Laccase isoenzymes of Pleurotus eryngii: characterization, catalytic properties, and participation in activation of molecular oxygen and Mn2+ oxidation.
Two laccase isoenzymes produced by Pleurotus eryngii were purified to electrophoretic homogeneity (42- and 43-fold) with an overall yield of 56.3%. Laccases I and II from this fungus are monomeric glycoproteins with 7 and 1% carbohydrate content, molecular masses (by sodium dodecyl sulfate-polyacrylamide gel electrophoresis) of 65 and 61 kDa, and pIs of 4.1 and 4.2, respectively. The highest rate of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) oxidation for laccase I was reached at 65 degrees C and pH 4, and that for laccase II was reached at 55 degrees C and pH 3.5. Both isoenzymes are stable at high pH, retaining 60 to 70% activity after 24 h from pH 8 to 12. Their amino acid compositions and N-terminal sequences were determined, the latter strongly differing from those of laccases of other basidiomycetes. Antibodies against laccase I reacted with laccase II, as well as with laccases from Pleurotus ostreatus, Pleurotus pulmonarius, and Pleurotus floridanus. Different hydroxy- and methoxy-substituted phenols and aromatic amines were oxidized by the two laccase isoenzymes from P. eryngii, and the influence of the nature, number, and disposition of aromatic-ring substituents on kinetic constants is discussed. Although both isoenzymes presented similar substrate affinities, the maximum rates of reactions catalyzed by laccase I were higher than those of laccase II. In reactions with hydroquinones, semiquinones produced by laccase isoenzymes were in part converted into quinones via autoxidation. The superoxide anion radical produced in the latter reaction dismutated, producing hydrogen peroxide. In the presence of manganous ion, the superoxide union was reduced to hydrogen peroxide with the concomitant production of manganic ion. These results confirmed that laccase in the presence of hydroquinones can participate in the production of both reduced oxygen species and manganic ions.


Efficacy of silver nanoparticles against the adults and eggs of monogenean parasites of fish.
Monogeneans are a diverse group of parasites that are commonly found on fish. Some monogenean species are highly pathogenic to cultured fish. The present study aimed to determine the in vitro anthelmintic effect of silver nanoparticles (AgNPs) against adults and eggs of monogeneans in freshwater using Cichlidogyrus spp. as a model organism. We tested two types of AgNPs with different synthesis methodologies and size diameters: ARGOVIT (35 nm) and UTSA (1-3 nm) nanoparticles. Damage to the parasite tegument was observed by scanning electron microscopy. UTSA AgNPs were more effective than ARGOVIT; in both cases, there was a concentration-dependent effect. A concentration of 36 μg/L UTSA AgNPs for 1 h was 100% effective against eggs and adult parasites, causing swelling, loss of corrugations, and disruption of the parasite's tegument. This is an interesting result considering that monogenean eggs are typically tolerant to antiparasite drugs and chemical agents. To the best of our knowledge, no previous reports have assessed the effect of AgNPs on any metazoan parasites of fish. Therefore, the present work provides a basis for future research on the control of fish parasite diseases.


Ketamine attenuates osteoarthritis of the knee via modulation of inflammatory responses in a rabbit model.
The aim of the present study was to investigate the efficacy of ketamine in attenuating osteoarthritis (OA) and modulating the expression of inflammatory mediators. A rabbit OA model was established by knee immobilization using plaster bandages. After six weeks, rabbits were randomly allocated into four groups (n=6/group): Normal saline, Ket60, Ket100, and Ket200 and twice a week for four weeks the rabbits received an intra‑articular injection of saline, or 60, 100 or 200 µmol/l ketamine, respectively. One week after the final injection, samples of synovial membrane, synovial fluid and articular cartilage were isolated. The pathological changes were assessed by general observation, hematoxylin and eosin staining and Alcian blue/periodic‑acid Schiff staining. Cartilage pathology was assessed using Mankin's scoring system. Tumor necrosis factor (TNF)‑α and interleukin (IL)‑10 levels in the synovial fluid were measured by enzyme‑linked immunosorbent assays. The nuclear factor (NF)‑κB p65 subunit expression level in cartilage samples was determined by immunohistochemistry. OA was characterized by morphological changes in the articular surface, cartilage lesions, infiltration of inflammatory cells and a significantly increased Mankin's score. Elevated TNF‑α and reduced IL-10 levels in the synovial fluid, along with increased p65 expression levels in the cartilage were observed in OA rabbits. Intra‑articular injection of ketamine ameliorated the pathological characteristics of OA, reduced the Mankin's score, decreased TNF‑α and NF‑κB p65 expression levels, and increased the level of IL‑10 expression in a dose-dependent manner. Thus is was demonstrated that Ketamine suppresses the inflammatory response in OA by modulating inflammatory mediator expression levels in a rabbit model of OA.


Substrate specificity switching of the flagellum-specific export apparatus during flagellar morphogenesis in Salmonella typhimurium.
During flagellar morphogenesis in Salmonella typhimurium, the flagellum-specific anti-sigma factor FlgM is exported out of the cells only after completion of hook assembly. In this study, we examined the export of the flagellar proteins, FlgD (hook capping protein), FlgE (hook protein), FlgK and FlgL (hook-filament junction proteins), FliD (filament capping protein), and FliC (flagellin), before and after completion of hook assembly. Like the FlgM protein, the FlgK, FlgL, FliD, and FliC proteins are exported efficiently only after completion of hook assembly. On the other hand, the FlgD and FlgE proteins are exported efficiently before, but poorly after, hook completion. These results indicate that the export properties are different between these two groups and that their export order exactly parallels the assembly order of the hook-filament structure. We propose that the substrate specificity switching occurs in the flagellum-specific export apparatus upon completion of hook assembly.


Indirect health effects of relative humidity in indoor environments.
A review of the health effects of relative humidity in indoor environments suggests that relative humidity can affect the incidence of respiratory infections and allergies. Experimental studies on airborne-transmitted infectious bacteria and viruses have shown that the survival or infectivity of these organisms is minimized by exposure to relative humidities between 40 and 70%. Nine epidemiological studies examined the relationship between the number of respiratory infections or absenteeism and the relative humidity of the office, residence, or school. The incidence of absenteeism or respiratory infections was found to be lower among people working or living in environments with mid-range versus low or high relative humidities. The indoor size of allergenic mite and fungal populations is directly dependent upon the relative humidity. Mite populations are minimized when the relative humidity is below 50% and reach a maximum size at 80% relative humidity. Most species of fungi cannot grow unless the relative humidity exceeds 60%. Relative humidity also affects the rate of offgassing of formaldehyde from indoor building materials, the rate of formation of acids and salts from sulfur and nitrogen dioxide, and the rate of formation of ozone. The influence of relative humidity on the abundance of allergens, pathogens, and noxious chemicals suggests that indoor relative humidity levels should be considered as a factor of indoor air quality. The majority of adverse health effects caused by relative humidity would be minimized by maintaining indoor levels between 40 and 60%. This would require humidification during winter in areas with cold winter climates. Humidification should preferably use evaporative or steam humidifiers, as cool mist humidifiers can disseminate aerosols contaminated with allergens.


Beyond the most willing audiences: a meta-intervention to increase exposure to HIV-prevention programs by vulnerable populations.
Enrollment in HIV-prevention interventions is more likely when the audience has safer rather than riskier HIV-relevant behavior. Thus, a meta-intervention was designed to increase participation by an audience of infrequent condom users in Florida. Participants (N = 400) were randomly assigned to 1 of 4 conditions varying the introduction to a counseling program. In the experimental condition, participants were told that the intervention gave participants options but might not change their behavior. In a standard-introduction condition, participants were told that the program was highly effective at changing participants' behaviors. There was also an information-control group containing a description of the program, and a no-information-control group solely containing an invitation. The outcome measure was actual participation in the offered counseling. Findings indicated that the experimental introduction was the most successful at yielding participation in the counseling program when the audience had low intentions to use condoms in the future. Intervention introductions countering participants' resistance to change increase participation in HIV-prevention counseling among reluctant clients. Other meta-interventions may be explored to systematically augment the effectiveness of evidence-based health-promotion interventions.


Increasing compliance with mass drug administration programs for lymphatic filariasis in India through education and lymphedema management programs.
Nearly 45% of people living at risk for lymphatic filariasis (LF) worldwide live in India. India has faced challenges obtaining the needed levels of compliance with its mass drug administration (MDA) program to interrupt LF transmission, which utilizes diethylcarbamazine (DEC) or DEC plus albendazole. Previously identified predictors of and barriers to compliance with the MDA program were used to refine a pre-MDA educational campaign. The objectives of this study were to assess the impact of these refinements and of a lymphedema morbidity management program on MDA compliance. A randomized, 30-cluster survey was performed in each of 3 areas: the community-based pre-MDA education plus community-based lymphedema management education (Com-MDA+LM) area, the community-based pre-MDA education (Com-MDA) area, and the Indian standard pre-MDA education (MDA-only) area. Compliance with the MDA program was 90.2% in Com-MDA+LM, 75.0% in Com-MDA, and 52.9% in the MDA-only areas (p<0.0001). Identified barriers to adherence included: 1) fear of side effects and 2) lack of recognition of one's personal benefit from adherence. Multivariable predictors of adherence amenable to educational intervention were: 1) knowing about the MDA in advance of its occurrence, 2) knowing everyone is at risk for LF, 3) knowing that the MDA was for LF, and 4) knowing at least one component of the lymphedema management techniques taught in the lymphedema management program. This study confirmed previously identified predictors of and barriers to compliance with India's MDA program for LF. More importantly, it showed that targeting these predictors and barriers in a timely and clear pre-MDA educational campaign can increase compliance with MDA programs, and it demonstrated, for the first time, that lymphedema management programs may also increase compliance with MDA programs.


Comparison between U-shaped structural deep learning models to detect landslide traces.
Landslides endanger lives and public infrastructure in mountainous areas. Monitoring landslide traces in real-time is difficult for scientists, sometimes costly and risky because of the harsh terrain and instability. Nowadays, modern technology may be able to identify landslide-prone locations and inform locals for hours or days when the weather worsens. This study aims to propose indicators to detect landslide traces on the fields and remote sensing images; build deep learning (DL) models to identify landslides from Sentinel-2 images automatically; and apply DL-trained models to detect this natural hazard in some particular areas of Vietnam. Nine DL models were trained based on three U-shaped architectures, including U-Net, U2-Net, and U-Net3+, and three options of input sizes. The multi-temporal Sentinel-2 images were chosen as input data for training all models. As a result, the U-Net, using an input image size of 32 × 32 and a performance of 97 % with a loss function of 0.01, can detect typical landslide traces in Vietnam. Meanwhile, the U-Net (64 × 64) can detect more considerable landslide traces. Based on multi-temporal remote sensing data, a different case study in Vietnam was chosen to see landslide traces over time based on the trained U-Net (32 × 32) model. The trained model allows mountain managers to track landslide occurrences during wet seasons. Thus, landslide incidents distant from residential areas may be discovered early to warn of flash floods.


Aplastic anemia and pure red cell aplasia associated with large granular lymphocyte leukemia.
Aplastic anemia (AA) and pure red cell aplasia (PRCA) are two of the various types of immune-mediated cytopenias that can be associated with large granular lymphocyte (LGL) leukemia. We review the experience on LGL leukemia-associated AA and PRCA in the published literature. In the setting of LGL leukemia, AA is found rarely, while PRCA is frequent. However, the diagnosis of LGL leukemia in the presence of pancytopenia is very challenging. In general, the clinical findings and treatment outcome are similar to the idiopathic or primary forms of AA and PRCA. Serial trials of immunosuppressive agents usually result in relatively durable remissions. In refractory cases, studies using newer immunosuppressive agents active against T cells and natural killer (NK) cells are necessary. There are many similarities in the currently known pathophysiologic mechanisms among these three disorders. As LGL leukemia is underdiagnosed, it is interesting to speculate that perhaps a significant proportion of idiopathic AA and PRCA may be, in fact, secondary to LGL leukemia.


Renin-angiotensin system inhibitors and risk of fractures: a prospective cohort study and meta-analysis of published observational cohort studies.
The renin-angiotensin system (RAS) represents an important target of antihypertensive medications. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), which are widely-used RAS inhibiting drugs, have been suggested to have beneficial effects on bone tissue. We aimed to assess the associations of use of ACEIs and/or ARBs with the risk of fractures using a population-based prospective cohort and a meta-analysis of published prospective cohort studies. Information on antihypertensive medication use (including both ACEIs and ARBs) were assessed in 1743 men and women of the Kuopio Ischemic Heart Disease prospective cohort study. Hazard ratios (HRs) [95% confidence intervals (CI)] of ACEIs or ARBs use with incident fractures were calculated. A total of 203 composite (hip, humeral, and wrist) fractures occurred during a median follow-up of 14.8 years. In multivariate adjusted analysis, the HR for composite fractures comparing users of ACEIs or ARBs with non-users was 1.00 (0.59-1.69). The corresponding adjusted HR for hip fractures comparing users versus non-users of ACEIs or ARBs was 0.89 (0.32-2.47). Including the current study, a total of 11 observational cohort studies involving 3526,319 participants and >323,355 fractures were included in a meta-analysis. Comparing ACEI users with non-users and ARB users with non-users, the HRs for composite fractures were 1.09 (0.89-1.33) and 0.87 (0.76-1.01) respectively. The corresponding HRs for hip fractures were 0.91 (0.86-0.95) and 0.80 (0.75-0.85) respectively. Use of RAS inhibitors was not associated with long-term risk of composite fractures in both primary and pooled analyses. Pooled evidence however suggests a beneficial effect of RAS blockers on hip fracture risk.


Color-complexity enabled exhaustive color-dots identification and spatial patterns testing in images.
Our computational developments and analyses on experimental images are designed to evaluate the effectiveness of chemical spraying via unmanned aerial vehicle (UAV). Our evaluations are in accord with the two perspectives of color-complexity: color variety within a color system and color distributional geometry on an image. First, by working within RGB and HSV color systems, we develop a new color-identification algorithm relying on highly associative relations among three color-coordinates to lead us to exhaustively identify all targeted color-pixels. A color-dot is then identified as one isolated network of connected color-pixel. All identified color-dots vary in shapes and sizes within each image. Such a pixel-based computing algorithm is shown robustly and efficiently accommodating heterogeneity due to shaded regions and lighting conditions. Secondly, all color-dots with varying sizes are categorized into three categories. Since the number of small color-dot is rather large, we spatially divide the entire image into a 2D lattice of rectangular. As such, each rectangle becomes a collective of color-dots of various sizes and is classified with respect to its color-dots intensity. We progressively construct a series of minimum spanning trees (MST) as multiscale 2D distributional spatial geometries in a decreasing-intensity fashion. We extract the distributions of distances among connected rectangle-nodes in the observed MST and simulated MSTs generated under the spatial uniformness assumption. We devise a new algorithm for testing 2D spatial uniformness based on a Hierarchical clustering tree upon all involving MSTs. This new tree-based p-value evaluation has the capacity to become exact.


Germ Line Mutations in the Thyroid Hormone Receptor Alpha Gene Predispose to Cutaneous Tags and Melanocytic Nevi.
Background: Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor α and β [TRα and TRβ]) to regulate transcription of target genes. Heterozygous dominant negative mutations in human TRα mediate resistance to thyroid hormone alpha (RTHα), characterized by features of hypothyroidism (e.g., skeletal dysplasia, neurodevelopmental retardation, constipation) in specific tissues, but near-normal circulating TH concentrations. Hitherto, 41 RTHα cases have been recorded worldwide. Methods: RTHα cases (n = 10) attending a single center underwent cutaneous assessment, recording skin lesions. Lesions excised from different RTHα patients were analyzed histologically and profiled for cellular markers of proliferation and oncogenic potential. Proliferative characteristics of dermal fibroblasts and inducible pluripotent stem cell (iPSC)-derived keratinocytes from patients and control subjects were analyzed. Results: Multiple skin tags and nevi were recorded in all cases, mainly in the head and neck area with a predilection for flexures. The affected patients had highly deleterious mutations (p.E403X, p.E403K, p.F397fs406X, p.A382PfsX7) involving TRα1 alone or mild/moderate loss-of-function mutations (p.A263V, p.L274P) common to TRα1 and TRα2 isoforms. In four patients, although lesions excised for cosmetic reasons were benign intradermal melanocytic nevi histologically, they significantly overexpressed markers of cell proliferation (K17, cyclin D1) and type 3 deiodinase. In addition, oncogenic markers typical of basal cell carcinoma (Gli-1, Gli-2, Ptch-1, n = 2 cases) and melanoma (c-kit, MAGE, CDK4, n = 1) were markedly upregulated in skin lesions. Cell cycle progression and proliferation of TRα mutation-containing dermal fibroblasts and iPSC-derived keratinocytes from patients were markedly increased. Conclusions: Our observations highlight frequent occurrence of skin tags and benign melanocytic nevi in RTHα, with cutaneous cells from patients being in a hyperproliferative state. Such excess of skin lesions, including nevi expressing oncogenic markers, indicates that dermatologic surveillance of RTHα patients, monitoring lesions for features that are suspicious for neoplastic change, is warranted.


Altered cognitive control network mediates the association between long-term pain and anxiety symptoms in primary dysmenorrhea.
Neuroimaging studies have demonstrated the association of the cognitive control network (CCN) with the maintenance of chronic pain. However, whether and how dorsolateral prefrontal cortex (DLPFC), a key region within the CCN, is altered in menstrual pain is unclear. In this study, we aimed to investigate alterations in the DLPFC functional connectivity network in patients with primary dysmenorrhea (PDM). The study comprised 41 PDM patients and 39 matched healthy controls (HCs), all of whom underwent a resting-state functional MRI scan during the menstrual stage. All participants were instructed to complete the clinical assessment before the MRI scan. We used the DLPFC as the seed in resting-state functional connectivity (rsFC) analysis to investigate the difference between PDM patients and HCs. Compared to HCs, PDM patients showed increased right DLPFC rsFC at the bilateral lingual gyrus, dorsal anterior cingulate cortex (dACC), and middle cingulate cortex, and decreased left DLPFC rsFC at the right orbital frontal cortex. In addition, increased right DLPFC-bilateral dACC connectivity mediated the association between disease duration and the self-rating anxiety scale (SAS) scores in PDM patients. We confirmed that the DLPFC-dACC rsFC was associated with higher SAS scores, which could mediate the association between disease duration and anxiety symptoms in patients with PDM. Our findings provide central pathological evidence for an abnormal rsFC of the CCN in PDM patients, which may contribute to a better understanding of the neuropathophysiological mechanisms underlying PDM.


A porcine beating heart model for robotic coronary artery surgery.
The application of robotically assisted coronary artery surgery continues to be investigated clinically. Consequently, there is a need for a simple method to train surgeons in performing these operations. The aim of the present study was to assess a model using an excised porcine heart for the training of surgeons in creating a robotically assisted arterial anastomosis. An ex vivo beating heart model was constructed with a porcine heart and was evaluated by 3 cardiac surgeons previously trained in robotic surgery. All anastomoses from the first half of the study were reviewed to measure anastomotic time, the number of sutures placed, and the rate of suture placement per minute and were compared to those completed in the second half of the study by means of a unpaired Student t test. Fifty-seven anastomoses were completed with the beating heart model, 28 in the first half of the study and 29 in the second half. The mean time to create an anastomosis in the first half of the study was 19.3 minutes (range, 10-28 minutes), compared with 15.0 minutes (range, 7-20 minutes) in the second half; the difference did not meet statistical significance. However, the number of sutures placed per minute did increase in the second half of the study with a mean of 0.77 sutures per minute (range, 0.55-1.25), compared with 0.56 sutures per minute (range, 0.40-0.80) in the first half of the study (P <.0001). The number of sutures per anastomosis also decreased in the second half of the study with a mean of 9.0 sutures (range, 8-11), compared with 10.6 sutures (range, 8-16) in the first half of the study (P =.0049). This preliminary experience demonstrated technical improvements in the second half of the study. Fewer sutures were placed per anastomosis with better precision, implying a learning curve that could be accelerated with our model. This porcine beating heart model represents an inexpensive training method that mimics the beating heart, complete with coronary blood flow, and may be used multiple times to train and assess a surgeon's skill in robotically assisted coronary surgery.


A cell wall-bound adenosine nucleosidase is involved in the salvage of extracellular ATP in Solanum tuberosum.
Extracellular ATP (eATP) has recently been demonstrated to play a crucial role in plant development and growth. To investigate the fate of eATP within the apoplast, we used intact potato (Solanum tuberosum) tuber slices as an experimental system enabling access to the apoplast without interference of cytosolic contamination. (i) Incubation of intact tuber slices with ATP led to the formation of ADP, AMP, adenosine, adenine and ribose, indicating operation of apyrase, 5'-nucleotidase and nucleosidase. (ii) Measurement of apyrase, 5'-nucleotidase and nucleosidase activities in fractionated tuber tissue confirmed the apoplastic localization for apyrase and phosphatase in potato and led to the identification of a novel cell wall-bound adenosine nucleosidase activity. (iii) When intact tuber slices were incubated with saturating concentrations of adenosine, the conversion of adenosine into adenine was much higher than adenosine import into the cell, suggesting a potential bypass of adenosine import. Consistent with this, import of radiolabeled adenine into tuber slices was inhibited when ATP, ADP or AMP were added to the slices. (iv) In wild-type plants, apyrase and adenosine nucleosidase activities were found to be co-regulated, indicating functional linkage of these enzymes in a shared pathway. (v) Moreover, adenosine nucleosidase activity was reduced in transgenic lines with strongly reduced apoplastic apyrase activity. When taken together, these results suggest that a complete ATP salvage pathway is present in the apoplast of plant cells.


In search of an effective treatment for recurrent mesangiocapillary glomerulonephritis in the renal allograft.
In patients with end-stage kidney disease (ESKD) secondary to mesangiocapillary glomerulonephritis (MCGN), recurrent disease post transplantation is a common cause of graft loss. We report a case of a 33-year-old female with ESKD due to idiopathic MCGN who developed recurrent disease in two consecutive renal allografts. Recurrent disease was diagnosed two months after receiving her primary transplant from a live related donor. Oral cyclophosphamide was initiated but discontinued after 10 months due to cystitis. This was followed by rapid deterioration in her renal function. Despite salvage therapy with rituximab, the graft was lost 2 years post transplantation. After 7 years on haemodialysis, the patient received a second graft from a deceased donor. Recurrent MCGN was once again diagnosed one year post transplantation. She was treated with plasma exchange and rituximab. Despite ongoing nephrotic range proteinuria, her graft function remained stable 2 years post transplantation. The optimal therapy for recurrent MCGN is unknown at this stage. It is hoped that a better understanding of its pathogenesis will enable the development of more effective and targeted therapies.


A chronometric exploration of high-resolution 'sensitive TMS masking' effects on subjective and objective measures of vision.
Transcranial magnetic stimulation (TMS) can induce masking by interfering with ongoing neural activity in early visual cortex. Previous work has explored the chronometry of occipital involvement in vision by using single pulses of TMS with high temporal resolution. However, conventionally TMS intensities have been high and the only measure used to evaluate masking was objective in nature. Recent studies have begun to incorporate subjective measures of vision, alongside objective ones. The current study goes beyond previous work in two regards. First, we explored both objective vision (an orientation discrimination task) and subjective vision (a stimulus visibility rating on a four-point scale), across a wide range of time windows with high temporal resolution. Second, we used a very sensitive TMS-masking paradigm: stimulation was at relatively low TMS intensities, with a figure-8 coil, and the small stimulus was difficult to discriminate already at baseline level. We hypothesized that this should increase the effective temporal resolution of our paradigm. Perhaps for this reason, we are able to report a rather interesting masking curve. Within the classical-masking time window, previously reported to encompass broad SOAs anywhere between 60 and 120 ms, we report not one, but at least two dips in objective performance, with no masking in-between. The subjective measure of vision did not mirror this pattern. These preliminary data from our exploratory design suggest that, with sensitive TMS masking, we might be able to reveal visual processes in early visual cortex previously unreported.


The inheritance of a Mesozoic landscape in western Scandinavia.
In-situ weathered bedrock, saprolite, is locally found in Scandinavia, where it is commonly thought to represent pre-Pleistocene weathering possibly associated with landscape formation. The age of weathering, however, remains loosely constrained, which has an impact on existing geological and landscape evolution models and morphotectonic correlations. Here we provide new geochronological evidence that some of the low-altitude basement landforms on- and offshore southwestern Scandinavia are a rejuvenated geomorphological relic from Mesozoic times. K-Ar dating of authigenic, syn-weathering illite from saprolitic remnants constrains original basement exposure in the Late Triassic (221.3±7.0-206.2±4.2 Ma) through deep weathering in a warm climate and subsequent partial mobilization of the saprolitic mantle into the overlying sediment cascade system. The data support the bulk geomorphological development of west Scandinavia coastal basement rocks during the Mesozoic and later, long-lasting relative tectonic stability. Pleistocene glaciations played an additional geomorphological role, selectively stripping the landscape from the Mesozoic overburden and carving glacial landforms down to Plio-Pleistocene times. Saprolite K-Ar dating offers unprecedented possibilities to study past weathering and landscape evolution processes.


Unilateral ureteral obstruction increases glomerular soluble guanylyl cyclase activity.
RBF and GFR are decreased in kidneys after ipsilateral unilateral ureteral obstruction (UUO) for 24 h. Despite net vasoconstriction, vasodilatory mechanisms respond to counterbalance the vasoconstriction: the inhibition of nitric oxide synthase activity is associated with a greater reduction in RBF with ipsilateral UUO. To determine whether the stimulation of soluble guanylyl cyclase differs between glomeruli from obstructed kidneys and normal kidneys, cGMP was measured after stimulation by 10(-3) M sodium nitroprusside (SNP) in glomeruli isolated from the kidneys of Sprague-Dawley rats after 24 h of UUO or sham operation. The generation of intracellular and extracellular (EC) cGMP (femtomoles of cGMP/100 glomeruli/per hour) was measured by RIA. After incubation with SNP, the EC accumulation of cGMP by UUO glomeruli was significantly greater than that by glomeruli from sham-operated rats (P < 0.05). When glomerular studies were repeated in the presence of the phosphodiesterase inhibitor isobutyl methylxanthine, there was no difference in the EC accumulation of cGMP. The direct measurement of cGMP hydrolysis by phosphodiesterase was significantly less in glomerular homogenate from UUO rats compared with sham-operated rats (P < 0.05). When 10(-5) M losartan, an angiotensin II receptor inhibitor, was included in glomerular incubations, there was a significant decrease in the EC glomerular cGMP response to SNP in UUO glomeruli (P < 0.05). This attenuated response was abolished by the addition of isobutyl methylxanthine. The addition of angiotensin II did not alter the accumulation of cGMP by UUO or sham glomeruli. These studies indicate that decreased phosphodiesterase activity in UUO glomeruli contributes to the enhanced accumulation of EC glomerular cGMP after the stimulation of soluble guanylyl cyclase by SNP. In addition, angiotensin II receptors modulate this response, suggesting a role for soluble guanylyl cyclase in countering angiotensin-mediated vasoconstriction due to UUO.


Unfolded protein response in hypothalamic cultures of wild-type and ATF6α-knockout mice.
Recent studies suggest that endoplasmic reticulum (ER) stress in the hypothalamus could affect systemic homeostatic regulation in areas such as energy and water balance. Activating transcription factor 6α (ATF6α) is an ER stress transducer which increases the expression of ER chaperones and ER-associated degradation (ERAD) components under ER stress. In the present study, we examined the regulation of the unfolding protein response (UPR) in mouse hypothalamic cultures of wild-type (WT) and ATF6α(-/-) mice. Thapsigargin (TG), an ER stressor, significantly increased the mRNA expression of immunoglobulin heavy chain binding protein (BiP), spliced X-box binding protein 1 (XBP1), activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), and ERAD components, in hypothalamic cultures of WT mice with the same threshold (0.1μM) and similar time courses. On the other hand, TG-induced upregulation of BiP and CHOP as well as most ERAD-related genes, but not spliced XBP1 or ATF4, was attenuated in ATF6α(-/-) mice compared with WT mice. Our data suggest that all the UPR arms are activated similarly in the mouse hypothalamus under ER stress conditions, where ATF6α regulates the expression of ER chaperones, CHOP, and ERAD components.


Bias due to participant overlap in two-sample Mendelian randomization.
Mendelian randomization analyses are often performed using summarized data. The causal estimate from a one-sample analysis (in which data are taken from a single data source) with weak instrumental variables is biased in the direction of the observational association between the risk factor and outcome, whereas the estimate from a two-sample analysis (in which data on the risk factor and outcome are taken from non-overlapping datasets) is less biased and any bias is in the direction of the null. When using genetic consortia that have partially overlapping sets of participants, the direction and extent of bias are uncertain. In this paper, we perform simulation studies to investigate the magnitude of bias and Type 1 error rate inflation arising from sample overlap. We consider both a continuous outcome and a case-control setting with a binary outcome. For a continuous outcome, bias due to sample overlap is a linear function of the proportion of overlap between the samples. So, in the case of a null causal effect, if the relative bias of the one-sample instrumental variable estimate is 10% (corresponding to an F parameter of 10), then the relative bias with 50% sample overlap is 5%, and with 30% sample overlap is 3%. In a case-control setting, if risk factor measurements are only included for the control participants, unbiased estimates are obtained even in a one-sample setting. However, if risk factor data on both control and case participants are used, then bias is similar with a binary outcome as with a continuous outcome. Consortia releasing publicly available data on the associations of genetic variants with continuous risk factors should provide estimates that exclude case participants from case-control samples.


Tissue factor pathway inhibitor primes monocytes for antiphospholipid antibody-induced thrombosis.
Antiphospholipid antibodies (aPLs) with complex lipid and/or protein reactivities cause complement-dependent thrombosis and pregnancy complications. Although cross-reactivities with coagulation regulatory proteins contribute to the risk for developing thrombosis in patients with antiphospholipid syndrome, the majority of pathogenic aPLs retain reactivity with membrane lipid components and rapidly induce reactive oxygen species-dependent proinflammatory signaling and tissue factor (TF) procoagulant activation. Here, we show that lipid-reactive aPLs activate a common species-conserved TF signaling pathway. aPLs dissociate an inhibited TF coagulation initiation complex on the cell surface of monocytes, thereby liberating factor Xa for thrombin generation and protease activated receptor 1/2 heterodimer signaling. In addition to proteolytic signaling, aPLs promote complement- and protein disulfide isomerase-dependent TF-integrin β1 trafficking that translocates aPLs and NADPH oxidase to the endosome. Cell surface TF pathway inhibitor (TFPI) synthesized by monocytes is required for TF inhibition, and disabling TFPI prevents aPL signaling, indicating a paradoxical prothrombotic role for TFPI. Myeloid cell-specific TFPI inactivation has no effect on models of arterial or venous thrombus development, but remarkably prevents experimental aPL-induced thrombosis in mice. Thus, the physiological control of TF primes monocytes for rapid aPL pathogenic signaling and thrombosis amplification in an unexpected crosstalk between complement activation and coagulation signaling.


Univariate and multivariate analyses of functional networks in absolute pitch.
Absolute pitch (AP) refers to the rare ability to identify the pitch of any given tone without an external reference tone. Previous studies have shown that during auditory processing, AP musicians activate the auditory cortex (AC), the prefrontal cortex (PFC), and parietal areas of the brain. Therefore, it has been hypothesized that AP is sustained by a widespread functional network. In the present functional magnetic resonance imaging (fMRI) study, we tested this hypothesis by employing a mass-univariate analysis of resting-state functional connectivity within the AC, the PFC, and parietal areas in a large sample of musicians with and without AP (N = 100). AP musicians showed increased functional connectivity in the left middle frontal gyrus (MFG), left intraparietal sulcus (IPS), and right superior parietal lobule (SPL). These results provide the first evidence for an AP-specific network characterized by increased functional connections in higher-order cognitive areas. Interestingly, AP was not associated with increases in functional connectivity of the AC, but AP was successfully decoded from functional connectivity patterns in the left AC using multi-voxel pattern analysis (MVPA, also known as multivariate pattern analysis), with group classification accuracy being highest for the left Heschl's gyrus (HG). MVPA can capture fine-grained patterns in the brain connectivity profile of AP musicians, whilst a mass-univariate analysis is sensitive to macroscopic trends in the data. The successful differentiation of AP musicians by MVPA but not by a mass-univariate analysis of connectivity in the AC thus indicates that AP musicians differ in the fine-grained rather than the macroscopic AC function. Based on our findings, and in light of current literature, we propose pitch-label associations, tonal working memory, pitch categorization, and multimodal integration as potential mechanisms underlying the AP ability. This set of psychological functions is controlled by a distributed functional network and a particular AC connectivity pattern only present in AP musicians.


Perforator-to-perforator musculocutaneous anterolateral thigh flap for reconstruction of a lumbosacral defect using the lumbar artery perforator as recipient vessel.
Reconstruction of large-sized lumbosacral or sacral defects often is not possible using local or regional flaps, making the use of free flaps necessary. However, the difficulty of any microsurgical procedure in this region is complicated by the need to search for potential recipient vessels to revascularize the flap. In the present case, a free musculocutaneous anterolateral thigh flap to cover a large-sized and deep lumbosacral defect was used. Arterial anastomosis was performed, connecting the cutaneous anterolateral thigh (ALT) perforator to the perforator of the second lumbar artery. In this fashion, the arterial circulation through the flap was flowing reversely through the muscle. The concomitant vein of the descending branch of the lateral circumflex femoral artery was hooked up to the thoracodorsal vein using a long interposition vein graft because the perforator of the second lumbar vein was too small. Postoperative healing was uneventful. In conclusion, a successful reconstruction of a lumbar defect has shown that local perforators in the lumbar area may be accessible for easier perforator-to-perforator anastomoses and that the muscular part of the musculocutaneous ALT flap can survive on retrograde arterial perfusion from a perforator of the skin island.


Long-term outcome of endoscopic dual pancreatobiliary sphincterotomy in patients with manometry-documented sphincter of Oddi dysfunction and normal pancreatogram.
For patients with sphincter of Oddi dysfunction and abnormal pancreatic basal sphincter pressure, additional pancreatic sphincterotomy has been recommended. The outcome of endoscopic dual pancreatobiliary sphincterotomy in patients with manometry-documented sphincter of Oddi dysfunction was evaluated. An ERCP database was searched for data entered from January 1995 to November 2000 on patients with sphincter of Oddi dysfunction who met the following parameters: sphincter of Oddi manometry of both ducts, abnormal pressure for at least 1 sphincter (> or =40 mm Hg), no evidence of chronic pancreatitis, and endoscopic dual pancreatobiliary sphincterotomy. Patients were offered reintervention by repeat ERCP if clinical symptoms were not improved. The frequency of reintervention was analyzed according to ducts with abnormal basal sphincter pressure, previous cholecystectomy, sphincter of Oddi dysfunction type, and endoscopic dual pancreatobiliary sphincterotomy method. A total of 313 patients were followed for a mean of 43.1 months (median, 41.0 months; interquartile range: 29.8-60.0 months). Immediate postendoscopic dual pancreatobiliary sphincterotomy complications occurred in 15% of patients. Reintervention was required in 24.6% of patients at a median follow-up (interquartile range) of 8.0 (5.5-22.5) months. The frequency of reintervention was similar irrespective of ducts with abnormal basal sphincter pressure, previous cholecystectomy, or endoscopic dual pancreatobiliary sphincterotomy method. Of patients with type III sphincter of Oddi dysfunction, 28.3% underwent reintervention compared with 20.4% with combined types I and II sphincter of Oddi dysfunction (p = 0.105). When compared with endoscopic biliary sphincterotomy alone in historical control patients from our unit, endoscopic dual pancreatobiliary sphincterotomy had a lower reintervention rate in patients with pancreatic sphincter of Oddi dysfuntion alone and a comparable outcome in those with sphincter of Oddi dysfunction of both ducts. Endoscopic dual pancreatobiliary sphincterotomy is useful in patients with pancreatic sphincter of Oddi dysfunction. Prospective randomized trials of endoscopic biliary sphincterotomy alone versus endoscopic dual pancreatobiliary sphincterotomy based on sphincter of Oddi manometry findings are in progress.


GM1485, a nonimmunosuppressive immunophilin ligand, promotes neurofunctional improvement and neural regeneration following stroke.
Stroke is the leading cause of disability in the industrialized world, and the development of pharmacologic strategies to promote poststroke recovery is of paramount importance. GM1485, a nonimmunosuppressive immunophilin ligand, promotes regeneration of multiple cell types following injury. In the present study, we evaluated the effect of GM1485 treatment on functional recovery and neurogenesis following rat stroke. Transient cerebral ischemia was induced in rats receiving daily GM1485 (5 mg/kg) beginning 24 hr postischemia and continuing for a total of 6 weeks. Neurological function was evaluated over this period using a battery of neurobehavioral tests, and immunostaining for stem-cell markers was performed following animal sacrifice. An in vitro model of oxidative stress was also employed to evaluate the ability of GM1485 to mediate stem-cell-like induction and plasticity. GM1485-treated rats demonstrated improved neurological function as well as increased Sox2(+) cells in the ipsilateral SVZ and striatum relative to vehicle-treated rats. Additionally, GM1485-treated fibroblasts subjected to oxidative stress were reprogrammed to a stem-cell-like phenotype and were able to differentiate down a neuronal lineage. These data demonstrate that GM1485 administration improves neurological function and is consistent with an upregulation of endogenous neurogenesis following stroke in rats. Further experiments are necessary to characterize the molecular pathways involved in these processes.


Single dose cabergoline versus bromocriptine in inhibition of puerperal lactation: randomised, double blind, multicentre study. European Multicentre Study Group for Cabergoline in Lactation Inhibition.
To compare the efficacy and safety of a single dose of 1 mg of cabergoline with that of bromocriptine 2.5 mg twice daily for 14 days in the inhibition of puerperal lactation. Prospective, randomised, double blind, parallel group, multicentre study. University of hospital departments of obstetrics and gynaecology in different European countries. 272 puerperal women not wishing to lactate (136 randomised to each drug). Women randomised to cabergoline received two 0.5 mg tablets of cabergoline and one placebo tablet within 27 hours after delivery and then placebo twice daily for 14 days. Those randomised to bromocriptine received 2.5 mg of bromocriptine and two placebo tablets within 27 hours and then 2.5 mg of bromocriptine twice daily for 14 days. Success of treatment (complete or partial) according to milk secretion, breast engorgement, and breast pain; rebound symptomatology; serum prolactin concentrations; and number of adverse events. Complete success was achieved in 106 of 136 women randomised to cabergoline and in 94 of 136 randomised to bromocriptine and partial success in 21 and 33 women respectively. Rebound breast symptomatology occurred respectively in five and 23 women with complete success up to day 15 (p less than 0.0001). Serum prolactin concentrations dropped considerably with both drugs from day 2 to day 15; a prolactin secretion rebound effect was observed in women treated with bromocriptine. cabergoline and 36 receiving bromocriptine (p = 0.054), occurring most during the first treatment day. A single 1 mg dose of cabergoline is at least as effective as bromocriptine 2.5 mg twice daily for 14 days in preventing puerperal lactation. Because of the considerably lower rate of rebound breast activity and adverse events and the simpler administration schedule cabergoline should be the drug of choice for lactation inhibition.


[Postoperative disease: evolution of the concept].
Leriche's La Maladie post-opératoire was described in 1934 as a specific and general reaction to surgery whose systemic symptoms could'nt be understood by the clinical appraisal alone. A laboratory analysis would be necessary. According to Leriche the syndrome could be observed also on other non-surgical trauma. Leriche's concept was ignored by the anglo-saxonic literature but a new scientific approach to the same problem came from Harvard. Walter Cannon with his concept of homeostasis and Henderson, Gamble, Peters and Van Slyke with their definition of the chemical anatomy of the organic fluids and their quantitative analysis, opened the way to Francis Moore's concept of surgery and trauma as metabolic problems. This new biological basis, and the broad enlargement of its spectrum to the whole body, gave a new scope to the surgical practice. Surgery must now be considered as an integrated process, a succession of phenomena defined as pre-operative, per-operative and post-operative representing, nevertheless, a true continuity. To its understanding the post-operative phase cannot be separated from the other phases. La maladie post-opératoire cannot be defined as an unity: there are several post-operative diseases. But the surgical patient must be considered always in the totality of his elements: the somatic or anatomical, the metabolic or physiological and the psychic, forming a complete unity. A global vision versus the old local vision of surgery. This enlarged concept of surgery enables the surgeon to have an intellectual approach similar to that of the physiologist.


Testing the Price of Healthy and Current Diets in Remote Aboriginal Communities to Improve Food Security: Development of the Aboriginal and Torres Strait Islander Healthy Diets ASAP (Australian Standardised Affordability and Pricing) Methods.
Aboriginal and Torres Strait Islander peoples suffer higher rates of food insecurity and diet-related disease than other Australians. However, assessment of food insecurity in specific population groups is sub-optimal, as in many developed countries. This study tailors the Healthy Diets ASAP (Australian Standardised Affordability and Pricing) methods protocol to be more relevant to Indigenous groups in assessing one important component of food security. The resultant Aboriginal and Torres Strait Islander Healthy Diets ASAP methods were used to assess the price, price differential, and affordability of healthy (recommended) and current (unhealthy) diets in five remote Aboriginal communities. The results show that the tailored approach is more sensitive than the original protocol in revealing the high degree of food insecurity in these communities, where the current diet costs nearly 50% of disposable household income compared to the international benchmark of 30%. Sixty-two percent of the current food budget appears to be spent on discretionary foods and drinks. Aided by community store pricing policies, healthy (recommended) diets are around 20% more affordable than current diets in these communities, but at 38.7% of disposable household income still unaffordable for most households. Further studies in urban communities, and on other socioeconomic, political and commercial determinants of food security in Aboriginal and Torres Strait Islander communities appear warranted. The development of the tailored method provides an example of how national tools can be adapted to better inform policy actions to improve food security and help reduce rates of diet-related chronic disease more equitably in developed countries.


[Peculiarities of human lung prenatal morphogenesis at the first trimester of pregnancy in different periods after Chernobyl accident].
The comparative histological and morphometric analysis of the bronchial structures of human fetal lungs was performed. Fetal lungs were taken from pregnant women living in radionuclide polluted zones (Novozibcov, Bryansk region) or in control regions (Moscow) in different periods after Chernobyl accident. Relative areas of the bronchial epithelial tubes and mesenchyme, quantity of bronchial branches and buds (end sections) of epithelial tubes on cut area unit were determined. The dates received in 1992-1993 showed the delay of fetal bronchial growth and branching in comparison with control. It can be estimated as tissue dysplasia of lungs from fetuses of mothers living in Novozibcov. The material received in 1995 showed the more intensive growth of bronchial branches in human fetal lungs than the material from Novozibcov and of the Moscow control, taken in 1992-1993. These date suggest the heterogenous character of lung prenatal morphogenesis reactions of offspring from pregnant women lived in different periods on controllable territories of Bryansk region.


BAILAMOS With mHealth Technology! Improving Physical Activity and Well-Being in Middle-Aged and Older Latinxs: A Pre-Post Feasibility Study.
Older Latinxs engage in lower levels of leisure-time physical activity (PA) compared with non-Latinx Whites. Latin dance is a culturally relevant type of leisure-time PA that may engage older Latinx populations, particularly when coupled with mobile health technologies (mHealth). This single group pre-post feasibility study described the PA and health outcomes of middle-aged and older Latinxs participating in BAILA TECH-an intervention that combines the BAILAMOS Latin dance program with mHealth (Fitbit Charge 2, Fitbit app, and motivational text messages). Participants (n = 20, Mage = 67 ± 7.1, female n = 15, 75%) were enrolled in the 16-week BAILA TECH intervention held twice a week. Participants received a Fitbit Charge 2 to assess PA at baseline, during the intervention, and postintervention. An mHealth platform (iCardia) collected Fitbit data and staff delivered weekly motivational and informational text messages. Participants completed questionnaires about PA, sedentary behavior, cardiorespiratory fitness, social support, quality of life, and cognitive function at baseline and postintervention. Paired t tests evaluated change in pre-post measures. There was a significant increase in device-assessed moderate-to-vigorous PA (d = 0.69), self-reported light-leisure (d = 1.91) and moderate-to-vigorous PA (d = 1.05), moderate-to-vigorous leisure PA (d = 1.55), predicted cardiorespiratory fitness (d = 1.10), and PA social support (d = 0.81 [family]; d = 0.95 [friends]) from baseline to postintervention. Although nonsignificant, there was a small effect on physical health-related quality of life (d = 0.32) and executive function (d = 0.29). These data describe an increase in PA levels and health-related outcomes of middle-aged and older Latinxs from participation in an mHealth-infused Latin dance intervention. An adequately powered trial is necessary to establish efficacy.


Accurate and precise measurement of oxygen isotopic fractions and diffusion profiles by selective attenuation of secondary ions (SASI).
The accuracy and precision of isotopic analysis in Time-of-Flight secondary ion mass spectrometry (ToF-SIMS) relies on the appropriate reduction of the dead-time and detector saturation effects, especially when analyzing species with high ion yields or present in high concentrations. Conventional approaches to avoid these problems are based on Poisson dead-time correction and/or an overall decrease of the total secondary ion intensity by reducing the target current. This ultimately leads to poor detection limits for the minor isotopes and high uncertainties of the measured isotopic ratios. An alternative strategy consists of the attenuation of those specific secondary ions that saturate the detector, providing an effective extension of the linear dynamic range. In this work, the selective attenuation of secondary ion signals (SASI) approach is applied to the study of oxygen transport properties in electroceramic materials by isotopic labeling with stable (18)O tracer and ToF-SIMS depth profiling. The better analytical performance in terms of accuracy and precision allowed a more reliable determination of the oxygen surface exchange and diffusion coefficients while maintaining good mass resolution and limits of detection for other minor secondary ion species. This improvement is especially relevant to understand the ionic transport mechanisms and properties of solid materials, such as the parallel diffusion pathways (e.g., oxygen diffusion through bulk, grain boundary, or dislocations) in electroceramic materials with relevant applications in energy storage and conversion devices.


The expression of interleukin-25 increases in human coronary artery disease and is associated with the severity of coronary stenosis.
Interleukin (IL) 25, also known as IL-17E, is an inflammatory cytokine and has been demonstrated to be closely related to cardiovascular diseases by regulating immunity and inflammation, including atherosclerosis. This study was aimed to evaluate the expression of IL-25 in patients with coronary artery disease (CAD). In this study, the expression of IL-25 in normal (n=6) and atherosclerotic (n=10) human coronary arteries was detected by immunofluorescent staining. In addition, the serum IL-25, IL-6, and tumor necrosis factor (TNF) α concentrations in stable angina pectoris (SAP, n=44), unstable angina pectoris (UAP, n=46), acute myocardial infarction (AMI, n=34), and non-CAD (control, n=36) were measured using enzyme-linked immunosorbent assay (ELISA) kits. IL-25 was significantly increased in coronary arteries of CAD patients when compared with normal coronary arteries, with macrophages and T lymphocytes being the sources of IL-25, especially macrophages. Moreover, the serum concentrations of IL-25 were markedly elevated in CAD patients and gradually increased in SAP, UAP, and AMI groups. In addition, IL-25 levels were positively correlated with the IL-6 and TNF-α levels, and Gensini score in CAD patients. Logistic regression analysis showed that IL-25 was independently positively correlated with the occurrence of acute coronary syndrome (ACS). A receiver operator characteristic curve suggested that IL-25 presented a significant diagnosis value in ACS. IL-25 is increased in the coronary arteries and serum of CAD patients and is associated with the severity of coronary stenosis and the occurrence of ACS, suggesting that IL-25 may be one of the biomarkers of ACS.


Influences of manganese on pubertal development.
The onset of puberty is the result of complex neuroendocrine interactions within hypothalamic region of the brain, as well as from genetic and environmental influences. These interactions ultimately result in the increased synthesis and release of luteinizing hormone-releasing hormone (LHRH). Manganese (Mn) is an essential environmental element known for years to be involved in numerous mammalian physiological processes, including growth and reproductive function. Studies in recent years have shown the ability of Mn to cross the blood-brain barrier and act within the hypothalamus to influence the timing of puberty. This review will depict research showing the molecular and physiological actions of Mn in the control of prepubertal LHRH and discuss the potential for the element to cause either helpful or harmful outcomes on the developmental process depending upon the age and accumulation of Mn within the hypothalamus.


Quantification of hepatic iron concentration in chronic viral hepatitis: usefulness of T2-weighted single-shot spin-echo echo-planar MR imaging.
To investigate the usefulness of single-shot spin-echo echo-planar imaging (SSEPI) sequence for quantifying mild degree of hepatic iron stores in patients with viral hepatitis. This retrospective study included 34 patients with chronic viral hepatitis/cirrhosis who had undergone histological investigation and magnetic resonance imaging with T2-weighted gradient-recalled echo sequence (T2-GRE) and diffusion-weighted SSEPI sequence with b-factors of 0 s/mm(2) (T2-EPI), 500 s/mm(2) (DW-EPI-500), and 1000 s/mm(2) (DW-EPI-1000). The correlation between the liver-to-muscle signal intensity ratio, which was generated by regions of interest placed in the liver and paraspinous muscles of each sequence image, and the hepatic iron concentration (µmol/g dry liver), which was assessed by spectrophotometry, was analyzed by linear regression using a spline model. Akaike information criterion (AIC) was used to select the optimal model. Mean ± standard deviation of the hepatic iron concentration quantified by spectrophotometry was 24.6 ± 16.4 (range, 5.5 to 83.2) µmol/g dry liver. DW-EPI correlated more closely with hepatic iron concentration than T2-GRE (R square values: 0.75 for T2-EPI, 0.69 for DW-EPI-500, 0.62 for DW-EPI-1000, and 0.61 for T2-GRE, respectively, all P<0.0001). Using the AIC, the regression model for T2-EPI generated by spline model was optimal because of lowest cross validation error. T2-EPI was sensitive to hepatic iron, and might be a more useful sequence for quantifying mild degree of hepatic iron stores in patients with chronic viral hepatitis.


ICNIRP Statement on Diagnostic Devices Using Non-ionizing Radiation: Existing Regulations and Potential Health Risks.
Use of non-ionizing radiation (NIR) for diagnostic purposes allows non-invasive assessment of the structure and function of the human body and is widely employed in medical care. ICNIRP has published previous statements about the protection of patients during medical magnetic resonance imaging (MRI), but diagnostic methods using other forms of NIR have not been considered. This statement reviews the range of diagnostic NIR devices currently used in clinical settings; documents the relevant regulations and policies covering patients and health care workers; reviews the evidence around potential health risks to patients and health care workers exposed to diagnostic NIR; and identifies situations of high NIR exposure from diagnostic devices in which patients or health care workers might not be adequately protected by current regulations. Diagnostic technologies were classified by the types of NIR that they employ. The aim was to describe the techniques in terms of general device categories which may encompass more specific devices or techniques with similar scientific principles. Relevant legally-binding regulations for protection of patients and workers and organizations responsible for those regulations were summarized. Review of the epidemiological evidence concerning health risks associated with exposure to diagnostic NIR highlighted a lack of data on potential risks to the fetus exposed to MRI during the first trimester, and on long-term health risks in workers exposed to MRI. Most of the relevant epidemiological evidence that is currently available relates to MRI or ultrasound. Exposure limits are needed for exposures from diagnostic technologies using optical radiation within the body. There is a lack of data regarding risk of congenital malformations following exposure to ultrasound in utero in the first trimester and also about the possible health effects of interactions between ultrasound and contrast media.


Ultrasound modulated optical tomography contrast enhancement with non-linear oscillation of microbubbles.
Ultrasound modulated optical tomography (USMOT) is an imaging technique used to provide optical functional information inside highly scattering biological tissue. One of the challenges facing this technique is the low image contrast. A contrast enhancement imaging technique based on the non-linear oscillation of microbubbles is demonstrated to improve image contrast. The ultrasound modulated signal was detected using a laser pulse based speckle contrast detection system. Better understanding of the effects of microbubbles on the optical signals was achieved through simultaneous measurement of the ultrasound scattered by the microbubbles. The length of the laser pulse was found to affect the system response of the speckle contrast method with shorter pulses suppressing the fundamental ultrasound modulated optical signal. Using this property, image contrast can be enhanced by detection of the higher harmonic ultrasound modulated optical signals due to nonlinear oscillation and destruction of the microbubbles. Experimental investigations were carried out to demonstrate a doubling in contrast by imaging a scattering phantom containing an embedded silicone tube with microbubbles flowing through it. The contrast enhancement in USMOT resulting from the use of ultrasound microbubbles has been demonstrated. Destruction of the microbubbles was shown to be the dominant effect leading to contrast improvement as shown by simultaneously detecting the ultrasound and speckle contrast signals. Line scans of a microbubble filled silicone tube embedded in a scattering phantom demonstrated experimentally the significant image contrast improvement that can be achieved using microbubbles and demonstrates the potential as a future clinical imaging tool.


Robustness and versatility of a nonlinear interdependence method for directional coupling detection from spike trains.
The detection of directional couplings between dynamics based on measured spike trains is a crucial problem in the understanding of many different systems. In particular, in neuroscience it is important to assess the connectivity between neurons. One of the approaches that can estimate directional coupling from the analysis of point processes is the nonlinear interdependence measure L. Although its efficacy has already been demonstrated, it still needs to be tested under more challenging and realistic conditions prior to an application to real data. Thus, in this paper we use the Hindmarsh-Rose model system to test the method in the presence of noise and for different spiking regimes. We also examine the influence of different parameters and spike train distances. Our results show that the measure L is versatile and robust to various types of noise, and thus suitable for application to experimental data.


Allergy to pigeon tick (Argas reflexus) in Upper Silesia, Poland.
The pigeon tick Argas reflexus is avian ectoparasite that typically feeds on pigeons. When devoid of a natural host, the ticks can also attack humans. In Upper Silesia, southern Poland, people living in the vicinity of the birds' nesting sites are frequently bitten by A. reflexus. The bites can provoke serious allergic reactions, including fatal anaphylactic shock. In the present study, residents of 9 apartments invaded by pigeon ticks were invited to undergo medical examination, skin prick tests (SPT) and determination of specific IgE to A. reflexus. The test allergens were prepared of ticks collected on-site. Out of 18 residents living in the infested apartments, 15 accepted the invitation. In this group, 8 persons complained of tick-related health problems, positive SPT to A. reflexus were found in all of them, and specific IgE was detectable in 3 persons (range: 0.38-0.84 kUA/l; CAP class 1-2). Final clinical diagnoses were established of generalised urticaria with asthma in 1 person, generalised urticaria in another 1, and local allergic reactions to tick bites in the remaining 6. Among 7 symptom-free residents, all test results were negative. Besides the study group, the paper also describes the case of a person who developed hypersensitivity to A. reflexus as a child, after a few visits to an abandoned dovecote. 30 years later, positive SPT (++) and specific IgE (0.78 kUA/l; CAP class 2) were still present despite no further re-exposures. The article also discusses available pest control measures against A. reflexus.


Membrane transport of clindamycin in alveolar macrophages.
The use of antibiotics which can penetrate phagocytic cells and kill intracellular organisms is desirable in the treatment of chronic facultative bacterial infections. Recently, we reported that several antibiotics were selectively concentrated by rabbit alveolar macrophages. Clindamycin accumulation was especially marked. In the present study we evaluated the plasma membrane transport (initial uptake) of clindamycin in alveolar macrophages. The transport of clindamycin is an active process, as documented by requirements for cellular viability, elevated environmental temperature, metabolic energy, and establishment of the 40- to 50-fold cellular/extracellular gradient. Energy for membrane transport of the drug depended at least in part upon mitochondrial oxidative respiration and cell membrane Na-K pump activity. Kinetic analysis of active clindamycin transport revealed it to be saturable, with a high binding affinity (Km = 1 mM) and a high velocity of uptake (Vmax = 15.8 nmol/45 s per 10(6) cells). Clindamycin uptake was not influenced by the presence of hexose or amino acids, but was inhibited by nucleosides (adenosine, puromycin). Decreased clindamycin transport in the presence of puromycin was typical of competitive inhibition (increased Km, unchanged Vmax). Conversely, competitive inhibition of adenosine transport by clindamycin was documented. Thus, clindamycin is transported into alveolar macrophages via the nucleoside system. The potential biological consequences of this unique antibiotic transport mechanism are of interest.


Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients.
Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients. Illumina's GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients. We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17. This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.


CRISPR/Cas9-generated mouse model of Duchenne muscular dystrophy recapitulating a newly identified large 430 kb deletion in the human DMD gene.
Exon skipping is a promising strategy for Duchenne muscular dystrophy (DMD) disease-modifying therapy. To make this approach safe, ensuring that excluding one or more exons will restore the reading frame and that the resulting protein will retain critical functions of the full-length dystrophin protein is necessary. However, in vivo testing of the consequences of skipping exons that encode the N-terminal actin-binding domain (ABD) has been confounded by the absence of a relevant animal model. We created a mouse model of the disease recapitulating a novel human mutation, a large de novo deletion of exons 8-34 of the DMD gene, found in a Russian DMD patient. This mutation was achieved by deleting exons 8-34 of the X-linked mouse Dmd gene using CRISPR/Cas9 genome editing, which led to a reading frame shift and the absence of functional dystrophin production. Male mice carrying this deletion display several important signs of muscular dystrophy, including a gradual age-dependent decrease in muscle strength, increased creatine kinase, muscle fibrosis and central nucleation. The degrees of these changes are comparable to those observed in mdx mice, a standard laboratory model of DMD. This new model of DMD will be useful for validating therapies based on skipping exons that encode the N-terminal ABD and for improving our understanding of the role of the N-terminal domain and central rod domain in the biological function of dystrophin. Simultaneous skipping of exons 6 and 7 should restore the gene reading frame and lead to the production of a protein that might retain functionality despite the partial deletion of the ABD.


Impact of a Professional Nutrition Program on a Female Cross Country Collegiate Athlete: A Case Report.
Low caloric intake or excessive energy expenditure can lead to a negative energy balance, which, in female athletes, may result in a condition called the female athlete triad. While several guidelines identified proper nutrition as a first line of treatment, little research has been reported to show the effect of a professional nutrition program (PNP) on the female athlete triad. The purpose of this case report was to measure the short- and long-term effects of a PNP on a female athlete presenting triad characteristics. A 20-year-old female track-and-field athlete at a Division I university who was in negative energy balance and amenorrheic underwent a one-month PNP. Short- and long-term effects measured by a dual X-ray absorptiometry scan prior to and after attending a PNP showed increased total energy intake from 2188 kcals to 3187 kcals, which resulted in an increase in body fat percent (BF%) from 4.7% to 6.7%. However, by the end of four months, energy intake and BF% (5.7% and 6.0%) values were reduced, respectively. After the twelve-month follow-up, BF% was increased (10.5%), suggesting that increasing energy intake to meet energy demands, without compromising athletic training, can be an effective treatment for the female athlete triad.


Spatial distribution of diffuse, primitive, and classic amyloid-beta deposits and blood vessels in the upper laminae of the frontal cortex in Alzheimer disease.
The spatial distribution of the diffuse, primitive, and classic amyloid-beta deposits was studied in the upper laminae of the superior frontal gyrus in cases of sporadic Alzheimer disease (AD). Amyloid-beta-stained tissue was counterstained with collagen IV to determine whether the spatial distribution of the amyloid-beta deposits along the cortex was related to blood vessels. In all patients, amyloid-beta deposits and blood vessels were aggregated into distinct clusters and in many patients, the clusters were distributed with a regular periodicity along the cortex. The clusters of diffuse and primitive deposits did not coincide with the clusters of blood vessels in most patients. However, the clusters of classic amyloid-beta deposits coincided with those of the large diameter (>10 microm) blood vessels in all patients and with clusters of small-diameter (< 10 microm) blood vessels in four patients. The data suggest that, of the amyloid-beta subtypes, the clusters of classic amyloid-beta deposits appear to be the most closely related to blood vessels and especially to the larger-diameter, vertically penetrating arterioles in the upper cortical laminae.


Rifampin-resistance-associated mutations in the rifampin-resistance-determining region of the rpoB gene of Mycobacterium tuberculosis clinical isolates in Shanghai, PR China.
Introduction. Resistance to rifampin (RIF) in Mycobacterium tuberculosis infection is associated with mutations in the rpoB gene coding for the β-subunit of RNA polymerase. The contribution of various rpoB mutations to the development and level of RIF resistance remains elusive.Hypothesis/Gap Statement. Various rpoB mutations may be associated with differential levels of RIF resistance.Aim. This study aimed to investigate the relationship between specific rpoB mutations and the MICs of RIF and rifabutin (RFB) against M. tuberculosis.Methodology. Of the 195 clinical isolates, 105 and 90 isolates were randomly selected from isolates resistant to RIF and sensitive to RIF, respectively. The MICs of 12 agents for M. tuberculosis isolates were determined using commercial Sensititre M. tuberculosis MIC plates and the broth microdilution method. Strains were screened for rpoB mutations by DNA extraction, rpoB gene amplification and DNA sequence analysis.Results. One hundred isolates (95.24 %) were found to have mutations in the RIF-resistance-determining region (RRDR) of the rpoB gene. Three rpoB mutations were identified in 90 RIF-susceptible isolates. Out of 105 isolates, 86 (81.90 %) were cross-resistant to both RIF and RFB. The most frequent mutation occurred at codons 450 and 445. We also found a novel nine-nucleotide (ATCATGCAT) deletion (between positions 1543 and 1551) in the rpoB gene in two strains (1.90 %) with resistance to RIF, but susceptibility to RFB. In addition, the mutation frequency at codon 450 was significantly higher in RIF-resistant/RFB-resistant (RIFR/RFBR) strains than in RIFR/RFBS strains (75.58 % versus 21.05 %, P<0.01), whereas the mutation frequency at codon 435 was significantly lower in RIFR/RFBR strains than in RIFR/RFBS strains (1.16 % versus 26.32 %, P<0.01).Conclusion. Our data support previous findings, which reported that various rpoB mutations are associated with differential levels of RIF resistance. The specific mutations in the rpoB gene in RIFR/RFBR isolates differed from those in the RIFR/RFBS isolates. A novel deletion mutation in the RRDR might be associated with resistance to RIF, but not to RFB. Further clinical studies are required to investigate the efficacy of RFB in the treatment of infections caused by M. tuberculosis strains harbouring these mutations.


Few-layered metallic 1T-MoS2/TiO2 with exposed (001) facets: two-dimensional nanocomposites for enhanced photocatalytic activities.
Titanium dioxide (TiO2) with exposed (001) facets (TiO2(001)) has attractive photocatalytic properties. However, the high recombination rate of the photo-excited charge carriers on this surface often limits its application. Here, we report that a few-layered 1T-MoS2 coating on TiO2(001) nanosheets (abbreviated as MST) can be a promising candidate that overcomes some of the challenges of TiO2(001). Computational and experimental results demonstrate that MST as a photocatalyst exhibits a significantly low-charge recombination rate as well as excellent long-term durability. The synthesized MST 2D nanocomposites show a 31.9% increase in photocatalytic activity for hydrogen (H2) production relative to the counterpart TiO2(001). MST offers a new route for further improvement of the photocatalytic activity of TiO2 with exposed high energy facets.


[Immunotherapy in superficial bladder carcinoma].
To review the current status of superficial bladder cancer treatment with several immune response modifiers. A review of the advances in the treatment of superficial bladder cancer with BCG, interferon, interleukin-2, bropirimine and keyhole-limpet hemocyanin was performed. Treatment with BCG has been demonstrated to be superior to intravesical chemotherapy and other immune response modifiers in the trials reviewed. BCG therapy, however, carries a higher toxicity. Several trials have demonstrated that in low and medium risk patients, it is better to administer low BCG doses to reduce the toxicity. Furthermore, the trials confirm the utility of maintenance schedules with BCG. The Calmette-Guérin Bacillus is the most effective adjuvant treatment in superficial bladder cancer, especially in the high risk patients. The other immune response modifiers are an alternative to this treatment.


The Pancreatic ß-cell Response to Secretory Demands and Adaption to Stress.
Pancreatic β cells dedicate much of their protein translation capacity to producing insulin to maintain glucose homeostasis. In response to increased secretory demand, β cells can compensate by increasing insulin production capability even in the face of protracted peripheral insulin resistance. The ability to amplify insulin secretion in response to hyperglycemia is a critical facet of β-cell function, and the exact mechanisms by which this occurs have been studied for decades. To adapt to the constant and fast-changing demands for insulin production, β cells use the unfolded protein response of the endoplasmic reticulum. Failure of these compensatory mechanisms contributes to both type 1 and 2 diabetes. Additionally, studies in which β cells are "rested" by reducing endogenous insulin demand have shown promise as a therapeutic strategy that could be applied more broadly. Here, we review recent findings in β cells pertaining to the metabolic amplifying pathway, the unfolded protein response, and potential advances in therapeutics based on β-cell rest.


Burden of COVID-19 during the omicron predominance in Brazil: a nationwide retrospective database study.
The coronavirus disease 2019 (COVID-19) pandemic has imposed significant burden on Brazil's health system. This study aimed to examine clinical characteristics, overall vaccine uptake, and to assess healthcare resource utilization (HCRU) and costs associated with acute COVID-19 in Brazil during the Omicron predominant period. A nationwide retrospective study was conducted using various Brazilian databases including, COVID-19 related databases, public health systems, and other surveillance/demographic datasets. Individuals with positive COVID-19 test results between January 1 2022 and April 30 2022, during Omicron BA.1/BA.2 wave, were identified. Patients' demographics, vaccine uptake, HCRU and corresponding costs were described by age groups. A total of 8,160,715 (3.80%) COVID-19 cases were identified in the study cohort, ranging from 2.43% in <5 years to 62.05% in 19-49 years. The uptake of partial (Dose 1) or full immunization (Dose 2) was less than 0.1% in children aged <5 years, whereas in individuals ≥ 19 years, it exceeded 89.78% for Dose 1 and 84.07% for Dose 2. Overall booster vaccine uptake was 38.06%, which was significantly higher among individuals aged ≥ 65 years, surpassing 74.79%. Regardless of vaccination status, 87.2% cases were symptomatic, and 1.48% were hospitalized due to acute COVID-19 (<5 years: 2.33%, 5-11 years: 0.99%, 12-18 years: 0.32%, 19-49 years: 0.40%; 50-64 years: 1.50%, 65-74 years: 5.43%, and ≥ 75 years: 17.89%). Among the hospitalized patients (n = 120,450), 32.57% were admitted to ICU, of whom 31,283 (79.75%) individuals required mechanical ventilation (MV) support. The average cost per day in normal ward and ICU without MV in public/general hospital settings was $104.36 and $302.81, respectively. While average cost per day in normal ward and ICU with MV was $75.91 and $301.22 respectively. This study quantified the burden of COVID-19 in Brazil, suggesting substantial healthcare resources required to manage the COVID-19 pandemic.


Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study.
Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1-infected subjects with genotypic evidence of RAL resistance. Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ≥0.7 log(10) copies/mL from baseline or was <400 copies/mL. A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen. Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL.


Cardiorenal syndrome in chronic kidney disease.
The purpose of this study is to review current perspectives regarding the pathogenesis of cardiorenal syndrome (CRS) in chronic kidney disease (CKD), and current treatment guidelines for this condition. The pathophysiological mechanisms underlying the development of CRS in CKD include neurohumoral, haemodynamic and CKD-related mechanisms. Recent evidence suggests that sympathetic nerve activity plays a role in CRS, but the SYMPLICITY HTN-3 trial failed to show a reduction of blood pressure after catheter-based renal denervation in patients with resistant hypertension. Kidney injury in patients with heart failure was previously considered to result from arterial underfilling due to low cardiac output, but the role of renal venous hypertension in this process has also recently been investigated. It would be useful to develop a reliable treatment option for CRS due to haemodynamic mechanism other than volume control using diuretics. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that has recently been identified as a CKD-related factor affecting CRS. FGF23 treatment has both advantages and disadvantages in terms of CRS progression. Multiple disorders underlie the development of CRS. Current treatment options include renin-angiotensin system blockade and volume control, but remain limited. A multidisciplinary approach is required to prevent CRS, including renal sympathetic denervation, treatment of renal venous hypertension and FGF23 treatment.


Current evidence allows multiple models for the peopling of the Americas.
Some recent academic and popular literature implies that the problem of the colonization of the Americas has been largely resolved in favor of one specific model: a Pacific coastal migration, dependent on high marine productivity, from the Bering Strait to South America, thousands of years before Clovis, the earliest widespread cultural manifestation south of the glacial ice. Speculations on maritime adaptations and typological links (stemmed points) across thousands of kilometers have also been advanced. A review of the current genetic, archeological, and paleoecological evidence indicates that ancestral Native American population expansion occurred after 16,000 years ago, consistent with the archeological record, particularly with the earliest securely dated sites after ~15,000 years ago. These data are largely consistent with either an inland (ice-free corridor) or Pacific coastal routes (or both), but neither can be rejected at present. Systematic archeological and paleoecological investigations, informed by geomorphology, are required to test each hypothesis.


C-O Coupling of Hydrazones with Diacetyliminoxyl Radical Leading to Azo Oxime Ethers-Novel Antifungal Agents.
Selective oxidative C-O coupling of hydrazones with diacetyliminoxyl is demonstrated, in which diacetyliminoxyl plays a dual role. It is an oxidant (hydrogen atom acceptor) and an O-partner for the oxidative coupling. The reaction is completed within 15-30 min at room temperature, is compatible with a broad scope of hydrazones, provides high yields in most cases, and requires no additives, which makes it robust and practical. The proposed reaction leads to the novel structural family of azo compounds, azo oxime ethers, which were discovered to be highly potent fungicides against a broad spectrum of phytopathogenic fungi (Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, Sclerotinia sclerotiorum).


A neutron activation technique for manganese measurements in humans.
Manganese (Mn) is an essential element for humans, animals, and plants and is required for growth, development, and maintenance of health. Studies show that Mn metabolism is similar to that of iron, therefore, increased Mn levels in humans could interfere with the absorption of dietary iron leading to anemia. Also, excess exposure to Mn dust, leads to nervous system disorders similar to Parkinson's disease. Higher exposure to Mn is essentially related to industrial pollution. Thus, there is a benefit in developing a clean non-invasive technique for monitoring such increased levels of Mn in order to understand the risk of disease and development of appropriate treatments. To this end, the feasibility of Mn measurements with their minimum detection limits (MDL) has been reported earlier from the McMaster group. This work presents improvement to Mn assessment using an upgraded system and optimized times of irradiation and counting for induced gamma activity of Mn. The technique utilizes the high proton current Tandetron accelerator producing neutrons via the (7)Li(p,n)(7)Be reaction at McMaster University and an array of nine NaI (Tl) detectors in a 4 π geometry for delayed counting of gamma rays. The neutron irradiation of a set of phantoms was performed with protocols having different proton energy, current and time of irradiation. The improved MDLs estimated using the upgraded set up and constrained timings are reported as 0.67 μgMn/gCa for 2.3 MeV protons and 0.71 μgMn/gCa for 2.0 MeV protons. These are a factor of about 2.3 times better than previous measurements done at McMaster University using the in vivo set-up. Also, because of lower dose-equivalent and a relatively close MDL, the combination of: 2.0 MeV; 300 μA; 3 min protocol is recommended as compared to 2.3 MeV; 400 μA; 45 s protocol for further measurements of Mn in vivo.


A fatal pulmonary embolus composed of gross liver tissue.
A snowmobile accident caused a pulp injury to the liver and tear of the vena cava of a 21-year-old man. Improvement after fluid resuscitation, right hepatic lobectomy and caval repair was followed by sudden hemodynamic collapse and death. Autopsy revealed pulmonary embolism caused by liver tissue. Presumably the pieces of liver entered the vena cava through the tear and travelled to the lung when blood flow improved. The authors believe that this is the first report of fatal pulmonary embolism caused by macroscopic liver tissue.


Impact of infection on transplantation tolerance.
Allograft tolerance is the ultimate goal of organ transplantation. Current strategies for tolerance induction mainly focus on inhibiting alloreactive T cells while promoting regulatory immune cells. Pathogenic infections may have direct impact on both effector and regulatory cell populations, therefore can alter host susceptibility to transplantation tolerance induction as well as impair the quality and stability of tolerance once induced. In this review, we will discuss existing data demonstrating the effect of infections on transplantation tolerance, with particular emphasis on the role of the stage of infection (acute, chronic, or latent) and the stage of tolerance (induction or maintenance) in this infection-tolerance interaction. While the deleterious effect of acute infection on tolerance is mainly driven by proinflammatory cytokines induced shortly after the infection, chronic infection may generate exhausted T cells that could in fact facilitate transplantation tolerance. In addition to pathogenic infections, commensal intestinal microbiota also has numerous significant immunomodulatory effects that can shape the host alloimmunity following transplantation. A comprehensive understanding of these mechanisms is crucial for the development of therapeutic strategies for robustly inducing and stably maintaining transplantation tolerance while preserving host anti-pathogen immunity in clinically relevant scenarios.


The changing shape of teaching physiology in South Asia: problems and prospects.
It is an established fact that the medical curriculum is not a static document and plays a central role in national health care programmes. Its pertinence to the health care needs is important for medical graduates to tackle the changing needs of the society. It is often a repeated criticism that medical colleges in the South Asian countries are producing graduates who are not well equipped to accept the fresh challenges. From time to time various sections of society emphasize the importance of teaching about primary health care, aging, cardiopulmonary resuscitation, alternative and complementary medicine. The challenging financial, political, consumers and technology trends are regarded as mounting hindrances to scholastic and community-oriented medicine in the south asian countries. A thorough understanding of the basic disciplines of biomedical sciences and provision of state of the art physical facilities are of primary importance.


Neutrophil-derived Oxidants and Proteinases as Immunomodulatory Mediators in Inflammation.
Neutrophils generate potent microbicidal molecules via the oxygen-dependent pathway, leading to the generation of reactive oxygen intermediates (ROI), and via the non-oxygen dependent pathway, consisting in the release of serine proteinases and metalloproteinases stored in granules. Over the past years, the concept has emerged that both ROI and proteinases can be viewed as mediators able to modulate neutrophil responses as well as the whole inflammatory process. This is well illustrated by the oxidative regulation of proteinase activity showing that oxidants and proteinases acts is concert to optimize the microbicidal activity and to damage host tissues. ROI and proteinases can modify the activity of several proteins involved in the control of inflammatory process. Among them, tumour necrosis factor-alpha and interleukin-8, are elective targets for such a modulation. Moreover, ROI and proteinases are also able to modulate the adhesion process of neutrophils to endothelial cells, which is a critical step in the inflammatory process.


Assessing emergency medical care in low income countries: a pilot study from Pakistan.
Emergency Medical Care is an important component of health care system. Unfortunately it is however, ignored in many low income countries. We assessed the availability and quality of facility-based emergency medical care in the government health care system at district level in a low income country - Pakistan. We did a quantitative pilot study of a convenience sample of 22 rural and 20 urban health facilities in 2 districts - Faisalabad and Peshawar - in Pakistan. The study consisted of three separate cross-sectional assessments of selected community leaders, health care providers, and health care facilities. Three data collection instruments were created with input from existing models for facility assessment such as those used by the Joint Commission of Accreditation of Hospitals and the National Center for Health Statistics in USA and the Medical Research Council in Pakistan. The majority of respondents 43/44(98%), in community survey were not satisfied with the emergency care provided. Most participants 36/44(82%) mentioned that they will not call an ambulance in health related emergency because it does not function properly in the government system. The expenses on emergency care for the last experience were reported to be less than 5,000 Pakistani Rupees (equivalent to US$ 83) for 19/29(66%) respondents. Most health care providers 43/44(98%) were of the opinion that their facilities were inadequately equipped to treat emergencies. The majority of facilities 31/42(74%) had no budget allocated for emergency care. A review of medications and equipment available showed that many critical supplies needed in an emergency were not found in these facilities. Assessment of emergency care should be part of health systems analysis in Pakistan. Multiple deficiencies in emergency care at the district level in Pakistan were noted in our study. Priority should be given to make emergency care responsive to needs in Pakistan. Specific efforts should be directed to equip emergency care at district facilities and to organize an ambulance network.


The predictive capacity of self-reported motivation vs. early observed motivational language in cognitive behavioural therapy for generalized anxiety disorder.
Client motivation to change is often considered a key factor in psychotherapy. To date, research on this client construct has largely relied on self-report, which is prone to response bias and ceiling effects. Moreover, self-reported motivation has been inconsistently related to treatment outcome. Early observed client in-session language may be a more valid measure of initial motivation and thus a promising predictor of outcome. The predictive ability of motivational factors has been examined in addiction treatment but has been limited in other populations. Addressing this lack, the present study investigated 85 clients undergoing cognitive behavioural therapy (CBT) alone and CBT infused with motivational interviewing (MI-CBT) for severe generalized anxiety disorder. There were two aims: (1) to compare the predictive capacity of motivational language vs. two self-report measures of motivation on worry reduction and (2) to examine the influence of treatment condition on motivational language. Findings indicated that motivational language explained up to 35% of outcome variance, event 1-year post-treatment. Self-reported motivation did not predict treatment outcome. Moreover, MI-CBT was associated with a significant decrease in the most detrimental type of motivational language compared to CBT alone. These findings support the importance of attending to in-session motivational language in CBT and learning to respond to these markers using motivational interviewing.


Sulfur mustard vapor effects on differentiated human lung cells.
Sulfur mustard (SM) causes skin blistering and long-term pulmonary dysfunction. Its adverse effects have been studied in battlefield-exposed humans, but lack of knowledge regarding confounding factors makes interpretation challenging. Animal studies are critical to understanding mechanisms, but differences between animals and humans must be addressed. Studies of cultured human cells can bridge animal studies and humans. Evaluate effects of SM vapor on airway cells. We examined responses of differentiated human tracheal/bronchial epithelial cells, cultured at an air-liquid interface, to SM vapors. SM effects on metabolic activity (Water Soluble Tetrazolium (WST) assay), cytokine and metalloproteinase secretion, and cellular heme oxygenase 1 (HO-1), an oxidative stress indicator, were measured after 24 h. At noncytotoxic levels of exposure, interleukin 8 and matrix metalloproteinase-13 were significantly increased in these cultures, but HO-1 was not significantly affected. Exposure of differentiated airway epithelial cells to sub-cytotoxic levels of SM vapor induced inflammatory and degradative responses that could contribute to the adverse health effects of inhaled SM.