent of improvement in survival is substantial. This is presumably mainly due to a broad spectrum of new therapeutic options and the introduction of clinical guidelines, and the increasing level of awareness and adherence. For the near future, the increasing implementation of disease management programs and complex interventions has the potential to have a further positive influence on the survival of patients with heart failure.

Assessing cognitive changes in the elderly: reliable change indices for the Mini-Mental State Examination.

OBJECTIVE: The diagnosis of dementia includes evidence of decline in cognitive functioning over time measured by objective cognitive tasks. Normative data for changes adjusted for the impact of socio-demographic factors on cognitive test performance are lacking to interpret changes in Mini-Mental State Examination (MMSE) test scores. METHOD: As part of the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe Study), a sample of 1090 cognitively healthy individuals, aged 75 years and older, was assessed at 1.5-year intervals over a period of 4.5 years using the MMSE. Age- and education-specific Reliable Change Indices (RCIs) were computed. RESULTS: Age and education were significantly associated with MMSE test performance, and gender indicated no impact. Across different age and education subgroups, changes from at least 2 up to 3 points indicated significant (i.e., reliable) changes in MMSE test scores at the 90% confidence level. Furthermore, the calculation of RCIs for individual patients is demonstrated. CONCLUSION: This study provides age- and education-specific MMSE norms based upon RCI methods to interpret cognitive changes in older age groups. The computation of RCI scores improves the interpretation of changes in MMSE test scores by controlling for measurement error, practice effects, or regression to the mean.

Risk factors for incident mild cognitive impairment--results from the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe).

OBJECTIVES: To provide age- and gender-specific incidence rates of MCI among elderly general practitioner (GP) patients (75+ years) and to identify risk factors for incident MCI. METHOD: Data were derived from the longitudinal German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). Incidence was calculated according to the 'person-years-at-risk' method. Risk factors were analysed using multivariate logistic regression models. RESULTS: During the 3-year follow-up period, 350 (15.0%) of the 2331 patients whose data were included in the calculation of incidence developed MCI [person-years (PY) = 6198.20]. The overall incidence of MCI was 56.5 (95% confidence interval = 50.7-62.7) per 1000 PY. Older age, vascular diseases, the apoE epsilon4 allele and subjective memory complaints were identified as significant risk factors for future MCI. CONCLUSION: Mild cognitive impairment is frequent in older GP patients. Subjective memory complaints predict incident MCI. Especially vascular risk factors provide the opportunity of preventive approaches.

Design and testing of Electrostatic Aerosol in Vitro Exposure System (EAVES): an alternative exposure system for particles.

Conventional in vitro exposure methods for cultured human lung cells rely on prior suspension of particles in a liquid medium; these have limitations for exposure intensity and may modify the particle composition. Here electrostatic precipitation was used as an effective method for such in vitro exposures. An obsolete electrostatic aerosol sampler was modified to provide a viable environment within the deposition field for human lung cells grown on membranous support. Particle deposition and particle-induced toxicological effects for a variety of particles including standardized polystyrene latex spheres (PSL) and diesel exhaust emission particle mixtures are reported. The Electrostatic Aerosol in Vitro Exposure System (EAVES) efficiently deposited particles from an air stream directly onto cells. Cells exposed to the electric field of the EAVES in clean air or in the presence of charged PSL spheres exhibited minimal cytotoxicity, and their release of inflammatory cytokines was indistinguishable from that of the controls. For the responses tested here, there are no significant adverse effects caused neither by the electric field alone nor by the mildly charged particles. Exposure to diesel exhaust emissions using the EAVES system induced a threefold increase in cytokines and cytotoxicity as compared to the control. Taken together, these data show that the EAVES can be used to expose human lung cells directly to particles without prior collection in media, thereby providing an efficient and effective alternative to the more conventional particle in vitro exposure methods.

[Outpatient management of stroke patients from the viewpoint of general practitioners in Hamburg--an exploratory study]. / Die ambulante Versorgung von Schlaganfallpatienten aus Sicht von Hamburger Hausärzten - eine explorative Studie.

OBJECTIVE: Stroke is the archetype of a chronic disease, with a considerable burden on ambulatory care. After discharge from hospital or inpatient rehabilitation, stroke patients are attended primarily by general practitioners (GPs). Little is known about the quality of outpatient care for stroke patients, so this study focused on the views of professionals involved in outpatient care. METHODS: A postal survey of 443 general practitioners from Hamburg, Germany was undertaken. Results were compared with a parallel survey carried out with physiotherapists and occupational therapists. RESULTS: 89 questionnaires were analysed. Based on a response rate of 28% the results cannot be seen as representative, but they do provide important information. As it seems, problems in ambulatory care do not start after discharge from hospital, but are partly caused by inpatient care. GPs see therapeutic benefits in ambulatory care for only half of their chronic stroke patients. They assess their own therapeutic efforts as effective in terms of medication, but they are less successful in changing their patients' behaviour with regard to lifestyle. Estimations of the prevalence of post-stroke depression vary substantially, with a mean of 47%. With regard to their daily practice, 60% of GPs do not find guidelines to be helpful. All in all, respondents describe the situation of chronic stroke patients and their families to be complex and difficult to manage. In addition to their professional performance, GPs carry out duties related to case management - as do the therapists. CONCLUSION: The care of stroke patients is not only the responsibility of a single group of professionals, but is a rather complex task involving different health-care professionals. The rehabilitation process and the interdisciplinary cooperation need to be further analysed to ensure a good cooperation between health-care professionals and to improve the quality of ambulatory care for stroke patients.

Topical treatment of tungiasis: a randomized, controlled trial.

Tungiasis is caused by the penetration of the female sand flea Tunga penetrans into the epidermis of its host. Human infestation with this ectoparasite is hyper-endemic in many resource-poor communities in sub-Saharan Africa, the Caribbean and South America and is associated with considerable morbidity. Currently, there is no effective drug available to treat tungiasis (or at least none for which a parasiticidal effect has been clearly demonstrated). In an attempt to fill this gap, the effects of treatment with topical ivermectin (lotion), thiabendazole (ointment and lotion), metrifonate (lotion) or placebo lotion were compared in a randomized trial. A total of 108 subjects with 169 tungiasis-infested feet participated in the study. The results show that topical ivermectin, metrifonate or thiabendazole can each significantly reduce the number of lesions caused by embedded sand fleas. Further studies are needed to optimise the doses and administration of these compounds.

Bacterial superinfection in human tungiasis.

Tungiasis is caused by penetration of the female sand flea Tunga penetrans into the epidermis of its host. It is endemic in many countries in Latin America, the Caribbean and sub-Saharan Africa. Although superinfection is a common clinical observation, the frequency and the pattern of bacterial pathogens associated with tungiasis have never been investigated systematically. We conducted a prospective clinico-bacteriological study with patients living in a shantytown in Fortaleza, capital of Ceará State (Northeast Brazil), where tungiasis is hyperendemic. Swabs were taken from 78 patients with multiple lesions after surgical extraction of the parasite, and the specimens were cultured for aerobic and anaerobic microorganisms. Ninety-nine specimens were investigated for aerobic bacteria, from which 146 pathogens were identified. The most common species were Staphyloccous aureus (35.5%) and various enterobacteriaceae (29.5%). Bacillus sp., Enteroccous faecalis, Streptococcus pyogenes and Pseudomonas sp. were also isolated. Eighty-four anaerobic cultures yielded 20 pathogens: in eight cases we detected Peptostreptococcus sp., in seven cases Clostridium sp., and in five cases non-identifiable gram-negative bacilli. These results show that secondary infection is very common in tungiasis, and caused by a variety of highly pathogenic microorganisms. It is proposed that T. penetrans acts as a foreign body facilitating biofilm formation within the epidermis. To prevent spreading of pathogens to the surrounding tissue and/or the systemic circulation, sand fleas should be surgically extracted immediately after penetration.

[Preventing prostate carcinoma in men with familial disposition]. / Prostatakarzinomvorsorge bei Männern mit familiärer Disposition.

A family history is one of the strongest risk factors for prostate cancer (PC). We evaluated the detection rate of PC in relatives of 119 German PC families that took part in ongoing linkage analyses. Brothers of patients with sporadic prostate cancer aged < 55 years at onset were included as well. Responses were received from 120/196 (61.2%) individuals of the familial and 67/120 (55.8%) of the sporadic group. Findings (DRE, TRUS, PSA) were more often suspicious for carcinoma in the PC families. Prostate cancer was diagnosed in 6 (5.0%) and 2 (2.99%) participants of the familial and the sporadic group, respectively. These detection rates tended to be higher than that of an age-matched subgroup of an unselected population in other European screening studies. The most important risk factor for the diagnosis of PC was a low average age at onset within the family. These data imply that prostate cancer screening in the high-risk group of men with familial predisposition cannot be assessed by population-based studies and should be evaluated separately.