Forest fuel reduction alters fire severity and long-term carbon storage in three Pacific Northwest ecosystems.
Two forest management objectives being debated in the context of federally managed landscapes in the U.S. Pacific Northwest involve a perceived trade-off between fire restoration and carbon sequestration. The former strategy would reduce fuel (and therefore C) that has accumulated through a century of fire suppression and exclusion which has led to extreme fire risk in some areas. The latter strategy would manage forests for enhanced C sequestration as a method of reducing atmospheric CO2 and associated threats from global climate change. We explored the trade-off between these two strategies by employing a forest ecosystem simulation model, STANDCARB, to examine the effects of fuel reduction on fire severity and the resulting long-term C dynamics among three Pacific Northwest ecosystems: the east Cascades ponderosa pine forests, the west Cascades western hemlock-Douglas-fir forests, and the Coast Range western hemlock-Sitka spruce forests. Our simulations indicate that fuel reduction treatments in these ecosystems consistently reduced fire severity. However, reducing the fraction by which C is lost in a wildfire requires the removal of a much greater amount of C, since most of the C stored in forest biomass (stem wood, branches, coarse woody debris) remains unconsumed even by high-severity wildfires. For this reason, all of the fuel reduction treatments simulated for the west Cascades and Coast Range ecosystems as well as most of the treatments simulated for the east Cascades resulted in a reduced mean stand C storage. One suggested method of compensating for such losses in C storage is to utilize C harvested in fuel reduction treatments as biofuels. Our analysis indicates that this will not be an effective strategy in the west Cascades and Coast Range over the next 100 years. We suggest that forest management plans aimed solely at ameliorating increases in atmospheric CO2 should forgo fuel reduction treatments in these ecosystems, with the possible exception of some east Cascades ponderosa pine stands with uncharacteristic levels of understory fuel accumulation. Balancing a demand for maximal landscape C storage with the demand for reduced wildfire severity will likely require treatments to be applied strategically throughout the landscape rather than indiscriminately treating all stands.


The evolutionary history of the development of the pelvic fin/hindlimb.
The arms and legs of man are evolutionarily derived from the paired fins of primitive jawed fish. Few evolutionary changes have attracted as much attention as the origin of tetrapod limbs from the paired fins of ancestral fish. The hindlimbs of tetrapods are derived from the pelvic fins of ancestral fish. These evolutionary origins can be seen in the examination of shared gene and protein expression patterns during the development of pelvic fins and tetrapod hindlimbs. The pelvic fins of fish express key limb positioning, limb bud induction and limb outgrowth genes in a similar manner to that seen in hindlimb development of higher vertebrates. We are now at a point where many of the key players in the development of pelvic fins and vertebrate hindlimbs have been identified and we can now readily examine and compare mechanisms between species. This is yielding fascinating insights into how the developmental programme has altered during evolution and how that relates to anatomical change. The role of pelvic fins has also drastically changed over evolutionary history, from playing a minor role during swimming to developing into robust weight-bearing limbs. In addition, the pelvic fins/hindlimbs have been lost repeatedly in diverse species over evolutionary time. Here we review the evolution of pelvic fins and hindlimbs within the context of the changes in anatomical structure and the molecular mechanisms involved.


A case of spinocerebellar ataxia accompanied by severe involvement of the motor neuron system.
We report a sporadic case of spinocerebellar ataxia accompanied by later but severe involvement of the motor neuron system. A 72-year-old man began to show ataxia and dysarthria at age 66 years. Neurological examinations revealed saccadic eye movement, slurred speech, truncal ataxia, pyramidal sign, and urinary disturbance. Neither history of alcoholism nor hereditary factors were found. He developed muscular atrophy of the lower and upper extremities and limb ataxia within three years. Superficial and deep sensations were diminished in both feet four years after onset. Thus, he presented with cerebellar ataxia, bulbar sign, upper and lower motor neuron symptoms, sensory disturbance, and autonomic sign after six years at age 72. The level of serum, creatine phosphokinase (CPK) was increased, and muscle biopsy showed marked neurogenic change. Magnetic resonance imaging (MRI) revealed mild cerebellar and pontine atrophy. Although the combination of spinocerebellar ataxia and motor neuron disease is very rare, the present case suggests the inter-relation of the spinocerebellar and motor neuron systems, and presents peripheral neuropathy as a subtype of multisystem atrophy.


The use of liver grafts from donors with bacterial meningitis.
The shortage of suitable donors for transplantation is a worldwide problem. The use of cadaveric donors with bacterial meningitis may be associated with an increased risk of sepsis. We report the results of orthotopic liver transplantation (OLT) from 33 such donors between 1989 and 1999. The hospital records of recipients from cadaveric donors with meningitis (study group) were retrospectively reviewed and compared with matched recipients from cadaveric donors dying from causes other than meningitis (recipient-matched control group). A total of 34 recipients underwent 21 whole, 10 reduced, and 3 split liver transplants from 33 cadaveric donor livers with bacterial meningitis. The donor meningitis pathogens were Neisseria meningitidis (n=14), Streptococcus pneumoniae (n=4), Haemophilus influenzae (n=1), Streptococcus species (n=2), and unknown (n=12). Twenty-seven patients had an elective OLT and seven patients had an emergency OLT. Adequate antimicrobial therapy before organ procurement and after transplant was administrated. The mean posttransplant follow-up was 37 months (range: 1 day-106 months). There was no difference in recipient and graft survival rates between the study and the recipient-matched groups. In the study group, there were no infectious complications caused by the meningeal pathogens. Overall patient survival rates were 79%, 76%, 72%, and 72% at 1, 6, 12, and 60 months, respectively. Graft survival was 77%, 70%, 65%, and 65% at 1, 6, 12, and 60 months, respectively. The survival rate in elective cases was significantly better than emergency cases (P<0.05). Liver transplantation from donors with bacterial meningitis is a safe procedure provided both donors and recipients receive adequate antimicrobial therapy.


[Prevalence of Risk Factors for Metabolic Syndrome and Its Components in Community Kitchen Users in a District in Lima, Peru].
. To estimate the prevalence of risk factors for metabolic syndrome in adults who are community kitchen-users in a district in Lima. . An observational, cross-sectional study was carried out with 20 to 59-year-old users of community kitchens selected from a two-stage cluster sampling. The metabolic syndrome was measured according to the International Diabetes Federation (IDF). Risk factors proposed by the WHO and the IDF were assessed, as well as the diet needs and intake average and its components at lunch. . The global prevalence of metabolic syndrome was 40.1%: women exhibited a 30.4% prevalence and men 24%. Prevalence of the metabolic syndrome components were, abdominal obesity 51.6%, low C-HDL 42.2%, hypertriglyceridemia 35.3%, obesity 43.3%, overweight 35.8%, arterial hypertension 21.0%, and hyperglycemia 14.1%. A sedentary lifestyle is present in 86.1% of participants. . Excess weight, abdominal obesity, and high cholesterol were the most prevalent risk factors in women. The metabolic syndrome component with the highest prevalence in community kitchen users in a district of Lima is abdominal obesity.


Disposition of RS-26306, a potent luteinizing hormone-releasing hormone antagonist, in monkeys and rats after single intravenous and subcutaneous administration.
The metabolic disposition of RS-26306, a new potent luteinizing hormone-releasing hormone antagonist, was studied in rats and monkeys after single i.v. and sc administration with the 3H-labeled compound. Plasma pharmacokinetics after iv administration were: CLs = 2.5 ml/min/kg, Vd beta = 0.29 liter/kg, t1/2 = 1.4 hr (rats), and CLs = 0.8 ml/min/kg, Vd beta = 0.32 liter/kg, t1/2 = 5.1 hr (monkeys). Cmax and Tmax in rats were 0.53 micrograms/ml and 4 hr after the 1 mg/kg sc dose, and were 1.07 micrograms/ml and 12 hr after the 10 mg/kg sc dose. AUC0-infinity after the 10 mg/kg sc dose in rats was seven times that after the 1 mg/kg sc dose. Apparent plasma disappearance t1/2 in rats were 3.6 and 15.2 hr, respectively, after the 1 and 10 mg/kg sc doses. An average of 12 and 4% of dose radioactivity remained at the injection site in rats 3 and 10 days, respectively, after a 10 mg/kg sc dose. In monkeys, Tmax after a 1 mg/kg sc dose was 0.5 hr for three animals but was 24 hr for the fourth animal, although plasma of this monkey contained substantial levels of RS-26306 between 15 min and 24 hr. Apparent plasma t1/2 in monkeys after a 1 mg/kg sc dose was at least 19 hr. Our data suggest depot formation after sc doses. In vitro plasma binding amounted to 82-84%. Excretion was mainly biliary: 12-25 and 55-84% of dose radioactivity was recovered in urine and feces, respectively, in both species. The biological samples contained only traces of 3H2O. Three metabolites, which were truncated peptides of the parent decapeptide, were identified in the rat bile. One of these was also present in the monkey plasma. The restricted enzymatic degradation of RS-26306, extensive plasma binding, and long circulating t1/2 of RS-26306 contribute to its prolonged activity in animal models and in humans.


STAT5 ablation in AgRP neurons increases female adiposity and blunts food restriction adaptations.
AgRP neurons are important players in the control of energy homeostasis and are responsive to several hormones. In addition, STAT5 signalling in the brain, which is activated by metabolic hormones and growth factors, modulates food intake, body fat and glucose homeostasis. Given that, and the absence of studies that describe STAT5 function in AgRP cells, the present study investigated the metabolic effects of Stat5a/b gene ablation in these neurons. We observed that STAT5 signalling in AgRP neurons regulates body fat in female mice. However, male and female STAT5-knockout mice did not exhibit altered food intake, energy expenditure or glucose homeostasis compared to control mice. The counter-regulatory response or glucoprivic hyperphagia induced by 2-deoxy-d-glucose treatment were also not affected by AgRP-specific STAT5 ablation. However, under 60% food restriction, AgRP STAT5-knockout mice had a blunted upregulation of hypothalamic Agrp mRNA expression and corticosterone serum levels compared to control mice, suggesting a possible role for STAT5 in AgRP neurons for neuroendocrine adaptations to food restriction. Interestingly, ad libitum fed knockout male mice had reduced Pomc and Ucp-1 mRNA expression compared to control group. Taken together, these results suggest that STAT5 signalling in AgRP neurons regulates body adiposity in female mice, as well as some neuroendocrine adaptations to food restriction.


Nearest-neighbor analysis of higher-plant photosystem I holocomplex.
Photosystem 1 (PSI) preparations from barley (Hordeum vulgare) and spinach (Spinacia oleracea) were subjected to chemical cross-linking using the cleavable homobifunctional cross-linkers dithiobis(succinimidylpropionate) and 3,3'-dithiobis(sulfosuccinimidyl-propionate). The overall pattern of cross-linked products was analyzed by the simple but powerful technique of diagonal electrophoresis, in which the disulfide bond in the cross-linker was cleaved between the first and second dimensions of the gel, and immunoblotting. A large number of cross-linked products were identified. Together with preexisting data on the structure of PSI, it was deduced that the subunits PSI-D, PSI-H, PSI-I, and PSI-L occupy one side of the complex, whereas PSI-E, PSI-F, and PSI-J occupy the other. PSI-K and PSI-G appear to be adjacent to Lhca3 and Lhca2, respectively, and not close to the other small subunits. Experiments with isolated light-harvesting complex I preparations indicate that the subunits are organized as dimers, which seem to associate to the PSI-A/PSI-B proteins independent of each other. We suggest which PSI subunit corresponds to each membrane-spanning helix in the cyanobacterial PSI structure, and present a model for higher-plant PSI.


Sequence Analysis of IncA/C and IncI1 Plasmids Isolated from Multidrug-Resistant Salmonella Newport Using Single-Molecule Real-Time Sequencing.
Multidrug-resistant (MDR) plasmids play an important role in disseminating antimicrobial resistance genes. To elucidate the antimicrobial resistance gene compositions in A/C incompatibility complex (IncA/C) plasmids carried by animal-derived MDR Salmonella Newport, and to investigate the spread mechanism of IncA/C plasmids, this study characterizes the complete nucleotide sequences of IncA/C plasmids by comparative analysis. Complete nucleotide sequencing of plasmids and chromosomes of six MDR Salmonella Newport strains was performed using PacBio RSII. Open reading frames were assigned using prokaryotic genome annotation pipeline (PGAP). To understand genomic diversity and evolutionary relationships among Salmonella Newport IncA/C plasmids, we included three complete IncA/C plasmid sequences with similar backbones from Salmonella Newport and Escherichia coli: pSN254, pAM04528, and peH4H, and additional 200 draft chromosomes. With the exception of canine isolate CVM22462, which contained an additional IncI1 plasmid, each of the six MDR Salmonella Newport strains contained only the IncA/C plasmid. These IncA/C plasmids (including references) ranged in size from 80.1 (pCVM21538) to 176.5 kb (pSN254) and carried various resistance genes. Resistance genes floR, tetA, tetR, strA, strB, sul, and mer were identified in all IncA/C plasmids. Additionally, blaCMY-2 and sugE were present in all IncA/C plasmids, excepting pCVM21538. Plasmid pCVM22462 was capable of being transferred by conjugation. The IncI1 plasmid pCVM22462b in CVM22462 carried blaCMY-2 and sugE. Our data showed that MDR Salmonella Newport strains carrying similar IncA/C plasmids clustered together in the phylogenetic tree using chromosome sequences and the IncA/C plasmids from animal-derived Salmonella Newport contained diverse resistance genes. In the current study, we analyzed genomic diversities and phylogenetic relationships among MDR Salmonella Newport using complete plasmids and chromosome sequences and provided possible spread mechanism of IncA/C plasmids in Salmonella Newport Lineage II.


Aristaless related homeobox gene, Arx, is implicated in mouse fetal Leydig cell differentiation possibly through expressing in the progenitor cells.
Development of the testis begins with the expression of the SRY gene in pre-Sertoli cells. Soon after, testis cords containing Sertoli and germ cells are formed and fetal Leydig cells subsequently develop in the interstitial space. Studies using knockout mice have indicated that multiple genes encoding growth factors and transcription factors are implicated in fetal Leydig cell differentiation. Previously, we demonstrated that the Arx gene is implicated in this process. However, how ARX regulates Leydig cell differentiation remained unknown. In this study, we examined Arx KO testes and revealed that fetal Leydig cell numbers largely decrease throughout the fetal life. Since our study shows that fetal Leydig cells rarely proliferate, this decrease in the KO testes is thought to be due to defects of fetal Leydig progenitor cells. In sexually indifferent fetal gonads of wild type, ARX was expressed in the coelomic epithelial cells and cells underneath the epithelium as well as cells at the gonad-mesonephros border, both of which have been described to contain progenitors of fetal Leydig cells. After testis differentiation, ARX was expressed in a large population of the interstitial cells but not in fetal Leydig cells, raising the possibility that ARX-positive cells contain fetal Leydig progenitor cells. When examining marker gene expression, we observed cells as if they were differentiating into fetal Leydig cells from the progenitor cells. Based on these results, we propose that ARX acts as a positive factor for differentiation of fetal Leydig cells through functioning at the progenitor stage.


Human serum paraoxonase gene polymorphisms, Q192R and L55M, are not associated with the risk of cerebral infarction in Chinese Han population.
It has been reported that human serum paraoxonase (PON1) gene is associated with coronary heart disease (CHD) and diabetes mellitus (DM). However, little is known about the role of PON1 gene polymorphism in cerebral infarction (CI). For this, we have investigated the relationship between PON1 gene polymorphisms, Q192R and L55M, and CI in Chinese Han population. The PON1 genotypes, Q192R and L55M, from 153 CI patients and 153 healthy individuals, were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. Their allele frequencies were then determined. The association of the PON1 gene polymorphism with the risk of CI was analysed by statistical analysis software. The frequencies of PON1-Q192R genotypes in CI and control group are 13.7 and 9.8% (QQ), 51.6 and 53.6% (QR), 34.6 and 36.6% (RR) respectively. There is no significant difference in PON1-Q192R genotype (p=0.566) and allele frequencies (p=0.505) between CI patients and controls. The frequencies of PON1-55 genotypes in the CI and control group are 96.7 and 93.5% (LL), 3.3 and 6.5% (LM) respectively. No MM genotype was found in both CI and control group. No significant difference in genotype (p=0.289) and allele (p=0.296) distribution between CI patients and controls was observed. Our results suggest that the human serum paraoxonase polymorphisms, Q192R and L55M, are not associated with the risk of cerebral infarction in Chinese Han population.


Reaching-related Neurons in Superior Parietal Area 5: Influence of the Target Visibility.
Reaching movements require the integration of both somatic and visual information. These signals can have different relevance, depending on whether reaches are performed toward visual or memorized targets. We tested the hypothesis that under such conditions, therefore depending on target visibility, posterior parietal neurons integrate differently somatic and visual signals. Monkeys were trained to execute both types of reaches from different hand resting positions and in total darkness. Neural activity was recorded in Area 5 (PE) and analyzed by focusing on the preparatory epoch, that is, before movement initiation. Many neurons were influenced by the initial hand position, and most of them were further modulated by the target visibility. For the same starting position, we found a prevalence of neurons with activity that differed depending on whether hand movement was performed toward memorized or visual targets. This result suggests that posterior parietal cortex integrates available signals in a flexible way based on contextual demands.


Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis.
We have demonstrated previously that local, adenoviral-mediated gene transfer of viral IL-10 to a single joint of rabbits and mice with experimental arthritis can suppress disease in both the treated and untreated contralateral joints. This contralateral effect is mediated in part by APCs able to traffic from the treated joint to lymph nodes as well as to untreated joints. Moreover, injection of dendritic cells (DC) genetically modified to express IL-4 or Fas ligand was able to reverse established murine arthritis. To examine the ability of exosomes derived from immunosuppressive DCs to reduce inflammation and autoimmunity, murine models of delayed-type hypersensitivity and collagen-induced arthritis were used. In this study, we demonstrate that periarticular administration of exosomes purified from either bone marrow-derived DCs transduced ex vivo with an adenovirus expressing viral IL-10 or bone marrow-derived DCs treated with recombinant murine IL-10 were able to suppress delayed-type hypersensitivity responses within injected and untreated contralateral joints. In addition, the systemic injection of IL-10-treated DC-derived exosomes was able suppress the onset of murine collagen-induced arthritis as well as reduce severity of established arthritis. Taken together, these data suggest that immature DCs are able to secrete exosomes that are involved in the suppression of inflammatory and autoimmune responses. Thus DC-derived exosomes may represent a novel, cell-free therapy for the treatment of autoimmune diseases.


Validity of self-reported lunch recalls in Swedish school children aged 6-8 years.
Previous studies have suggested that young children are inaccurate reporters of dietary intake. The purpose of this study was to validate a single recall of the previous day's school lunch reported by 6-8 year old Swedish children and to assess teacher-recorded intake of the same meal in a standardized food journal. An additional research question was whether parents could report their child's intake of the previous day's lunch. Subjects constituted a convenience sample from the large, multi-country study Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS (IDEFICS). Validations of both children's recalls and teachers' records were made by comparing results with the duplicate plate reference method. Twenty-five children (12 boys/13 girls) aged 6-8 years participated in the validation study at one school in western Sweden. Children were accurate self-reporters of their dietary intake at lunch, with no significant difference between reported and weighed intake (Mean difference (SD): 7(50) kcals, p=0.49). Teachers significantly over-reported intake (Mean difference (SD): 65(79) kcals, p=0.01). For both methods, child-reported and teacher-recorded, correlations with weighed intake were strong (Pearson's correlations r=0.92, p<0.001 and r=0.83, p<0.001 respectively). Bland-Altman plots showed strong agreement between child-reported and weighed intakes but confirmed systematic differences between teacher-records and weighed intakes. Foods were recalled by children with a food-match rate of 90%. In all cases parents themselves were unable to report on quantities consumed and only four of 25 children had parents with knowledge regarding food items consumed. Children 6-8 years of age accurately recalled their school lunch intake for one occasion while teachers recorded with less accuracy. Our findings suggest that children as young as six years of age may be better able to report on their dietary intake than previously suggested, at least for one main meal at school. Teacher-recorded intake provides a satisfactory estimate but with greater systematic deviation from the weighed intake. Parents were not able to report on their children's school lunches consumed on the previous day.


Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4.
One line of mice harboring a cardiac-specific epoxygenase transgene developed head swelling and rapid neurological decline in young adulthood, and had marked hydrocephalus of the lateral and third ventricles. The transgene was found to be inserted into an intron in the mouse Rfx4 locus. This insertion apparently prevented expression of a novel variant transcript of RFX4 (RFX4_v3), a member of the regulatory factor X family of winged helix transcription factors. Interruption of two alleles resulted in profound failure of dorsal midline brain structure formation and perinatal death, presumably by interfering with expression of downstream genes. Interruption of a single allele prevented formation of the subcommissural organ, a structure important for cerebrospinal fluid flow through the aqueduct of Sylvius, and resulted in congenital hydrocephalus. These data implicate the RFX4_v3 variant transcript as being crucial for early brain development, as well as for the genesis of the subcommissural organ. These findings may be relevant to human congenital hydrocephalus, a birth defect that affects approximately 0.6 per 1000 newborns.


A new prognostic score for AIDS-related lymphomas in the rituximab-era.
While the International Prognostic Index is commonly used to predict outcomes in immunocompetent patients with aggressive B-cell non-Hodgkin lymphomas, HIV-infection is an important competing risk for death in patients with AIDS-related lymphomas. We investigated whether a newly created prognostic score (AIDS-related lymphoma International Prognostic Index) could better assess risk of death in patients with AIDS-related lymphomas. We randomly divided a dataset of 487 patients newly diagnosed with AIDS-related lymphomas and treated with rituximab-containing chemoimmunotherapy into a training (n=244) and validation (n=243) set. We examined the association of HIV-related and other known risk factors with overall survival in both sets independently. We defined a new score (AIDS-related lymphoma International Prognostic Index) by assigning weights to each significant predictor [age-adjusted International Prognostic Index, extranodal sites, HIV-score (composed of CD4 count, viral load, and prior history of AIDS)] with three risk categories similar to the age-adjusted International Prognostic Index (low, intermediate and high risk). We compared the prognostic value for overall survival between AIDS-related lymphoma International Prognostic Index and age-adjusted International Prognostic Index in the validation set and found that the AIDS-related lymphoma International Prognostic Index performed significantly better in predicting risk of death than the age-adjusted International Prognostic Index (P=0.004) and better discriminated risk of death between each risk category (P=0.015 vs. P=0.13). Twenty-eight percent of patients were defined as low risk by the ARL-IPI and had an estimated 5-year overall survival (OS) of 78% (52% intermediate risk, 5-year OS 60%; 20% high risk, 5-year OS 50%).


Information and communication technology use by female residents of public housing.
Evidence suggests that Internet, mobile, or social media based-interventions may promote obesity-lowering behavior change, which has implications for cancer prevention and control interventions. However, the uptake of communication technologies among low socioeconomic status individuals, who need obesity management strategies most, is unclear. Using the baseline data from a cluster-randomized behavioral intervention trial, we examined the cross-sectional associations of frequency of information and communication technologies (ICT) use among female public housing residents, as well as the variation of ICT use across demographic and health-related variables. ICT use was common among female public housing residents, with mobile use for calls and texts most prevalent (97% and 84%, respectively). Internet, social media, and health information users tended to be younger compared to non-users. Email, Internet, multimodal, and health information users were more likely to be born in the U.S. and be more highly educated than non-users. Social media and health information users were more likely to be Spanish speakers and people of Hispanic ethnicity compared to non-users, although this was not statistically significant. There were few differences according to obesity or physical activity level. Our findings of differential socio-demographics between users vs. non-users suggests that future cancer prevention and control interventions among public housing residents should consider selecting ICT that are aligned with the usage patterns of different groups making up the intended audience.


Cancer in systemic sclerosis.
To determine whether the frequency of cancer is increased among patients with systemic sclerosis (SSc). A retrospective chart review of 248 patients who were followed up prospectively was conducted. Cancers developed in 18 patients (7.3%) during 2,001 patient-years at risk. The most frequent types were cancers of the lung (7 patients) and breast (5 patients). Older age at diagnosis of SSc was a significant risk factor for cancer. Lung cancer was associated with the presence of pulmonary fibrosis. The age-standardized incidence rate for all cancers (7.9/1,000) was 2.1 times the overall rate in the Ontario population (P < 0.0001). The frequency of cancer is increased in patients with SSc.


Assessing protected area vulnerability to climate change in a case study of South African national parks.
Climate change is challenging the ability of protected areas (PAs) to meet their objectives. To improve PA planning, we developed a framework for assessing PA vulnerability to climate change based on consideration of potential climate change impacts on species and their habitats and resource use. Furthermore, the capacity of PAs to adapt to these climate threats was determined through assessment of PA management effectiveness, adjacent land use, and financial resilience. Users reach a PA-specific vulnerability score and rank based on scoring of these categories. We applied the framework to South Africa's 19 national parks. Because the 19 parks are managed as a national network, we explored how resources might be best allocated to address climate change. Each park's importance to the network's biodiversity conservation and revenue generation was estimated and used to weight overall vulnerability scores and ranks. Park vulnerability profiles showed distinct combinations of potential impacts of climate change and adaptive capacities; the former had a greater influence on vulnerability. Mapungubwe National Park emerged as the most vulnerable to climate change, despite its relatively high adaptive capacity, largely owing to large projected changes in species and resource use. Table Mountain National Park scored the lowest in overall vulnerability. Climate change vulnerability rankings differed markedly once importance weightings were applied; Kruger National Park was the most vulnerable under both importance scenarios. Climate change vulnerability assessment is fundamental to effective adaptation planning. Our PA assessment tool is the only tool that quantifies PA vulnerability to climate change in a comparative index. It may be used in data-rich and data-poor contexts to prioritize resource allocation across PA networks and can be applied from local to global scales.


Blockchain in healthcare and health sciences-A scoping review.
Blockchain can be described as an immutable ledger, logging data entries in a decentralized manner. This new technology has been suggested to disrupt a wide range of data-driven domains, including the health domain. The purpose of this study was to systematically review, assess and synthesize peer-reviewed publications utilizing/proposing to utilize blockchain to improve processes and services in healthcare, health sciences and health education. A structured literature search on the topic was conducted in October 2018 relevant bibliographic databases. 39 publications fulfilled the inclusion criteria. The result indicates that Electronic Health Records and Personal Health Records are the most targeted areas using blockchain technology. Access control, interoperability, provenance and data integrity are all issues that are meant to be improved by blockchain technology in this field. Ethereum and Hyperledger fabric seem to be the most used platforms/frameworks in this domain. This study shows that the endeavors of using blockchain technology in the health domain are increasing exponentially. There are areas within the health domain that potentially could be highly impacted by blockchain technology.


Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis.
Myelofibrosis (MF) is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, and progressive bone marrow (BM) fibrosis. The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib has been shown to improve splenomegaly, symptom burden, and overall survival in patients with intermediate-2 or high-risk MF compared with placebo or best available therapy (BAT). The effects of ruxolitinib therapy for up to 66 months on BM morphology in 68 patients with advanced MF with variable BM fibrosis grade were compared with those in 192 matching patients treated with BAT. Available trephine biopsies underwent independent, blinded review by three hematopathologists for consensus-based adjudication of grades for reticulin fibrosis, collagen deposition, and osteosclerosis. Ruxolitinib treatment versus BAT was associated with greater odds of BM fibrosis improvement or stabilization and decreased odds of BM fibrosis worsening based on changes from baseline in reticulin fibrosis grade. Generally, these changes were accompanied by a sustained higher level of individual spleen size reduction and regression of leukoerythroblastosis. Patients with more advanced baseline fibrosis showed lower spleen size response. The finding that long-term ruxolitinib therapy may reverse or markedly delay BM fibrosis progression in advanced MF suggests that sustained JAK inhibition may be disease-modifying. INCB18424-251, ClinicalTrials.gov identifier NCT00509899 .


Statistical structure of neural spiking under non-Poissonian or other non-white stimulation.
Nerve cells in the brain generate sequences of action potentials with a complex statistics. Theoretical attempts to understand this statistics were largely limited to the case of a temporally uncorrelated input (Poissonian shot noise) from the neurons in the surrounding network. However, the stimulation from thousands of other neurons has various sorts of temporal structure. Firstly, input spike trains are temporally correlated because their firing rates can carry complex signals and because of cell-intrinsic properties like neural refractoriness, bursting, or adaptation. Secondly, at the connections between neurons, the synapses, usage-dependent changes in the synaptic weight (short-term plasticity) further shape the correlation structure of the effective input to the cell. From the theoretical side, it is poorly understood how these correlated stimuli, so-called colored noise, affect the spike train statistics. In particular, no standard method exists to solve the associated first-passage-time problem for the interspike-interval statistics with an arbitrarily colored noise. Assuming that input fluctuations are weaker than the mean neuronal drive, we derive simple formulas for the essential interspike-interval statistics for a canonical model of a tonically firing neuron subjected to arbitrarily correlated input from the network. We verify our theory by numerical simulations for three paradigmatic situations that lead to input correlations: (i) rate-coded naturalistic stimuli in presynaptic spike trains; (ii) presynaptic refractoriness or bursting; (iii) synaptic short-term plasticity. In all cases, we find severe effects on interval statistics. Our results provide a framework for the interpretation of firing statistics measured in vivo in the brain.


Management of hepatitis B after renal transplantation: an update.
Hepatitis B Virus (HBV) infection remains an important cause of liver disease in renal transplant (RT) recipients and the outcome of HBV infected RT recipients is less favorable than that of noninfected RT recipients. The concern about graft loss induced by interferon (IFN) therapy precludes its use; lamivudine, a second-generation analog, has been recently approved for the treatment of hepatitis B and promises to be highly effective in this setting. Several uncontrolled trials have reported a high rate of biochemical (ranging between 80% and 100%) and virological (ranging between 67% and 100%) response in RT recipients, comparable to immunocompetent patients. Lamivudine has an excellent safety profile in RT recipients. However, the emergence of viral mutations leading to resistance has been reported during lamivudine therapy in RT recipients. In addition, numerous issues remain to be clarified about lamivudine use after RT including the management of viral resistance, the role of HBV genotypes in the response to lamivudine, and the duration of therapy and response. The combination of newer nucleoside analogues with lamivudine, analogous to HIV, may further improve the efficacy of antiviral therapy against HBV after RT.


The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profiling and Implications for Treatment.
The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 guidelines for HER2 assessment have increased the number of HER2 equivocal breast carcinomas following in situ hybridization reflex testing, that is, HER2 "double equivocal" (equivocal protein expression and equivocal gene copy number). Forty-five double-equivocal carcinomas were subjected to Prosigna analysis. Twenty-seven cases were investigated for the expression of genes found to be differentially expressed between estrogen receptor (ER)-positive/HER2-positive (N=22) and ER-positive/HER2-negative (N=22) control cases. Twenty-nine of the 45 cases were also analyzed by targeted sequencing using a panel of 14 genes. We then explored the pathologic complete response rates in an independent series of double-equivocal carcinoma patients treated with trastuzumab-containing chemotherapy. All cases were ER-positive, with a mean Ki67 of 28%. Double-equivocal carcinomas were predominantly luminal B (76%); 9 cases (20%) were luminal A, and 2 cases (4%) HER2-enriched. The majority (73%) showed a high risk of recurrence by Prosigna, even when the carcinomas were small (<2 cm), node-negative/micrometastatic, and/or grade 2. Double-equivocal carcinomas showed TP53 (6/29, 20%), PIK3CA (3/29, 10%), HER2 (1/29, 3%), and MAP2K4 (1/29, 3%) mutations. Compared with grade-matched ER-positive/HER2-negative breast carcinomas from METABRIC, double-equivocal carcinomas harbored more frequently TP53 mutations and less frequently PIK3CA mutations (P<0.05). No significant differences were observed with grade-matched ER-positive/HER2-positive carcinomas. Lower pathologic complete response rates were observed in double-equivocal compared with HER2-positive patients (10% vs. 60%, P=0.009). Double-equivocal carcinomas are preferentially luminal B and show a high risk of recurrence. A subset of these tumors can be labeled as HER2-enriched by transcriptomic analysis. HER2 mutations can be identified in HER2 double-equivocal cases.


The influence of trait-negative affect and compassion satisfaction on compassion fatigue in Australian nurses.
For this study, we examined the nature of the unique relationships trait-negative affect and compassion satisfaction had with compassion fatigue and its components of secondary traumatic stress and burnout in 273 nurses from 1 metropolitan tertiary acute hospital in Western Australia. Participants completed the Professional Quality of Life Scale (Stamm, 2010), Depression Anxiety Stress Scale (Lovibond & Lovibond, 2004), and the State-Trait Anxiety Inventory (Spielberger, Gorsuch, Lushene, Vagg, & Jacobs, 1983). Bivariate correlation and hierarchical regression analyses were performed to examine and investigate 4 hypotheses. The results demonstrate a clear differential pattern of relationships with secondary traumatic stress and burnout for both trait-negative affect and compassion satisfaction. Trait-negative affect was clearly the more important factor in terms of its contribution to overall compassion fatigue and secondary traumatic stress. In contrast, compassion satisfaction's unique protective relationship only related to burnout, and not secondary traumatic stress. The results are therefore consistent with the view that compassion satisfaction may be an important internal resource that protects against burnout, but is not directly influential in protecting against secondary traumatic stress for nurses working in an acute-care hospital environment. With the projected nursing workforce shortages in Australia, it is apparent that a further understanding is warranted of how such personal variables may work as protective and risk factors.


Addressing the needs of older adults receiving alcohol treatment during the COVID-19 pandemic: a qualitative study.
The COVID-19 global pandemic resulted in major changes to the provision of alcohol treatment in the UK, these changes coincided with increases in the use of alcohol. This study sought to understand the impact of the pandemic on older adults in alcohol treatment, and to explore how changes in the provision of alcohol treatment were experienced. Semi-structured interviews were completed with older adults (aged 55+) in alcohol treatment, as well as alcohol practitioners providing support to older adults. Data were analysed using thematic analysis. Alcohol use was assessed using the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C). Thirty older adults in alcohol treatment and fifteen alcohol practitioners were recruited. The COVID-19 pandemic was found to result in both increases and decreases in alcohol use; changes in alcohol use depended on a number of factors, such as living arrangements, family support, physical and mental health. Many alcohol treatment services moved to a model of remote support during the pandemic. However, face-to-face service provision was considered to be essential by both older adults in alcohol treatment and alcohol practitioners. Engagement with online support was low, with older adults facing barriers in using online technology. The study highlights the importance of face-to-face treatment and intervention for older adults in alcohol treatment. Addiction services may see increased demand for treatment as a result of the pandemic; it is important that services consider the needs of older adults, many of whom may be marginalised by a remote model of service provision.


Groundwater risk assessment at a heavily industrialised catchment and the associated impacts on a peri-urban wetland.
Industrial and agricultural activities often impose significant pressures to the groundwater quality and consequently degrade wetland ecosystems that depend mostly on subsurface water flow. Groundwater vulnerability and risk mapping is a widely used approach to assess the natural protection of aquifers and the associated pollution potential from human activities. In the particular study, the relatively new Pan-European methodology (COP method) has been applied in a highly industrialized peri-urban wetland catchment, located close to Athens city, to map the intrinsic vulnerability of the aquifer and evaluate the risk potential originating from local land uses. Groundwater analysis results for various parameters, including Phenols, PCBs and nutrients, have been used to validate the vulnerability and risk estimations while a biological assessment occurred to associate the mapping results with the wetland's ecological status. The results indicated that even though the natural protection of the aquifer is relatively high due to the dominant hydrogeologic and geomorphologic conditions, the groundwater pollution risk is considerable, mainly because of the existing hazardous land uses. The water quality of the groundwater accredited these findings and the ecological status of this peri-urban wetland also indicated significant impacts from industrial effluents.


Gold nanoparticles stabilized with MPEG-grafted poly(l-lysine): in vitro and in vivo evaluation of a potential theranostic agent.
As the number of diagnostic and therapeutic applications utilizing gold nanoparticles (AuNPs) increases, so does the need for AuNPs that are stable in vivo, biocompatible, and suitable for bioconjugation. We investigated a strategy for AuNP stabilization that uses methoxypolyethylene glycol-graft-poly(l-lysine) copolymer (MPEG-gPLL) bearing free amino groups as a stabilizing molecule. MPEG-gPLL injected into water solutions of HAuCl4 with or without trisodium citrate resulted in spherical (Zav = 36 nm), monodisperse (PDI = 0.27), weakly positively charged nanoparticles (AuNP3) with electron-dense cores (diameter: 10.4 ± 2.5 nm) and surface amino groups that were amenable to covalent modification. The AuNP3 were stable against aggregation in the presence of phosphate and serum proteins and remained dispersed after their uptake into endosomes. MPEG-gPLL-stabilized AuNP3 exhibited high uptake and very low toxicity in human endothelial cells, but showed a high dose-dependent toxicity in epithelioid cancer cells. Highly stable radioactive labeling of AuNP3 with (99m)Tc allowed imaging of AuNP3 biodistribution and revealed dose-dependent long circulation in the blood. The minor fraction of AuGNP3 was found in major organs and at sites of experimentally induced inflammation. Gold analysis showed evidence of a partial degradation of the MPEG-gPLL layer in AuNP3 particles accumulated in major organs. Radiofrequency-mediated heating of AuNP3 solutions showed that AuNP3 exhibited heating behavior consistent with 10 nm core nanoparticles. We conclude that PEG-pPLL coating of AuNPs confers "stealth" properties that enable these particles to exist in vivo in a nonaggregating, biocompatible state making them suitable for potential use in biomedical applications such as noninvasive radiofrequency cancer therapy.


Physical function and exercise training in older patients with heart failure.
Heart failure (HF) is a common end point for numerous cardiovascular conditions, including coronary artery disease, valvular disease, and hypertension. HF predominantly affects older individuals (aged ≥70 years), particularly those living in developed countries. The pathophysiological sequelae of HF progression have a substantial negative effect on physical function. Diminished physical function in older patients with HF, which is the result of combined disease-related and age-related effects, has important implications on health. A large body of research spanning several decades has demonstrated the safety and efficacy of regular physical activity in improving outcomes among the HF population, regardless of age, sex, or ethnicity. However, patients with HF, especially those who are older, are less likely to engage in regular exercise training compared with the general population. To improve initiation of regular exercise training and subsequent long-term compliance, there is a need to rethink the dialogue between clinicians and patients. This Review discusses the need to improve physical function and exercise habits in patients with HF, focusing on the older population.


Kinome-Wide RNA Interference Screening Identifies Mitogen-Activated Protein Kinases and Phosphatidylinositol Metabolism as Key Factors for Rabies Virus Infection.
Throughout the rabies virus (RABV) infectious cycle, host-virus interactions define its capacity to replicate, escape the immune response, and spread. As phosphorylation is a key regulatory mechanism involved in most cellular processes, kinases represent a target of choice to identify host factors required for viral replication. A kinase and phosphatase small interfering RNA (siRNA) high-content screening was performed on a fluorescent protein-recombinant field isolate (Tha RABV). We identified 57 high-confidence key host factors important for RABV replication with a readout set at 18 h postinfection and 73 with a readout set at 36 h postinfection, including 24 common factors at all stages of the infection. Amongst them, gene clusters of the most prominent pathways were determined. Up to 15 mitogen-activated protein kinases (MAPKs) and effectors, including MKK7 (associated with Jun N-terminal protein kinase [JNK] signalization) and DUSP5, as well as 17 phosphatidylinositol (PI)-related proteins, including PIP5K1C and MTM1, were found to be involved in the later stage of RABV infection. The importance of these pathways was further validated, as small molecules Ro 31-8820 and PD 198306 inhibited RABV replication in human neurons.IMPORTANCE Rabies virus relies on cellular machinery for its replication while simultaneously evading the host immune response. Despite their importance, little is known about the key host factors required for rabies virus infection. Here, we focused on the human kinome, at the core of many cellular pathways, to unveil a new understanding of the rabies virus infectious cycle and to discover new potential therapeutic targets in a small interfering RNA screening. The mitogen-activated protein kinase pathway and phosphatidylinositol metabolism were identified as prominent factors involved in rabies virus infection, and those findings were further confirmed in human neurons. While bringing a new insight into rabies virus biology, we also provide a new list of host factors involved in rabies virus infection.


Density dependence and cooperation: theory and a test with bacteria.
Although cooperative systems can persist in nature despite the potential for exploitation by noncooperators, it is often observed that small changes in population demography can tip the balance of selective forces for or against cooperation. Here we consider the role of population density in the context of microbial cooperation. First, we account for conflicting results from recent studies by demonstrating theoretically that: (1) for public goods cooperation, higher densities are relatively unfavorable for cooperation; (2) in contrast, for self-restraint-type cooperation, higher densities can be either favorable or unfavorable for cooperation, depending on the details of the system. We then test our predictions concerning public goods cooperation using strains of the pathogenic bacterium Pseudomonas aeruginosa that produce variable levels of a public good-iron-scavenging siderophore molecules. As predicted, we found that the relative fitness of cheats (under-producers) was greatest at higher population densities. Furthermore, as assumed by theory, we show that this occurs because cheats are better able to exploit the cooperative siderophore production of other cells when they are physically closer to them.


Circulating aldosterone and natriuretic peptides in the general community: relationship to cardiorenal and metabolic disease.
We sought to investigate the role of aldosterone as a mediator of disease and its relationship with the counter-regulatory natriuretic peptide (NP) system. We measured plasma aldosterone (n=1674; aged≥45 years old) in a random sample of the general population from Olmsted County, MN. In a multivariate logistic regression model, aldosterone analyzed as a continuous variable was associated with hypertension (odds ratio [OR]=1.75; 95% confidence interval [CI]=1.57-1.96; P<0.0001), obesity (OR=1.34; 95% CI=1.21-1.48; P<0.0001), chronic kidney disease (OR=1.39; 95% CI=1.22-1.60; P<0.0001), central obesity (OR=1.47; 95% CI=1.32-1.63; P<0.0001), metabolic syndrome (OR=1.41; 95% CI=1.26-1.58; P<0.0001), high triglycerides (OR=1.23; 95% CI=1.11-1.36; P<0.0001), concentric left ventricular hypertrophy (OR=1.22; 95% CI=1.09-1.38; P=0.0007), and atrial fibrillation (OR=1.24; 95% CI=1.01-1.53; P=0.04), after adjusting for age and sex. The associations with hypertension, central obesity, metabolic syndrome, triglycerides, and concentric left ventricular hypertrophy remained significant after further adjustment for body mass index, NPs, and renal function. Furthermore, aldosterone in the highest tertile correlated with lower NP levels and increased mortality. Importantly, most of these associations remained significant even after excluding subjects with aldosterone levels above the normal range. In conclusion, we report that aldosterone is associated with hypertension, chronic kidney disease, obesity, metabolic syndrome, concentric left ventricular hypertrophy, and lower NPs in the general community. Our data suggest that aldosterone, even within the normal range, may be a biomarker of cardiorenal and metabolic disease. Further studies are warranted to evaluate a therapeutic and preventive strategy to delay the onset and progression of disease, using mineralocorticoid antagonists or chronic NP administration in high-risk subjects identified by plasma aldosterone.


Adult Plant Slow Rusting Genes Confer High Levels of Resistance to Rusts in Bread Wheat Cultivars From Mexico.
Rust diseases continuously threaten global wheat production: stem rust, leaf rust, and yellow rust caused by Puccinia graminis f. sp. tritici, Puccinia triticina, and Puccinia striiformis f. sp. tritici, respectively. Recent studies indicated that the average losses from all these three rusts reached up to 15.04 million tons per year, which is equivalent to an annual average loss of around US $2.9 billion per year. The major focus of Mexican and worldwide breeding programs is the release of rust resistant cultivars, as this is considered the best option for controlling rust diseases. In Mexico, the emphasis has been placed on genes that confer partial resistance in the adult plant stage and against a broad spectrum of rust races since the 1970s. In this study, a set of the first-generation tall varieties developed and released in the 1940s and 1950s, the first semi-dwarfs, and other releases in Mexico, all of which showed different levels of rust resistance have been phenotyped for the three rust diseases and genotyped. Results of the molecular marker detection indicated that Lr34, Lr46, Lr67, and Lr68 alone or in different gene combinations were present among the wheat cultivars. Flag leaf tip necrosis was present in all cultivars and most were positive for brown necrosis or Pseudo Black Chaff associated with the Sr2 stem rust resistance complex. The phenotypic responses to the different rust infections indicate the presence of additional slow rusting and race-specific resistance genes. The study reveals the association of the slow rusting genes with durable resistance to the three rusts including Ug99 in cultivars bred before the green revolution such as Frontera, Supremo 211, Chapingo 48, Yaqui 50, Kentana 52, Bajio 52, Bajio 53, Yaqui 53, Chapingo 53, Yaktana Tardio 54, and Mayo 54 and their descendants after intercrossing and recombination. These slow rusting genes are the backbone of the resistance in the current Mexican germplasm.


Determination of optimal liquid medium for enzyme expression by Helicobacter pylori.
To determine the best medium for the growth and enzyme expression of Helicobacter pylori. Twelve H pylori isolates from histologically confirmed infected patients were cultured on Brucella broth (BB), Brucella broth minus bisulphite (BLBB), and brain-heart infusion broth (BHIB), all supplemented with 5% (v/v) fetal calf serum. Growth rates and enzyme expressions of all H pylori isolates cultivated in these media were evaluated. Although both BLBB and BHIB supported good growth of H pylori under microaerophilic conditions, the total protein content of H pylori detected was much higher with BHIB cultivation. Measurement of the specific activities of urease, phospholipase C, and sphingomyelinase for 12 H pylori isolates cultivated in these media, showed that BHIB supported the highest expression of these enzymes. Although BLBB supported better growth of H pylori than BB, it did not increase enzyme expression. Cultivation of H pylori in BHIB is recommended for studies on the physiology, metabolism, and enzyme expression of the organism.


Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study.
To estimate the real world effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S vaccines against confirmed covid-19 symptoms (including the UK variant of concern B.1.1.7), admissions to hospital, and deaths. Test negative case-control study. Community testing for covid-19 in England. 156 930 adults aged 70 years and older who reported symptoms of covid-19 between 8 December 2020 and 19 February 2021 and were successfully linked to vaccination data in the National Immunisation Management System. Vaccination with BNT162b2 or ChAdOx1-S. Primary outcomes were polymerase chain reaction confirmed symptomatic SARS-CoV-2 infections, admissions to hospital for covid-19, and deaths with covid-19. Participants aged 80 years and older vaccinated with BNT162b2 before 4 January 2021 had a higher odds of testing positive for covid-19 in the first nine days after vaccination (odds ratio up to 1.48, 95% confidence interval 1.23 to 1.77), indicating that those initially targeted had a higher underlying risk of infection. Vaccine effectiveness was therefore compared with the baseline post-vaccination period. Vaccine effects were noted 10 to 13 days after vaccination, reaching a vaccine effectiveness of 70% (95% confidence interval 59% to 78%), then plateauing. From 14 days after the second dose a vaccination effectiveness of 89% (85% to 93%) was found compared with the increased baseline risk. Participants aged 70 years and older vaccinated from 4 January (when ChAdOx1-S delivery commenced) had a similar underlying risk of covid-19 to unvaccinated individuals. With BNT162b2, vaccine effectiveness reached 61% (51% to 69%) from 28 to 34 days after vaccination, then plateaued. With ChAdOx1-S, effects were seen from 14 to 20 days after vaccination, reaching an effectiveness of 60% (41% to 73%) from 28 to 34 days, increasing to 73% (27% to 90%) from day 35 onwards. On top of the protection against symptomatic disease, a further 43% (33% to 52%) reduced risk of emergency hospital admission and 51% (37% to 62%) reduced risk of death was observed in those who had received one dose of BNT162b2. Participants who had received one dose of ChAdOx1-S had a further 37% (3% to 59%) reduced risk of emergency hospital admission. Follow-up was insufficient to assess the effect of ChAdOx1-S on mortality. Combined with the effect against symptomatic disease, a single dose of either vaccine was about 80% effective at preventing admission to hospital with covid-19 and a single dose of BNT162b2 was 85% effective at preventing death with covid-19. Vaccination with either one dose of BNT162b2 or ChAdOx1-S was associated with a significant reduction in symptomatic covid-19 in older adults, and with further protection against severe disease. Both vaccines showed similar effects. Protection was maintained for the duration of follow-up (>6 weeks). A second dose of BNT162b2 was associated with further protection against symptomatic disease. A clear effect of the vaccines against the B.1.1.7 variant was found.


Fluorescent microplate assay for cancer cell-associated cathepsin B.
Cathepsin B and in particular cell-surface and secreted cathepsin B has been implicated in the invasive and metastatic phenotype of numerous types of cancer. We describe here a method to easily survey cancer cell lines for cathepsin B activity using the highly selective substrate Z-Arg-Arg-AMC. Intact human U87 glioma cells hydrolyze Z-Arg-Arg-AMC with a Km of 460 microM at pH 7.0 and 37 degrees C. This is nearly the same as the Km of 430 microM obtained with purified cathepsin B assayed under the same conditions. The pericellular (i.e. both cell-surface and released) cathepsin B activity was inhibited by the cysteine protease inhibitors E-64, leupeptin, Mu-Np2-HphVS-2Np, Mu-Leu-HpHVSPh and the cathepsin B selective inhibitor Mu-Tyr(3,5 I2)-HphVSPh with IC50 values similar to those observed for the inhibition of purified human liver cathepsin B. Other human cancer cell lines with measurable pericellular cathepsin B activity included HT-1080 fibrosarcoma, MiaPaCa pancreatic, PC-3 prostate and HCT-116 colon. Cathepsin B activity correlated with protein levels of cathepsin B as determined by immunoblot analysis. Pericellular cathepsin B activity was also detected in the rat cell lines MatLyLu prostate and Mat B III adenocarcinoma and in the murine lines B16a melanoma and Lewis lung carcinoma. The ability to determine pericellular cathepsin B activity will be useful in selecting appropriate cell lines for use in vivo when analyzing the effects of inhibiting cathepsin B activity on tumor growth and metastasis.


The isolated retina of mammals: A useful preparation for enzymatic-(adenylyl cyclase) and/or binding studies of dopamine receptors.
Rabbit and bovine retinae were used for investigations in vitro related to dopamine receptors. Dose-dependent stimulations of cyclic AMP formation induced by dopamine (or dopamine-like drugs including ADTN and some ergot alkaloid derivatives), which can be blocked by dopamine antagonists (neuroleptics), lithium or d-LSD, were found either in intact retinae or in homogenates. The neuroleptic sulpiride was the only exception since it was devoid of inhibitory effects. Binding studies of retinal dopamine receptors were also achieved with homogenates. By using (3)H-spiroperidol as a ligand, saturability (in the amolar range), stereospecificity (by using butaclamol- or thioxanthene-isomers), tissue linearity, and pH- or temperature-dependence were all demonstrated. Furthermore, displacement curves of (3)H-spiroperidol stereospecifically bound generated by various dopamineand/or catecholamine-related drugs seem to indicate that dopamine receptors are the only monoamine receptors in this tissue and that a coupling possibly exists between binding- and catalytic-sites. These results suggest that by studying both dopamine-sensitive adenylyl cyclase and drug-induced displacement of (3)H-spiroperidol binding the mammalian retina is appropriate to selectively characterize the type of action of various drugs with CNS dopamine receptors.


Optimizing outpatient total hip arthroplasty: perspectives of key stakeholders.
Advances in surgical techniques combined with multimodal analgesia and early rehabilitation have potentiated early mobilization in patients undergoing total hip arthroplasty (THA). Given an increasing push from patients to accelerate recovery and health care budgetary limitations, there has been growing interest in the implementation of outpatient THA in selected patients. Understanding the patient and primary caregiver experience of outpatient THA is important to optimize care. We aimed to gain insight into patient and caregiver perspectives regarding the perceived advantages and disadvantages of same-day discharge to identify areas of care that can be improved. Using a qualitative descriptive approach, we conducted in-depth semistructured interviews with patient-primary caregiver dyads who experienced same-day discharge or standard care after primary THA with the direct anterior approach in 2016-2017. Two members of the research team coded the data independently, implementing a thematic and content analysis. Twenty-eight participants (16 same-day discharge, 12 standard care) were included. Both groups experienced high levels of satisfaction with their care pathway. Concerns and challenges identified in both groups pertained to mobility, pain, self-care and caregiver support. Challenges and concerns unique to same-day discharge were identified regarding expectations for recovery, medications and their impact on mobility, the timing of postoperative education and the availability of formal care. Outpatient THA can be implemented with high patient and caregiver satisfaction. Preoperative education, clarification of recovery processes and expectations, and proactively addressing concerns related to caregiving are important.


Activation of the Basal Plane in Two Dimensional Transition Metal Chalcogenide Nanostructures.
Achieving a molecular level understanding of chemical reactions on the surface of solid-state nanomaterials is important, but challenging. For example, the fully saturated basal plane is believed to be practically inert and its surface chemistry has been poorly explored, while two-dimensional (2D) layered transition-metal chalcogenides (TMCs) display unique reactivities due to their unusual anisotropic nature, where the edges consisting of unsaturated metals and chalcogens are sites for key chemical reactions. Herein, we report the use of Lewis acids/bases to elucidate the chemical reactivity of the basal plane in 2D layered TMCs. Electrophilic addition by Lewis acids (i.e., AlCl3) selectively onto sulfides in the basal plane followed by transmetalation and subsequent etching affords nanopores where such chemical activations are initiated and propagated from the localized positions of the basal plane. This new method of surface modification is generally applicable not only to various chemical compositions of TMCs, but also in crystal geometries such as 1T and 2H. Nanoporous NbS2 obtained by this method was found to have an enhanced electrochemical energy storage capacity, offering this chemical strategy to obtain functional 2D layered nanostructures.


A large-scale survey of adverse events experienced in yoga classes.
Yoga is a representative mind-body therapy of complementary and alternative medicine. In Japan, yoga is practiced widely to promote health, but yoga-associated adverse events have also been reported. To date, the frequencies and characteristics of yoga-related adverse events have not been elucidated. This study was conducted to elucidate the frequencies and characteristics of adverse events of yoga performed in classes and the risk factors of such events. The subjects were 2508 people taking yoga classes and 271 yoga therapists conducting the classes. A survey for yoga class attendees was performed on adverse events that occurred during a yoga class on the survey day. A survey for yoga therapists was performed on adverse events that the therapists had observed in their students to date. Adverse events were defined as "undesirable symptoms or responses that occurred during a yoga class". Among 2508 yoga class attendees, 1343 (53.5%) had chronic diseases and 1063 (42.3%) were receiving medication at hospitals. There were 687 class attendees (27.8%) who reported some type of undesirable symptoms after taking a yoga class. Musculoskeletal symptoms such as myalgia were the most common symptoms, involving 297 cases, followed by neurological symptoms and respiratory symptoms. Most adverse events (63.8%) were mild and did not interfere with class participation. The risk factors for adverse events were examined, and the odds ratios for adverse events were significantly higher in attendees with chronic disease, poor physical condition on the survey day, or a feeling that the class was physically and mentally stressful. In particular, the occurrence of severe adverse events that interfered with subsequent yoga practice was high among elderly participants (70 years or older) and those with chronic musculoskeletal diseases. The results of this large-scale survey demonstrated that approximately 30% of yoga class attendees had experienced some type of adverse event. Although the majority had mild symptoms, the survey results indicated that attendees with chronic diseases were more likely to experience adverse events associated with their disease. Therefore, special attention is necessary when yoga is introduced to patients with stress-related, chronic diseases.


Results of a content analysis of electronic messages (email) sent between patients and their physicians.
Email is the most important mechanism introduced since the telephone for developing interpersonal relationships. This study was designed to provide insight into how patients are using email to request information or services from their healthcare providers. Following IRB approval, we reviewed all electronic mail (e-mail) messages sent between five study clinicians and their patients over a one-month period. We used a previously described taxonomy of patient requests to categorize all patient requests contained in the messages. We measured message volume, frequency, length and response time for all messages sent to and received by these clinicians. On average the 5 physicians involved in this study received 40 messages per month, each containing approximately 139 words. Replies sent by the physicians contained 39 words on average and 59.4% of them were sent within 24 hours. Patients averaged 1 request per message. Requests for information on medications or treatments, specific symptoms or diseases, and requests for actions regarding medications or treatments accounted for 75% of all requests. Physicians fulfilled 80.2% of all these requests. Upon comparison of these data to that obtained from traditional office visits, it appears that the potential exists for email encounters to substitute for some percentage of office visits. Electronic messaging is an important method for physicians and patients to communicate and further develop their relationship. While many physicians worry that either the number or length of messages from their patients will overwhelm them, there is no evidence to support this. In fact, the evidence suggests that many patient requests, formerly made over the telephone or during office visits, can be addressed via email thus potentially saving both patients and physicians time.


Does delaying discharge from intensive care until after tracheostomy removal affect 30-day mortality? Propensity score matched cohort study.
To investigate the short-term mortality effect of discharge from an intensive care unit (ICU) with a tracheostomy in place in comparison to delaying discharge until after tracheostomy removal. A propensity score matched cohort study using data from the TracMan study. Seventy-two UK ICUs taking part in the TracMan study, a randomised controlled trial comparing early tracheostomy (within 4 days of critical care admission) with deferred tracheostomy (after 10 days if still indicated). 622 patients who underwent a tracheostomy while in the TracMan study between November 2004 and November 2008. 144 patients left ICU with a tracheostomy. 999 days of observation from 294 patients were included in the control pool. We matched patients discharged with a tracheostomy in place 1:1 with patients who remained in an ICU until either their tracheostomy was removed or they died with the tracheostomy in place. Propensity models were developed according to discharge destination, accounting for likely confounding factors. The primary outcome was 30-day mortality from the matching day. For the 'discharged with a tracheostomy' group, this was death within 30 days after the discharge day. For the 'remained in ICU' group, this was death within 30 days after the matched day. 22 (15.3%) patients who left ICU with a tracheostomy died within 30 days compared with 26 (18.1%) who remained in ICU (relative risk 0.98, 95% CI 0.43 to 2.23). Keeping patients on an ICU to provide tracheostomy care was not found to affect mortality. Tracheostomy presence may indicate a higher risk of mortality due to underlying diseases and conditions rather than posing a risk in itself.The TracMan trial was registered on the ISRCTN database (ISRCTN28588190).


A novel TCR transgenic model reveals that negative selection involves an immediate, Bim-dependent pathway and a delayed, Bim-independent pathway.
A complete understanding of negative selection has been elusive due to the rapid apoptosis and clearance of thymocytes in vivo. We report a TCR transgenic model in which expression of the TCR during differentiation occurs only after V(D)J-like recombination. TCR expression from this transgene closely mimics expression of the endogenous TCRalpha locus allowing for development that is similar to wild type thymocytes. This model allowed us to characterize the phenotypic changes that occurred after TCR-mediated signaling in self-reactive thymocytes prior to their deletion in a highly physiological setting. Self-reactive thymocytes were identified as being immature, activated and CD4(lo)CD8(lo). These cells had upregulated markers of negative selection and were apoptotic. Elimination of Bim reduced the apoptosis of self-reactive thymocytes, but it did not rescue their differentiation and the cells remained at the immature CD4(lo)CD8(lo) stage of development. These cells upregulate Nur77 and do not contribute to the peripheral T cell repertoire in vivo. Remarkably, development past the CD4(lo)CD8(lo) stage was possible once the cells were removed from the negatively selecting thymic environment. In vitro development of these cells occurred despite their maintenance of high intracellular levels of Nur77. Therefore, in vivo, negatively selected Bim-deficient thymocytes are eliminated after prolonged developmental arrest via a Bim-independent pathway that is dependent on the thymic microenvironment. These data newly reveal a layering of immediate, Bim-dependent, and delayed Bim-independent pathways that both contribute to elimination of self-reactive thymocytes in vivo.


CAPZA1 modulates EMT by regulating actin cytoskeleton remodelling in hepatocellular carcinoma.
Epithelial-mesenchymal transition (EMT) elicits dramatic changes, including cytoskeleton remodelling as well as changes in gene expression and cellular phenotypes. During this process, actin filament assembly plays an important role in maintaining the morphology and movement of tumour cells. Capping protein, a protein complex referred to as CapZ, is an actin-binding complex that can regulate actin cytoskeleton remodelling. CAPZA1 is the α1 subunit of this complex, and we hypothesized that CAPZA1 regulates EMT through the regulation of actin filaments assembly, thus reducing the metastatic ability of hepatocellular carcinoma (HCC) cells. Immunohistochemistry was used to detect CAPZA1 expression in 129 HCC tissues. Western blotting and qPCR were used to detect CAPZA1, EMT markers and EMT transcription factors in HCC cells. Transwell migration and invasion assays were performed to observe the migration and invasion of HCC cells. Cell Counting Kit-8 (CCK-8) was used to detect the proliferation of HCC cells. Immunoprecipitation was used to detect the interaction between CAPZA1 and actin filaments. Finally, a small animal magnetic resonance imager (MRI) was used to observe metastases in HCC cell xenografts in the liver. CAPZA1 expression levels were negatively correlated with the biological characteristics of primary HCC and patient prognosis. CAPZA1 expression was negatively correlated with the migration and invasion of HCC cells. CAPZA1 down regulation promoted the migration and invasion of HCC cells. Conversely, CAPZA1 overexpression significantly inhibited the migration and invasion of HCC cells. Moreover, CAPZA1 expression levels were correlated with the expression of the EMT markers E-cadherin, N-cadherin and Vimentin. Furthermore, the expression of Snail1 and ZEB1 were negatively correlated with CAPZA1 expression levels. Similarly, CAPZA1 significantly inhibited intrahepatic metastases of HCC cells in an orthotopic transplantation tumour model. CAPZA1 inhibits EMT in HCC cells by regulating actin cytoskeleton remodelling, thereby reducing the metastatic ability of the cells. Together, our data suggest that CAPZA1 could be a useful biomarker for clinical determination of the prognosis of HCC patients.


The MRN complex: coordinating and mediating the response to broken chromosomes.
The MRE11-RAD50-NBS1 (MRN) protein complex has been linked to many DNA metabolic events that involve DNA double-stranded breaks (DSBs). In vertebrate cells, all three components are encoded by essential genes, and hypomorphic mutations in any of the human genes can result in genome-instability syndromes. MRN is one of the first factors to be localized to the DNA lesion, where it might initially have a structural role by tethering together, and therefore stabilizing, broken chromosomes. This suggests that MRN could function as a lesion-specific sensor. As well as binding to DNA, MRN has other roles in both the processing and assembly of large macromolecular complexes (known as foci) that facilitate efficient DSB responses. Recently, a novel mediator protein, mediator of DNA damage checkpoint protein 1 (MDC1), was shown to co-immunoprecipitate with the MRN complex and regulate MRE11 foci formation. However, whether the initial recruitment of MRN to DSBs requires MDC1 is unclear. Here, we focus on recent developments in MRN research and propose a model for how DSBs are sensed and the cellular responses to them are mediated.


Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responses.
Glucose-induced β-cell action potential (AP) repolarization is regulated by potassium efflux through voltage gated (Kv) and calcium activated (K(Ca)) potassium channels. Thus, ablation of the primary Kv channel of the β-cell, Kv2.1, causes increased AP duration. However, Kv2.1(-/-) islet electrical activity still remains sensitive to the potassium channel inhibitor tetraethylammonium. Therefore, we utilized Kv2.1(-/-) islets to characterize Kv and K(Ca) channels and their respective roles in modulating the β-cell AP. The remaining Kv current present in Kv2.1(-/-) β-cells is inhibited with 5 μM CP 339818. Inhibition of the remaining Kv current in Kv2.1(-/-) mouse β-cells increased AP firing frequency by 39.6% but did not significantly enhance glucose stimulated insulin secretion (GSIS). The modest regulation of islet AP frequency by CP 339818 implicates other K(+) channels, possibly K(Ca) channels, in regulating AP repolarization. Blockade of the K(Ca) channel BK with slotoxin increased β-cell AP amplitude by 28.2%, whereas activation of BK channels with isopimaric acid decreased β-cell AP amplitude by 30.6%. Interestingly, the K(Ca) channel SK significantly contributes to Kv2.1(-/-) mouse islet AP repolarization. Inhibition of SK channels decreased AP firing frequency by 66% and increased AP duration by 67% only when Kv2.1 is ablated or inhibited and enhanced GSIS by 2.7-fold. Human islets also express SK3 channels and their β-cell AP frequency is significantly accelerated by 4.8-fold with apamin. These results uncover important repolarizing roles for both Kv and K(Ca) channels and identify distinct roles for SK channel activity in regulating calcium- versus sodium-dependent AP firing.


Diverse cortical codes for scene segmentation in primate auditory cortex.
The temporal coherence of amplitude fluctuations is a critical cue for segmentation of complex auditory scenes. The auditory system must accurately demarcate the onsets and offsets of acoustic signals. We explored how and how well the timing of onsets and offsets of gated tones are encoded by auditory cortical neurons in awake rhesus macaques. Temporal features of this representation were isolated by presenting otherwise identical pure tones of differing durations. Cortical response patterns were diverse, including selective encoding of onset and offset transients, tonic firing, and sustained suppression. Spike train classification methods revealed that many neurons robustly encoded tone duration despite substantial diversity in the encoding process. Excellent discrimination performance was achieved by neurons whose responses were primarily phasic at tone offset and by those that responded robustly while the tone persisted. Although diverse cortical response patterns converged on effective duration discrimination, this diversity significantly constrained the utility of decoding models referenced to a spiking pattern averaged across all responses or averaged within the same response category. Using maximum likelihood-based decoding models, we demonstrated that the spike train recorded in a single trial could support direct estimation of stimulus onset and offset. Comparisons between different decoding models established the substantial contribution of bursts of activity at sound onset and offset to demarcating the temporal boundaries of gated tones. Our results indicate that relatively few neurons suffice to provide temporally precise estimates of such auditory "edges," particularly for models that assume and exploit the heterogeneity of neural responses in awake cortex.


An in vitro effect of triiodothyronine on rat adipose tissue.
Triiodo-L-thyronine (T(3)) added in vitro to fat pads from normal, or propylthiouracil-treated rats enhanced the rate of release of glycerol and free fatty acids (FFA) in the presence of epinephrine. An effect of T(3) was also demonstrated in the presence of adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone, or glucagon in studies with tissue from normal rats. The minimal effective concentration of T(3) was approximately 2.5 x 10(-5) mole/liter for intact fat pads and 3 x 10(-6) mole/liter for fat cells. With fat pads from propylthiouracil-treated rats the effect of T(3) was not apparent until the 3rd hr of incubation. Enhancement of epinephrine-stimulated lipolysis by T(3) was evident during the 1st hr of incubation of fat pads from normal rats, and fat cells responded almost immediately to the presence of T(3). When added alone or in the presence of theophylline, 3',5'-adenosine monophosphate or its dibutyryl derivative, T(3) had little or no effect on lipolysis. The effect of T(3) was observed with or without glucose in the medium, and was not inhibited by cycloheximide or actinomycin D. It did not persist when tissues, after incubation in the presence of T(3) were transferred to medium without T(3). No effect of T(3) on glucose uptake in the presence of epinephrine, ACTH, or insulin was demonstrated.


Genome sequence of Ensifer adhaerens OV14 provides insights into its ability as a novel vector for the genetic transformation of plant genomes.
Recently it has been shown that Ensifer adhaerens can be used as a plant transformation technology, transferring genes into several plant genomes when equipped with a Ti plasmid. For this study, we have sequenced the genome of Ensifer adhaerens OV14 (OV14) and compared it with those of Agrobacterium tumefaciens C58 (C58) and Sinorhizobium meliloti 1021 (1021); the latter of which has also demonstrated a capacity to genetically transform crop genomes, albeit at significantly reduced frequencies. The 7.7 Mb OV14 genome comprises two chromosomes and two plasmids. All protein coding regions in the OV14 genome were functionally grouped based on an eggNOG database. No genes homologous to the A. tumefaciens Ti plasmid vir genes appeared to be present in the OV14 genome. Unexpectedly, OV14 and 1021 were found to possess homologs to chromosomal based genes cited as essential to A. tumefaciens T-DNA transfer. Of significance, genes that are non-essential but exert a positive influence on virulence and the ability to genetically transform host genomes were identified in OV14 but were absent from the 1021 genome. This study reveals the presence of homologs to chromosomally based Agrobacterium genes that support T-DNA transfer within the genome of OV14 and other alphaproteobacteria. The sequencing and analysis of the OV14 genome increases our understanding of T-DNA transfer by non-Agrobacterium species and creates a platform for the continued improvement of Ensifer-mediated transformation (EMT).


Challenging a Preconception: Optoacoustic Spectrum Differs from the Optical Absorption Spectrum of Proteins and Dyes for Molecular Imaging.
Optoacoustic (photoacoustic) imaging has seen marked advances in detection and data analysis, but there is less progress in understanding the photophysics of common optoacoustic contrast agents. This gap blocks the development of novel agents and the accurate analysis and interpretation of multispectral optoacoustic images. To close it, we developed a multimodal laser spectrometer (MLS) to enable the simultaneous measurement of optoacoustic, absorbance, and fluorescence spectra. Herein, we employ MLS to analyze contrast agents (methylene blue, rhodamine 800, Alexa Fluor 750, IRDye 800CW, and indocyanine green) and proteins (sfGFP, mCherry, mKate, HcRed, iRFP720, and smURFP). We found that the optical absorption spectrum does not correlate with the optoacoustic spectrum for the majority of the analytes. We determined that for dyes, the transition underlying an aggregation state has more optoacoustic signal generation efficiency than the monomer transition. For proteins we found a favored optoacoustic relaxation that stems from the neutral or zwitterionic chromophores and unreported photoswitching behavior of tdTomato and HcRed. We then crystalized HcRed in its photoswitch optoacoustic state, confirming structurally the change in isomerization with respect to HcReds' fluorescence state. Finally, on the example of the widely used label tdTomato and the dye indocyanine green, we show the importance of correct photophysical (e.g., spectral and kinetic) information as a prerequisite for spectral-unmixing for in vivo imaging.


Effect of organo and inorganic lithium salt on human blood plasma glutathione- A comparative study.
Investigation of toxicological effect of various metals is the field of interest for toxicological scientists since four to five decades and especially the toxicological effect of those drugs containing metals and there use is common because there is no other choice except to use these metal containing drugs. Inorganic as well as organic salts of lithium are commonly used in prophylaxis and treatments of many psychiatric disorders. The aim of the present study was to see the difference between the effect of organic and inorganic salt of lithium commonly used in psychiatric disorders on the GSH of human blood plasma. It is the scientific fact that ionic dissociation of organic and inorganic salts of any metal is always quite different hence to prove this fact, the effect of lithium citrate (organic salt of lithium) and lithium carbonate (inorganic salt of lithium) was investigated on human blood plasma GSH to find the difference between the effect of two. Ellman's method was used for the quantification of glutathione contents in plasma. It was found that lithium citrate decrease plasma GSH contents less than lithium carbonate indicating that organic salts of lithium are safe than inorganic salts of lithium when are used in psychiatric disorders. Further to analyze the effect of organic and inorganic salt of lithium on blood plasma GSH with the increase in incubation time was also evaluated and was found that both concentration and time dependent effect of organic salt of lithium shows that this salt has decreased plasma GSH contents of human blood less than inorganic salt of lithium either by promoting oxidation of GSH into GSSG or by lithium glutathione complex formation. These results suggest the physicians that the use of organic lithium salts is much safer than inorganic salts of lithium in terms of depletion of blood plasma GSH contents.


The impact of invisibility on the health of migrant farmworkers in the southeastern United States: a case study from georgia.
Migrant farmworkers represent one of the most marginalized and underserved populations in the United States. Acculturation theory cannot be easily mapped onto the transnational experience of migrant farmworkers, who navigate multiple physical and cultural spaces yearly, and who are not recognized by the state they constitute, "the Citizen's Other" (Kerber, 2009). This paper utilizes narrative analysis of a case study to illustrate, through the relationship of the narrator to migrant farmworkers and years of participant observation by the coauthors, how isolation from family and community, as well as invisibility within institutions, affect the health and well-being of migrant farmworkers in southeastern Georgia. Invisibility of farmworkers within institutions, such as health care, the educational system, social services, domestic violence shelters, and churches contribute to illness among farmworkers. The dominant American discourse surrounding immigration policy addresses the strain immigrants put on the social systems, educational system, and the health care system. Nurses who work with farmworkers are well positioned to bring the subjective experience of farmworkers to light, especially for those engaged with socially just policies. Those who contribute to the abundant agricultural produce that feeds Americans deserve the recognition upon which social integration depends.


Analysis of loss of heterozygosity on chromosome 10 in patients with malignant astrocytic tumors: correlation with patient age and survival.
The most frequent genetic abnormality in human malignant gliomas is loss of heterozygosity (LOH) on chromosome 10. Candidate genes on chromosome 10 that are associated with the prognosis of patients with anaplastic astrocytoma (AA) and glioblastoma (GBM) were evaluated. The authors used 12 fluorescent microsatellite markers on both arms of chromosome 10 to study LOH in 108 primary astrocytic tumors. The LOH on chromosome 10 was observed in 11 (32%) of 34 AAs and 34 (56%) of 61 GBMs. No LOH was detected in 13 low-grade gliomas. Loss of heterozygosity was not detected in any AA in the seven patients younger than 35 years, but it was discovered in 41% of the patients older than 35 years. The prognostic significance of LOH at each locus was evaluated in 89 patients older than 15 years; 33 (37%) had supratentorial AAs and 56 (63%) had supratentorial GBMs. The Cox proportional hazards model, adjusted for patient age at surgery, the preoperative Karnofsky Performance Scale score, and the extent of surgical resection revealed that LOH on marker D10S209 near the FGFR2 and DMBT1 genes was significantly associated with shorter survival in patients with AA. The LOH on markers D10S215 and D10S541, which contain the PTEN/MMAC1 gene between them, was significantly associated with shorter survival in patients with GBM. In the present study it is found that LOH on chromosome 10 is an age-dependent event for patients with AAs and that LOH on marker D10S209 near the FGFR2 and DMBT1 loci is a significantly unfavorable prognostic factor. It is also reported that LOH on the PTEN/MMAC1 gene is a significantly unfavorable prognostic factor in patients with GBM.


Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia.
Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from feverfew and protocols for growing, extracting and derivatising it are reported. A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on in vitro anti-leukaemic activity and calculated "drug-likeness" properties, in vitro and in vivo pharmacokinetics studies and hERG liability testing. In vitro studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and in silico molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine 7 used in the generation of 5f.


Sex differences in TTC12/ANKK1 haplotype associations with daily tobacco smoking in Black and White Americans.
The 11q23.1 genomic region has been associated with nicotine dependence in Black and White Americans. By conducting linkage disequilibrium analyses of 7 informative single nucleotide polymorphisms (SNPs) within the tetratricopeptide repeat domain 12 (TTC12)/ankyrin repeat and kinase containing 1 (ANKK1)/dopamine (D2) receptor gene cluster, we identified haplotype block structures in 270 Black and 368 White (n = 638) participants, from the Baltimore Epidemiologic Catchment Area cohort study, spanning the TTC12 and ANKK1 genes consisting of three SNPs (rs2303380-rs4938015-rs11604671). Informative haplotypes were examined for sex-specific associations with daily tobacco smoking initiation and cessation using longitudinal data from 1993-1994 and 2004-2005 interviews. There was a Haplotype x Sex interaction such that Black men possessing the GTG haplotype who were smokers in 1993-2004 were more likely to have stopped smoking by 2004-2005 (55.6% GTG vs. 22.0% other haplotypes), while Black women were less likely to have quit smoking if they possessed the GTG (20.8%) versus other haplotypes (24.0%; p = .028). In Whites, the GTG haplotype (vs. other haplotypes) was associated with lifetime history of daily smoking (smoking initiation; odds ratio = 1.6; 95% CI = 1.1-2.4; p = .013). Moreover, there was a Haplotype x Sex interaction such that there was higher prevalence of smoking initiation with GTG (77.6%) versus other haplotypes (57.0%; p = .043). In 2 different ethnic American populations, we observed man-woman variation in the influence of the rs2303380-rs4938015-rs11604671 GTG haplotype on smoking initiation and cessation. These results should be replicated in larger cohorts to establish the relationship among the rs2303380-rs4938015-rs11604671 haplotype block, sex, and smoking behavior.


Effect of repetitive yogic squats with specific hand position (Thoppukaranam) on selective attention and psychological states.
Research on the effect of Thoppukaranam is limited despite it being practiced as a form of worship to the elephant-headed deity Lord Ganapati and punishment in schools. The purpose of this study was to examine the effect of Thoppukaranam on selective attention and psychological states in a sample of young adults. A randomized self-as-control within subjects design was employed. Thirty undergraduate students (4 females and 26 males) from a residential Yoga University in Southern India were recruited for this study (group mean age ± standard deviation, 20.17 ± 2.92). The d2 test, State Anxiety Inventory-Short Form and State Mindful Attention Awareness Scale (SMAAS) were used to measure cognitive performance and psychological states. Assessments were made in three sessions: Baseline, control (squats), and experimental (Thoppukaranam) on 3 separate days. Data were analyzed using one-way repeated measures analyses of variance between three sessions, that is, baseline, squat, and Thoppukaranam. There was a significant improvement in all measures of the d2 test of attention (TN, E, TN-E, E%, and concentration performance) and state mindfulness after Thoppukaranam. Further state anxiety reduced significantly after the experimental session. These findings indicate Thoppukaranam results in enhancement of cognitive functioning and psychological states.


An Evaluation of Family-Based Treatment for OCD in Japan: A Pilot Randomized Controlled Trial.
Objective: Although family involvement in the treatment of obsessive-compulsive disorder (OCD) produces a reduction in OCD symptoms and has significant effects on global functioning, few studies have focused on family intervention as part of OCD treatment in Japan. This study aims to examine the feasibility and efficacy of the family-based exposure and response prevention (FERP) program for adult patients with OCD and their family members. Design: Randomized controlled pilot study. Methods: A total of 18 outpatients aged 18-65 years with a primary diagnosis of OCD and one family member of each patient were randomized to an intervention group or a control group (1:1). The intervention group received the FERP program, which consisted of 16 weekly face-to-face cognitive behavioral therapy (CBT) sessions, including eight joint sessions with family members, in addition to treatment-as-usual (TAU). The control group received TAU alone. The primary outcome was the alleviation of OCD symptoms, as measured by changes in the total Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score from baseline to posttreatment. Analyses were provided on an intention-to-treat basis, and linear mixed models were used to test for significant group differences. Results: After 16 weeks, patients allocated to the FERP program showed improvement in OCD symptom severity, as measured by the total change score of the Y-BOCS (Hedges' g = -1.58), as compared to the control group. Two patients (22.2%) in the FERP group reached remission, and five patients (55.6%) in the FERP group achieved treatment response. Clinical global improvement measured by the FAS-SR scores, K6 scores, and CGI-S scores was also observed (Hedges' g = -1.35, -1.25, and -1.26, respectively) in the FERP group as compared to the control group. The dropout rate from the study was low (n = 2, 11.8%), and no adverse events were reported in the FERP group. Conclusion: Our results suggest that FERP may be an effective program for reducing patients' OCD symptoms. Clinical Trial Registration: www.umin.ac.jp/ctr/, identifier UMIN000021763.


The relationship between dosing of alosetron and discontinuation patterns reported by patients participating in a follow-up programme.
Alosetron was reintroduced for treatment of irritable bowel syndrome with a risk management programme in November 2002. Recommended starting dosage was 1 mg/day for 4 weeks. If symptoms remained uncontrolled, dosage could be changed to 2 mg/day. To describe alosetron dosages and associated patient characteristics from the Lotronex follow-up survey programme. Patients reported dosages of alosetron at start and regular follow-up intervals. Analyses were limited to patients with the potential to have at least 1 year of follow-up (enrolled between 9 December 2002 and 31 December 2003). At baseline, 75% of 2817 respondents reported starting on 1 mg/day, 17% on 2 mg/day and 8% on other doses. Adherence to recommended starting dosage did not vary by status at end of follow-up, previous alosetron experience or age. At last reported dose, 50% of respondents were using 1 mg/day; 29% were using 2 mg/day. Discontinuation was not related to baseline doses. Longer times to discontinuation were associated with previous use, symptoms for more than 6 months and dose change throughout follow-up. High adherence to recommended dosing at baseline and follow-up suggests that the risk management programme is encouraging safe use of alosetron, including adherence to dosing recommendations.