Recent Advances in Modeling Mitochondrial Cardiomyopathy Using Human Induced Pluripotent Stem Cells.
Around one third of patients with mitochondrial disorders develop a kind of cardiomyopathy. In these cases, severity is quite variable ranging from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. ATP is primarily generated in the mitochondrial respiratory chain via oxidative phosphorylation by utilizing fatty acids and carbohydrates. Genes in both the nuclear and the mitochondrial DNA encode components of this metabolic route and, although mutations in these genes are extremely rare, the risk to develop cardiac symptoms is significantly higher in this patient cohort. Additionally, infants with cardiovascular compromise in mitochondrial deficiency display a worse late survival compared to patients without cardiac symptoms. At this point, the mechanisms behind cardiac disease progression related to mitochondrial gene mutations are poorly understood and current therapies are unable to substantially restore the cardiac performance and to reduce the disease burden. Therefore, new strategies are needed to uncover the pathophysiological mechanisms and to identify new therapeutic options for mitochondrial cardiomyopathies. Here, human induced pluripotent stem cell (iPSC) technology has emerged to provide a suitable patient-specific model system by recapitulating major characteristics of the disease in vitro, as well as to offer a powerful platform for pre-clinical drug development and for the testing of novel therapeutic options. In the present review, we summarize recent advances in iPSC-based disease modeling of mitochondrial cardiomyopathies and explore the patho-mechanistic insights as well as new therapeutic approaches that were uncovered with this experimental platform. Further, we discuss the challenges and limitations of this technology and provide an overview of the latest techniques to promote metabolic and functional maturation of iPSC-derived cardiomyocytes that might be necessary for modeling of mitochondrial disorders.


A qualitative study of participants' experiences with dietary assessment.
This article reports on the use of focus groups and an experimental participatory activity to investigate factors influencing participants' decisions about what to eat and what to report on food records and food frequency questionnaires. Four focus groups examined participants' experience with diet records and 3 focus groups explored the topic of food portions using a group consensus activity. Twenty-two women participated in the diet record focus groups, and 15 participated in portion estimation groups. Focus group participants were equally distributed by age and body mass index values. Each woman completed a 10-day doubly labeled water protocol to measure total energy expenditure, 7 days of diet records (before and during total energy expenditure), and a food frequency questionnaire after the total energy expenditure. Transcripts of the focus groups were coded to index categories of responses and to identify themes within and across those responses. Themes discussed in this article are those that were discussed most often and at greatest length by all groups. The diet record focus groups revealed that 2 major factors influenced reporting on diet records: honesty vs social acceptability, and simplifying food intake. The portion estimation focus groups revealed 5 factors that influenced perceptions of portion size: the role of food in the meal, the type of food, personal preferences, product serving sizes, and comparison of personal servings with those of others. The validity and reliability of self-reported food consumption is greatly influenced by the ways people interpret and respond to dietary assessment instruments. These findings indicate that dietetics professionals need to take extra steps to address issues of accurately recording "bad" foods when training patients to complete diet records. Extra probing is needed when dietary records do not include snacks and include simple meals and a large amount of prepared and packaged food because this may indicate that changes in normal dietary patterns were made in order to more easily complete a dietary record.


Tetraspanin 7 regulates osteoclast function through association with the RANK/αvβ3 integrin complex.
Actin rings are unique structures that facilitate the attachment of osteoclasts to the bone matrix during bone resorption. Previous studies have shown that tetraspanin7 (TSPAN7) plays an important role in the reorganization of the cytoskeleton necessary for the bone-resorbing activity of osteoclasts. However, questions remain as to the mechanisms by which TSPAN7 regulates this cytoskeletal rearrangement. In this study, we investigated the roles of TSPAN7 in osteoclasts by deleting the Tm4sf2 gene in mice, which encodes TSPAN7. The Tm4sf2 global knockout model showed protective effects on pathological bone loss, but no discernible changes in bone phenotypes under physiological conditions. In vitro study revealed that ablation of Tm4sf2 caused significant defects in integrin-mediated actin ring formation, thereby leading to significantly decreased bone resorption. Additionally, we demonstrated an association between TSPAN7 and the receptor activator of nuclear factor-кB/αvβ3 integrin. Overall, our findings suggest that TSPAN7 acts as a novel modulator regulating the bone-resorbing function of osteoclasts.


Arm posture influences on regional supraspinatus and infraspinatus activation in isometric arm elevation efforts.
This study aimed to evaluate the effect of arm posture on activation of the anterior and posterior regions of supraspinatus and the superior and middle regions of infraspinatus during resisted isometric arm elevations. Thirty-one healthy participants performed 18 isometric resistance exertions against a force cube in three elevation planes (flexion, scaption, abduction) and three elevation angles (30°, 90°, 150°) in maximal and sub-maximal resistance conditions. EMG data were obtained using four pairs of fine wire electrodes. The mean activation of each region and the activation ratios were compared across postures using ANOVAs. Supraspinatus anterior was significantly more active during abduction and scaption, and in higher elevation angles, while the posterior region showed similar activation levels across postures. Infraspinatus regions were more active during flexion with more relative activation of the infraspinatus superior at 90° flexion. The results suggest that regional activation of supraspinatus and infraspinatus should be considered for assessment and rehabilitation purposes. In any clinical setting where it is important to reduce the stress on the supraspinatus anterior, isometric flexion exercises performed with arm in low elevation angles could provide the opportunity to strengthen the posterior region of supraspinatus with limited stress on the anterior region. Beside external rotation exertions, resisted flexion tests may be useful for evaluation of infraspinatus regions.


The control of nitric oxide dynamics and interaction with substituted zinc-phthalocyanines.
Phthalocyanines are artificial macrocycles that can harbour a central metal atom with four symmetric coordinations. Similar to metal-porphyrins, metal-phthalocyanines (M-PCs) may bind small molecules, especially diatomic gases such as NO and O2. Furthermore, various chemical chains can be grafted at the periphery of the M-PC macrocycle, which can change its properties, including the interaction with diatomic gases. In this study, we synthesized Zn-PCs with two different substituents and investigated their effects on the interaction and dynamics of nitric oxide (NO). Time-resolved absorption spectroscopy from picosecond to millisecond revealed that NO dynamics dramatically depends on the nature of the groups grafted to the Zn-PC macrocycle. These experimental results were rationalized by DFT calculations, which demonstrate that electrostatic interactions between NO and the quinoleinoxy substituent modify the potential energy surface and decrease the energy barrier for NO recombination, thus controlling its affinity.


Vitamin E supplementation reduces oxidative stress in beta thalassaemia intermedia.
The aim of this investigation was to study the effect of vitamin E treatment in oxidative stress of red and white cells of beta-thalassaemia intermedia patients. Nine patients undergoing occasional transfusions (5 females/4 males), median age 39 years (range 15-74), were recruited for oral daily administration of 400 IU vitamin E for 3 months. Twenty-seven milliliters of peripheral blood was obtained before and after 3 months of treatment, and 3 months after treatment completion. In the case of transfused patients (n = 4), blood was obtained at least 30 days after transfusion. Reactive oxygen species (ROS) was measured by flow cytometry; red blood cell (RBC) reduced glutathione (GSH) was measured by dinitrothiocyanobenzene reduction, serum malondialdehyde was measured in terms of thiobarbituric acid-reactive substances (TBARS), and alpha-haemoglobin-stabilizing protein (AHSP) mRNA expression was measured by real-time polymerase chain reaction of reticulocyte RNA extracts. beta-Thalassaemia patients presented basal levels of RBC ROS, GSH and serum TBARS statistically different compared with healthy controls. However, after vitamin E administration, patients presented a significant reduction in erythrocyte RBC ROS and serum TBARS levels. In parallel, red cell GSH was significantly increased after treatment. Peripheral mononuclear cells and T lymphocytes also demonstrated a reduction in ROS production. Therefore, after treatment, no significant differences were detected comparing patients and normal controls. Three months after treatment completion, all measurements showed a tendency of returning to basal values. A significant reduction in reticulocyte number was observed after vitamin E treatment. Vitamin E treatment did not modify levels of haemoglobin or AHSP mRNA expression. Although vitamin E is not capable of reducing anaemia in these patients, it could be useful for reducing oxidative damage in other target organs of beta-thalassaemic patients. Finally, this is the first study to analyse the effects of vitamin E on ROS production in red and white blood cells and AHSP mRNA expression.


High Anti-Müllerian Hormone Strongly Correlates with Reproductive Outcomes in Women Undergoing Assisted Reproduction.
In a retrospective cohort of 881 women with gynecologic and unexplained infertility, we aimed to study the relationship between serum AMH levels and ART outcomes. This retrospective cohort includes 881 infertile women aged 20 - 45 who underwent their first fresh autologous non-preimplantation genetic diagnosis ART cycles between 2012 and 2020. We assessed the correlation between AMH levels and reproductive outcomes among infertile women with different causes of infertility (including endometriosis, polycystic ovary syndrome (PCOS), and unexplained infertility). We found a strong correlation between high AMH levels and reproductive outcomes independent of age and the cause of infertility in women undergoing ART. In all patients with gynecologic and unexplained infertility, higher AMH correlated with the improved number of oocytes (p < 0.001), MII oocytes (p < 0.001), good-quality embryos (p < 0.001), chemical pregnancy rate (p < 0.001 in women < 37; and p = 0.002 in women over 37), clinical pregnancy rate (p < 0.05), and live birth rate (p = 0.05). Serum AMH concentrations can be invaluable for predicting ovarian reserve and reproductive outcomes in young and advanced-age infertile patients undergoing ART. However, it should not be used as the sole predictive marker for disqualifying infertile women from ART treatment. Further large cohort studies are warranted to determine an exact cutoff point for AMH to provide an accurate ART success prediction.


Planning for, implementing and assessing the impact of health promotion and behaviour change interventions: a way forward for health psychologists.
Researchers in the field of health psychology have increasingly been involved in translating a body of knowledge about psychological factors associated with health-relevant behaviours, into the development and evaluation of interventions that seek to apply that knowledge. In this paper we argue that a changing economic and political climate, and the strong behavioural contribution to disease morbidity and mortality in developed nations, requires health psychologists to plan more rigorously for, and communicate more effectively, about how health promotion, social cognition and behaviour change interventions will have impact and be increasingly embedded into health services or health promotion activity. We explain academic and wider socio-economic uses of 'impact' in health services research. We describe the relationship between impact and dissemination, and impact as distinct from, but often used interchangeably with the terms 'implementation', 'knowledge transfer' and 'knowledge translation' (KT). The evidence for establishing impact is emergent. We therefore draw on a number of impact planning and KT frameworks, with reference to two self- management interventions, to describe a framework that we hope will support health psychologists in embedding impact planning and execution in research. We illustrate this further in an on-line annexe with reference to one of our own interventions, Mums-and-MS (see Supplemental Material).


Investigation of Bacterial Contents From Persistent Endodontic Infection and Evaluation of Their Inflammatory Potential.
This clinical study investigated and quantified cultivable bacteria and their levels of endotoxins in persistent endodontic infection, determining their antigenicity against macrophages and fibroblast cells by IL-1β and TNF-α secretion and evaluating their relationship with clinical and radiographic features. Samples from the root canals were obtained after root filling removal. Culture techniques were used to determine the bacterial count and the endotoxins were determined by LAL-assay. PCR analysis (16S rDNA) was used for bacterial detection. Raw 264.5 macrophages and V79 fibroblast were stimulated with endodontic contents. ELISA assay measured the amounts of IL-1ß/TNF-?#61537; secretion. Bacteria and endotoxin medians were 1.24x105 CFU/mL and 9.62 EU/mL, respectively. Porphyromonas endodontalis was the most frequently detected species. Higher levels of endotoxins were found in teeth with pain on palpation (23.56 EU/mL) rather than in its absence (8.21 EU/mL). Larger areas of bone destruction were related to higher levels of endotoxins and IL-1β and TNF-α secretion. The study findings revealed the presence of Gram-negative bacteria species in persistent endodontic infection, with their endotoxins related to both severity of bone destruction and development of symptomatology. Moreover, larger areas of bone destruction were related to higher levels of IL-1β and TNF-α secreted by macrophages and fibroblast cells.


Genetic similarity and hatching success in birds.
The ecological correlates of fitness costs of genetic similarity in free-living, large populations of organisms are poorly understood. Using a dataset of genetic similarity as reflected by band-sharing coefficients of minisatellites, we show that bird species with higher genetic similarity experience elevated hatching failure of eggs, increasing by a factor of six across 99 species. Island distributions and cooperative breeding systems in particular were associated with elevated genetic similarity. These findings provide comparative evidence of detrimental fitness consequences of high genetic similarity across a wide range of species, and help to identify ecological factors potentially associated with increased risk of extinction.


H(2)O(2)-mediated permeability: role of MAPK and occludin.
H(2)O(2)-mediated elevation in endothelial solute permeability is associated with pathological events such as ischemia-reperfusion and inflammation. To understand how H(2)O(2) mediates increased permeability, we investigated the effects of H(2)O(2) administration on vascular endothelial barrier properties and tight junction organization and function. We report that H(2)O(2) exposure caused an increase in endothelial solute permeability in a time-dependent manner through extracellularly regulated kinase 1 and 2 (ERK1/ERK2) signal pathways. H(2)O(2) exposure caused the tight junctional protein occludin to be rearranged from endothelial cell-cell junctions. Occludin rearrangement involved redistribution of occludin on the cell surface and dissociation of occludin from ZO-1. Occludin also was heavily phosphorylated on serine residues upon H(2)O(2) administration. H(2)O(2) mediates changes in ERK1/ERK2 phosphorylation, increases endothelial solute permeability, and alters occludin localization and phosphorylation were all blocked by PD-98059, a specific mitogen-activated protein (MAP) or ERK kinase 1 inhibitor. These data strongly suggest that H(2)O(2)-mediated increased endothelial solute permeability involves the loss of endothelial tight junction integrity through increased ERK1/ERK2 activation.


Whole genome duplication is an early event leading to aneuploidy in IDH-wild type glioblastoma.
Glioblastoma, the most frequent and lethal form of glioma, displays chromosome instability and recurrent somatic copy number alterations (SCNA). Chromothripsis and whole genome duplication (WGD) have been recently identified in cancer. In the present study, we analyzed SCNA and determine the ploidy pattern in 123 IDH-wild-type glioblastomas, using SNP array data. WGD and chromothripsis events were validated using, respectively, FISH and CTLPScanner. WGD was detected in 11.4% glioblastomas (14/123) and was associated with TP53 mutation (p = 0.0068). It was an early event occurring after the recurrent SCNA observed in diffuse high-grade gliomas. Glioblastomas with WGD were more aneuploid compared to glioblastomas without WGD (p < 0.0001). Chromothripsis occurred in 29.3% glioblastomas (36/123) and mostly affected chromosomes 7, 9 and 12, with amplification of oncogenes (EGFR, MDM2/CDK4), and homozygous deletion of tumor suppressor genes (CDKN2A). There was a significant association between chromothripsis and gene rearrangement at a given locus. WGD is an early genetic event significantly associated to TP53 mutation and leading to chromosome instability and aneuploidy in IDH-wild-type glioblastoma. Chromothripsis recurrently targets oncogenes and tumor suppressor genes that are key players in gliomagenesis and tumor progression. The occurrence of chromothripsis points to underlying gene rearrangements (including gene fusions), potential therapeutic targets in glioblastoma.


Impact of Tibial Runoff on Outcomes of Endovascular Treatment for Femoropopliteal Atherosclerotic Lesions.
The aim of this study is to investigate the impact of tibial runoff on outcomes of femoropopliteal interventions for atherosclerotic lesions. A retrospective review of 243 endovascular procedures for femoropopliteal atherosclerotic lesions on 243 limbs of 197 patients was performed. The distribution rates of good tibial runoff (runoff score <7) and poor tibial runoff (runoff score ≥7) were 37.0% and 63.0%, respectively. In the poor tibial runoff group, the patients were older ( P = .019), and the proportion of male was lower ( P = .014). There was a significantly higher proportion of rest pain or tissue loss ( P < .001), and the prevalence of stroke ( P = .031) and renal insufficiency ( P = .005) was significantly higher in the poor runoff group. After femoropopliteal intervention, the amputation-free survival ( P = .03) and freedom from ischemia ( P = .003) were significantly lower in the poor runoff group. The interventions targeting below-the-knee (BTK) lesions performed concomitantly for critical limb ischemia or tissue loss with poor tibial runoff did not show a significant advantage in terms of freedom from ischemia; however, minor trends of longer lasting freedom from ischemia were observed when BTK intervention was combined. The patients with poor runoff showed significantly lower amputation-free survival and freedom from ischemia. In poor tibial runoff limbs with critical limb ischemia or tissue loss, BTK intervention did not demonstrate additional significant beneficial outcomes; however, there was a minor trend of longer lasting freedom from ischemia after concomitant BTK intervention.


Vitamin C and common cold incidence: a review of studies with subjects under heavy physical stress.
Several studies have observed an increased risk of respiratory infections in subjects doing heavy physical exercise. Vitamin C has been shown to affect some parts of the immune system, and accordingly it seems biologically conceivable that it could have effects on the increased incidence of respiratory infections caused by heavy physical stress. In this report the results of three placebo-controlled studies that have examined the effect of vitamin C supplementation on common cold incidence in subjects under acute physical stress are analyzed. In one study the subjects were school-children at a skiing camp in the Swiss Alps, in another they were military troops training in Northern Canada, and in the third they were participants in a 90 km running race. In each of the three studies a considerable reduction in common cold incidence in the group supplemented with vitamin C(0.6-1.0 g/day) was found. The pooled rate ratio (RR) of common cold infections in the studies was 0.50 (95% CI: 0.35-0.69) in favour of vitamin C groups. Accordingly, the results of the three studies suggest that vitamin C supplementation may be beneficial for some of the subjects doing heavy exercise who have problems with frequent upper respiratory infections.


The evolution of environmental tolerance and range size: a comparison of geographically restricted and widespread Mimulus.
The geographic ranges of closely related species can vary dramatically, yet we do not fully grasp the mechanisms underlying such variation. The niche breadth hypothesis posits that species that have evolved broad environmental tolerances can achieve larger geographic ranges than species with narrow environmental tolerances. In turn, plasticity and genetic variation in ecologically important traits and adaptation to environmentally variable areas can facilitate the evolution of broad environmental tolerance. We used five pairs of western North American monkeyflowers to experimentally test these ideas by quantifying performance across eight temperature regimes. In four species pairs, species with broader thermal tolerances had larger geographic ranges, supporting the niche breadth hypothesis. As predicted, species with broader thermal tolerances also had more within-population genetic variation in thermal reaction norms and experienced greater thermal variation across their geographic ranges than species with narrow thermal tolerances. Species with narrow thermal tolerance may be particularly vulnerable to changing climatic conditions due to lack of plasticity and insufficient genetic variation to respond to novel selection pressures. Conversely, species experiencing high variation in temperature across their ranges may be buffered against extinction due to climatic changes because they have evolved tolerance to a broad range of temperatures.


Alzheimer's Disease: Dawn of a New Era?
Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by a progressive decline in cognition and memory, leading to significant impairment in daily activities and ultimately death. It is the most common cause of dementia, the prevalence of which increases with age; however, age is not the only predisposing factor. The pathology of this cognitive impairing disease is still not completely understood, which has limited the development of valid therapeutic options. Recent years have witnessed a wide range of novel approaches to combat this disease, so that they greatly increased our understanding of the disease and of the unique drug development issues associated with this disease. In this paper, we provide a brief overview of the history, the clinical presentation and diagnosis, and we undertake a comprehensive review of the various approaches that have been brought to clinical trials in recent years, including immunotherapeutic approaches, tau-targeted strategies, neurotransmitter-based therapies, neurotropic and hematopoietic growth factors, and antioxidant therapies, trying to highlight the lessons learned from these approaches. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Cognitive-behavioral interventions to manage depression in patients with cancer: research and theoretical initiatives.
The incidence of depression is rising worldwide, possibly due to urban crowding and insufficient resources. This pandemic raises the possibility that disabling depression among patients with cancer will increase. Already, about one-third of patients with cancer present with depression. Although many progressive cancer centers are instituting psychooncology services, the projected decline in numbers of psychiatrists in the coming decade suggests that these programs may flounder unless nurses are able to provide adjuvant support. Consequently, this article describes the theoretical and emerging research data base regarding the treatment of cancer-related depression with cognitive-behavioral therapy. Implications drawn from this review suggest that nurses can take an active role in preventing and managing cancer-related depression in direct care environments by developing critical pathways for screening, prevention, treatment, and outcomes assessment using theory-based research.


Time course of cortical activations in implicit and explicit recall.
The distinction between implicit and explicit retrieval of learned material is central to recent thinking about the neural systems underlying memory. Word stem completion is one task in which subjects can be instructed either to make a deliberate recall (explicit instruction) or to be told to complete the stem with any appropriate word (implicit instruction). Positron emission tomography (PET) studies have indicated that during implicit retrieval, there is reduced blood flow in right posterior areas, whereas some tasks of explicit retrieval involve frontal and hippocampal activation. However, there is no information about the timing of these activations or how implicit and explicit retrieval might be related. We used word stem completion tasks similar to those used in the PET studies, but used high-density electrical recording designed to allow localization of the regions involved in the tasks and to provide temporal information. We found reduced activity for primed words in right posterior cortex corresponding to previous PET results. The reduction occurred within the first 200 msec after input, suggesting early interaction with the information stored in this area. Similar reductions observed during explicit recall of the previously presented words indicate that priming is similar under implicit and explicit conditions. In addition, when priming was not an adequate basis for response, then frontal areas were active. Retrieval of unprimed words under implicit instruction elicited right frontal activation, whereas explicit retrieval activated frontal areas bilaterally. Left frontal and hippocampal activations appear to occur only when the retrieval involved use of the words from the list studied previously.


Open-Label, Single-Arm, Multicenter, Phase II Trial of Lenvatinib for the Treatment of Patients With Anaplastic Thyroid Cancer.
Anaplastic thyroid cancer (ATC), an aggressive malignancy, is associated with a poor prognosis and an unmet need for effective treatment, especially for patients without BRAF mutations or NTRK or RET fusions. Lenvatinib is US Food and Drug Administration-approved for radioiodine-refractory differentiated thyroid cancer and has previously demonstrated activity in a small study of patients with ATC (n = 17). We aimed to further evaluate lenvatinib in ATC. This open-label, multicenter, international, phase II study enrolled patients with ATC, who had ≥ 1 measurable target lesion, to receive lenvatinib 24 mg once daily. The primary end points were objective response rate (ORR) by investigator assessment per RECIST v1.1 and safety. Responses were confirmed ≥ 4 weeks after the initial response. Additional end points included progression-free survival and overall survival (OS). The study was halted for futility as the minimum ORR threshold of 15% was not met upon interim analysis. The interim analysis set included the first 20 patients. The full analysis set includes all 34 enrolled and treated patients. In the full analysis set, one patient achieved a partial response (ORR, 2.9%; 95% CI, 0.1 to 15.3). More than half of the evaluable patients experienced tumor shrinkage; three patients experienced a > 30% tumor reduction. The median progression-free survival was 2.6 months (95% CI, 1.4 to 2.8); the median overall survival was 3.2 months (95% CI, 2.8 to 8.2). The most common treatment-related adverse events (AEs) were hypertension (56%), decreased appetite (29%), fatigue (29%), and stomatitis (29%). No major treatment-related bleeding events or grade 5 treatment-related AEs occurred. The safety profile of lenvatinib in ATC was manageable, and many AEs were attributable to the progression of ATC. The results suggest that lenvatinib monotherapy may not be an effective treatment for ATC; further investigation may be warranted.


Contribution of the rib cage to breathing in tetraplegia.
In tetraplegia there is often paradoxical inward motion of the rib cage during inspiration. The volume of this negative contribution is difficult to estimate but can be obtained by optical mapping. The partitioning of ventilation between the rib cage and abdomen in six normal subjects, 10 stable tetraplegic patients, and one tetraplegic patient at intervals during rehabilitation has been studied by this technique. In normal subjects the tidal volume and the vital capacity were the sum of positive contributions from the rib cage and abdomen. In stable tetraplegic subjects with similar neurological levels, the rib cage contribution varied widely but the total chest wall displacement could not be predicted from the vital capacity. In the patient studied sequentially rib cage paradox reversed with time after injury, and this was associated with an absolute increase in vital capacity and an improvement in the action of the diaphragm.


One size does not fit all: a diagnostic post-occupancy evaluation model for an emergency department.
This study presents a detailed account of processes and multiple methodologies used in conducting a diagnostic post-occupancy evaluation (POE) in an urban hospital emergency department. Healthcare design POE research findings can lead to improved work environments for healthcare providers and higher levels of staff, patient, and visitor satisfaction. This evaluation was conducted in two separate phases over 12 months, with data analysis occurring after each phase. Phase 1 involved 200 hours of observation, physical measurements, and occupancy counts. Phase 2 included surveys (n = 315) of staff, visitors, and patients. In addition, eight distinct staff focus groups (e.g., Nursing, Housekeeping, Physician, etc.) were conducted. To illustrate the process, one healthcare design-related issue, privacy and confidentiality, was assessed in light of the linear design model with a central core. Phase 1 observation results indicated that most confidential conversations were contained within the linear core. However, Phase 2 focus groups revealed that many staff members had concerns regarding the level of privacy and confidentiality due to the core's open design. The use of multiple methods provided greater information and a more comprehensive picture of the emergency department environment and design. This study presents a comprehensive framework for diagnostic post-occupancy evaluation in healthcare design. The findings indicate that a systematic, multi-methodological approach developed around a conceptual framework can lead to higher quality evaluations. Diagnostic POEs should be grounded in extant literature and customized based on the setting, the client's guiding principles, and the design team's objectives. In diagnostic POEs, one size does not fit all. Case study, design process, interdisciplinary, post-occupancy, privacy and confidentiality.


Catalysis of CO2 reduction by diazapyridinophane complexes of Fe, Co, and Ni: CO2 binding triggered by combined frontier MO associations involving a SOMO.
Our previous study on the photochemical CO2 reduction into CO catalyzed by the diazapyridinophane complexes of Fe, Co, and Ni revealed that (i) the Co catalyst shows the highest TOF but degrades rapidly, (ii) the Fe catalyst exhibits a lower TOF relative to Co but shows higher robustness, giving a higher TON, and (iii) the Ni complex shows no activity (Sakaguchi et al., Chem. Commun., 2019, 55, 8552). Here we show our DFT results unveiling that the Fe and Co catalysts can utilize multiple sets of frontier MO associations at the CO2 binding by including one of the SOMOs in a high-spin d7 Fe(I) and d8 Co(I) center, respectively, giving an increased driving force for these oxidative addition steps. Remarkably, two-electron reduction of CO2 to CO22- at the binding step is driven by the two electrons transferred from different d-based orbitals. The CoI species binds CO2 at the rate-limiting step with an activation barrier of 15.0 kcal mol-1, rationalizing the high initial TOF observed. However, the CoI(CO) species is given as a dead-end product, consistent with its relatively rapid deactivation. The Fe catalyst possesses a slightly higher barrier in CO2 binding (ΔG‡ = 15.8 kcal mol-1) but does not stabilize the FeI(CO) species which readily releases CO (ΔG = 3.5 kcal mol-1). The Ni catalyst has the smallest barrier in CO2 binding (ΔG‡ = 11.5 kcal mol-1) but the CO release is largely prohibited by the dead-end NiI(CO) species, consistent with its inactive character towards CO2 reduction. The combined results all satisfactorily explain the observed catalytic behaviors.


Fournier's gangrene current approaches.
Fournier's gangrene is a rare but highly mortal infectious disease characterised by fulminant necrotising fasciitis involving the genital and perineal regions. The objective of this study is to analyse the demographics, clinical feature and treatment approaches as well as outcomes of Fournier's gangrene. Data were collected retrospectively from medical records and operative notes. Patient data were analysed by demographics, aetiological factors, clinical features, treatment approaches and outcomes. Twelve patients (five female and seven male) were enrolled in this study. The most common aetiology was perianal abscess (41·6%). Wound cultures showed a mixture of microorganisms in six (50%) patients. For faecal diversion, while colostomy was performed in six cases (50%), Flexi-Seal was used in two cases (16·6%). In four patients (33·4%), no faecal diversion was performed. Negative pressure wound therapy (NPWT) system was effective in the last four patients (33·4%). The mean hospitalisation period in patients who used NPWT was 18 days, while it was 20 days in the others. NPWT in Fournier's gangrene is a safe dressing method. It promotes granulation formation. Flexi-Seal faecal management is an alternative method to colostomy and provides protection from its associated complications. The combination of two devices (Flexi-Seal and NPWT) is an effective and comfortable method in the management of Fournier's gangrene in appropriate patients.


Conversion from BioPAX to CSO for system dynamics and visualization of biological pathway.
The vast accumulation of biological pathway data scattered in various sources presents challenges in the exchange and integration of these data. Major new standards for representation of pathway data and the ability to check inconsistency in pathways are inevitable for the development of a reliable pathway data repository. Within the context of biological pathways, the cell system ontology (CSO) had been developed as a general framework to model system dynamics and visualization of diverse biological pathways. CSO provides an excellent environment for modeling, visualizing, and simulating complex molecular mechanisms at different levels of details. This paper examines whether CSO addresses the integration capability of pathway data with system dynamics. We present a conversion tool for converting BioPAX to CSO. Transforming the data from BioPAX to CSO not only allows an analysis of the dynamic behaviors in molecular interactions but also allows the results to be stored for further biological investigations, which is not possible in BioPAX. The conversion is done using simple inference algorithms with the addition of view- and simulation-related properties. We demonstrate how CSO can be used to build a complete and consistent pathway repository and enhance the interoperability among applications.


Apoptotic changes in the aged brain are triggered by interleukin-1beta-induced activation of p38 and reversed by treatment with eicosapentaenoic acid.
Among the several changes that occur in the aged brain is an increase in the concentration of the proinflammatory cytokine interleukin-1beta that is coupled with a deterioration in cell function. This study investigated the possibility that treatment with the polyunsaturated fatty acid eicosapentaenoic acid might prevent interleukin-1beta-induced deterioration in neuronal function. Assessment of four markers of apoptotic cell death, cytochrome c translocation, caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and terminal dUTP nick-end staining, revealed an age-related increase in each of these measures, and the evidence presented indicates that treatment of aged rats with eicosapentaenoate reversed these changes as well as the accompanying increases in interleukin-1beta concentration and p38 activation. The data are consistent with the idea that activation of p38 plays a significant role in inducing the changes described since interleukin-1beta-induced activation of cytochrome c translocation and caspase-3 activation in cortical tissue in vitro were reversed by the p38 inhibitor SB203580. The age-related increases in interleukin-1beta concentration and p38 activation in cortex were mirrored by similar changes in hippocampus. These changes were coupled with an age-related deficit in long term potentiation in perforant path-granule cell synapses, while eicosapentaenoate treatment was associated with reversal of age-related changes in interleukin-1beta and p38 and with restoration of long term potentiation.


Infinite number of solutions to the hemodynamic inverse problem.
Investigators have had much success solving the "hemodynamic forward problem," i.e., predicting pressure and flow at the entrance of an arterial system given knowledge of specific arterial properties and arterial system topology. Recently, the focus has turned to solving the "hemodynamic inverse problem," i.e., inferring mechanical properties of an arterial system from measured input pressure and flow. Conventional methods to solve the inverse problem rely on fitting to data simple models with parameters that represent specific mechanical properties. Controversies have arisen, because different models ascribe pressure and flow to different properties. However, an inherent assumption common to all model-based methods is the existence of a unique set of mechanical properties that yield a particular pressure and flow. The present work illustrates that there are, in fact, an infinite number of solutions to the hemodynamic inverse problem. Thus a measured pressure-flow pair can result from an infinite number of different arterial systems. Except for a few critical properties, conventional approaches to solve the inverse problem for specific arterial properties are futile.


Clinical holistic medicine: problems in sex and living together.
When the problems of sex and living together are understood as symptoms of underlying old existential wounds in need of healing, and when the physician accepts the role as coach supporting the patient to confront these emotional pains, then the patient can heal existentially in order to obtain the wanted closeness and intimacy. The change of perspective from: "He or she is not all right in..." to "I see that this is really about me, and what I have to learn is..." is where the patient assumes responsibility and this is often efficient in helping the patient with problems in his/her sex- and love life. Intimacy is the most difficult art, where sexuality cannot exist without trust, vulnerability, and surrender. This is often only possible after the patient has found his or her true self, including the purpose of life. The physician who will give "holding" (care) and processing to the patient with the intention of healing the "wounded child inside" who cannot love and open up, can often help the patient to improve self-insight and change the whole quality and atmosphere of the relationship. The healing will end a series of symptoms of poor thriving, physically, emotionally, and mentally, and make life worth living. Sometimes a few successful holistic sessions are enough to change the whole picture and solve an emotional "knot" that has the potential to destroy the relationship.


Pyrolysis of Al-Based Metal-Organic Frameworks to Carbon Dot-Porous Al2 O3 Composites With Time-Dependent Phosphorescence Colors for Advanced Information Encryption.
Phosphorescent materials with time-dependent phosphorescence colors (TDPCs) have great potential in advanced optical applications. Synthesis of such materials is attractive but challenging. Here, a series of carbon dot-porous Al2 O3 composites exhibiting distinctive TDPC characteristics is prepared by high-temperature pyrolysis of Al-based metal-organic frameworks NH2 -MIL-101(Al). The composite synthesized at 700 °C (CDs@Al2 O3 -700) shows an obvious change in phosphorescence color from blue to green after removing the excitation light of 280 nm. Photophysical analysis reveals that two emission centers in CDs, namely carbon core and surface states, are responsible for the short-lived blue phosphorescence (96 ms) and long-lived green phosphorescence (911 ms), respectively. The combination of blue and green phosphorescence with different decay rates triggering the interesting TDPC phenomenon. CDs@Al2 O3 -700 has a significantly high phosphorescence quantum yield of up to 41.7% and possesses an excellent optical stability against water, organic solvents, and strong oxidants, which benefits from the multi-confinement of CDs by the porous Al2 O3 matrix through rigid network, strong space constraint, and stable covalent bonding. Based on the TDPC property, multilevel coding patterns composed of CDs@Al2 O3 are successfully fabricated for advanced dynamic information encryption.


Antigen binding of an ovomucoid-specific antibody is affected by a carbohydrate chain located on the light chain variable region.
We cloned the variable regions of heavy and light chain genes of an anti-ovomucoid monoclonal antibody (MAb-OM21) produced by the mouse hybridoma cell line OM21. DNA sequence analysis showed that the light chain of the MAb-OM21 has only one potential N-glycosylation consensus sequence in the complementarity determining region 2 of the light chain. To find whether carbohydrate chains are located on the light chain, we assayed for the size of the light chain, after treatment with N-glycosidase, by western blotting, and also detection of the carbohydrate chains on the light chain was done using the lectin blot assay. A N-linked carbohydrate chain has been shown to bind to the light chain. To clarify the role of this carbohydrate chain in the light chain, we produced carbohydrate variant antibodies by N-deglycosylation using glycosidase or by expressing the antibody from different host cells. The N-deglycosylated variant antibody has greater antigen binding, and the antibody produced from the different host cells showed a reduced antigen binding activity and acquired the ability to react to ovalbumin. These results suggest that antigen binding of the ovomucoid specific antibody MAb-OM21 can be affected by the carbohydrate chain on the light chain variable region.


Effect of psychosocial factors on low back pain in industrial workers.
To test the hypothesis that workplace psychosocial factors such as demand, control, support, job satisfaction and job appreciation can predict the future onset of disabling low back pain (LBP). The present study involved a prospective cohort of 4500 Iranian industrial workers. Data were gathered by means of a self-reported questionnaire about LBP, as well as working life exposure, lifestyle factors, social exposures, co-morbidity, life events and psychosomatic complaints in 2004. All new episodes of disabling LBP resulting in medically certified sick leave during the 1-year follow-up registered by occupational health clinic inside the factory. The participation rate was good (85%). A total of 744 subjects reported current LBP (point prevalence cases). A total of 52 (<2%) new episodes of disabling LBP were observed during the 1-year follow-up (incident cases). Male employees reported higher demands, lower control and lower support than female employees. Employees with high demands, low control, job strain, low job satisfaction and low job appreciation showed increased odds ratios, and these results were statistically significant. Few prospective studies in this field have been published, but all of them are related to industrialized countries. This prospective study suggests the aetiological role of job strain for LBP. The findings of this study indicate a substantial potential for disease prevention and health promotion at the workplace.


Effect of dosing time of angiotensin II receptor blockade titrated by self-measured blood pressure recordings on cardiorenal protection in hypertensives: the Japan Morning Surge-Target Organ Protection (J-TOP) study.
To study the impact of the dosing time of an angiotensin II receptor blocker (ARB) titrated by self-measured home blood pressure (HBP) on cardiorenal damage in hypertensives. We conducted an open-label multicenter trial, the J-TOP study, that enrolled 450 hypertensives with self-measured systolic HBP more than 135 mmHg. The study patients were stratified into three groups according to the difference between their morning and evening SBPs difference: a morning hypertension group (morning and evening difference at least 15 mmHg; n = 170), a morning and evening hypertension group (0 mmHg < or = morning and evening difference <15 mmHg; n = 198), and an evening hypertension group (morning and evening difference <0 mmHg; n = 82). Individuals were then randomly allocated to receive bedtime dosing or awakening dosing of candesartan (+/- diuretic as needed) titrated to achieve a target systolic HBP less than 135 mmHg. The 6-month change in the urinary albumin/creatinine ratio (UACR) was assessed. In total patients, the UACR was more markedly reduced in the bedtime-dosing group than in the awakening-dosing group (-45.7 vs. -34.5%, P = 0.02), whereas there were no differences in the reduction of any of the HBPs including the sleep blood pressures (BPs) between the two groups. Among the three subgroups stratified by the morning and evening difference, the difference in the UACR reduction between the bedtime-dosing and awakening-dosing groups was only significant in the morning hypertension group (-50.6 vs. -31.3%, P = 0.02). In HBP-guided antihypertensive treatment in hypertensives, bedtime dosing of an ARB may be superior to awakening dosing for reducing microalbuminuria.


Renovascular hypertension after transplantation of a kidney perfused via multiple renal arteries.
A case presented in which a kidney with multiple (four) renal arteries was perfused by cannulating the two larger vessels. In spite of precautions to minimize damage at the sites of cannulation, stenosis developed at the orifices of the two principal vessels. This resulted in renovascular hypertension and led eventually to transplant nephrectomy. A technique has subsequently been developed to permit perfusion preservation without direct cannulation of the renal arteries. This completely eliminates cannula-related injury as a cause of renal artery stenosis.


On the relationship between discrete and repetitive lifting performance in military tasks.
Military manual handling requirements range from discrete lifts to continuous and repetitive lifting tasks. For the military to introduce a discrete lifting assessment, the assessment must be predictive of the various submaximum lifting tasks personnel are required to perform. This study investigated the relationship between discrete and repetitive military lifting to assess the validity of implementing a discrete lifting test. Twenty-one soldiers from the Australian Army completed a whole-body box-lifting assessment as a one repetition maximum (1RM) and a series of submaximal lifting repetitions (% 1RM). Performance was measured between the number of lifting repetitions that could be performed at different intensities between 58 and 95% 1RM. A strong curvilinear relationship existed across the entire submaximal lifting range (r = 0.72, p ≤ 0.05). The model developed demonstrated a low predictive error (standard error of the estimate = 7.2% 1RM) with no differences detected in the relationship when comparing individuals of high and low strength. Findings support the use of a discrete functional lifting assessment in providing coverage of a broad range of military lifting tasks. Parallels can be drawn between the trend reported in the current study and weight-training exercises reported in the literature.


Community-based program to increase use of hearing conservation practices among farm and rural youth: a cluster randomized trial of effectiveness.
Noise exposure and associated hearing loss affects an estimated 2 million farm youth who are exposed as farm residents, farm family workers, hired workers, children of migrant or seasonal workers, and farm visitors. Risk factors for farm youth include frequent exposure to high farm noise; farm work from an early age, and exposure to high recreational noise (e.g., firearms, ATVs, and personal listening devices). This study compared the effectiveness of two interventions and control. The programs included a community-based interactive youth educational program alone (Group A), a community-based interactive youth educational program followed by an Internet-based booster (Group B), and a no-interaction control (Group C). The study used a cluster randomized control design, with equal allocation ratio to each cluster, without blinding. Inclusion criteria included enrollment in grade 4, parental consent, English speaking, and attending a community-based educational event included in the cluster sampling. A total of 1979 youth were enrolled at 36 sites distributed across the 3 study arms in the following distribution: N = 662 in 13 sites (Group A), N = 680 in 12 sites (Group B), and N = 637 in 11 sites (Group C). Comparison with pre-intervention data showed no difference in intent to use hearing conservation strategies in experimental groups. However, knowledge and attitudes toward hearing conservation were improved in the groups receiving the Internet-based booster. Participants reported frequent exposure to sources of hazardous noise (e.g., loud sporting events, firecrackers, personal listening devices). It is feasible and acceptable to incorporate hearing health education into an already existing system designed to deliver health and safety educational programming to farm and rural youth. The program was adopted by the partner agency for dissemination to up to 100,000 youth annually. Results of this study inform future intervention studies, interventions aimed at farm youth, and interventions to increase use of hearing conservation strategies, as well as offer a base for developing programs for non-English speaking children. Clinicaltrials.gov registration CT02472821. Date of trial registration: 06/09/2015 (retrospectively registered).


Heat treatment induces an increase in intracellular cyclic AMP content in human epidermoid A-431 cells.
The basal level of intracellular cyclic AMP (cAMPi) in A-431 cells incubated at 37 degrees C in Na(+)-containing Hanks solution is 2086 +/- 139 fmol/10(6) cells. When cells are exposed to 45 degrees C for 10 min, cAMPi increases by 40 +/- 4%, and then returns to basal levels within 30 min. Incubating cells in Ca(2+)-free or Mg(2+)-free Hanks solution has no effect on the heat-induced increase in cAMPi, but the increase is inhibited by acid-loading cells to intracellular pH 7.0 or 6.8. In unheated cells, cAMPi increases by 16 +/- 8%, 53 +/- 7%, or 39 +/- 8%, when incubated with isobutyl-1-methylxanthine (1 mM), Ro 20-1724 (0.5 mM), or theophylline (1 mM) respectively. However, heat treatment further elevates cAMPi in cells treated with phosphodiesterase inhibitors, indicating that heat treatment and phosphodiesterase inhibitors elevate cAMPi by a different pathway(s). Heat treatment increases adenylate cyclase activity 2.5-fold. When forskolin (150 microM), an adenylate cyclase stimulator, is applied to cells, the basal cAMPi increases 28 +/- 6-fold compared with controls. Subsequent heating of these cells lowers cAMPi levels to 7.0 +/- 0.5 times that in control cells. This decrease is prevented by pretreatment with pertussis toxin (30 ng/ml, 24 h), suggesting that G-proteins are involved in the process of heat-induced cAMPi increase. 2-Deoxy-D-glucose (10 mM), NaN3 (10 mM) and 2,4-dinitrophenol (1 mM) also increase cAMPi in A-431 cells. However, application of these metabolic inhibitors to cells before heat treatment does not result in cAMPi levels greater than that observed in cells with heat alone. Similar observations are obtained in heat-treated cells previously exposed to adenosine, but not to AMP or ADP. These data are the first to suggest that thermally induced increase in cAMPi is due to a combination of activation of adenylate cyclase and G-proteins, and an increase in adenosine owing to ATP breakdown caused by hyperthermia.


Epidemiology of candidaemia and invasive candidiasis. A changing face.
Invasive candidiasis is a leading cause of mortality. Candidaemia is the most common clinical presentation of invasive candidiasis but more that 30% of these infections do not yield positive blood cultures. Candida albicans remains the predominant aetiology, accounting for 50% of all cases. However, there has been an epidemiological shift in the last decades. Some species of Candida different to C. albicans have emerged as an important cause of severe candidaemia as they can exhibit resistance to fluconazole and other antifungal agents. Moreover, there is a different distribution of non C. albicans Candida species in relationship to patients' and hospital characteristics. Thus, Candida parapsilosis has been associated to candidaemia in neonates and young adults. This species usually has an exogenously origin and contaminates medical devices, causing central venous catheter-associated candidaemias. Candida glabrata, Candida tropicalis and Candida krusei are isolated in blood cultures from older patients (>65 years) with important risk factors, such as major abdominal surgery, solid tumours and haematologic malignancies, transplants, and/or prolonged treatment with corticoids. Moreover, important geographical differences in the distribution of the Candida species different to C. albicans causing invasive candidiasis have been reported: C. parapsilosis predominates in Australia, Latin America and Mediterranean countries of Africa, Asia and Europe. In contrast, C. glabrata has an important aetiological role in USA and Central and Northern Europe. Finally, an important and worrying issue is that mortality due to invasive candidiasis remains unacceptably high. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012).


Costs of illness due to hypeercholesterolemia in Portugal.
Cardiovascular diseases are the main cause of death in Portugal, in developed countries and, indeed, worldwide. Hypercholesterolemia is a major risk factor for these diseases, including ischemic heart disease, cerebrovascular disease, and peripheral vascular disease. This paper reports the results of a study of the cost of illness associated with hypercholesterolemia and the costs directly attributable to hypercholesterolemia in Portugal, estimated from data for the year 2000. The results indicate that the cost of the health care provided to deal with illnesses associated with hypercholesterolemia was Euros 735.9 million (direct costs) and the costs of lost production due to disability of patients of working age was Euros 74.82 million (indirect costs). The costs attributable to hypercholesterolemia, those that would be avoided if hypercholesterolemia were completely eliminated, amount to Euros 358.84 million in direct costs and Euros 28.31 million in indirect costs. These results confirm that hypercholesterolemia is a source of major health costs. This means that hypercholesterolemia deserves special attention from those who formulate health policy and should be given priority in implementing such policies.


2,2- and 2,6-Diarylpiperidines by aryl migration within lithiated urea derivatives of tetrahydropyridines.
2-Aryltetrahydropyridines formed by anionic cyclization or ring-closing metathesis were converted to their N'-aryl urea derivatives. Depending on the position of the unsaturation within the tetrahydropyridine ring, metalation by deprotonative lithiation or carbolithiation led to migration of the N'-aryl substituent to the 2- or 6-position via intramolecular nucleophilic attack of a benzylic organolithium on the aryl ring. The products are a range of 2,2-, 2,2,3-, and 2,6-polysubstituted piperidine derivatives. Related chemistry was observed in pyrroline homologues.


QSAR based design of new antitubercular compounds: improved isoniazid derivatives against multidrug-resistant TB.
Tuberculosis (TB) is the second cause of death from a single infectious agent, the M. tuberculosis bacillus. Nearly two billion people are infected and about 8.7 million new cases and 1.4 million deaths were reported by the World Health Organization (WHO) in 2013. Despite the availability of effective treatment, the alarming emergence of multidrug resistant (MDR) strains (with 310.000 estimated cases in 2011 among notified patients with pulmonary TB), simultaneously resistant to the two most effective anti-TB drugs, isoniazid (INH) and rifampicin, has urged the need to develop new molecular scaffolds, either structurally original or based on old and active drugs. The aim of this review is to summarize the current status of different QSAR based strategies for the design of novel anti-TB drugs based upon the most active anti-TB agent known, INH. A case study puts in evidence that the judicious application of quantitative structure- activity relationships can be successfully used to rationally design new INH-based derivatives, active against INH-resistant strains harboring mutations in the most frequent resistance related target (katG), and therefore develop candidate-compounds against MDR-TB, thus revisiting the unique effectiveness of INH against TB.


Trajectories of change in quality of life in 12-month survivors of lung or heart transplant.
Survival and functional outcomes for lung transplant recipients continue to lag behind those for heart recipients. Whether these poorer physical outcomes translate into poorer quality of life (QOL) for lung recipients relative to heart recipients is unknown. Lung versus heart transplant recipients' perceptions of QOL were longitudinally compared at three time-points across the first year posttransplant. Additionally, potentially important predictors of patient QOL were examined. Adult transplant recipients (N = 199) participated in semi-structured interviews that included measures of QOL, optimism, mastery, social support, religiosity and coping. Temporal patterns of QOL change were compared between lung and heart recipients who survived until 1 year posttransplant using mixed-model, hierarchical analysis of variance (ANOVA). Demographic and psychosocial predictors were examined with multiple regression analysis to identify the unique effects of each variable on QOL 1 year posttransplant. While heart recipients' QOL across several domains was higher shortly after transplant, lung patients' QOL improved and was equivalent to that of heart recipients by 1 year posttransplant. Greater optimism and support from friends predicted better QOL in physical, psychological and social domains. Conversely, avoidant coping strategies predicted poorer physical functioning. Thus, while clinical interventions designed to improve QOL posttransplant should be tailored to transplant recipients' initial psychosocial assets and liabilities, they need not be distinguished by transplant type.


Dietary patterns and metabolic control in diabetic diets: a prospective study of 51 outpatient men on unmeasured and exchange diets.
In a prospective, single blind study, 51 adult diabetic, male outpatients at or below ideal body weight (IBW), all but four of whom were insulin-treated, were randomly assigned to a calorically defined exchange diet (EXCH) or an unmeasured diet avoiding refined sugars (UNMEAS). Fasting chemistries, weights and 48-hr dietary recalls were obtained every 3 months for 3 years. There was no difference between groups in mean body weight, mean caloric intake, percentages of carbohydrate or fat intake, day to day consistency of caloric intake, or fasting chemistries. The patients whose actual weight tended to be less than IBW consumed more calories than their theoretical calculated needs (p = 0.002) without effect on glycemic control or stability of weight. Patients with low carbohydrate intake (less than 30%) had significantly higher triglyceride levels (p = 0.015). Otherwise, variations in dietary patterns were not reflected in fasting clinical chemistries. Individual fasting serum glucose levels were not related to consistency of carbohydrate intake, caloric distribution throughout the day or composition of diets. These results suggest that actual dietary patterns of subjects following exchange diabetic diets with precise caloric prescriptions are similar to those resulting from unmeasured diets with restriction of simple sugars. Other than correlation between carbohydrate intake and triglycerides, there was no detectable effect of variations in dietary patterns upon conventional chemical metabolic levels.


β-FeOOH Nanorods/Carbon Foam-Based Hierarchically Porous Monolith for Highly Effective Arsenic Removal.
Arsenic pollution in waters has become a worldwide issue, constituting a severe hazard to whole ecosystems and public health worldwide. Accordingly, it is highly desirable to design high-performance adsorbents for arsenic decontamination. Herein, a feasible strategy is developed for in situ growth of β-FeOOH nanorods (NRs) on a three-dimensional (3D) carbon foam (CF) skeleton via a simple calcination process and subsequent hydrothermal treatment. The as-fabricated 3D β-FeOOH NRs/CF monolith can be innovatively utilized for arsenic remediation from contaminated aqueous systems, accompanied by remarkably high uptake capacity of 103.4 mg/g for arsenite and 172.9 mg/g for arsenate. The superior arsenic uptake performance can be ascribed to abundant active sites and hydroxyl functional groups available as well as efficient mass transfer associated with interconnected hierarchical porous networks. In addition, the as-obtained material exhibits exceptional sorption selectivity toward arsenic over other coexisting anions at high levels, which can be ascribed to strong affinity between active sites and arsenic. More importantly, the free-standing 3D porous monolith not only makes it easy for separation and collection after treatment but also efficiently prevents the undesirable potential release of nanoparticles into aquatic environments while maintaining the outstanding properties of nanometer-scale building blocks. Furthermore, the monolith absorbent is able to be effectively regenerated and reused for five cycles with negligible decrease in arsenic removal. In view of extremely high adsorption capacities, preferable sorption selectivity, satisfactory recyclability, as well as facile separation nature, the obtained 3D β-FeOOH NRs/CF monolith holds a great potential for arsenic decontamination in practical applications.


Photo-thermal modulation of surface plasmon polariton propagation at telecommunication wavelengths.
We report on photo-thermal modulation of thin film surface plasmon polaritons (SPP) excited at telecom wavelengths and traveling at a gold/air interface. By operating a modulated continuous-wave or a Q-switched nanosecond pump laser, we investigate the photo-thermally induced modulation of SPP propagation mediated by the temperature-dependent ohmic losses in the gold film. We use a fiber-to-fiber characterization set-up to measure accurately the modulation depth of the SPP signal under photo-thermal excitation. On the basis of these measurements, we extract the thermo-plasmonic coefficient of the SPP mode defined as the temperature derivative of the SPP damping constant. Next, we introduce a figure of merit which is relevant to characterize the impact of temperature onto the properties of bounded or weakly leaky SPP modes supported by a given metal at a given wavelength. By combining our measurements with tabulated values of the temperature-dependent imaginary part of gold dielectric function, we compute the thermo-optical coefficients (TOC) of gold at telecom wavelengths. Finally, we investigate a pulsed photo-thermal excitation of the SPP in the nanosecond regime. The experimental SPP depth of modulation obtained in this situation are found to be in fair agreement with the modulation depths computed by using our values of gold TOC.


An Automatic R and T Peak Detection Method Based on the Combination of Hierarchical Clustering and Discrete Wavelet Transform.
The detection and delineation of QRS-complexes and T-waves in Electrocardiogram (ECG) is an important task because these features are associated with the cardiac abnormalities including ventricular arrhythmias that may lead to sudden cardiac death. In this paper, we propose a novel method for the R-peak and the T-peak detection using hierarchical clustering and Discrete Wavelet Transform (DWT) from the ECG signal. In the first step, a template of the single ECG beat is identified. Secondly, all R-peaks are detected by using hierarchical clustering. Then, each corresponding T-wave boundary is delineated based on the template morphology. Finally, the determination of T wave peaks is achieved based on the Modulus-Maxima Analysis (MMA) of the DWT coefficients. We evaluated the algorithm by using all records from the MIT-BIH arrhythmia database and QT database. The R-peak detector achieved a sensitivity of 99.89%, a positive predictivity of 99.97% and 99.83% accuracy over the validation MIT-BIH database. In addition, it shows a sensitivity of 100%, a positive predictivity of 99.83% in manually annotated QT database. It also shows 99.92% sensitivity and 99.96% positive predictivity over the automatic annotated QT database. In terms of the T-peak detection, our algorithm is verified with 99.91% sensitivity and 99.38% positive predictivity in manually annotated QT database.


[Properties of cancer cell DNA affects the prognosis].
When diagnosing cancer, it is often difficult to predict the further growth and spread of the tumour. One of the features of cancer is an abnormality in the amount of DNA in cancer cell nuclei, so-called DNA aneuploidy. Extensive abnormalities are often due to an unstable genome, which leads to an accumulation of mutations, dysregulation of genes and loss of cell cycle control. This article aims to provide an overview of the prognostic value of DNA ploidy analyses in ovarian, endometrial, prostate and colorectal carcinoma. This review article is based on literature searches in PubMed for the period 2000–2016. The search resulted in 308 articles. Thirty-three of these, representing an analysis of more than 18 000 tumours, fulfilled the inclusion criteria. In 30 of the 33 articles, a significant correlation was found between DNA ploidy and disease outcome for patients with ovarian, endometrial, prostate and colorectal carcinoma. Patients with aneuploid tumours had a poorer prognosis than those with diploid tumours. DNA ploidy analysis is a prognostic method for patients with ovarian and endometrial carcinoma, and is used as a guide to options for supplemental treatment and fertility-sparing surgery. A review of publications in recent years of DNA ploidy analyses for prostate and colorectal carcinoma reveals that these patient groups may also benefit from these measurements. In general terms, DNA ploidy analyses may help to increase knowledge of who needs supplemental treatment and who does not – which may be advantageous in avoiding overtreatment.


Low molecular weight heparin (LMWH) for primary thrombo-prophylaxis in patients with solid malignancies - systematic review and meta-analysis.
Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism (VTE). We performed a meta-analysis of all randomized controlled trials (RCTs) which evaluated low molecular weight heparin (LMWH) as primary prophylaxis in ambulatory patients with solid malignancies. A comprehensive search was conducted until October 2013. Primary outcome was symptomatic VTE. Secondary outcomes were pulmonary embolism (PE), any VTE, deep vein thrombosis (DVT), mortality and adverse events. Eleven trials met the inclusion criteria, and evaluated a total of 6942 patients. Primary prophylaxis with LMWH reduced symptomatic VTE (RR 0.46, 95% CI 0.32-0.67) and the rate of PE (RR 0.49, 95% CI 0.29-0.84). In the subgroup analysis of VTE in patients with lung and pancreatic cancers LMWH further reduced VTE [RR 0.42 (95% CI 0.25-0.71); RR 0.31 (95% CI 0.18-0.55), respectively]. Meta-analysis of six trials which reported survival outcomes revealed no statistically significant benefit for LMWH in one-year mortality rates (RR 0.93, 95% CI 0.83-1.04). There was no significant increase in major bleeding events (RR 1.28, 95% CI 0.84-1.95). LMWH reduces the incidence of symptomatic VTE and PE in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding. The benefit is most apparent in pancreatic cancer and also lung cancer. VTE prophylaxis should be considered for these specific populations.


Congenital deficiency of the tibia.
The late results of treatment of 24 legs in 21 children with congenital deficiency of the tibia are presented. A new classification is proposed which correlates well with recommendations for treatment and with the final functional result. Three types of deficiency were recognised: Type I, total absence of the tibia; Type II, distal absence; Type III, distal deficiency with tibiofibular diastasis. The early radiographic appearances, the functional status of the quadriceps and the severity of flexion contracture of the knee were important factors in the selection of the operations likely to give the best function.


Hereditary cystatin C amyloid angiopathy: monitoring the presence of the Leu-68-->Gln cystatin C variant in cerebrospinal fluids and monocyte cultures by MS.
Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant condition in which the patients suffer at an early age from repeated cerebral haemorrhages. The development of HCCAA is directly linked to a Leu-68-->Gln (L68Q) mutation in the cystatin C protein sequence. The concentration of cystatin C in cerebrospinal fluid (CSF) of HCCAA patients is markedly diminished and cultivated monocytes from affected individuals accumulate cystatin C. The goal of this work was to characterize cystatin C isolated from CSF and monocyte cultures originating from healthy persons and HCCAA patients with respect to the L68Q mutation. Cystatin C was isolated by carboxymethylpapain affinity chromatography. Proteins from CSF and monocyte cultures that bound specifically to the carboxymethylated papain column were resolved by reverse-phase HPLC chromatography and tryptic peptides were subsequently analysed by matrix-assisted laser desorption ionization MS. No evidence for mutated cystatin C protein was found in CSF samples from healthy subjects or HCCAA patients, but approx. 60% of the protein was found to be hydroxylated on Pro-3. No evidence was found for secretion of mutated cystatin C from HCCAA monocytes. However, we obtained evidence for the presence of mutated cystatin C in HCCAA monocytes. These results support the conclusion that the mutated cystatin C is retained in association with the monocytes and not secreted. An increased intracellular concentration would presumably promote the aggregation and denaturation of the mutated cystatin C, leading to the formation of amyloid fibrils and cell death.


Use of anti-inflammatory drugs and lower esophageal sphincter-relaxing drugs and risk of esophageal and gastric cancers.
The incidence of esophageal and gastric cardia adenocarcinoma has increased in Western countries in recent decades for largely unknown reasons. We investigated whether use of LES-relaxing drugs was related to an increased risk of esophageal and gastric cardia adenocarcinoma, and whether use of NSAIDs was related to a reduced risk of esophageal and gastric cancers. We examined these associations by using administrative databases in a case-control study in 2 integrated health care delivery systems. Cases were incident esophageal adenocarcinomas (n = 163) and squamous cell carcinomas (n = 114) and gastric cardia (n = 176) and non-cardia adenocarcinomas (n = 320), diagnosed between 1980-2002 in one health system and between 1993-2002 in the other. Matched controls (n = 3996) were selected. Complete prescription information was available for the study period. Prescription of corticosteroids was associated with a decreased risk of esophageal adenocarcinoma (odds ratio [OR], 0.6; 95% confidence interval [CI], 0.4-0.9), esophageal squamous cell carcinoma (OR, 0.4; 95% CI, 0.2-0.6), and gastric non-cardia carcinoma (OR, 0.4, 95% CI, 0.3-0.6). Ever use of pharmacy-purchased aspirin was associated with 30%-60% decreased risks of the studied cancers. As a group, LES-relaxing drugs showed little evidence of association with increased risk of any esophageal or gastric cancer. Corticosteroid and aspirin use were associated with significantly decreased risks of esophageal and gastric cancer. LES-relaxing drugs as a group did not affect these risks, although we had limited power to assess individual drugs. The possibility that corticosteroids and aspirin might reduce esophageal cancer risk warrants further consideration.


On-line analysis of nitrogen stable isotopes in NO from ambient air samples.
A method was developed for the on-line analysis of nitrogen stable isotopes at the natural abundance level in NO in order to study the NO contribution to the nitrogen cycle in ecosystems and in the atmosphere. The method enables a quick and accurate determination of 15N/14N ratios for NO and consists of the following steps: (a) accumulation of NO from air samples on a molecular sieve of 5 A, (b) desorption of NO from the molecular sieve during 15 min of heating at 350 degrees C (an offset of Deltadelta 4.6% must be corrected for), (c) trapping and cryofocusation of the desorbed NO on a PoraPlot Q matrix at -196 degrees C during heating, (d) release of the trapped NO from the PoraPlot Q matrix followed by chromatographic separation, reduction to N2, and isotopic composition analysis. A minimum sample size of 125 nmol of NO is recommended. A correction function for the calculation of the delta15N-NO values was introduced for sample sizes from 125 to 220 nmol of NO. Measurements of NO in automobile exhaust have proven the applicability of the developed method.


Analysis of the Relationship Between Muscle Tones and Abnormal Postures in a Computational Model.
Patients with Parkinson's disease (PD), a neurodegenerative disorder, exhibit a characteristic posture known as a forward flexed posture. Increased muscle tone is suggested as a possible cause of this abnormal posture. For further analysis, it is necessary to measure muscle tone, but the experimental measurement of muscle tone during standing is challenging. The aim of this study was to examine the hypothesis that "In patients with PD, abnormal postures are those with a small sway at increased muscle tones" using a computational model. The muscle tones of various magnitudes were estimated using the computational model and standing data of patients with PD. The postures with small sway at the estimated muscle tones were then calculated through an optimization method. The postures and sway calculated using the computational model were compared to those of patients with PD. The results showed that the differences in posture and sway between the simulation and experimental results were small at higher muscle tones compared to those considered plausible in healthy subjects by the simulations. This simulation result indicates that the reproduced sway at high muscle tones is similar to that of actual patients with PD and that the reproduced postures with small sway locally at high muscle tones in the simulations are similar to those of patients with PD. The result is consistent with the hypothesis, reinforcing the hypothesis.Clinical relevance- This study implies that improving the increased muscle tone in patients with PD may lead to an improved abnormal posture.


Characteristics of deaths by suicide in postmortem studies in Brazil: A systematic review and meta-analysis.
Suicide is one of the leading causes of death, with a trend for its increase in Brazil in past decades. This study aimed to review the characteristics of suicides in Brazilian postmortem studies. Studies investigating suicide deaths in Brazil, and based on autopsy or psychological autopsy were included. Proportions were pooled across studies with the use of random and fixed effects models. 6777 references were retrieved from six databases (searches up to January, 2023), and 45 studies included. In autopsy studies (k = 37, n = 16,231), substance use at toxicological analysis was found in 36.42% of cases (95% CI: 30.05-43.32), previous suicide attempts in 23.92% (95% CI: 6.73-57.78). In psychological autopsy studies (k = 8, n = 139), previous suicide attempts were reported in 28.09% (95% CI: 19.74-38.28), psychiatric conditions/symptoms in 90.67% (95% CI: 67.79-97.82), family history of suicidality in 21.33% (95% CI: 13.5-32.03). Most suicide deaths were reported in males and took place at the victim's home, hanging was the most frequent suicide method. Included studies presented significant limitations in quality assessment. Future studies should present more robust methodology, including bigger samples, the use of controls, and validated methodology.


Genetic susceptibility to a complex disease: the key role of functional redundancy.
Complex diseases involve both a genetic component and a response to environmental factors or lifestyle changes. Recently, genome-wide association studies (GWAS) have succeeded in identifying hundreds of polymorphisms that are statistically associated with complex diseases. However, the association is usually weak and none of the associated allelic forms is either necessary or sufficient for the disease occurrence. We argue that this promotes a network view, centred on functional redundancy. We adapted reliability theory to the concerned sub-network, modelled as a parallel array of functional modules. In our model, as long as one module remains active, the function correlated with the respective disease is ensured and disease does not occur. Genetic factors reduce the initial number of available modules while environment, contingent surroundings, personal history, epigenetics, and some intrinsic stochasticity influence their persistence time. This model reproduces age-specific incidence curves and explains the influence of environmental changes. It offers a new paradigm, according to which disease occurs due to a lack of functional elements, depending on many idiosyncratic factors. Genetic risk assessed from GWAS is only a statistical notion with no direct interpretation at the individual level. However, genomic profiling could be useful at population level in devising models to guide decisions in health care policy.


Mucosal gastrin concentration, molecular forms of gastrin, number and ultrastructure of G-cells in patients with duodenal ulcer.
The mean antral immunoreactive gastrin (IRG) concentration of 38 duodenal ulcer (DU) patients was significantly higher (35-9+/-5-2 mug/g) than that of 21 controls (15-9+/-2-6 mug/g). Also the mean IRG concentration in the proximal duodenal mucosa of 15 DU patients (3-2+/-0-8 mug/g) was higher (but not significantly) than that of 10 controls (1-8+/-0-5 mug/g). The number of G-cells in the antral mucosa of 58 DU patients and in the duodenal mucosa of 29 DU patients was not larger than that of controls. The distribution of immunoreactivity in gastrin components has been investigated in the antral and duodenal mucosa of six DU patients and six controls. In the antral mucosa the mean percentage of G-17 was 93-3% in DU patients and 92-0% in controls. G-34 amounted to 4-0% in DU patients and to 5-0% in controls. The G-34 percentage in the duodenal mucosa was higher (however not significantly) in the DU patients than in the controls (50-1% versus 35-8%). Ultrastructurally, the antral G-cells of DU patients had a significantly lower density index of their secretory granules suggesting higher functional activity. It is concluded that the exaggerated serum IRG response of DU patients to different stimuli is not a consequence of an increased G-cell mass.


Pathway of nitrous oxide consumption in isolated Pseudomonas stutzeri strains under anoxic and oxic conditions.
The microbial consumption of nitrous oxide (N2O) has gained great interest since it was revealed that this process could mitigate the greenhouse effect of N2O. The consumption of N2O results from its reduction to dinitrogen gas (N2) as part of the denitrification process. However, there is ongoing debate regarding an alternative pathway, namely reduction of N2O to NH4(+), or assimilatory N2O consumption. To date, this pathway is poorly investigated and lacks unambiguous evidence. Enrichment of denitrifying activated sludge using a mineral nitrogen-free medium rendered a mixed culture capable of anoxic and oxic N2O consumption. Dilution plating, isolation and deoxyribonucleic acid fingerprinting identified a collection of Pseudomonas stutzeri strains as dominant N2O consumers in both anaerobic and aerobic enrichments. A detailed isotope tracing experiment with a Pseudomonas stutzeri isolate showed that consumption of N2O via assimilatory reduction to NH4(+) was absent. Conversely, respiratory N2O reduction was directly coupled to N2 fixation.


Principles for learning single-joint movements. I. Enhanced performance by practice.
This study investigated changes in myoelectric and mechanical variables for movements made "as fast as possible" as a function of practice in the context of the dual-strategy hypothesis of motor control (Gottlieb et al. 1989b). Five male subjects made 1400 rapid elbow flexion movements in ten blocks of 20 trials over seven experimental sessions. Improved performance was defined as increased peak movement velocity, decreased peak velocity variability, increased acceleration and deceleration, a proportionately greater increase in peak deceleration than peak acceleration, and greater consistency in terminal location. The changes observed over experimental sessions were very similar to (but larger and more consistent than) those seen for the first experimental session, with the partial exception of the timing of the antagonist electromyogram (EMG). In general, the increases in the values of the measured mechanical variables covary with myoelectric measures in the same way as when subjects are asked to intentionally change speed in accordance with the rules of the speed-sensitive strategy (Corcos et al. 1989). However, there are differences between subjects in the extent to which speed changes can be attributable to the agonist muscle, the antagonist muscle, or in the timing between the muscles. In one of the five subjects, the latency of the antagonist EMG decreased over blocks on the 1st day but increased over experimental sessions and was consequently activated proportionately later in the movement. This suggests that extended practice can give at least some subjects flexibility in modifying the motor programs that underlie movement.


[Colloid-physical characterization of supramolecular drug delivery systems].
Cyclodextrins are well-known biocompatible oligosaccharides capable of forming inclusion complexes with suitable guest molecules. They can be expediently used as solubilizers for hydrophobic pharmacon molecules in aqueous solutions. In this study, the effect of colloidal and non-colloidal additives on the solubility of statins is described. Two statin-derivatives (lovastatin and simvastatin), beta-cyclodextrin (-CD) and randomly methylated beta-cyclodextrin (RAMEB) were used as complexing agents. Those pharmacons are widely used in the management of cardiovascular diseases involving high or elevated blood cholesterol levels. Complexation of the highly lipophilic statin molecules with beta-CD and RAMEB was studied in the presence and the absence of dissolved polyvinyl-pyrrolidone (PVP). For the characterization of the stability of statin-CD complexes, association constant of binary associates have been calculated. It was found that inclusion complexation can beneficially enhance the solubility of both statin-derivatives. In binary statin-CD solutions predominantly associates of 1:1 molar ratio form, which show significant surface activity. In polymer-containing ternary systems, the solubility of the pharmacons can further be increased. This phenomenon can presumably be explained with the formation of statin-CD-polymer ternary associates of supramolecular structure. In such supramolecular assemblies the amphiphilic statin-CD complexes are likely bound to the macromolecules' chains. The wetting properties of solid, dried and powdered complexes were studied by immersion enthalpy measurements. Both in binary and ternary systems a significant increase in the immersion enthalpy values could be detected, which indicates that the complexes exhibit fairly hydrophilic character.


Variation in clinical and patient-reported outcomes among complex heart failure with preserved ejection fraction phenotypes.
The aim of this study is to use six previously described heart failure with preserved ejection fraction (HFpEF) phenotypes to describe differences in (i) the biological response to spironolactone, (ii) clinical endpoints, and (iii) patient-reported health status by HFpEF phenotype and treatment arm in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT). We analysed 1767 patients in TOPCAT from the Americas. Using 11 clinical variables, patients were classified according to six HFpEF phenotypes previously identified in the I-PRESERVE and CHARM-Preserved studies. Kansas City Cardiomyopathy Questionnaire (KCCQ) measured health status. All phenotypes showed increase in potassium with spironolactone, although only three phenotypes showed significant increase in creatinine, and two phenotypes showed significant decrease in systolic blood pressure. Rate of the TOPCAT primary outcome (cardiovascular death, aborted cardiac arrest, or heart failure hospitalization) differed by HFpEF phenotype (P < 0.001) but not by treatment arm within each HFpEF phenotype. Baseline KCCQ score differed by HFpEF phenotype (P < 0.001), although some phenotypes with poor health status had lower rates of the TOPCAT primary outcome, and some phenotypes with better health status had higher rates of the TOPCAT primary outcome. However, within 3/6 phenotypes, higher baseline KCCQ score was associated with lower risk of the TOPCAT primary outcome. Change in KCCQ scores at 4 and 12 months did not differ among HFpEF phenotypes overall or by treatment arm. Complex, data-driven HFpEF phenotypes differ according to biological response to spironolactone, baseline health status, and clinical endpoints. These differences may inform the design of targeted clinical trials focusing on improvement in outcomes most relevant for specific HFpEF phenotypes.


Use of PBPK Modeling To Evaluate the Performance of Dissolv It, a Biorelevant Dissolution Assay for Orally Inhaled Drug Products.
The dissolution of inhaled drug particles in the lungs is a challenge to model using biorelevant methods in terms of (i) collecting a respirable emitted aerosol fraction and dose, (ii) presenting this to a small volume of medium that is representative of lung lining fluid, and (iii) measuring the low concentrations of drug released. We report developments in methodology for each of these steps and utilize mechanistic in silico modeling to evaluate the in vitro dissolution profiles in the context of plasma concentration-time profiles. The PreciseInhale aerosol delivery system was used to deliver Flixotide aerosol particles to Dissolv It apparatus for measurement of dissolution. Different media were used in the Dissolv It chamber to investigate their effect on dissolution profiles, these were (i) 1.5% poly(ethylene oxide) with 0.4% l-alphaphosphatidyl choline, (ii) Survanta, and (iii) a synthetic simulated lung lining fluid (SLF) based on human lung fluid composition. For fluticasone proprionate (FP) quantification, solid phase extraction was used for sample preparation with LC-MS/MS analysis to provide an assay that was fit for purpose with a limit of quantification for FP of 312 pg/mL. FP concentration-time profiles in the flow-past perfusate were similar irrespective of the medium used in the Dissolv It chamber (∼0.04-0.07%/min), but these were significantly lower than transfer of drug from air-to-perfusate in isolated perfused lungs (0.12%/min). This difference was attributed to the Dissolv It system representing slower dissolution in the central region of the lungs (which feature nonsink conditions) compared to the peripheral regions that are represented in the isolated lung preparation. Pharmacokinetic parameters ( Cmax, Tmax, and AUC0-∞) were estimated from the profiles for dissolution in the different lung fluid simulants and were predicted by the simulation within 2-fold of the values reported for inhaled FP (1000 μg dose) administered via Flixotide Evohaler 250 μg strength inhaler in man. In conclusion, we report methods for performing biorelevant dissolution studies for orally inhaled products and illustrate how they can provide inputs parameters for physiologically based pharmacokinetic (PBPK) modeling of inhaled medicines.


The role of indigenous microorganisms in suppression of Salmonella regrowth in composted biosolids.
Composting is commonly used as an effective means of stabilizing wastewater biosolids and reducing pathogens to very low concentrations. However, it has been shown that under certain conditions Salmonella can regrow in previously composted biosolids. Growth of seeded Salmonella typhimurium in composted biosolids ranging from two weeks to two years maturity was monitored. Results from sterile and non-sterile composted biosolids were compared. Seeded S. typhimurium colonized rapidly in sterilized biosolids reaching a maximum population density of more than 10(8) g(-1). Growth of seeded S. typhimurium was suppressed in non-sterilized compost with a maximum population density of less than 10(3) g(-1). There was a significant decline in the growth rate of seeded Salmonella in sterilized compost when the compost was stored, suggesting that bio-available nutrients declined with storage. However, in non-sterilized compost this was not the case. This suggests that the indigenous microflora play a significant role in suppression of Salmonella regrowth in composted biosolids. There was a strong negative correlation (-0.85) between the Salmonella inactivation rate and the maturity of compost in non-sterilized compost. The Salmonella inactivation rate was seven times higher in biosolids composting for two weeks as compared to compost stored for two years. This suggests that the antagonistic effect of indigenous microorganisms towards Salmonella declined with compost storage. It was concluded that all composted biosolids had a Salmonella regrowth potential. However, the indigenous microflora significantly reduced this regrowth potential. Long-term storage of compost is not recommended as this may increase the pathogen regrowth potential.


Des-tyrosine-gamma-endorphin administration in chronic schizophrenics. A preliminary report.
The beta-lipotrophin fragment des-tyrosine-gamma-endorphin (DT gamma E) has been reported to have antipsychotic properties. We administered the compound without other psychoactive drugs to a subpopulation of schizophrenic subjects. Male patients with chronic psychotic illness and previous long-term neuroleptic therapy were given DT gamma E at a similar dose and duration of treatment that have been reported to be effective. No improvement in psychotic symptoms occurred; plasma prolactin level, a parameter characteristically altered by neuroleptic treatment, did not change. The beneficial effects of DT gamma E in schizophrenia may be specific to a diagnostic category, may be dependent on past pharmacologic treatment, or may occur only in combination with other drugs.


Ten-year outcomes of the Arpe prosthesis for the treatment of osteoarthritis of the trapeziometacarpal joint.
Outcomes of 66 Arpe prostheses in 50 patients treated for osteoarthritis of the trapeziometacarpal joint were investigated with a mean follow-up of ten years. Ten-year survival was 87% when failure was defined as implant removal followed by trapeziectomy and tendon interposition. Ten-year survival was 82% when revision of the cup was also considered as failure and it was 80% when replacement of the neck alone was also chosen as an endpoint. Of the 52 prostheses that were not revised mean DASH score was 11, mean pain score 1.2 and mean score for satisfaction 9.5. It can be concluded that the majority of patients who did not underwent revision surgery were satisfied and had little or no pain. However, long-term survival of the Arpe prosthesis was moderate and patients should be warned that after ten years the risk for reoperation might be up to 20%.


Roles of amino acid residues near the chromophore of photoactive yellow protein.
To investigate the roles of amino acid residues around the chromophore in photoactive yellow protein (PYP), new mutants, Y42A, E46A, and T50A were prepared. Their spectroscopic properties were compared with those of wild-type, Y42F, E46Q, T50V, R52Q, and E46Q/T50V, which were previously prepared and specified. The absorption maxima of Y42A, E46A, and T50A were observed at 438, 469, and 454 nm, respectively. The results of pH titration for the chromophore demonstrated that the chromophore of PYP mutant, like the wild-type, was protonated and bleached under acidic conditions. The red-shifts of the absorption maxima in mutants tended toward a pK(a) increase. Mutation at Glu46 induced remarkable shifts in the absorption maxima and pK(a). The extinction coefficients were increased in proportion to the absorption maxima, whereas the oscillator strengths were constant. PYP mutants that conserved Tyr42 were in the pH-dependent equilibrium between two states (yellow and colorless forms). However, Y42A and Y42F were in the pH-independent equilibrium between additional intermediate state(s) at around neutral pH, in which yellow form was dominant in Y42F whereas the other was dominant in Y42A. These findings suggest that Tyr42 acts as the hinge of the protein, and the bulk as well as the hydroxyl group of Tyr42 controls the protein conformation. In all mutants, absorbance at 450 nm was decreased upon flash irradiation and afterwards recovered on a millisecond time scale. However, absorbance at 340--370 nm was increased vice versa, indicating that the long-lived near-UV intermediates are formed from mutants, as in the case of wild-type. The lifetime changes with mutation suggest the regulation of proton movement through a hydrogen-bonding network.


Characteristics of Abortion Care Seekers in Western Nigeria.
Induced abortion remains a major challenge in Nigeria and indeed the developing world because of its contribution to maternal morbidity and mortality. In Nigeria, abortion law is restrictive, and therefore abortion is provided clandestinely. Information on characteristics of abortion care seekers is available but requires updating. Hence, the need to carry out this study in order to suggest effective and proper intervention strategies to combat the problem of unwanted pregnancy and unsafe abortion. This was a prospective hospital-based study. Data collection was done by making use of a pretested standardized questionnaire. About two-fifths (42.8%) of the respondents were between the ages of 15 and 24 years, of which the adolescents between the ages of 15 and 19 years constituted 11.7%. Slightly less than half (48.4%) of the respondents were unmarried, while married women constituted 51%. Students were the single highest group (32.4%), closely followed by trading, which was the predominant economic activity (32.3%). Respondents terminated their pregnancies mainly because they were unmarried, students or did not desire to have children. Most of the respondents (43.4%) obtained abortion service from health facility they had used previously as a family clinic, while 38.6% of the women were introduced to providers by friends. Average contraceptive prevalence among the abortion care seekers was 29.9%. Abortion needs cut across all reproductive age groups. Reproductive health services including sexuality education and contraception should be provided for women while major governmental policy changes should be made to make abortion care accessible and safe.