Short-Term Amoxicillin-Induced Perturbation of the Gut Microbiota Promotes Acute Intestinal Immune Regulation in Brown Norway Rats.
The intestinal gut microbiota is essential for maintaining host health. Concerns have been raised about the possible connection between antibiotic use, causing microbiota disturbances, and the increase in allergic and autoimmune diseases observed during the last decades. To elucidate the putative connection between antibiotic use and immune regulation, we have assessed the effects of the antibiotic amoxicillin on immune regulation, protein uptake, and bacterial community structure in a Brown Norway rat model. Daily intra-gastric administration of amoxicillin resulted in an immediate and dramatic shift in fecal microbiota, characterized by a reduction of within sample (α) diversity, reduced variation between animals (β diversity), increased relative abundance of Bacteroidetes and Gammaproteobacteria, with concurrent reduction of Firmicutes, compared to a water control group. In the small intestine, amoxicillin also affected microbiota composition significantly, but in a different way than observed in feces. The small intestine of control animals was vastly dominated by Lactobacillus, but this genus was much less abundant in the amoxicillin group. Instead, multiple different genera expanded after amoxicillin administration, with high variation between individual animals, thus the small intestinal α and β diversity were higher in the amoxicillin group compared to controls. After 1 week of daily amoxicillin administration, total fecal IgA level, relative abundance of small intestinal regulatory T cells and goblet cell numbers were higher in the amoxicillin group compared to controls. Several bacterial genera, including Escherichia/Shigella, Klebsiella (Gammaproteobacteria), and Bifidobacterium, for which the relative abundance was higher in the small intestine in the amoxicillin group than in controls, were positively correlated with the fraction of small intestinal regulatory T cells. Despite of epidemiologic studies showing an association between early life antibiotic consumption and later prevalence of inflammatory bowel diseases and food allergies, our findings surprisingly indicated that amoxicillin-induced perturbation of the gut microbiota promotes acute immune regulation. We speculate that the observed increase in relative abundance of small intestinal regulatory T cells is partly mediated by immunomodulatory lipopolysaccharides derived from outgrowth of Gammaproteobacteria.


Hierarchically structured cobalt oxide (Co3O4): the morphology control and its potential in sensors.
A polyol process was developed to synthesize Co3O4 with controllable superstructures. By tuning the reaction conditions, the prepared Co3O4 were readily regulated in its morphologies, which could vary from nanosphere to two-dimensional (2D) nanoplates and 3D hierarchical structures, and finally to microspheres. The growth kinetics of such a process was also studied. The synthesized Co3O4 exhibited good sensitivity, remarkable selectivity, and high stability as an alcohol sensor material.


[Long-term survival in a case of advanced hepatocellular carcinoma with tumor thrombus in the portal vein and the right atrium (vp4,vv3 ) treated successfully with multidisciplinary therapies].
The prognosis for hepatocellular carcinoma (HCC) with severe vascular invasion is dismal. Surgery alone is not enough to control recurrence. Here, we report long-term survival in a case of HCC with tumor thrombus in the portal vein and right atrium, which was successfully treated through multidisciplinary therapies including surgery. The patient, a 74-year-old man, had undergone several rounds of local ablation and transarterial chemoembolization for HCC recurrence, in another hospital. He was referred to us for recurrent HCC with vascular invasion in July 2011. An abdominal computed tomography (CT) revealed a mass lesion(4 cm in diameter)in the left hepatic lobe. It also detected a tumor thrombus in the main trunk of the portal vein (Vp4), and in the right atrium (Vv3). Consequently, the patient underwent an extended left lobectomy and removal of the tumor thrombus in the portal vein and right atrium. Subsequently, fluorouracil (FU) arterial infusion and interferon therapy (FAIT) was initiated, and followed with sorafenib administration. However, multiple recurrent lesions were found in the liver, lungs, and lymph nodes. The dose of sorafenib was increased and maintained for 10 months. So far, the patient has been alive for 35 months after the operation.


Correlation between Medication Administration-Related Errors in Patients with Parkinson Disease and Timing of Pharmacy-Led Best Possible Medication Histories.
Poor prescribing and incomplete medication administration have been linked to increased lengths of hospitalization for patients with Parkinson disease. The Institute for Safe Medication Practices (ISMP) has recommended that patients with Parkinson disease receive a pharmacy consultation within 2 h of admission to hospital. To examine whether the time for a pharmacy team member to obtain a best possible medication history (BPMH) was associated with administration-related medication errors. The primary outcome was the proportion of doses with a medication error during a patient's admission in relation to the time to completion of the initial BPMH by a registered pharmacist (RPh) or registered pharmacy technician (RPhT). The secondary objective was to compare the proportion of doses with a medication error in relation to whether the BPMH was completed by an RPh or an RPhT. This retrospective chart review involved patients with Parkinson disease who were admitted to the medicine services at London Health Sciences Centre from September 30, 2014, to September 30, 2018. Patients were included if they had Parkinson disease and a medication regimen that included levodopa-carbidopa. For all patients, an RPhT or RPh conducted the initial BPMH or updated the BPMH. Pearson correlation analysis was used to determine whether a correlation existed between administration-related errors and completion of the BPMH by a pharmacy staff member. A total of 84 patients with 104 admissions were included. There was no significant correlation between the time to completion of the initial BPMH by a pharmacy team member and the proportion of doses with medication errors (p = 0.32). Although RPhTs completed the BPMHs more quickly than RPhs (p < 0.001), there was no significant difference between pharmacy team members in terms of the proportion of doses with medication errors (p = 0.86). Completing a BPMH within 2 h of a patient's admission, as per the ISMP recommendation, is unlikely to affect administration-related medication errors, given that no correlation was identified. Expediting BPMH without addressing other factors is insufficient, and initiatives are required to improve the medication administration process.


Numerical study of structural and magnetic properties of thin films obliquely deposited on rippled substrates.
Structural modulation in thin films plays a substantial role in the formation of their magnetic properties. By producing topographic patterns in thin films, it is possible to engineer their magnetic response. Here, we report on the numerical study of the relationship between structural and static magnetic properties of thin films obliquely deposited on substrates with the sinusoidal surface. 3D Monte Carlo film growth simulations show that, under certain deposition conditions, an inhomogeneous columnar morphology can form in the films caused by the shadowing effect and the rippled substrate. Calculations of the demagnetizing tensors for these films demonstrate that their columnar structure is the source of the shape-induced uniaxial magnetic anisotropy that varies nonmonotonically with the deposition angle. Micromagnetic simulations of the generated films confirm the uniaxial character of the shape-induced anisotropy, and also show that magnetization reversal occurs via an incoherent rotation of magnetic moments.


Purification and properties of uroporphyrinogen III synthase (co-synthetase) from Euglena gracilis.
Uroporphyrinogen III synthase (co-synthetase) purified from Euglena gracilis is a monomer of Mr 38 500 by gel-filtration studies and 31 000 by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. The pI is apparently in the range 4.8-5.1. No evidence for any cofactors was found, and folate derivatives were shown to be absent; no metal ions appear to be present in the enzyme. The Km for hydroxymethylbilane is in the range 12-40 microM, and the product, uroporphyrinogen III, is an inhibitor. Modification studies suggest that arginine residues are essential for the activity of co-synthetase; lysine residues may also be essential, but histidine, cysteine and tyrosine residues are not.


Unusual phenotypic features in a patient with a novel splice mutation in the GHRHR gene.
Isolated growth hormone deficiency (IGHD) may be of genetic origin. One of the few genes involved in that condition encodes the growth hormone releasing hormone receptor (GHRHR) that, through its ligand (GHRH), plays a pivotal role in the GH synthesis and secretion by the pituitary. Our objective is to describe the phenotype of two siblings born to a consanguineous union presenting with short stature (IGHD) and Magnetic Resonance Imaging (MRI) abnormalities, and to identify the molecular basis of this condition. Our main outcome measures were clinical and endocrinological investigations, MRI of the pituitary region, study of the GHRHR gene sequence and transcripts. In both patients, the severe growth retardation (-5SD) was combined with anterior pituitary hypoplasia. In addition to these classical phenotypic features for IGHD, one of the patients had a Chiari I malformation, an arachnoid cyst, and a dysmorphic anterior pituitary. A homozygous sequence variation in the consensus donor splice site of intron 1 (IVS1 + 2T > G) of the GHRHR gene was identified in both patients. Using in vitro transcription assay, we showed that this mutation results in abnormal splicing of GHRHR transcripts. In this report, which broadens the phenotype associated with GHRHR defects, we discuss the possible role of the GHRHR in the proper development of extrapituitary structures, through a mechanism that could be direct or secondary to severe GH deficiency.


The relationship between atrial fibrillation and NLRP3 inflammasome: a gut microbiota perspective.
Atrial fibrillation (AF) is a common clinical arrhythmia whose pathogenesis has not been fully elucidated, and the inflammatory response plays an important role in the development of AF. The inflammasome is an important component of innate immunity and is involved in a variety of pathophysiologic processes. The NLRP3 inflammasome is by far the best studied and validated inflammasome that recognizes multiple pathogens through pattern recognition receptors of innate immunity and mediates inflammatory responses through activation of Caspase-1. Several studies have shown that NLRP3 inflammasome activation contributes to the onset and development of AF. Ecological dysregulation of the gut microbiota has been associated with the development of AF, and some evidence suggests that gut microbiota components, functional byproducts, or metabolites may induce or exacerbate the development of AF by directly or indirectly modulating the NLRP3 inflammasome. In this review, we report on the interconnection of NLRP3 inflammasomes and gut microbiota and whether this association is related to the onset and persistence of AF. We discuss the potential value of pharmacological and dietary induction in the management of AF in the context of the association between the NLRP3 inflammasome and gut microbiota. It is hoped that this review will lead to new therapeutic targets for the future management of AF.


The effects of the antitumor protein auromomycin on HeLa S3 nuclei. Release of soluble chromatin.
The protein antitumor agent auromomycin releases chromatin from intact HeLa S3 nuclei by introducing strand scissions in DNA linker regions. The ability of auromomycin to solubilize nuclear chromatin was compared with the well-characterized action of micrococcal nuclease. Production of acid-soluble material (DNA 10-20 base pairs or less) did not increase significantly over a range of drug levels or incubation times. Release of chromatin from auromomycin-treated nuclei was not affected by EDTA but required dithiothreitol for optimal activity. The soluble chromatin, when resolved by agarose gel electrophoresis, consisted of discrete nucleosome bands ranging from monomer to hexamer size and unresolved higher molecular weight oligomers. Sufficiently high concentrations of drug convert most of the higher molecular weight oligonucleosomes to dimer and monomer material. These nucleosome bands were quite broad and could indicate strand scission occurring at random throughout the linker region. The average size of the drug-generated mononucleosomes from multiple experiments was 175 +/- 4 base pairs. In contrast to micrococcal nuclease, higher concentrations of drug did not degrade mononucleosomes to core particles. Solubilized chromatin is detectable following drug treatments as short as 5 min. Chromatin produced at early time points was mostly small and very heterogeneous. Chromatin from drug-digested nuclei analyzed under denaturing conditions appeared as discrete bands similar to those observed on native gels. The ratio of single- to double-stranded breaks may be close to 2:1. When chromophore isolated from the holantibiotic was incubated with nuclei, a similar pattern of chromatin degradation was observed.


Two sides of the same coin: caring for a person with bipolar disorder.
The aim of this paper was to gain an in-depth understanding of the way the lives of individuals supporting someone diagnosed with bipolar disorder. Bipolar disorder is a severe, recurrent and chronic mental disorder that has a significant impact on the lives of those who experience it and the people supporting them. It is often the subsyndromal symptoms that cause major impairment in functioning and can have financial, social, interpersonal and health impacts for carers. A qualitative thematic analysis was chosen to enable an in-depth exploration of participants' experiences. Twelve participants were interviewed using a semi-structured interview and the data were analysed to identify the themes that represented the participants' experiences. The predominant theme that emerged, two sides of the same coin, described the positive and negative aspects of being an informal carer for a person with bipolar disorder. This theme is constituted by two sub-themes: (1) 'I am a much more compassionate person'; and (2) 'It's tough and it's a sacrifice'. Mental health nurses could support informal caregivers more by providing care that demonstrates an understanding of the complexities associated with bipolar disorder and utilizes a collaborative approach to care that actively involves informal caregivers.


A case of recurrent takotsubo-like cardiomyopathy associated with pheochromocytoma exhibiting different patterns of left ventricular wall motion abnormality and coronary vasospasm: a case report.
Takotsubo-like cardiomyopathy associated with pheochromocytoma (Pheo-TTS) is a recognized but uncommon disorder. While Pheo-TTS might more often recur and the pattern of left ventricular (LV) wall motion abnormality is more diverse compared with primary TTS, it remains to be elucidated whether coronary functional abnormalities are also involved. A 50-year-old woman was referred with a chief complaint of transient chest pain, dyspnoea, and paroxysmal thyroid swelling that usually developed after meals. In the past, she had been admitted to emergency rooms three times due to pulmonary oedema following the above attacks. Serial cardiac catheterizations showed normal coronary arteries and morphologically different types of LV dysfunction each time; apical LV ballooning at the first, basal LV ballooning at the second, and diffuse LV hypokinesis at the last admission. Acetylcholine (ACh) provocation testing for coronary vasospasm was negative at the second admission. During hospitalization in our department, abdominal ultrasonography for screening detected a right adrenal mass and the urinary normetanephrine level was increased. The adrenal tumour was urgently removed surgically and finally she was diagnosed as having norepinephrine-secreting pheochromocytoma. Acetylcholine testing was again performed just after the operation, showing both epicardial and microvascular coronary spasms. Since the operation, she has been free of symptoms. Importantly, ACh testing at 1-year follow-up showed that epicardial spasm was no longer noted, whereas coronary microvascular spasm persisted. Adrenal pheochromocytoma could cause recurrent attacks of catecholamine surges with different patterns of LV dysfunction, where coronary vasospasm may also be involved along the coronary arteries.


Peer reputation in middle childhood as a predictor of adaptation in adolescence: a seven-year follow-up.
This investigation examines the predictive significance of peer reputation in elementary school for the quality of adaptation in adolescence. A normative sample (N = 207) of third to sixth graders was administered the Revised Class Play (RCP). Each received 3 scores (Sociability-Leadership, Aggression-Disruption, and Sensitivity-Isolation). 7 years later, 88% of these children and their parents participated in a questionnaire follow-up study utilizing a broad range of adolescent outcome measures (e.g., social and athletic competence, academic performance, behavioral symptoms, well-being). The 3 RCP scores were significantly related to both adolescent competence and psychopathology, supporting the predictive validity of the RCP as well as the continuity of general adaptation. Each dimension of peer reputation had a different pattern of prediction depending on the outcome criteria under consideration, suggesting the importance of a multidimensional approach to peer reputation. Positive peer reputation proved to be an important predictor of later adjustment. Sex differences were examined; results suggested somewhat different patterns of prediction for boys and girls, especially for the sensitive-isolated dimension.


[Changes in social psychological and functional variables among older people attending a day care center].
Older people attending day care centers improve their social activities, perception of quality of life and reduce their institutionalization rate and risk of mortality in the medium term. To evaluate the changes in the integral geriatric assessment and frailty of a group of older people attending a day care center in Santiago. Health self-perception, integral geriatric assessment, Barthel scale, frailty indicators, mini-mental state scale, Yesavage depression score and a scale about solitude perception were evaluated in 35 participants aged 73 ± 6 years on admission and at discharge from a day care center for older people. At discharge, significant improvements were observed for depression, perception of social support and physical frailty. However, no changes in functional status, cognitive function and perception of solitude were observed. Older people attending improve their perception of social support and decrease their frailty and depression scores.


Actions of a polypeptide toxin from the marine snail Conus striatus on voltage-sensitive sodium channels.
The effects of a polypeptide toxin of 25,000 Da from the marine snail Conus striatus (CsTx) on sodium channels in mouse neuroblastoma cells and rat brain synaptosomes were studied. CsTx slowed sodium channel inactivation without altering the time course of activation of the channels. The voltage dependence of sodium channel inactivation was shifted to more negative membrane potentials and made less steep. Peak sodium currents were increased, and the voltage dependence of activation was shifted to more negative membrane potentials. The action of the toxin was voltage-dependent. Maximum toxin effects were observed at membrane potentials in the range of -100 to -60 mV. Apparent KD values were calculated assuming a one-to-one binding interaction. At more positive membrane potentials, the apparent KD for toxin action increased e-fold for each 19-mV depolarization. Apparent KD also increased at membrane potentials more negative than -100 mV. CsTx did not have significant effects on the binding of saxitoxin or Leiurus alpha-scorpion toxin to their receptor sites on sodium channels. CsTx enhanced the binding of batrachotoxinin A 20-alpha-benzoate to sodium channels in the same concentration range as its physiological effects. It is concluded that CsTx interacts with a new receptor site on the extracellular surface of the sodium channel at which specific effects on channel inactivation can occur.


Delayed maturation in brain electrical activity partially explains the association between early environmental deprivation and symptoms of attention-deficit/hyperactivity disorder.
Children raised in institutional settings are exposed to social and environmental circumstances that may deprive them of expected environmental inputs during sensitive periods of brain development that are necessary to foster healthy development. This deprivation is thought to underlie the abnormalities in neurodevelopment that have been found in previously institutionalized children. It is unknown whether deviations in neurodevelopment explain the high rates of developmental problems evident in previously institutionalized children, including psychiatric disorders. We present data from a sample of children raised in institutions in Bucharest, Romania (n = 117) and an age- and sex-matched sample of community control subjects (n = 49). Electroencephalogram data were acquired following entry into the study at age 6 to 30 months, and a structured diagnostic interview of psychiatric disorders was completed at age 54 months. Children reared in institutions evidenced greater symptoms of attention-deficit/hyperactivity disorder, anxiety, depression, and disruptive behavior disorders than community controls. Electroencephalogram revealed significant reductions in alpha relative power and increases in theta relative power among children reared in institutions in frontal, temporal, and occipital regions, suggesting a delay in cortical maturation. This pattern of brain activity predicted symptoms of hyperactivity and impulsivity at age 54 months, and significantly mediated the association between institutionalization and attention-deficit/hyperactivity disorder symptoms. Electroencephalogram power was unrelated to depression, anxiety, or disruptive behaviors. These findings document a potential neurodevelopmental mechanism underlying the association between institutionalization and psychiatric morbidity. Deprivation in social and environmental conditions may perturb early patterns of neurodevelopment and manifest as psychiatric problems later in life.


Low vision practitioner and the paraoptometric.
The low vision patient is a complex individual who requires understanding by not only the optometrist but by the paraoptometric. The paraoptometric in effect can determine the outcome of the optical portion of the evaluation. By setting the stage for the evaluation, and by carrying out the recommendations, the paraoptometric plays an invaluable role in determining the success of the low vision patient.


Batrachochytrium dendrobatidis in amphibians confiscated from illegal wildlife trade and used in an ex situ breeding program in Brazil.
This paper describes an outbreak of chytridiomycosis affecting a group of Dendrobates tinctorius, a Neotropical anuran species, confiscated from the illegal wildlife trade and housed in a private zoo in Brazil as part of an ex situ breeding program. We examined histological sections of the skin of 30 D. tinctorius and 20 Adelphobates galactonotus individuals. Twenty D. tinctorius (66.7%) and none of the A. galactonotus were positive for Batrachochytrium dendrobatidis (Bd). Multiple development stages of Bd infection were observed. The reasons for the inter-specific difference in the rate of infection could not be determined, and further studies are advised. Because the examined population consisted of confiscated frogs, detailed epidemiological aspects could not be investigated, and the source of the fungus remains uncertain. The existence of ex situ amphibian populations is important for protecting species at higher risk in the wild, and ex situ amphibian conservation and breeding programs in Brazil may be established using confiscated frogs as founders. However, this paper alerts these programs to the urgency of strict quarantine procedures to prevent the introduction of potential pathogens, particularly Bd, into ex situ conservation programs.


Steroid concentrations in fluid from human ovarian antral follicles during pregnancy.
Steroid concentrations in fluid from 138 ovarian antral follicles obtained from 30 pregnant women were measured and compared with those in aspirates of 151 follicles of similar size (i.e. diameter 2-6 mm) from 61 non-pregnant women who had normal regular menstruations. The follicles were classified as healthy or atretic by flow cytometric DNA measurement of the granulosa cells contained in the follicular fluid aspirate. Nine (7%) of the follicles from pregnant women and 21 (14%) of those from non-pregnant women were healthy, and the remainder atretic (P greater than 0.05). Androstenedione was the most abundant steroid in all follicles. Mean progesterone levels in follicular fluid from pregnant women were significantly (P less than 0.05) higher than in follicular fluid from non-pregnant women. In pregnant women progesterone levels were significantly (P less than 0.01) higher in fluid from healthy than from atretic follicles. In contrast, no significant differences in steroid concentrations were found between fluid from healthy and atretic follicles in non-pregnant women. We conclude that antral ovarian follicles may develop normally to a diameter of around 6 mm during the third trimester of human pregnancy. We also conclude that these follicles accumulate steroids in the follicular fluid in amounts which equal those found in follicles of similar size in the ovaries of non-pregnant women, but that the composition of intrafollicular steroids during pregnancy is modified towards higher concentration of progesterone. The reason for this increased intrafollicular progesterone level is unclear.


Expression of nucleolin, nucleophosmin, upstream binding transcription factor genes and propolis in wound models.
Nucleolar proteins have important functions in the regulation of cell homeostasis and play a crucial role in sensing various types of stress, such as genotoxic stress. Propolis has epithelial, analgesic, antibacterial, antifungal and antiviral effects. This study aimed to evaluate the gene expression levels of nucleolar proteins: nucleolin (NCL); nucleophosmin (NPM1); and upstream binding transcription factor (UBTF), as well as the benefits of propolis in wound healing. This experimental study was conducted by creating clean and clean-contaminated wounds according to the Surgical Site Infection Guidelines, 2016. A total of seven animal groups were included in the study: control; laparotomy; anastomosis; fucidic acid with/without anastomosis; propolis with/without anastomosis Results: Statistically significant differences of levels of gene expression among the groups were detected for NCL (p=0.004), NPM1 (p=0.011) and UBTF (p=0.000). When the expression levels of the related genes and blood parameters are considered, the relationship between NCL, NPM1 and UBTF expression levels and blood parameters (NE, EO, NE(%), LY, LY(%), EO, EO(%), MO, MO(%), RBC, HB, HCT, MCV, MCHC, RDW, RDW(%), PLT, PDW and PCT) were statistically significant. The nucleolar proteins such as NCL, NPM1 and UBTF have important functions in cell viability and its maintenance under various condition such as stress and injury. Additionally, propolis has positive benefits in wound healing and in the prevention of wound infection. Our findings provide the first insights into the putative role of those proteins in wound healing.


[The ideal computer for ECG analysis (author's transl)].
An on-line minicomputer with a suitable structure turns out to be the ideal system for ECG interpretation. The motivations for this conclusion come both from the nature of the ECG analysis process and from the solution that the present state of the process and from the solution that the present state of the computer technology suggests for the controversy on large-scale computers versus minicomputers in the medical environment. In this paper both these aspects of the problem are briefly discussed and an ideal structure is proposed for a system based on a minicomputer. The main goals of this system are flexibility, adequate man-machine interfacing, low cost, high reliability and minimal maintenance, minimum installation space and site preparation.


Nonlinear computations underlying temporal and population sparseness in the auditory system of the grasshopper.
Sparse coding schemes are employed by many sensory systems and implement efficient coding principles. Yet, the computations yielding sparse representations are often only partly understood. The early auditory system of the grasshopper produces a temporally and population-sparse representation of natural communication signals. To reveal the computations generating such a code, we estimated 1D and 2D linear-nonlinear models. We then used these models to examine the contribution of different model components to response sparseness. 2D models were better able to reproduce the sparseness measured in the system: while 1D models only captured 55% of the population sparseness at the network's output, 2D models accounted for 88% of it. Looking at the model structure, we could identify two types of computation, which increase sparseness. First, a sensitivity to the derivative of the stimulus and, second, the combination of a fast, excitatory and a slow, suppressive feature. Both were implemented in different classes of cells and increased the specificity and diversity of responses. The two types produced more transient responses and thereby amplified temporal sparseness. Additionally, the second type of computation contributed to population sparseness by increasing the diversity of feature selectivity through a wide range of delays between an excitatory and a suppressive feature. Both kinds of computation can be implemented through spike-frequency adaptation or slow inhibition-mechanisms found in many systems. Our results from the auditory system of the grasshopper are thus likely to reflect general principles underlying the emergence of sparse representations.


High household economic burden caused by hospitalization of patients with severe dengue fever cases in Can Tho province, Vietnam.
During 2006-2007, a cohort of 144 confirmed dengue cases in Can Tho Province, Vietnam were compared with a matching set of 144 households that had no dengue cases. Approximately 6-9 months after sickness, there were no significant differences in terms of knowledge of the etiology of dengue, mosquito breeding habitats, and prevention measures in respondents from both sets of households. There was also no difference in the abundance of Aedes aegypti (Linn.) adults but the average numbers of late instar and pupal Ae. aegypti per household were greater in the negative control houses. Thus, the risk seemed to be no higher in case households, although it is conceivable that changes may have occurred in either group over the intervening period. The average cost for a dengue patient was 2,798,000 Vietnamese Dong (VND) (US$167.77), 2,154,000 VND for direct costs, and 644,000 VND for indirect costs. There was a 22% difference in cost for those with and without health insurance. In terms of impact on family economies, 47.2% had to borrow money for treatment, and after 6 months, 71.7% had not begun or had only managed part repayments. Approximately 72.9% indicated that the cost of supporting a dengue patient had impacted on the family economy, with the loss averaging 36% of the annual income in the lowest economic quartile.


Immunity to a pulmonary Cryptococcus neoformans infection requires both CD4+ and CD8+ T cells.
The role of CD4+ and CD8+ T cells in mediating pulmonary clearance of a cryptococcal infection was investigated. Intratracheal inoculation of BALB/c and C.B-17 mice with a moderately virulent strain of Cryptococcus neoformans (52D) resulted in a pulmonary infection, which was cleared by a T cell-dependent mechanism. During this clearance, there was a significant influx of both CD4+ and CD8+ T cells into the lungs. Depletion of CD4+ T cells by injections of CD4-specific monoclonal antibody (mAb) prevented pulmonary clearance and also resulted in significant colonization of the brain and spleen of infected mice. CD4 depletion did not prevent the influx of CD8+ T cells into the lungs. Surprisingly, depletion of CD8+ T cells by mAb also ablated pulmonary clearance. CD8-depleted mice also had a small but significant increase in brain and spleen colony-forming unit compared to control mice by the end of the study. CD4+ T cell pulmonary influx was independent of the presence of CD8+ T cells. The lungs of T cell-depleted mice were examined histologically. CD4+ and CD8+ T cells each mediated a degree of inflammatory influx seen in the lungs of infected mice and raised the possibility that CD4+ and CD8+ T cells may synergize to generate the inflammatory response in the lungs. Numerous phagocytized but intact cryptococci were seen in the inflammatory foci of CD8-depleted mice but not in control or CD4-depleted mice. We propose that CD4+ T cells may recruit and activate effector phagocytes while CD8+ T cells predominantly function to lyse cryptococcus-laden unactivated phagocytes similar to the function of CD8+ T cells during listeria and mycobacteria infections.


Determinants of the differential antizyme-binding affinity of ornithine decarboxylase.
Ornithine decarboxylase (ODC) is a ubiquitous enzyme that is conserved in all species from bacteria to humans. Mammalian ODC is degraded by the proteasome in a ubiquitin-independent manner by direct binding to the antizyme (AZ). In contrast, Trypanosoma brucei ODC has a low binding affinity toward AZ. In this study, we identified key amino acid residues that govern the differential AZ binding affinity of human and Trypanosoma brucei ODC. Multiple sequence alignments of the ODC putative AZ-binding site highlights several key amino acid residues that are different between the human and Trypanosoma brucei ODC protein sequences, including residue 119, 124,125, 129, 136, 137 and 140 (the numbers is for human ODC). We generated a septuple human ODC mutant protein where these seven bases were mutated to match the Trypanosoma brucei ODC protein sequence. The septuple mutant protein was much less sensitive to AZ inhibition compared to the WT protein, suggesting that these amino acid residues play a role in human ODC-AZ binding. Additional experiments with sextuple mutants suggest that residue 137 plays a direct role in AZ binding, and residues 119 and 140 play secondary roles in AZ binding. The dissociation constants were also calculated to quantify the affinity of the ODC-AZ binding interaction. The K(d) value for the wild type ODC protein-AZ heterodimer ([ODC_WT]-AZ) is approximately 0.22 μM, while the K(d) value for the septuple mutant-AZ heterodimer ([ODC_7M]-AZ) is approximately 12.4 μM. The greater than 50-fold increase in [ODC_7M]-AZ binding affinity shows that the ODC-7M enzyme has a much lower binding affinity toward AZ. For the mutant proteins ODC_7M(-Q119H) and ODC_7M(-V137D), the K(d) was 1.4 and 1.2 μM, respectively. These affinities are 6-fold higher than the WT_ODC K(d), which suggests that residues 119 and 137 play a role in AZ binding.


Biodiversity versus emergencies: the impact of restocking on Animal Genetic Resources after disaster.
Restocking is a favoured option in supporting livelihoods after a disaster. With the depletion of local livestock populations, the introduction of new species and breeds will clearly affect biodiversity. Nevertheless, the impact of restocking on Animal Genetic Resources has been largely ignored. The aim of this paper, therefore, is to examine the consequences of restocking on biodiversity via a simple model. Utilising a hypothetical project based on cattle, the model demonstrates that more than one-third of the population was related to the original restocked animals after three generations. Under conditions of random breed selection, the figure declined to 20 per cent. The tool was then applied to a donor-led restocking project implemented in Bosnia-Herzegovina. By restocking primarily with Simmental cattle, the model demonstrated that the implementation of a single restocking project is likely to have accelerated the decline of the indigenous Busa breed by a further nine per cent. Thus, greater awareness of the long-term implications of restocking on biodiversity is required.


High dose methotrexate for pediatric high grade glioma: results of the HIT-GBM-D pilot study.
We conducted a phase II study to test methotrexate (5 g/m(2)), as a single agent prior to radiochemotherapy for pediatric high-grade glioma and diffuse intrinsic pontine glioma. Thirty patients (19 male, median age 10.8) were enrolled. Tumors were located as follows: cortex 10, pons 7, other 13. Tumor resection was classified as gross total in 6, subtotal in 6, partial in 4, biopsy in 11 and not performed in 3. WHO grading of the histology was: IV: 11, III: 12 and II: 3. Patients received methotrexate 5 g/m(2) in 24-hour infusions on days 1 and 15. Subsequently 54 Gy radiation was administered with simultaneous chemotherapy including cisplatin, etoposide, vincristine and ifosfamide as previously described. Eight 6-weeks cycles of maintenance chemotherapy consisted of vincristine 1.5 mg/m(2) on days 1, 8 and 15; lomustine 100 mg/m(2) on day 2 and prednisone 40 mg/kg on days 1-17. Event-free survival rates in the whole group of 30 patients were: 43, 20, and 13% after 1, 2 and 5 years, respectively. The response evaluation after methotrexate was available in 19 of the 24 patients who started treatment with measurable disease: CR: 0, PR: 1, SD 18, PD: 0. After radiochemotherapy the response of 24 patients with measurable disease was CR: 1, PR 10, SD 12, PD 1. Both response and event-free survival were superior to the control group of 330 patients treated in various protocols of the same cooperative group. In subgroup analyses the use of dexamethasone during early treatment was linked to poor event free survival. Giving two cycles of high-dose methotrexate prior to radiochemotherapy was feasible, and the approach was taken forward to a randomized phase III trial.


Myc enhances B-cell receptor signaling in precancerous B cells and confers resistance to Btk inhibition.
Dysregulation of the oncogenic transcription factor MYC induces B-cell transformation and is a driver for B-cell non-Hodgkin lymphoma (B-NHL). MYC overexpression in B-NHL is associated with more aggressive phenotypes and poor prognosis. Although genomic studies suggest a link between MYC overexpression and B-cell receptor (BCR) signaling molecules in B-NHL, signaling pathways essential to Myc-mediated B-cell transformation have not been fully elucidated. We utilized intracellular phospho-flow cytometry to investigate the relationship between Myc and BCR signaling in pre-malignant B cells. Utilizing the Eμ-myc mouse model, where Myc is overexpressed specifically in B cells, both basal and stimulated BCR signaling were increased in precancerous B lymphocytes from Eμ-myc mice compared with wild-type littermates. B cells overexpressing Myc displayed constitutively higher levels of activated CD79α, Btk, Plcγ2 and Erk1/2. Notably, Myc-overexpressing B cells maintained elevated BCR signaling despite treatment with ibrutinib, a Bruton's tyrosine kinase inhibitor. Furthermore, PI3K/Akt pathway signaling was also increased in Eμ-myc B cells, and this increase was partially suppressed with ibrutinib. In addition, experiments with Btk-null B cells revealed off-target effects of ibrutinib on BCR signaling. Our data show that in pre-malignant B cells, Myc overexpression is sufficient to activate BCR and PI3K/Akt signaling pathways and further enhances signaling following BCR ligation. Therefore, our results indicate that precancerous B cells have already acquired enhanced survival and growth capabilities before transformation, and that elevated MYC levels confer resistance to pharmacologic inhibitors of BCR signaling, which has significant implications for B-NHL treatment.


Internal medicine residency education in ambulatory settings.
To establish a benchmark for ambulatory educational practice in internal medicine in the mid-1990s using descriptive data from a representative sample of residency programs. Data were obtained from the program directors and residents of 103 internal medicine residencies in 1994 and 1995. The program directors supplied information about general medicine, subspecialty, and non-internal medicine ambulatory experiences; the types of settings where the experiences occurred; the duration of the experiences; the number of residents, patients, and attending physicians in the settings; and demographic characteristics of the patients. The 2,598 residents provided responses to 39 questionnaire items about continuity-of-care experience, educational environment, and services. In addition, the residents rated the quality of facilities, services, and supervision in the ambulatory settings. The program directors' reports showed that the median program provided the opportunity for training in general medicine continuity and non-continuity settings in seven subspecialties and five to six non-internal medicine specialties. The majority of the programs provided the opportunity for ambulatory experiences in hospital clinics, freestanding clinics (non-health maintenance organizations), and private offices. The residents strongly affirmed the existence of continuity experiences that provided first-contact, comprehensive and continuing care, and the availability of consultations. The residents responded that they were supervised in their continuity experiences by physicians experienced in general internal medicine. Most of the residents thought that facilities were more than adequate. Services provided by some non-medical personnel were among the lowest-rated aspects of the ambulatory experience. This study suggests that the overall ambulatory experience of internal medicine residents appears to be good. Continuity experiences are clearly in place, faculty and consultants are available, and facilities are adequate. Some aspects of ambulatory education have improved since the middle-to-late 1980s, when an earlier series of studies of the general characteristics of ambulatory education was conducted.


The mei-9 alpha mutant of Drosophila melanogaster increases mutagen sensitivity and decreases excision repair.
The mei-9(a) mutant of Drosophila melanogaster , which reduces meiotic recombination in females (Baker and Carpenter 1972), is deficient in the excision of UV-induced pyrimidine dimers in both sexes. Assays were performed in primary cultures and established cell lines derived from embryos. An endonuclease preparation from M. luteus , which is specific for pyrimidine dimers, was employed to monitor UV-induced dimers in cellular DNA. The rate of disappearance of endonuclease-sensitive sites from DNA of control cells is 10-20 times faster than that from mei-9(a) cells. The mutant mei-218, which is also deficient in meiotic recombination, removes nuclease-sensitive sites at control rates. The mei-9(a) cells exhibit control levels of photorepair, postreplication repair and repair of single strand breaks. In mei-9 cells DNA synthesis and possibly postreplication repair are weakly sensitive to caffeine. Larvae which are hemizygous for either of the two mutants that define the mei-9 locus are hypersensitive to killing by the mutagens methyl methanesulfonate, nitrogen mustard and 2-acetylaminofluorene. Larvae hemizygous for the mei-218 mutant are insensitive to each of these reagents. These data demonstrate that the mei-9 locus is active in DNA repair of somatic cells. Thus functions involved in meiotic recombination are also active in DNA repair in this higher eukaryote. The results are consistent with the earlier suggestions (Baker and Carpenter 1972; Carpenter and Sandler 1974) that the mei-9 locus functions in the exchange events of meiosis. The mei-218 mutation behaves differently in genetic tests and our data suggest its function may be restricted to meiosis. These studies demonstrate that currently recognized modes of DNA repair can be efficiently detected in primary cell cultures derived from Drosophila embryos.


Phylogenetic complexities of the members of Rivulariaceae with the re-creation of the family Calotrichaceae and description of Dulcicalothrix necridiiformans gen nov., sp nov., and reclassification of Calothrix desertica.
A freshwater dwelling, tapering, heterocytous cyanobacterium (strain V13) was isolated from an oligotrophic pond in the Shrirampur taluka, Ahmednagar district of Maharashtra in India. Initial morphological examination indicated that strain V13 belonged to the genus Calothrix. Subsequent molecular and phylogenetic assessment based on 16S rRNA gene, led us to describe the freshwater/terrestrial clade of Calothrix strains without terminal hairs as a new genus Dulcicalothrix gen. nov., with the type species Dulcicalothrix necridiiformans sp. nov. (Strain V13) on the basis of the necridia forming ability of the strain. Also, the 16S-23S ITS secondary structure analysis clearly differentiated strain V13 from the other members of the clade. Past studies and the current state of knowledge makes it imperative to separate the groups Calothrix (marine/freshwater Calothrix), Macrochaete and Dulcicalothrix (freshwater/terrestrial Calothrix) into separate genera in accordance with the International Code of Nomenclature for Algae, Fungi and Plants. Robust phylogenetic evidence and previous reports strongly support the re-erection of the family Calotrichaceae distinct from the existing family Rivulariaceae.


Magnetic-field tunable defect modes in a photonic-crystal/liquid-crystal cell.
Light transmission spectrum of a multilayer photonic crystal with a central liquid-crystal defect layer placed between crossed polarizers has been studied. Transmittance was varied due to the magnetically induced reorientation of the nematic director from homeotropic to planar alignment. Two notable effects were observed for this scheme: the spectral shift of defect modes corresponding to the extraordinary light wave and its superposition with the ordinary one. As a result, the optical cell allows controlling the intensity of interfering defect modes by applied magnetic field.


Implementation of the Varian EDW into a commercial RTP system.
An enhanced dynamic wedge system (EDW) has been installed onto our Clinac 600C (6 MV) linear accelerator. This paper addresses and describes the measurements taken and subsequent analysis required to enable the planning of EDW using our commercial radiotherapy treatment planning (RTP) system. This implementation into a 'closed' commercial system is performed without the use of specialized measurement equipment or the necessity of introducing new calculation algorithms and is therefore independent of the RTP manufacturer. We consider that, for incorporation of techniques such as EDW into routine clinical use, a simple verifiable method of inclusion into the RTP system must be achieved. This paper also presents a methodology for quality control of dynamic fields chosen for clinical use which is quick and easy to use by virtue of its use of film dosimetry. We present the method of film calibration used in this work.


The mouse fidgetin gene defines a new role for AAA family proteins in mammalian development.
The mouse mutation fidget arose spontaneously in a heterogeneous albino stock. This mutant mouse is characterized by a side-to-side head-shaking and circling behaviour, due to reduced or absent semicircular canals. Fidget mice also have small eyes, associated with cell-cycle delay and insufficient growth of the retinal neural epithelium, and lower penetrance skeletal abnormalities, including pelvic girdle dysgenesis, skull bone fusions and polydactyly. By positional cloning, we found the gene mutated in fidget mice, fidgetin (Fign), which encodes a new member of the 'meiotic' or subfamily-7 (SF7; ref. 7) group of ATPases associated with diverse cellular activities (AAA proteins). We also discovered two closely related mammalian genes. AAA proteins are molecular chaperones that facilitate a variety of functions, including membrane fusion, proteolysis, peroxisome biogenesis, endosome sorting and meiotic spindle formation, but functions for the SF7 AAA proteins are largely unknown. Fidgetin is the first mutant AAA protein found in a mammalian developmental mutant, thus defining a new role for these proteins in embryonic development.


Chronic coronary artery disease: diagnosis and management.
Coronary artery disease (CAD) is the single most common cause of death in the developed world, responsible for about 1 in every 5 deaths. The morbidity, mortality, and socioeconomic importance of this disease make timely accurate diagnosis and cost-effective management of CAD of the utmost importance. This comprehensive review of the literature highlights key elements in the diagnosis, risk stratification, and management strategies of patients with chronic CAD. Relevant articles were identified by searching the PubMed database for the following terms: chronic coronary artery disease or stable angina. Novel imaging modalities, pharmacological treatment, and invasive (percutaneous and surgical) interventions have revolutionized the current treatment of patients with chronic CAD. Medical treatment remains the cornerstone of management, but revascularization continues to play an important role. In the current economic climate and with health care reform very much on the horizon, the issue of appropriate use of revascularization is important, and the indications for revascularization, in addition to the relative benefits and risks of a percutaneous vs a surgical approach, are discussed.


Use of a Portable Electronic Interface Improves Clinical Handoffs and Adherence to Lung Protective Ventilation.
Mechanical ventilation (MV) is used to support patients with respiratory impairment. Evidence supports the use of lung-protective ventilation (LPV) during MV to improve outcomes. However, studies have demonstrated poor adherence to LPV guidelines. We hypothesized that an electronic platform adapted to a hand-held tablet receiving real-time ventilatory parameters could increase clinician awareness of key LPV parameters. Furthermore, we speculated that an electronic shift-change tool could improve the quality of clinician handoffs. Using a specially designed Wi-Fi dongle to transmit data from three ventilators and a respiratory monitor, we implemented a system that displays data from all ventilators under the care of a Respiratory Care Practitioner (RCP) on an electronic tablet. In addition, the tablet created a handoff checklist to improve shift-change communication. In a simulated ICU environment, we monitored the performance of eight RCPs at baseline and while using the system. Using the system, the time above guideline Pplat decreased by 74% from control, and the time outside the VT range decreased by 60% from control, p = 0.007 and 0.015, respectively. The handoff scores improved quality significantly from 2.8 to 1.6 on a scale of 1 to 5 (1 being best), p = 0.03. In a simulated environment, an electronic RT tool can significantly improve shift-change communication and increase the RCP's level of LPV adherence.


Integrating genomic analysis with the genetic basis of gene expression: preliminary evidence of the identification of causal genes for cardiovascular and metabolic traits related to nutrition in Mexicans.
Whole-transcriptome expression profiling provides novel phenotypes for analysis of complex traits. Gene expression measurements reflect quantitative variation in transcript-specific messenger RNA levels and represent phenotypes lying close to the action of genes. Understanding the genetic basis of gene expression will provide insight into the processes that connect genotype to clinically significant traits representing a central tenet of system biology. Synchronous in vivo expression profiles of lymphocytes, muscle, and subcutaneous fat were obtained from healthy Mexican men. Most genes were expressed at detectable levels in multiple tissues, and RNA levels were correlated between tissue types. A subset of transcripts with high reliability of expression across tissues (estimated by intraclass correlation coefficients) was enriched for cis-regulated genes, suggesting that proximal sequence variants may influence expression similarly in different cellular environments. This integrative global gene expression profiling approach is proving extremely useful for identifying genes and pathways that contribute to complex clinical traits. Clearly, the coincidence of clinical trait quantitative trait loci and expression quantitative trait loci can help in the prioritization of positional candidate genes. Such data will be crucial for the formal integration of positional and transcriptomic information characterized as genetical genomics.


Addressing Big Data Time Series: Mining Trillions of Time Series Subsequences Under Dynamic Time Warping.
Most time series data mining algorithms use similarity search as a core subroutine, and thus the time taken for similarity search is the bottleneck for virtually all time series data mining algorithms, including classification, clustering, motif discovery, anomaly detection, and so on. The difficulty of scaling a search to large datasets explains to a great extent why most academic work on time series data mining has plateaued at considering a few millions of time series objects, while much of industry and science sits on billions of time series objects waiting to be explored. In this work we show that by using a combination of four novel ideas we can search and mine massive time series for the first time. We demonstrate the following unintuitive fact: in large datasets we can exactly search under Dynamic Time Warping (DTW) much more quickly than the current state-of-the-art Euclidean distance search algorithms. We demonstrate our work on the largest set of time series experiments ever attempted. In particular, the largest dataset we consider is larger than the combined size of all of the time series datasets considered in all data mining papers ever published. We explain how our ideas allow us to solve higher-level time series data mining problems such as motif discovery and clustering at scales that would otherwise be untenable. Moreover, we show how our ideas allow us to efficiently support the uniform scaling distance measure, a measure whose utility seems to be underappreciated, but which we demonstrate here. In addition to mining massive datasets with up to one trillion datapoints, we will show that our ideas also have implications for real-time monitoring of data streams, allowing us to handle much faster arrival rates and/or use cheaper and lower powered devices than are currently possible.


Notes From the Field: Direct Observation Versus Rating by Videos for the Assessment of Central Venous Catheterization Skills.
Blinded assessments of technical skills using video-recordings may offer more objective assessments than direct observations. This study seeks to compare these two modalities. Two trained assessors independently assessed 18 central venous catheterization performances by direct observation and video-recorded assessments using two tools. Although sound quality was deemed adequate in all videos, portions of the video for wire handling and drape handling were frequently out of view (n = 13, 72% for wire-handling; n = 17, 94% for drape-handling). There were no differences in summary global rating scores, checklist scores, or pass/fail decisions for either modality (p > 0.05). Inter-rater reliability was acceptable for both modalities. Of the 26 discrepancies identified between direct observation and video-recorded assessments, three discrepancies (12%) were due to inattention during video review, while one (4%) discrepancy was due to inattention during direct observation. In conclusion, although scores did not differ between the two assessment modalities, techniques of video-recording may significantly impact individual items of assessments.


MiRNA-26a promotes angiogenesis in a rat model of cerebral infarction via PI3K/AKT and MAPK/ERK pathway.
To investigate the specific role of microRNA-26 (miRNA-26a) in a rat model of cerebral ischemic stroke and the underlying mechanism. A rat model of middle cerebral artery occlusion (MCAO) was established to induce permanent cerebral infarction. Neuro-behavior was observed and scored after model establishment. The expression of miRNA-26a in brain tissue and brain microvascular endothelial cells (BMECs) of rats after cerebral ischemic stroke was detected by quantitative polymerase chain reaction (qPCR). The formation of the endothelial lumen was detected by Matrigel assay after BMECs were transfected with miR-26a mimics or inhibitors. Besides, cell proliferation after miRNA-26a transfection was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The protein levels related to PI3K/AKT and MAPK/ERK signaling pathway were detected by Western blot. miRNA-26a expression was elevated after cerebral infarction injury. Further investigation showed that miRNA-26a mimics could promote endothelial lumen formation and cell proliferation in BMECs, while miRNA-26a inhibitor inhibited the capacity of lumen formation and cell proliferation. Notably, we found that miRNA-26a might up-regulate the expression of HIF-1a via activating the AKT and ERK1/2 pathway, thus mediating the transcriptional activity of VEGF and promoting lumen formation and cell proliferation in BMECs. MiRNA-26a promotes angiogenesis in a rat model of cerebral ischemic via PI3K/AKT and MAPK/ERK pathway.


Development of a 4-valent genotyping assay for direct identification of the most frequent Pseudomonas aeruginosa serotypes from respiratory specimens of pneumonia patients.
Pseudomonas aeruginosa is a common cause of nosocomial infections and is associated with high rates of mortality. In order to facilitate rapid and sensitive identification of the most prevalent serotypes of P. aeruginosa, we have developed a 4-valent real-time PCR-based assay using oligonucleotides specific for open-reading frames constituting the O-antigen-specific lipopolysaccharide loci of P. aeruginosa. The assay simultaneously detects and differentiates between each of the four serotypes IATS-O1, -O6, -O11 and serogroup 2 (IATS-O2, -O5, and -O16) with high sensitivity and specificity in a single-tube reaction. No cross-reactivity was observed with other serotypes of P. aeruginosa or other microbial species, and reproducibility was demonstrated regardless of template, i.e. purified DNA, bacterial culture and clinical specimens (broncho-alveolar lavage). The limit of detection of the assay was approximately 100 copies per reaction for IATS-O1, -O2 and -O11, and 50 copies per reaction for IATS-O6. Comparison of the assay specificity with a commercially available slide agglutination kit showed consistent results; however, the number of non-typable isolates was reduced by 15 % using the genotyping assay. Use of the 4-valent genotyping assay in the context of a clinical trial resulted in identification of pneumonia patients positive for the IATS-O11 serotype, and hence eligible for therapy with panobacumab (an investigational monoclonal antibody against the O-polysaccharide of serotype IATS-O11).


The Obama plan: more regulation, unsustainable spending.
The health reform plan put forth by Sen. Barack Obama (D-IL) focuses on expanding insurance coverage and provides new subsidies to individuals, small businesses, and businesses experiencing catastrophic expenses. It greatly increases the federal regulation of private insurance but does not address the core economic incentives that drive health care spending. This omission along with the very substantial short-term savings claimed raise serious questions about its fiscal sustainability. Heavy regulation coupled with a fallback National Health Plan and a play-or-pay financing choice also raise questions about the future of the employer insurance market.


Cost-effectiveness of photobiomodulation therapy for the prevention and management of cancer treatment toxicities: a systematic review.
To identify and summarize the evidence on the cost-effectiveness of photobiomodulation (PBM) therapy for the prevention and treatment of cancer treatment-related toxicities. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE). Scopus, MEDLINE/PubMed, and Embase were searched electronically. A total of 1490 studies were identified, and after a two-step review, 4 articles met the inclusion criteria. The included studies analyzed the cost-effectiveness of PBM therapy used in the context of lymphedema for breast cancer and oral mucositis (OM) induced by chemotherapy and radiotherapy. Better outcomes were associated with PBM therapy. The incremental cost-effectiveness ratio ranged from 3050.75 USD to 5592.10 USD per grade 3-4 OM case prevented. PBM therapy cost 21.47 USD per percentage point reduction in lymphedema in comparison with 80.51 USD for manual lymph drainage and physical therapy. There is limited evidence that PBM therapy is cost-effective in the prevention and treatment of specific cancer treatment-related toxicities, namely, OM and breast cancer-related lymphedema. Studies may have underreported the benefits due to a lack of a comprehensive cost evaluation. This suggests a wider acceptance of PBM therapy at cancer treatment centers, which has thus far been limited by the number of robust clinical studies that demonstrate cost-effectiveness for the prevention and treatment of toxicities.


Emerging drugs for ichthyosis.
The ichthyoses constitute a large and heterogeneous group of disorders characterised by varying degrees of skin scaling. Most forms are rare but between them, they affect tens of thousands of people worldwide. Treatment presently consists primarily of topical keratolytic agents, aimed at removing the ichthyotic scales, and emollients. If an ichthyosis cannot be controlled by topical therapy alone, retinoids can be used. Although effective in several forms of ichthyosis, side effects and teratogenicity severely limit their use. The recent development of retinoic acid metabolism blocking agents (RAMBAs) offers new possibilities. With these drugs, retinoid effects may be obtained with less side effects and a shorter post-treatment teratogenicity period. This review discusses the RAMBAs that are now in clinical trials and outlines possible future developments.


[Development of an immunoenzyme test for determining herpes simplex type 1 virus using monoclonal antibodies].
Conditions of the enzyme immunoassay for the detection of HSV-I by the "sandwich"-method at all stages of the testing were optimized using monoclonal antibodies (monoAB). When identical concentrations of monoclonal antibodies and durations of their adsorption on polystyrene plates were used, the signal in EIA (A405) with carbonate buffer was by 30% higher than that for PBS. A similar increase in the signal was observed at a temperature of incubation of 37 degrees C as compared with that at 4 degrees C. Even during 18-hour incubation at 37 degrees C no inactivation of monoAB occurred. It was further shown that saturation of the surface of wells with protein was achieved at a concentration of monoAB 5-10 micrograms/ml, and under these conditions the optimal dilution of the conjugate was that corresponding to antibody concentration of 1.5 micrograms/ml. When ABDC peroxidase and 5-aminosalycilic acid were used as the substrate, the presence of HSV-I was regularly detected even with a concentrated virus preparation diluted 500-1000-fold (corresponding to approximately 5.0 1g TCID50).


Determinants of vancomycin use in adult intensive care units in 41 United States hospitals.
We analyzed data from a prospective observational cohort study that included 108 adult intensive care units (ICUs) in 41 United States hospitals. Use of vancomycin (defined daily doses per 1,000 patient-days), nosocomial infection rates, and proportion of all Staphylococcus aureus isolates resistant to methicillin (MRSA rate) were recorded from January 1996 through November 1997. The median rate of vancomycin use was lowest in coronary care ICUs and highest in general surgical ICUs. Prior approval before use of vancomycin was required in only 26 (24%) of the 108 ICUs. In a multivariate linear regression model, rates of MRSA, central line-associated bloodstream infection, and the type of ICU were independent predictors of vancomycin use. None of the vancomycin control practices was associated with lower rates of vancomycin use; however, it is important to recognize that this database was not designed to measure rates of inappropriate use. Vancomycin use is heavily determined by rates of endemic MRSA and central line-associated bloodstream infection. Efforts to reduce these rates through infection control activities should be included in hospitals' efforts to reduce vancomycin use.


De novo assembly and characterization of Camelina sativa transcriptome by paired-end sequencing.
Biofuels extracted from the seeds of Camelina sativa have recently been used successfully as environmentally friendly jet-fuel to reduce greenhouse gas emissions. Camelina sativa is genetically very close to Arabidopsis thaliana, and both are members of the Brassicaceae. Although public databases are currently available for some members of the Brassicaceae, such as A. thaliana, A. lyrata, Brassica napus, B. juncea and B. rapa, there are no public Expressed Sequence Tags (EST) or genomic data for Camelina sativa. In this study, a high-throughput, large-scale RNA sequencing (RNA-seq) of the Camelina sativa transcriptome was carried out to generate a database that will be useful for further functional analyses. Approximately 27 million clean "reads" filtered from raw reads by removal of adaptors, ambiguous reads and low-quality reads (2.42 gigabase pairs) were generated by Illumina paired-end RNA-seq technology. All of these clean reads were assembled de novo into 83,493 unigenes and 103,196 transcripts using SOAPdenovo and Trinity, respectively. The average length of the transcripts generated by Trinity was 697 bp (N50 = 976), which was longer than the average length of unigenes (319 bp, N50 = 346 bp). Nonetheless, the assembly generated by SOAPdenovo produced similar number of non-redundant hits (22,435) with that of Trinity (22,433) in BLASTN searches of the Arabidopsis thaliana CDS sequence database (TAIR). Four public databases, the Kyoto Encyclopedia of Genes and Genomes (KEGG), Swiss-prot, NCBI non-redundant protein (NR), and the Cluster of Orthologous Groups (COG), were used for unigene annotation; 67,791 of 83,493 unigenes (81.2%) were finally annotated with gene descriptions or conserved protein domains that were mapped to 25,329 non-redundant protein sequences. We mapped 27,042 of 83,493 unigenes (32.4%) to 119 KEGG metabolic pathways. This is the first report of a transcriptome database for Camelina sativa, an environmentally important member of the Brassicaceae. We showed that C. savita is closely related to Arabidopsis spp. and more distantly related to Brassica spp. Although the majority of annotated genes had high sequence identity to those of A. thaliana, a substantial proportion of disease-resistance genes (NBS-encoding LRR genes) were instead more closely similar to the genes of other Brassicaceae; these genes included BrCN, BrCNL, BrNL, BrTN, BrTNL in B. rapa. As plant genomes are under long-term selection pressure from environmental stressors, conservation of these disease-resistance genes in C. sativa and B. rapa genomes implies that they are exposed to the threats from closely-related pathogens in their natural habitats.


[Forming teachers: the educational practice in a graduate nursing program].
This study aimed at understanding the educational practices operated in the Graduate Nursing Program of the Center of Sciences of the Health of the Federal University of Paraiba-UFPB and at identifying the produced contradictions, to the light of emancipatory pedagogic references and also non-emancipatory ones. This is a study of qualitative approach. The teachers and students of the Graduate Nursing Program of UFPB were the subject of the study. The semi-structured interview was used, and the analysis of the data happened through the technique of speech analysis. The evidenced empiric categories were: Contradictions in the Process of Formation of Teachers and Influence of the Educational Emancipatory ando non-Emancipatory Practices. It was verified that the teachers' Educational Practice is found in bases of non-Emancipatory, fact ratified by the speech of the students.


Efficacy of marine bioactive compound fucoidan for bone regeneration and implant fixation in sheep.
The need for a substitute for allograft and autograft is rising as bone graft surgeries exceed available supplies. We investigated the efficacy of the low-molecular weight marine bioactive compound fucoidan (FUC) on bone regeneration and implant fixation in seven female sheep, as FUC has shown great promise as a bone substitute. Titanium implants were inserted bilaterally in the distal femurs to test three hydroxyapatite/fucoidan (HA/FUC) groups and compared to allograft. The HA was coated with either 500 or 1500 μg of FUC, obtained by microwave-assisted chemical extraction, or 500 μg of FUC obtained by an enzyme-assisted extraction method. The concentric 2-mm gap around the implant was filled with either one of the HA/FUCs or allograft from the donor sheep. After 12 weeks, implant-bone blocks were harvested and divided into three parts for mechanical push-out testing, immunohistochemistry, and micro-CT and histomorphometry. Pronounced bone formations were observed by micro-CT and histomorphometry in all groups, but higher bone volume fractions were seen in the allograft group compared to the three HA/FUC groups. The trabecular thickness, trabecular separation, and architectural anisotropy were all significantly higher in the allograft group compared to the three HA/FUC groups. In conclusion, adequate bone formation was observed in all groups, although the bone formation was significantly greater in the allograft group. Also, no significant differences existed in the shear mechanical properties between groups, suggesting that the combination of HA and FUC can achieve a similar fixation strength to allograft in this model.


Restrictive dermopathy in two brothers.
Restrictive dermopathy is an autosomal recessive phenotype characterized by universal tautness of skin resulting in fetal akinesia and death during the neonatal period. The clinical signs and symptoms of this uncommon disease are described in two brothers, and evidence is provided that fetal biopsy specimens obtained during the 20th week of gestational age are nondiagnostic. The first patient was a growth-retarded preterm boy suffering from generalized desquamation, marked joint contractures, and facial hypoplasia. Prominent light microscopic findings were hyperorthokeratosis intermingled with parakeratosis and absence of the elastic fibers in a thinned dermis. Electron microscopic examination of the epidermis revealed a lack of keratin filaments and an abnormal globular shape of the keratohyalin granules. The child died 4 days after birth. A following pregnancy resulted in birth of a preterm boy who died of the same disease within 2 hours. In the 20th week of gestational age, fetal biopsy specimens were obtained, but light and electron microscopy failed to reveal any abnormalities. Restrictive dermopathy is a genuine skin disease resulting in fetal akinesia that precludes a normal intrauterine development. The clinical features of this disorder are so distinctive that an on-the-spot diagnosis can be established. In view of the data obtained in this case, the feasibility of prenatal diagnosis should be regarded with great caution.


Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes.
Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear. In this double-blind trial, we randomly assigned patients with CKD and type 2 diabetes to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m2 of body-surface area (stage 2 to 4 CKD) or a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of at least 60 ml per minute per 1.73 m2 (stage 1 or 2 CKD). Patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The first secondary outcome was a composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes. Safety was assessed as investigator-reported adverse events. A total of 7437 patients underwent randomization. Among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and in 519 of 3666 (14.2%) in the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P = 0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure (hazard ratio, 0.71; 95% CI, 0.56 to 0.90). The secondary composite outcome occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01). The overall frequency of adverse events did not differ substantially between groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%). Among patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo. (Funded by Bayer; FIGARO-DKD ClinicalTrials.gov number, NCT02545049.).


Patient experience in safety-net hospitals: implications for improving care and value-based purchasing.
Whether safety-net hospitals (SNHs) provide patient-centered care has important implications both for patient outcomes and for how these hospitals will fare under value-based purchasing (VBP). We sought to determine performance and improvement on measures of patient-reported hospital experience among SNHs compared with non-SNHs. Our sample consisted of 3096 US hospitals. We defined safety-net hospitals as those hospitals in the highest quartile of the Disproportionate Share Hospital (DSH) index, and we used national data on patient experience from the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey in 2007 and 2010 to examine overall hospital performance and improvement over time. Safety-net hospitals had lower performance than non-SNHs on nearly all measures of patient experience. The greatest differences were in overall hospital rating, where patients in SNHs were less likely to rate the hospital a 9 or 10 on a 10-point scale compared with patients in non-SNHs (63.9% vs 69.5%; P < .001). Gaps were also sizeable for the proportion of patients who reported receiving discharge information (2.6 percentage point difference; P < .001) and who thought they always communicated well with physicians (2.2 percentage point difference; P < .001). Although both groups of hospitals improved from 2007 through 2010, the gap between SNHs and non-SNHs increased (3.8% in 2007 vs 5.6% in 2010; P = .08). Finally, SNHs had a 60% lower odds of meeting VBP performance benchmarks for hospital payments (odds ratio, 0.4; 95% CI, 0.3-0.5; P < .001) compared with non-SNHs. Safety-net hospitals have lower performance than non-SNHs on metrics of patient-reported experience, improved somewhat more slowly under public reporting, and are likely to fare poorly under VBP.


The role of mononuclear phagocytes in HTLV-III/LAV infection.
Cells with properties characteristic of mononuclear phagocytes were evaluated for infectivity with five different isolates of the AIDS virus, HTLV-III/LAV. Mononuclear phagocytes cultured from brain and lung tissues of AIDS patients harbored the virus. In vitro-infected macrophages from the peripheral blood, bone marrow, or cord blood of healthy donors produced large quantities of virus. Virus production persisted for at least 40 days and was not dependent on host cell proliferation. Giant multinucleated cells were frequently observed in the macrophage cultures and numerous virus particles, often located within vacuole-like structures, were present in infected cells. The different virus isolates were compared for their ability to infect macrophages and T cells. Isolates from lung- and brain-derived macrophages had a significantly higher ability to infect macrophages than T cells. In contrast, the prototype HTLV-III beta showed a 10,000-fold lower ability to infect macrophages than T cells and virus production was one-tenth that in macrophage cultures infected with other isolates, indicating that a particular variant of HTLV-III/LAV may have a preferential tropism for macrophages or T cells. These results suggest that mononuclear phagocytes may serve as primary targets for infection and agents for virus dissemination and that these virus-infected cells may play a role in the pathogenesis of the disease.


Immigration and the health of Asian and Pacific Islander adults in the United States.
The authors used the 1992-1995 National Health Interview Survey to examine the effect of immigrant status (both nativity and duration of residence in the United States) on the health of Asian and Pacific Islander adults by constructing models in which national origin was also specified. In logistic regression models adjusted for age, marital status, living arrangement, family size, and several socioeconomic indicators, immigrants were found to be in better health than their US-born counterparts, but their health advantages consistently decreased with duration of residence. For example, for Asian and Pacific Islander immigrants whose duration of residence was less than 5 years, 5-9 years, and 10 years or more, the odds ratios for activity limitations were 0.45 (95% confidence interval (CI): 0.33, 0.62), 0.65 (95% CI: 0.46, 0.93), and 0.73 (95% CI: 0.60, 0.90), respectively. Similar findings emerged for respondent-reported health and bed days due to illness. These results support the validity and complementarity of the migration selectivity and acculturation hypotheses. However, the picture was not uniformly positive. The health of certain Asian and Pacific Islander groups, notably Pacific Islanders and Vietnamese, was found to be less favorable than average. Finally, after adjustment for health status, immigrants seemed to have less adequate access to formal medical care.


Appearance of mycovirus-like double-stranded RNAs in the white root rot fungus, Rosellinia necatrix, in an apple orchard.
In general, mycoviruses are transmitted through hyphal anastomosis between vegetatively compatible strains of the same fungi, and their entire intracellular life cycle within host fungi limits transmission to separate species and even to incompatible strains belonging to the same species. Based on field observations of the white root rot fungus, Rosellinia necatrix, we found two interesting phenomena concerning mycovirus epidemiology. Specifically, apple trees in an orchard were inoculated with one or two R. necatrix strains that belonged to different mycelial compatibility groups (MCGs), strains W563 (virus-free, MCG139) and NW10 (carrying a mycovirus-like double-stranded (ds) RNA element (N10), MCG442). Forty-two sub-isolates of R. necatrix, which were retrieved 2-3 years later, were all genetically identical to W563 or NW10: however, 22 of the sub-isolates contained novel dsRNAs. Six novel dsRNAs (S1-S6) were isolated: S1 was a new victorivirus; S2, S3, and S4 were new partitiviruses; and S5 and S6 were novel viruses that could not be assigned to any known mycovirus family. N10 dsRNA was detected in three W563 sub-isolates. These findings indicated that novel mycoviruses, from an unknown source, were infecting strains W563 and NW10 of R. necatrix in the soil, and that N10 dsRNA was being transmitted between incompatible strains, NW10 to W563.


Sulfide nanocrystal inks for dense Cu(In1-xGa(x))(S1-ySe(y))2 absorber films and their photovoltaic performance.
Recent developments in the colloidal synthesis of high quality nanocrystals have opened up new routes for the fabrication of low-cost efficient photovoltaic devices. Previously, we demonstrated the utility of CuInSe(2) nanocrystals in the fabrication of CuInSe(2) thin film solar cells. In those devices, sintering the nanocrystal film yields a relatively dense CuInSe(2) film with some void space inclusions. Here, we present a general approach toward eliminating void space in sintered nanocrystal films by utilizing reactions that yield a controlled volume expansion of the film. This is demonstrated by first synthesizing a nanocrystal ink composed of Cu(In(1-x)Ga(x))S(2) (CIGS). After nanocrystal film formation, the nanocrystals are exposed to selenium vapor during which most of the sulfur is replaced by selenium. Full replacement produces a approximately 14.6% volume expansion and reproducibly leads to good dense device-quality CIGSSe absorber films with reduced inclusion of void space. Solar cells made using the CIGSSe absorber films fabricated by this method showed a power conversion efficiency of 4.76% (5.55% based on the active nonshadowed area) under standard AM1.5 illumination.


Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species.
Previous studies have shown that longevity is associated with enhanced cellular stress resistance. This observation supports the disposable soma theory of aging, which suggests that the investment made in cellular maintenance will be proportional to selective pressures to extend lifespan. Maintenance of protein homeostasis is a critical component of cellular maintenance and stress resistance. To test the hypothesis that enhanced protein repair and recycling activities underlie longevity, we measured the activities of the 20S/26S proteasome and two protein repair enzymes in liver, heart and brain tissues of 15 different mammalian and avian species with maximum lifespans (MLSP) ranging from 3 to 30 years. The data set included Snell dwarf mice, in which lifespan is increased by ∼50% compared to their normal littermates. None of these activities in any of the three tissues correlated positively with MLSP. In liver, 20S/26S proteasome and thioredoxin reductase (TrxR) activities correlated negatively with body mass. In brain tissue, TrxR was also negatively correlated with body mass. Glutaredoxin (Grx) activity in brain was negatively correlated with MLSP and this correlation remained after residual analysis to remove the effects of body mass, but was lost when the data were analysed using Felsenstein's independent contrasts. Snell dwarf mice had marginally lower 20S proteasome, TrxR and Grx activities than normal controls in brain, but not heart tissue. Thus, increased longevity is not associated with increased protein repair or proteasomal degradation capacities in vertebrate endotherms.


Assessing Second Debridement Timing and Mortality in Necrotizing Soft Tissue Infections.
Patients with necrotizing soft tissue infection undergo an average of 4-5 debridements per hospital admission. Optimal timing for initial debridement is emergent. Second debridement is universally recommended to occur within 24 hours of the first, but no studies have successfully evaluated this time frame. Prior work has suggested that delays in second debridement are associated with increased mortality, and that few patients receive second debridement within 24 hours. We performed a retrospective cohort study at a single center from 01/01/08 to 09/01/2021. The explanatory variable was whether the subject received second debridement within 24 hours of initial debridement. The primary outcome was in-hospital mortality. Baseline characteristics were collected. Subjects were stratified into 2 groups by time between first and second debridement: <24 and ≥24 hours. Variables were compared using Fisher's exact and Wilcoxon rank-sum tests. 77 patients met inclusion criteria. The median overall time to second debridement was 40 hours. 12 subjects received second debridement within 24 hours (15.6%). There was no difference in in-hospital mortality between the <24 (n = 3, 25.0%) and ≥24-hour second debridement groups (n = 4, 6.2%; P = .07). The 2 groups did not differ by secondary outcomes, including total number of debridements, ICU LOS, or wound closure. No difference in mortality was observed between subjects undergoing second debridement within 24 vs after 24 hours. Only 16% of subjects received second debridement within the recommended 24-hour time interval. Further study is required to identify the optimal timing of second debridement.


Bioinspired materials for regenerative medicine: going beyond the human archetypes.
The evolution of life has given rise to innumerable biomaterials with high levels of functional sophistication and performance among many thousands of different environments. The inexhaustible range of strategies and the intrinsic good design they possess can be readily included in the design of biomedical devices and materials, such as wound healing bandages and antibacterial surface coating implants. We highlight topical examples where various ingenious design strategies from biological models, originating more broadly from zoology and botany, have been appropriated into novel synthetic materials and structures for regenerative and material-based tissue engineering. Bioinspired materials engineering informed and enriched by the vast array of adaptations and strategies in nature, beyond human biology, will be instrumental in the future evolution of new more clinically acceptable pan-functional materials and structures with a broad range of uses in the regenerative sciences.


Analysis of spike and accessory 3c genes mutations of less virulent and FIP-associated feline coronaviruses in Beijing, China.
Mutations in S and 3c genes of feline coronavirus (FCoV) have been associated with the development of feline infectious peritonitis (FIP). In the present study, FCoV S and 3c genes mutations were analyzed in healthy and FIP cats. M1058L mutation was found in 13.64% (3/22) feces from FIP cats, but not in feces from healthy cats (0/39). The intact 3c gene was found in feces from both healthy cats (19/19) and FIP cats (12/12). All parenteral samples from FIP cats carried one or more of the M1058L mutation, S1060A mutation and mutated 3c gene. FCoV reverse-transcriptase polymerase chain reaction (RT-PCR) of parenteral samples (including ascites, pleural effusions and tissue) is recommended as the gold standard for clinical diagnosis of FIP rather than detection of the M1058L mutation, but when cats have severe gastrointestinal symptoms and lesions, detection of the M1058L mutation in feces may be helpful in diagnosing FIP.


Versatile N2S2 nickel-dithiolates as mono- and bridging bidentate, S-donor ligands to gold(I).
Development of square planar cis-dithiolate nickel complexes as metallo S-donor ligands focuses on the synthesis and structures of gold(I) heterometallic clusters derived from assemblage with three NiN2S2 complexes: Ni(bme-daco), Ni(bme-dach) and Ni(ema)(2-) (bme-daco = (bismercaptoethanediazacyclooctane); bme-dach = bismercaptoethanediazacycloheptane; and ema = N,N'-ethylenebis-2-mercaptoacetamide). With Ph3PAuCl as the gold source, examples of simple S-aurolation retaining the PPh3 on Au(+) were obtained for [{Ni(bme-daco)}AuPPh3](+)Cl(-) and [{Ni(ema)}2Au4(PPh3)4], where the latter complex demonstrated unsupported aurophilic interactions between [{Ni(ema)}Au2(PPh3)2] units in its X-ray crystal structure (Au-Au = 3.054 and 3.127 Å). Three compounds containing fully-supported digold units with Au-Au distances in the aurophilic range of 3.11 to 3.13 Å were found as stair-step structures in which planar NiN2S2 step treads are connected by planar S2Au2S2 risers at ca. 90°: [{Ni(bme-daco)}2Au2](2+)(Cl(-))2; [{Ni(bme-dach)}2Au2](2+)(Cl(-))2; and (Et4N(+))2[{Ni(ema)}2Au2](2-). Electrochemical data from cyclic voltammograms demonstrated a positive shift in Ni(II/I) couples for the [{NiN2S2}xAuy] complexes as compared to the NiN2S2 precursors and a ca. 700 mV decrease in communication between multiple NiN2S2 units as compared to [{NiN2S2}2Ni](2+) analogues in slant chair conformation. The analogy between NiN2S2 metallodithiolate ligands and diphosphine ligands holds here as in other examples of inorganic and organometallic complexes.


The REDUCED LEAFLET genes encode key components of the trans-acting small interfering RNA pathway and regulate compound leaf and flower development in Lotus japonicus.
The endogenous trans-acting small interfering RNA (ta-siRNA) pathway plays a conserved role in adaxial-abaxial patterning of lateral organs in simple-leafed plant species. However, its function in compound-leafed species is largely unknown. Using the compound-leafed species Lotus japonicus, we identified and characterized two independent mutants, reduced leaflet1 (rel1) and rel3, whose most conspicuous defects in compound leaves are abaxialized leaflets and reduction in leaflet number. Concurrent mutations in REL genes also compromise flower development and result in radial symmetric floral organs. Positional cloning revealed that REL1 and REL3 encode the homologs of Arabidopsis (Arabidopsis thaliana) SUPPRESSOR OF GENE SILENCING3 and ARGONAUTE7/ZIPPY, respectively, which are key components of the ta-siRNA pathway. These observations, together with the expression and functional data, demonstrated that the ta-siRNA pathway plays conserved yet distinct roles in the control of compound leaf and flower development in L. japonicus. Moreover, the phenotypic alterations of lateral organs in ta-siRNA-deficient mutants and the regulation of downstream targets by the ta-siRNA pathway in L. japonicus were similar to those in the monocots but different from Arabidopsis, indicating many parallels between L. japonicus and the monocots in the control of lateral organ development by the ta-siRNA pathway.


Proteome and immune responses of extracellular vesicles derived from macrophages infected with the periodontal pathogen Tannerella forsythia.
Periodontitis is a chronic inflammatory disease caused by periodontal pathogens in subgingival plaque and is associated with systemic inflammatory diseases. Extracellular vesicles (EVs) released from host cells and pathogens carry a variety of biological molecules and are of interest for their role in disease progression and as diagnostic markers. In the present study, we analysed the proteome and inflammatory response of EVs derived from macrophages infected with Tannerella forsythia, a periodontal pathogen. The EVs isolated from the cell conditioned medium of T. forsythia-infected macrophages were divided into two distinct vesicles, macrophage-derived EVs and T. forsythia-derived OMVs, by size exclusion chromatography combined with density gradient ultracentrifugation. Proteome analysis showed that in T. forsythia infection, macrophage-derived EVs were enriched with pro-inflammatory cytokines and inflammatory mediators associated with periodontitis progression. T. forsythia-derived OMVs harboured several known virulence factors, including BspA, sialidase, GroEL and various bacterial lipoproteins. T. forsythia-derived OMVs induced pro-inflammatory responses via TLR2 activation. In addition, we demonstrated that T. forsythia actively released OMVs when T. forsythia encountered macrophage-derived soluble molecules. Taken together, our results provide insight into the characterisation of EVs derived from cells infected with a periodontal pathogen.


Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex.
Although many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin) and found that synaptic development in human primary visual cortex (V1) continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (<1 year) when only Gephyrin has high inter-individual variability. We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the 1 year or 2 of life. A multidimensional analysis (principle component analysis) showed that most of the variance was captured by the sum of the four synaptic proteins. We used that sum to compare development of human and rat visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.


Paradoxical Growth of Optochiasmatic Tuberculoma during the Treatment of Tuberculous Meningitis.
Intracranial brain parenchymal tuberculomas may form paradoxically, days to months after starting antituberculous drug therapy. They may develop in and around optic chiasm and optic nerves after antituberculous treatment as a quite rare occurrence in tuberculous meningitis (TBM) this may lead to severe visual loss if not treated properly. We describe a 5 year-old child with documented TBM being treated with first line antituberculous drugs which developed visual impairment 3 months after starting the treatment. MRI after gadolinium administration revealed multiple perichiasmatic ring enhancing lesions due to tuberculomas. Visual impairment developing in a patient on treatment with antituberculous drugs should give rise to a suspicion of rare optochiasmatic tuberculomas; this necessitates urgent contrast-enhanced MRI of the brain and prompt treatment with steroids.


Emotion differentiation through features of eye-tracking and pupil diameter for monitoring well-being.
Emotions are an important contributor to human self-expression and well-being. However, many populations express their emotions differently from what is considered "typical". Previous literature has indicated a possible relationship between emotion and eye-movement. The objective of this paper is to further explore this proposed relationship by identifying specific features of eye-movement that relate to six emotion categories: joy, surprise, indifference, disgust, sadness, and fear. Features of eye-movement are extracted from measurements of pupil diameter, saccades, and fixations. These measurements are collected as participants view images from the International Affective Picture System, a validated image deck used to evoke known levels of pleasure, arousal, and dominance. Example features of eye-movement measurements such as pupil diameter include maximum or minimum values, means, and standard deviations. Statistical analyses indicate that the extracted features of eye-tracking in this paper can identify fear and sadness with relative accuracy, while more work is needed to differentiate among joy, indifference, disgust, and surprise. Future work aims to understand differences between typically developing populations such as the individuals included in this analysis, and clinical populations such as individuals with cerebral palsy.Clinical Relevance- This pilot study suggests a link between emotion and features of eye-movement. The information will later be used to develop assistive communication devices that better meet the self-expression needs of individuals with motor and communication challenges.