Initial factor exploration of disability identity.
This article describes the initial factor exploration of disability identity and preliminary psychometric characteristics based on an adult self-report tool. Disability was defined broadly, and the sample included individuals with visible and/or hidden disabilities across many disability groups (i.e., physical, intellectual, learning, mental illness). Items were developed (n = 102) and a pilot measure was administered to a sample of adults with disabilities (n = 566). An exploratory factor analysis (EFA) using the mean and variance adjusted weighted least squares (WLSMV) estimator was conducted. The resulting items were sent to expert reviewers for evaluation. Following the exploratory analyses, 37 items were retained that made up four factors: internal beliefs about own disability and the disability community, anger and frustration with disability experiences, adoption of disability community values, and contribution to the disability community. The pilot measure aligned well with the theoretical framework that guided its development. This factor exploration is a contribution to a growing body of literature supporting, and investigating, disability identity development. This work presents a more comprehensive understanding of disability identity development. Armed with a better understanding, this will serve as a basis to inform future scale development and validation. After this validation work is completed, there is the potential to apply findings to tailor interventions and clinical work, so that psychologists and rehabilitation professionals may be better prepared to meet the developmental needs of disabled clients. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


4-Hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: a novel inhibitor of the canonical NF-κB cascade.
The NF-κB signaling pathway is a validated oncological target. Here, we applied scaffold hopping to IMD-0354, a presumed IKKβ inhibitor, and identified 4-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide (4) as a nM-inhibitor of the NF-κB pathway. However, both 4 and IMD-0354, being potent inhibitors of the canonical NF-κB pathway, were found to be inactive in human IKKβ enzyme assays.


Gliding mutants of Mycoplasma mobile: relationships between motility and cell morphology, cell adhesion and microcolony formation.
The present study characterizes gliding motility mutants of Mycoplasma mobile which were obtained by UV irradiation. They were identified by their abnormal colony shapes in 0.1% agar medium, showing a reduced number of satellite colonies compared to the wild-type. A total of ten mutants were isolated based on their colony phenotype. Using dark-field and electron microscopy, two classes of mutants, group I and group II, were defined. Cells of group I mutants had irregular, flexible and sometimes elongated head-like structures and showed a tendency to aggregate. Neither binding to glass nor gliding motility was observed in these mutants. Cells of group II mutants were rather spherical in shape, with the long axis reduced to 80% and the short axis enlarged to 120% of that of wild-type cells, respectively. Their gliding speed was 20% faster than that of wild-type cells. Three of the ten mutants remained unclassified. Mutant m6 had a reduced binding activity to glass and a reduced gliding motility with 50% of the speed of the wild-type strain. The ability of wild-type and mutant colonies to adsorb erythrocytes was found to correlate with the binding activity required for gliding, indicating that mycoplasma gliding depends on cytadherence-associated components. Finally, the ability to form microcolonies on surfaces was shown to correlate with the gliding activity, suggesting a certain role of gliding motility in the parasitic life-cycle of mycoplasmas.


Tuberculosis epidemiology in islands: insularity, hosts and trade.
Because of their relative simplicity and the barriers to gene flow, islands are ideal systems to study the distribution of biodiversity. However, the knowledge that can be extracted from this peculiar ecosystem regarding epidemiology of economically relevant diseases has not been widely addressed. We used information available in the scientific literature for 10 old world islands or archipelagos and original data on Sicily to gain new insights into the epidemiology of the Mycobacterium tuberculosis complex (MTC). We explored three nonexclusive working hypotheses on the processes modulating bovine tuberculosis (bTB) herd prevalence in cattle and MTC strain diversity: insularity, hosts and trade. Results suggest that bTB herd prevalence was positively correlated with island size, the presence of wild hosts, and the number of imported cattle, but neither with isolation nor with cattle density. MTC strain diversity was positively related with cattle bTB prevalence, presence of wild hosts and the number of imported cattle, but not with island size, isolation, and cattle density. The three most common spoligotype patterns coincided between Sicily and mainland Italy. However in Sicily, these common patterns showed a clearer dominance than on the Italian mainland, and seven of 19 patterns (37%) found in Sicily had not been reported from continental Italy. Strain patterns were not spatially clustered in Sicily. We were able to infer several aspects of MTC epidemiology and control in islands and thus in fragmented host and pathogen populations. Our results point out the relevance of the intensity of the cattle commercial networks in the epidemiology of MTC, and suggest that eradication will prove more difficult with increasing size of the island and its environmental complexity, mainly in terms of the diversity of suitable domestic and wild MTC hosts.


Attenuation of renal ischemia/reperfusion injury by oleanolic acid preconditioning via its antioxidant, anti‑inflammatory, and anti‑apoptotic activities.
Ischemia/reperfusion (I/R)‑associated acute kidney injury is a major clinical problem in both native and transplanted kidneys. Renal I/R, and subsequent renal injury, may be attributed to oxidative stress, inflammation, and apoptosis. Oleanolic acid (OA) is a natural product, which possesses antioxidant, anti‑inflammatory, and anti‑apoptotic activities. The present study aimed to examine the effects of OA preconditioning on renal I/R and the possible underlying mechanisms. In a renal I/R model, rats were administered OA (12.5, 25 and 50 mg/kg) for 15 consecutive days prior to bilateral renal I/R induction. Serum samples and kidneys were then collected and stored for subsequent determination. The results of the present study demonstrated that OA significantly and dose‑dependently attenuated I/R‑induced renal damage. OA prevented renal I/R injury, as evidenced by decreased levels of blood urea nitrogen, creatinine, kidney injury molecule‑1 and lactate dehydrogenase. In addition, OA defended against oxidative stress, as reflected by decreased levels of methane dicarboxylic aldehyde, increased activities of superoxide dismutase, catalase and glutathione peroxidase, and increased glutathione (GSH) levels. Levels of proinflammatory cytokines, interferon‑γ, interleukin (IL)‑6) and myeloperoxidase, were also reduced by OA, whereas the anti‑inflammatory cytokine IL‑10 was increased. Furthermore, OA prevented I/R‑induced apoptotic cell death, and prevented decreases in the mRNA expression levels of nuclear factor erythroid 2‑related factor 2 (Nrf2) and γ‑glutamylcysteine ligase (GCLc). Conversely, buthionine sulphoximine attenuated the protective effects of OA on renal I/R injury. These results indicated that OA preconditioning may prevent I/R‑induced renal damage via antioxidant, anti‑inflammatory, and anti‑apoptotic activities. Stabilization of Nrf2/GCLc signaling and subsequent maintenance of the GSH pool is critical for the protective effects of OA against renal I/R injury. The present study reported a novel therapeutic strategy for the treatment of renal I/R injury.


Multiple Models Can Concurrently Explain Fatigue During Human Performance.
One of the most commonly and thoroughly studied paradigms of human performance is fatigue. However, despite volumes of research there remains considerable controversy among scientists regarding definitive conclusions about the specific mechanism(s) contributing to fatigue. Within the literature there are three primary yet distinctly different governing ideas of fatigue; the traditionally referenced central model and peripheral model as well as the emerging central governor model (CGM). The CGM has recently been advocated by a limited number of researchers and is suggestive of a more integrative model of fatigue when compared the traditional peripheral and central models. However, more work is needed to determine the specific and perhaps synergistic roles of each paradigm during exercise or sport activity. This article contains three components; (1) a brief overview of the problems associated with defining fatigue, (2) a description of the models governing interpretation of fatigue and, (3) a presentation of multiple interpretations of selected data to demonstrate that some results can be reasonably explained using multiple models of fatigue, often concurrently. The purposes of this paper are to reveal that a) perhaps it is not the results that suggest a certain paradigm of regulation, yet that it may be a product of an a priori definition that is being employed and b) an integrative model of central and peripheral fatigue may present a plausible explanation for fatigue vs. adherence to the notion that each paradigm is mutually exclusive.


Renal artery dissections.
Renal artery dissections encountered in 15 patients, aged 3 to 75 years, were categorized as to pathogenesis (blunt abdominal trauma, catheter injury, and spontaneous). Blunt traumatic dissections (seven patients) were characterized by hypertension, gross hematuria, and pain. Catheter-induced dissections (four patients) were asymptomatic, although two exhibited accelerated hypertension. Spontaneous dissections (four patients) were all associated with preexistent arterial disease. Symptoms in these patients were uncommon, despite accelerated hypertension in three cases. Intravenous pyelography lacked specific diagnostic value for renal artery dissections. Early arteriographic examination proved essential in diagnosis and surgical treatment. Criteria for operative intervention included existence of technically correctable dissections causing (1) hemodynamically significant occlusions of the main or major segmental renal arteries, (2) documented renovascular hypertension, or (3) significant deterioration of renal function.


Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study.
Medulloblastoma is the most common malignant brain tumor of childhood. After treatment with surgery and radiation therapy, approximately 60% of children with medulloblastoma are alive and free of progressive disease 5 years after diagnosis, but many have significant neurocognitive sequelae. This study was undertaken to determine the feasibility and efficacy of treating children with nondisseminated medulloblastoma with reduced-dose craniospinal radiotherapy plus adjuvant chemotherapy. Over a 3-year period, 65 children between 3 and 10 years of age with nondisseminated medulloblastoma were treated with postoperative, reduced-dose craniospinal radiation therapy (23.4 Gy) and 55.8 Gy of local radiation therapy. Adjuvant vincristine chemotherapy was administered during radiotherapy, and lomustine, vincristine, and cisplatin chemotherapy was administered during and after radiation. Progression-free survival was 86% +/- 4% at 3 years and 79% +/- 7% at 5 years. Sites of relapse for the 14 patients who developed progressive disease included the local tumor site alone in two patients, local tumor site and disseminated disease in nine, and nonprimary sites in three. Brainstem involvement did not adversely affect outcome. Therapy was relatively well tolerated; however, the dose of cisplatin had to be modified in more than 50% of patients before the completion of treatment. One child died of pneumonitis and sepsis during treatment. These overall survival rates compare favorably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. The results suggest that reduced-dose craniospinal radiation therapy and adjuvant chemotherapy during and after radiation is a feasible approach for children with nondisseminated medulloblastoma.


Management of perceived devastating brain injury after hospital admission: a consensus statement from stakeholder professional organizations.
Patients with severe grades of life-threatening brain injury are commonly characterized as having devastating brain injury (DBI), which we have defined as: 'any neurological condition that is assessed at the time of hospital admission as an immediate threat to life or incompatible with good functional recovery AND where early limitation or withdrawal of therapy is being considered'. The outcome in patients with DBI is often death or severe disability, and as a consequence rapid withdrawal of life sustaining therapies is commonly contemplated or undertaken. However, accurate prognostication in life-threatening brain injury is difficult, particularly at an early stage. Evidence from controlled studies to guide decision-making is limited, and there is a risk of a 'self-fulfilling prophecy', with early prognostication leading to early withdrawal of life sustaining therapies and death. The Joint Professional Standards committee of the Faculty of Intensive Care Medicine and the Intensive Care Society convened a consensus group with representation from stakeholder professional organizations to develop clear professional guidance in this area. It recognized that the weak evidence base makes GRADE guidelines difficult to justify. We have made 12 practical, pragmatic recommendations to help clinicians deliver safe, effective, equitable, and justifiable care within resource constrained healthcare systems. In the situation where patient-centred outcomes are recognized to be unacceptable, regardless of the extent of neurological improvement, then early transition to palliative care is appropriate. These recommendations are intended to apply where the primary pathology is DBI, rather than where DBI has compounded a progressive and irreversible deterioration in other life-threatening comorbidities.


Health care for older persons: a country profile-Korea.
The Korean healthcare system is faced with a crisis caused by rapidly changing social values tending toward westernization, increasing insurance benefit requests for elder health care, financial instability of the National Health Insurance (NHI) program, and a lack of social infrastructure for the elderly. The demand for health care for the elderly has increased markedly, because of a rapidly aging population, growing female participation in the labor market, elevated expectations for health care, and a change in the pattern of medical conditions in the elderly from acute illness to chronic disability. NHI lacks the finances to meet the benefit request for long-term care (LTC). Only 0.39% of the elderly can be accommodated in LTC beds. Consequently, the chronically disabled elderly overflow to acute care beds in general hospitals, which places an undue burden on the already strained NHI system in terms of longer stays and higher cost of treatment in hospitals compared with care specific to the elderly in LTC facilities. It is clear that the Korean healthcare system does not have the facilities to meet such challenges and is in a state of disorder. Korea has failed to predict and prepare for population needs before they arise, including financing and the development of appropriate care models, particularly concerning the adequate provision of LTC. This paper advocates the necessity of international discussion of the prospects for developing health care for aging populations and encourages the sharing of differing national experiences concerning care for the elderly.


Reasons for the low uptake of adult male circumcision for the prevention of HIV transmission in Swaziland.
Swaziland is currently experiencing the worst impact of HIV and AIDS of any country in the world. In an effort to curb further spread of the virus, the country adopted mass male circumcision (MC) as recommended by the World Health Organization in 2007. Despite intense campaigns to promote the procedure over the past three years, the uptake of circumcision remains very low for reasons that are not very clear. The purpose of this study was to explore the reasons for the low uptake of MC in Swaziland despite the massive national MC campaigns. A qualitative research design was used, in which all men who were targeted by the mass MC campaign were eligible. Participants were identified as they came for sexual and reproductive health services at the Family Life Association of Swaziland (FLAS) Clinic, Mbabane. In-depth, individual face-to-face unstructured interviews were conducted to elicit the reasons why men were not going for circumcision. A total of 17 men were interviewed. Results showed that these reasons include fear of the procedure and the possible outcome, perception of no significant benefit of the procedure, impatience about waiting for the procedure or the healing process, religious/cultural beliefs, and worries about the fate of the foreskin. These reasons were attributed to misconceptions and lack of accurate and specific information about some aspects of the circumcision strategy of HIV preventions. Physiological changes and economic activities associated with adulthood were also found to be hindrances to MC uptake. The study recommended that a comprehensive description of the procedure and more precise facts and scientific bases of the MC strategy be incorporated and emphasised in the MC campaigns. Involvement of religious leaders will also facilitate clarification of religious or cultural misunderstandings or misconceptions. A focus on neonatal MC would also help.


A low-molecular-weight oil cleaner for removal of leftover silicone oil intraocular tamponade.
Silicone oil (SO) has been used as a long-term intraocular tamponade in treating retinal diseases for more than half a decade. However, its propensity to form tiny SO droplets is associated with a number of complications. Currently there is no effective way to remove such droplets from the eye cavity. In this work, a novel cleaner was developed for effective removal of these droplets. The cleaner promotes the formation of an oil-in-water-in-oil (O/W/O) double-emulsion that consists of the unwanted droplets as the innermost oil phase. The cleaner's ability to encapsulate SO droplets was tested using both in vitro microdevices and ex vivo porcine eye models. The efficiency of the cleaner in removing the SO droplets was quantified using the three-dimensional (3D) printed eye model. Both the volatility and in vitro cytotoxicity of the cleaner were evaluated on three retinal cell lines. Cleaner 1.0 is volatile and has an evaporation rate of 0.14 mL/h at room temperature. The formation of O/W/O double-emulsion indicates the encapsulation of SO droplets by the cleaner. In the 3D printed eye model, rinsing with cleaner 1.0 led to a significant reduction of leftover SO droplets compared with 1× phosphate-buffered saline (PBS; P < 0.05; n = 6). Cleaner 1.0 did not cause significant cell death (3%-6%) compared with balance salt solution (BSS; 1%-3%) in all three cell lines. The reduction in the cell viability due to cleaner 1.0, relative to that of BSS, was significant only in ARPE-19 cells (27%; P < 0.05) but not in the other two cell lines (8% and 17%, respectively; P > 0.05). The double-emulsification approach was effective in removing remnant droplets from the eye cavities, and the cleaner was compatible with common cell types encountered in human eyes. The mechanism of toxicity of the proposed cleaner is still unknown, therefore, further in vivo animal tests are needed for full evaluation of the physiological response before the proposed cleaner can be advanced to clinical trials for retinal surgeries.


Deep venous thrombosis after general surgical operations at a university hospital: two-year data from the ACS NSQIP.
To characterize the location, incidence, and timing of deep venous thrombosis (DVT) after general surgical procedures. Retrospective data review. University hospital. Of 2189 patients who underwent general surgical operation, 35 (1.6%) developed DVT afterward. Main outcome measures included patient characteristics, location of DVT (lower vs upper), time of DVT diagnosis from the index operation (days), time of diagnosis according to discharge (inpatient vs outpatient), any associated pulmonary embolism, and mortality. There were 22 men and 13 women with a mean age of 58 years. The index general surgical operations included pancreatic surgery (n = 10), esophagogastric surgery (n = 8), intestinal/colorectal surgery (n = 13), and other (n = 5). Diagnosis of DVT was based on symptoms in 94.3% of cases and based on routine duplex screening in 5.7% of cases. Upper extremity DVTs occurred in 40%; lower extremity DVTs occurred in 45.7%; and combined upper and lower extremity DVTs occurred in 14.3% of patients. The mean time between diagnosis of DVT and the index operation was 8.6 days with 29 of 35 patients (83%) with DVT diagnosed as an inpatient and 17% diagnosed in the outpatient setting. Catheter-associated DVT occurred in 21 of 35 patients (60%); 19 patients had an upper extremity catheter and 2 patients had a femoral catheter. Twenty-two of 35 patients (62.9%) with postoperative DVT had other concomitant complications such as ventilator dependency, sepsis, renal failure, surgical site infection, and pneumonia. Deep venous thrombosis with concomitant pulmonary embolism occurred in 4 of 35 patients (11.4%), with 1 of these 4 patients having only upper extremity DVT. The 30-day mortality in this study cohort was 14.2%. In the presence of prophylaxis, the incidence of DVT after general surgical operation is low, with more than 80% of cases diagnosed in the inpatient setting. Since more than half of the DVTs are catheter induced, efforts for DVT prevention should include more attention to the need for a central catheter, limiting the amount of time of a central catheter, and possibly the use of anticoagulation in the presence of a central catheter.


Duration of post-COVID-19 symptoms is associated with sustained SARS-CoV-2-specific immune responses.
A subset of COVID-19 patients exhibit post-acute sequelae of COVID-19 (PASC), but little is known about the immune signatures associated with these syndromes. We investigated longitudinal peripheral blood samples in 50 individuals with previously confirmed SARS-CoV-2 infection, including 20 who experienced prolonged duration of COVID-19 symptoms (lasting more than 30 days; median = 74 days) compared with 30 who had symptom resolution within 20 days. Individuals with prolonged symptom duration maintained antigen-specific T cell response magnitudes to SARS-CoV-2 spike protein in CD4+ and circulating T follicular helper cell populations during late convalescence, while those without persistent symptoms demonstrated an expected decline. The prolonged group also displayed increased IgG avidity to SARS-CoV-2 spike protein. Significant correlations between symptom duration and both SARS-CoV-2-specific T cells and antibodies were observed. Activation and exhaustion markers were evaluated in multiple immune cell types, revealing few phenotypic differences between prolonged and recovered groups, suggesting that prolonged symptom duration is not due to persistent systemic inflammation. These findings demonstrate that SARS-CoV-2-specific immune responses are maintained in patients suffering from prolonged post-COVID-19 symptom duration in contrast to those with resolved symptoms and may suggest the persistence of viral antigens as an underlying etiology.


Instruments to measure outcomes of post-intensive care syndrome in outpatient care settings - Results of an expert consensus and feasibility field test.
There is no consensus on the instruments for diagnosis of post-intensive care syndrome (PICS). We present a proposal for a set of outcome measurement instruments of PICS in outpatient care. We conducted a three-round, semi-structured consensus-seeking process with medical experts, followed each by exploratory feasibility investigations with intensive care unit survivors (n1 = 5; n2 = 5; n3 = 7). Fourteen participants from nine stakeholder groups participated in the first and second consensus meeting. In the third consensus meeting, a core group of six clinical researchers refined the final outcome measurement instrument set proposal. We suggest an outcome measurement instrument set used in a two-step process. First step: Screening with brief tests covering PICS domains of (1) mental health (Patient Health Questionnaire-4 (PHQ-4)), (2) cognition (MiniCog, Animal Naming), (3) physical function (Timed Up-and-Go (TUG), handgrip strength), and (4) health-related quality of life (HRQoL) (EQ-5D-5L). Single items measure subjective health before and after the intensive care unit stay. If patients report new or worsened health problems after intensive care unit discharge and show relevant impairment in at least one of the screening tests, a second extended assessment follows: (1) Mental health (Patient Health Questionnaire-8 (PHQ-8), Generalized Anxiety Disorder Scale-7 (GAD-7), Impact of Event Scale - revised (IES-R)); (2) cognition (Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Trail Making Test (TMT) A and B); (3) physical function (2-Minute Walk Test (2-MWT), handgrip strength, Short Physical Performance Battery (SPPB)); and (4) HRQoL (EQ-5D-5L, 12-Item WHO Disability Assessment Schedule (WHODAS 2.0)). We propose an outcome measurement instrument set used in a two-step measurement of PICS, combining performance-based and patient-reported outcome measures. First-step screening is brief, free-of-charge, and easily applicable by health care professionals across different sectors. If indicated, specialized healthcare providers can perform the extended, second-step assessment. Usage of the first-step screening of our suggested outcome measurement instrument set in outpatient clinics with subsequent transfer to specialists is recommended for all intensive care unit survivors. This may increase awareness and reduce the burden of PICS. This study was registered at ClinicalTrials.gov (Identifier: NCT04175236; first posted 22 November 2019).


Squamous-cell carcinoma of the scrotum.
Squamous-cell carcinoma of the scrotum has a poor prognosis unless locally confined. Patients with stage A1 disease have approximately a 75% or better chance for long-term survival. Occupation-related and -induced scrotal carcinomas are less frequent now because of better hygiene, protective clothing, and awareness of the carcinogenicity of industrial oils. A rise in the incidence of the disease might result from the HPV epidemic. The basic treatment of squamous-cell carcinomas of the scrotum still depends on wide local excision of the primary lesion. Patients should be treated with a broad-spectrum antibiotic for 4 to 6 weeks prior to sentinel node biopsy or ilioinguinal lymphadenectomy. Sentinel node biopsy should be performed to rule out micrometastasis and to establish the need for a formal ilioinguinal lymphadenectomy. Radiation therapy has little therapeutic benefit in the management of squamous-cell carcinoma of the scrotum. Bleomycin might be useful as adjuvant therapy for widespread ilioinguinal disease before attempted resection, although this has yet to be proved.


Effect of L-ornithine L-aspartate on Liver Injury Due to Acute Ethyl Alcohol Intoxication in Rats.
Ethyl alcohol is a substance that is widely used worldwide and known to exert toxic effects on liver. In this study, we aimed to examine the effect of L-ornithine L-aspartate (LOLA) on the toxicity of a single dose of ethyl alcohol in rats. We used 32 randomly selected male Sprague-Dawley rats weighing 200-250 g. The rats were grouped into four groups with each group containing eight rats: Group 1: the control group, Group 2: the ethyl alcohol group, Group 3: the LOLA group and Group 4: the ethyl alcohol+LOLA group. Ethyl alcohol was administered orally through a nasogastric tube at a dose of 6 g/kg after diluting with distilled water. One hour after ethyl alcohol administration, LOLA was administered to pre-specified groups orally through a nasogastric tube at a dose of 200 mg/kg after diluting with distilled water. Liver tissue and blood samples were obtained from all rats 24 hours later to study total antioxidant capacity (TAC), total oxidant status (TOS) and oxidative stress index (OSI) levels in liver samples, and aspartate aminotransferase (AST), alanine transferase (ALT), TAC, TOS and OSI levels in blood samples. Serum TAC, TOS and OSI levels were higher in the groups that were administered ethyl alcohol. In addition, tissue TAC level was higher and TOS and OSI levels were lower in groups that were given ethyl alcohol. No significant changes were observed in serum and tissue TAC, TOS, OSI, ALT and AST levels in the LOLA administered groups. This study showed that LOLA was not biochemically effective and exerts no oxidative stress reducing activity in liver injury due to acute ethyl alcohol toxicity.


Ten years post-GAO assessment, FDA remains uninformed of potentially harmful GRAS substances in foods.
It has been approximately 10 years since the Government Accountability Office (GAO) published its report to Congress entitled, FDA Should Strengthen Its Oversight of Food Ingredients Determined to be Generally Recognized as Safe (GRAS), which strongly criticized FDA noting that its "oversight process does not help ensure the safety of all new GRAS determinations." Congress requested GAO to undertake this audit as a result of concerns that GRAS substances added to foods did not require FDA approval. Since 2010, FDA has addressed only a few of the criticisms regarding its process for establishing a food substance as GRAS. However, several of the most important GAO recommendations remain unaddressed, and most critically, FDA has chosen to remain uninformed about food substances self-determined as GRAS by manufacturers. In its 2016 final rule Substances Generally Recognized as Safe, FDA did not take the opportunity to include a provision for creation of a master list of all GRAS chemicals used in food, nor did the FDA request the authority to do so from Congress. FDA cannot fulfill its statutory obligation for ensuring the chemical safety of the U.S. food supply if it does not know which substances, in which quantities, have been added to foods.


ETHNICITY AND THE IMMIGRATION OF HIGHLY SKILLED WORKERS TO THE UNITED STATES.
This paper examines ethnicity among highly skilled immigrants to the United States. The paper focuses on five classic components of ethnicity - country of birth, race, skin color, language, and religion - among persons admitted to legal permanent residence in the United States in 2003 in the three main employment categories (EB-1, EB-2, and EB-3), using data collected in the U.S. New Immigrant Survey. Initial findings include: (1) The visa categories have distinctive ethnic configurations. India dominates EB-2 and European countries EB-1. (2) The ethnicity portfolio contains more languages than religions. (3) Language is shed before religion, and religion may not be shed at all, except among the ultra highly skilled of EB-1. (4) Highly skilled immigrants are mostly male; they are not immune from lapsing into illegality; they have a shorter visa process than their cohortmates; smaller proportions than in the cohort overall intend to remain in the United States. (5) Larger proportions in EB-2 and EB-3 sent remittances than in the cohort overall. (6) A little measure of assimilation - using dollars to describe earnings in the country of last residence, even when requested to use the country's currency - suggests that highly skilled immigrants are more likely to "think in dollars" than their cohortmates. Further work is taking a deeper look at these patterns in a multivariate context, attentive to selectivity processes and the Globalista impulse.


IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a GIMEMA AL WP report.
The causes of the aggressive nature of BCR-ABL1-positive adult acute lymphoblastic leukemia (ALL) are unknown. To identify, at the submicroscopic level, oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed an investigation of genomic copy number alterations using single nucleotide polymorphism array, genomic polymerase chain reaction, and sequencing of candidate genes. Eighty-three patients with de novo adult Philadelphia chromosome (Ph) -positive ALL were enrolled onto institutional (n = 17) or Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Working Party delle Leucemia Acute (n = 66) clinical trials. Treatments included tyrosine kinase inhibitor (TKI) alone, conventional chemotherapy, or a combination of TKI and chemotherapy. A 7p12 deletion of IKZF1 (Ikaros) was identified in 52 (63%) of 83 patients. The pattern of deletion varied among different patients, but the two most common deletion types were loss of exons 4 to 7 in 31 (37%) of 83 patients and loss of exons 2 to 7 in 17 (20%) of 83 patients. Disease-free survival (DFS) was shorter in patients with IKZF1 deletion versus patients with IKZF1 wild type (10 v 32 months, respectively; P = .02). Furthermore, a significantly shorter cumulative incidence of relapse was recorded in patients with IKZF1 deletion versus patients with IKZF1 wild type (10.1 v 56.1 months, respectively; P = .001). Multivariate analysis confirmed the negative prognostic impact of IKZF1 deletion on DFS (P = .04). We conclude that IKZF1 deletions are likely to be a genomic alteration that significantly affects the prognosis of Ph-positive ALL in adults.


Risk Factors and Outcomes Associated With Treatment of Asymptomatic Bacteriuria in Hospitalized Patients.
Treatment of asymptomatic bacteriuria (ASB) with antibiotics is a common factor in inappropriate antibiotic use, but risk factors and outcomes associated with treatment of ASB in hospitalized patients are not well defined. To evaluate factors associated with treatment of ASB among hospitalized patients and the possible association between treatment and clinical outcomes. A retrospective cohort study was conducted from January 1, 2016, through February 1, 2018, at 46 hospitals participating in the Michigan Hospital Medicine Safety Consortium. A total of 2733 hospitalized medical patients with ASB, defined as a positive urine culture without any documented signs or symptoms attributable to urinary tract infection, were included in the analysis. One or more antibiotic dose for treatment of ASB. Estimators of antibiotic treatment of ASB. Secondary outcomes included 30-day mortality, 30-day hospital readmission, 30-day emergency department visit, discharge to post-acute care settings, Clostridioides difficile infection (formerly known as Clostridium difficile) at 30 days, and duration of hospitalization after urine testing. Of 2733 patients with ASB, 2138 were women (78.2%); median age was 77 years (interquartile range [IQR], 66-86 years). A total of 2259 patients (82.7%) were treated with antibiotics for a median of 7 days (IQR, 4-9 days). Factors associated with ASB treatment included older age (odds ratio [OR], 1.10 per 10-year increase; 95% CI, 1.02-1.18), dementia (OR, 1.57; 95% CI, 1.15-2.13), acutely altered mental status (OR, 1.93; 95% CI, 1.23-3.04), urinary incontinence (OR, 1.81; 95% CI, 1.36-2.41), leukocytosis (white blood cell count >10 000/μL) (OR, 1.55; 95% CI, 1.21-2.00), positive urinalysis (presence of leukocyte esterase or nitrite, or >5 white blood cells per high-power field) (OR, 2.83; 95% CI, 2.05-3.93), and urine culture with a bacterial colony count greater than 100 000 colony-forming units per high-power field (OR, 2.30; 95% CI, 1.83-2.91). Treatment of ASB was associated with longer duration of hospitalization after urine testing (4 vs 3 days; relative risk, 1.37; 95% CI, 1.28-1.47). No other differences in secondary outcomes were identified after propensity weighting. Hospitalized patients with ASB commonly receive inappropriate antibiotic therapy. Antibiotic treatment did not appear to be associated with improved outcomes; rather, treatment may be associated with longer duration of hospitalization after urine testing. To possibly reduce inappropriate antibiotic use, stewardship efforts should focus on improving urine testing practices and management strategies for elderly patients with altered mental status.


Analysis of the karyotype of expanded human adipose-derived stem cells for bone reconstruction of the maxillo-facial region.
Mesenchymal stem cells (MSC) and adipose-derived stem cells (ASC) were recently proposed for bone maxillofacial reconstruction in association with biomaterials. For this application MSC must be ex-vivo expanded in order to obtain, for a given volume of implanted biomaterial, a relevant number of bone forming cells. Previously conducted pre-clinical studies suggested that a concentration of 6 x 10(8) ASC associated with 900 mg of anorganic bovine bone (ABB) could be effective for human maxillary sinus floor elevation. A keystone issue to guarantee the quality and safety of Advanced Therapy Medicinal Products containing expanded MSC and ASC is their chromosome stability in culture: this topic has been widely investigated and conflicting results have been published. Abnormal karyotype of human ex-vivo expanded MSC and ASC was found by some authors, while, at the same time, several other studies showed the MSC and ASC karyotype to be normal. It is therefore important that all the results obtained on MSC and ASC karyotype analysis be published. Given this context, the aim of this manuscript, aim of this manuscript is to verify the karyotype stability of ASC in view of their applications in clinical trials. ASC obtained from the adipose tissue of 4 donors were expanded over extended culture time. Based on previous ASC expansions we hypothesized to be able to obtain 6 x 10(8) cells by passage 7. Karyotype analysis of 30 metaphases was planned to be investigated at passage 2, 7, and 15 in all the cultures. No abnormalities were found in the karyotype of two donors at all the passages tested, while a translocation was found in 2 metaphases of a donor at passage 7, but not at passage 15, and in the fourth donor in 5 metaphases a trisomy was found at passage 15. Chromosomal abnormalities were detected only after extended ASC expansion. Whether these anomalies can be related to risk for the patient's safety will have to be demonstrated by in-vivo studies.


CBS mutations and MTFHR SNPs causative of hyperhomocysteinemia in Pakistani children.
Three index patients with hyperhomocysteinemia and ocular anomalies were screened for cystathionine beta synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Genotyping of hyperhomocysteinemia associated MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) was done by PCR-restriction fragment length polymorphism. Sanger sequencing was performed for CBS exonic sequences along with consensus splice sites. In the case of MTHFR polymorphisms, all the patients were heterozygous CT for the single nucleotide polymorphism (SNP) C677T and were therefore carriers of the risk allele (T), while the patients were homozygous CC for the risk genotype of the SNP A1298C. CBS sequencing resulted in the identification of two novel mutations, a missense change (c.467T>C; p.Leu156Pro) in exon 7 and an in-frame deletion (c.808_810del; p.Glu270del) in exon 10. In addition, a recurrent missense mutation (c.770C>T; p.Thr257Met) in exon 10 of the gene was also identified. The mutations were present homozygously in the patients and were inherited from the carrier parents. This is the first report from Pakistan where novel as well as recurrent CBS mutations causing hyperhomocysteinemia and lens dislocation in three patients from different families are being reported with the predicted effect of the risk allele of the MTHFR SNP in causing hyperhomocysteinemia.


Patterns of infertility in Poland - multicenter study.
Infertility seems to be a great worldwide problem. Many publications present the epidemiology of infertility, but the percentage distribution of factors responsible for infertility varies significantly. The objective was to define infertility profiles in Poland assessed according to the information provided by 4 large infertility centers: Bialystok, Poznan, Szczecin and Warsaw. Multicenter study was performed. Couples with primary infertility, attending one of the four centers in Poland, were asked to fulfill a questionnaire. Overall 1517 questionaires were analysed: Bialystok - 468, Poznan - 325, Szczecin - 341, Warsaw - 383. Only semen analyses fulfilling WHO Manual 1999 criteria were used in the study and were afterwards compared with 2010 WHO standards. Results from 4 Polish centers showed that the average age of infertile women was 31.41 years and of infertile men 33.2 years. The mean duration of infertility equaled 3.31 years. Among 1517 surveyed women, no pathological findings concerning reproductive abilities were observed in 1088 cases (71.72%). In the remaining patients the following were diagnosed: uterine factor in 26 (6.02%) women, ovulation disorders in 134 (31.33%), including 70 (16.27%) of PCOS patients, tubal factor in 165 (38.55%) and endometriosis in 145 (33.73%). The average of 18.9% of couples had a mixed cause of infertility, while idiopathic factor was assigned to 15.99%. In the study male factor accounted for 55.73% of cases. Change of reference values for semen analysis implemented in 2010 caused an increase in the number of normal results and asthenozoospermia. According to the data provided by Polish infertility centers the rate of male factor as a reason of infertility has reached 55.73%. However, the implementation of new reference values for semen analysis in 2010 led to the decrease in male factor frequency and the increase in the rate of idiophatic infertility. Anovulatory cycles and endometriosis are the main reasons affecting the female reproductive potential.


Preliminary evidence of reduced combined output of dopamine and its metabolites in chronic schizophrenia.
The mean combined total body excretion of dopamine (DA) and its metabolites, measured by summing the molar excretion of DA and its metabolites in 24-hour urine samples (Sum DA), was reduced in 20 patients with schizophrenia who had not been receiving medication for at least two weeks. These patients were relatively resistant to treatment, as they were unable to live independently outside institutional settings despite conventional neuroleptic therapy. In contrast, sum norepinephrine (Sum NE), measured by summing the molar excretion of NE and its metabolites, was not reduced. These results are highlighted by expressing the data in terms of the ratio of Sum DA/Sum NE. Patients with schizophrenia had a significantly lower ratio. Treatment with haloperidol normalized the low ratio. Urinary excretion of 5-hydroxyindoleacetic acid was normal in the schizophrenic patients. These results suggest that chronic schizophrenia is more likely to be associated with a low rather than a high state of DA activity.


New approach for optimal electricity planning and dispatching with hourly time-scale air quality and health considerations.
Integrating accurate air quality modeling with decision making is hampered by complex atmospheric physics and chemistry and its coupling with atmospheric transport. Existing approaches to model the physics and chemistry accurately lead to significant computational burdens in computing the response of atmospheric concentrations to changes in emissions profiles. By integrating a reduced form of a fully coupled atmospheric model within a unit commitment optimization model, we allow, for the first time to our knowledge, a fully dynamical approach toward electricity planning that accurately and rapidly minimizes both cost and health impacts. The reduced-form model captures the response of spatially resolved air pollutant concentrations to changes in electricity-generating plant emissions on an hourly basis with accuracy comparable to a comprehensive air quality model. The integrated model allows for the inclusion of human health impacts into cost-based decisions for power plant operation. We use the new capability in a case study of the state of Georgia over the years of 2004-2011, and show that a shift in utilization among existing power plants during selected hourly periods could have provided a health cost savings of $175.9 million dollars for an additional electricity generation cost of $83.6 million in 2007 US dollars (USD2007). The case study illustrates how air pollutant health impacts can be cost-effectively minimized by intelligently modulating power plant operations over multihour periods, without implementing additional emissions control technologies.


Dizziness and loss of consciousness. Cardiovascular causes.
Dizziness and loss of consciousness are common clinical problems presenting in general practice. This article aims to provide the practitioner with a pragmatic and logical approach to identifying the cardiovascular causes of dizziness and loss of consciousness. A range of disorders with varying pathology cause a transient loss of consciousness associated with postural collapse (syncope) by interruption of blood flow to the brain. Syncope and seizures are the only common causes of recurrent episodes of loss of consciousness. The vasovagal reaction or 'common faint' and postural hypotension are both common and benign causes of syncope. Syncope can also result from cardiac causes that include disorders of cardiac rhythm and mechanical obstruction to cardiac output. Cardiac causes of syncope are associated with much higher morbidity and mortality than postural hypotension or fainting. Specific treatment is available for the various cardiac causes of syncope and thus accurate diagnosis is imperative.


Cat scratch disease: U.S. clinicians' experience and knowledge.
Cat scratch disease (CSD) is a zoonotic infection caused primarily by the bacterium Bartonella henselae. An estimated 12,000 outpatients and 500 inpatients are diagnosed with CSD annually, yet little is known regarding clinician experience with and treatment of CSD in the United States. Questions assessing clinical burden, treatment and prevention of CSD were posed to 3,011 primary care providers (family practitioners, internists, paediatricians and nurse practitioners) during 2014-2015 as part of the annual nationwide DocStyles survey. Among the clinicians surveyed, 37.2% indicated that they had diagnosed at least one patient with CSD in the prior year. Clinicians in the Pacific and Southern regions were more likely to have diagnosed CSD, as were clinicians who saw paediatric patients, regardless of specialty. When presented with a question regarding treatment of uncomplicated CSD, only 12.5% of clinicians chose the recommended treatment option of analgesics and monitoring, while 71.4% selected antibiotics and 13.4% selected lymph node aspiration. In a scenario concerning CSD prevention in immunosuppressed patients, 80.6% of clinicians chose some form of precaution, but less than one-third chose the recommended option of counseling patients to treat their cats for fleas and avoid rough play with their cats. Results from this study indicate that a substantial proportion of U.S. clinicians have diagnosed CSD within the past year. Although published guidelines exist for treatment and prevention of CSD, these findings suggest that knowledge gaps remain. Therefore, targeted educational efforts about CSD may benefit primary care providers.


Rate and Predictors of 1-year Readmission in Tertiary Psychiatric Hospitals.
To obtain the rate of 1-year readmission among psychiatric patients in tertiary centers in Oman and to study the association between readmission and sociodemographic and clinical factors. This is a retrospective study using data from patients' medical records. All patients aged ≥18 years who were admitted to Al Masarra Hospital and the psychiatric ward at Sultan Qaboos University Hospital over a 6-month period were included in the study. Each patient was followed up for 1 year after discharge to determine whether they had been readmitted during that period. The analysis was conducted as a comparative study between patients with early readmission and those who had not been readmitted during the 1-year period. Fifteen factors were examined for association with readmission within the 1-year period. A total of 466 patients were admitted to the two hospitals during the study period, with 39% of these patients readmitted within 1 year. The univariate analysis revealed that 11 factors were significantly associated with 1-year readmission (P < 0.05). The multivariate logistic regression analysis identified four factors as independent significant predictors for 1-year rehospitalization: male gender, unemployment, nonadherence to medications and a history of previous hospitalization. The rate of 1-year readmission was found to be high, in line with the findings of other studies. Specific sociodemographic factors and clinical factors were strongly associated with early readmission in psychiatric hospitals in Oman. Strategies for aftercare and community psychiatric services need to be implemented.


Size-extensivity-corrected multireference configuration interaction schemes to accurately predict bond dissociation energies of oxygenated hydrocarbons.
Oxygenated hydrocarbons play important roles in combustion science as renewable fuels and additives, but many details about their combustion chemistry remain poorly understood. Although many methods exist for computing accurate electronic energies of molecules at equilibrium geometries, a consistent description of entire combustion reaction potential energy surfaces (PESs) requires multireference correlated wavefunction theories. Here we use bond dissociation energies (BDEs) as a foundational metric to benchmark methods based on multireference configuration interaction (MRCI) for several classes of oxygenated compounds (alcohols, aldehydes, carboxylic acids, and methyl esters). We compare results from multireference singles and doubles configuration interaction to those utilizing a posteriori and a priori size-extensivity corrections, benchmarked against experiment and coupled cluster theory. We demonstrate that size-extensivity corrections are necessary for chemically accurate BDE predictions even in relatively small molecules and furnish examples of unphysical BDE predictions resulting from using too-small orbital active spaces. We also outline the specific challenges in using MRCI methods for carbonyl-containing compounds. The resulting complete basis set extrapolated, size-extensivity-corrected MRCI scheme produces BDEs generally accurate to within 1 kcal/mol, laying the foundation for this scheme's use on larger molecules and for more complex regions of combustion PESs.


Microenvironment changes in mild traumatic brain injury.
Traumatic brain injury (TBI) is a major public-health problem for which mild TBI (MTBI) makes up majority of the cases. MTBI is a poorly-understood health problem and can persist for years manifesting into neurological and non-neurological problems that can affect functional outcome. Presently, diagnosis of MTBI is based on symptoms reporting with poor understanding of ongoing pathophysiology, hence precluding prognosis and intervention. Other than rehabilitation, there is still no pharmacological treatment for the treatment of secondary injury and prevention of the development of cognitive and behavioural problems. The lack of external injuries and absence of detectable brain abnormalities lend support to MTBI developing at the cellular and biochemical level. However, the paucity of suitable and validated non-invasive methods for accurate diagnosis of MTBI poses as a substantial challenge. Hence, it is crucial that a clinically useful evaluation and management procedure be instituted for MTBI that encompasses both molecular pathophysiology and functional outcome. The acute microenvironment changes post-MTBI presents an attractive target for modulation of MTBI symptoms and the development of cognitive changes later in life.


Factors involved in the development of polymerization shrinkage stress in resin-composites: a systematic review.
Polymerization shrinkage stress of resin-composite materials may have a negative impact on the clinical performance of bonded restorations. The purpose of this systematic review is to discuss the primary factors involved with polymerization shrinkage stress development. According to the current literature, polymerization stress of resin composites is determined by their volumetric shrinkage, viscoelastic behavior and by restrictions imposed to polymerization shrinkage. Therefore, the material's composition, its degree of conversion and reaction kinetics become aspects of interest, together with the confinement and compliance of the cavity preparation. Information provided in this review was based on original scientific research published in Dental, Chemistry and Biomaterials journals. Textbooks on Chemistry and Dental Materials were also referenced for basic concepts. Shrinkage stress development must be considered a multi-factorial phenomenon. Therefore, accessing the specific contribution of volumetric shrinkage, viscoelastic behavior, reaction kinetics and local conditions on stress magnitude seems impractical. Some of the restorative techniques aiming at stress reduction have limited applicability, because their efficiency varies depending upon the materials employed. Due to an intense research activity over the years, the understanding of this matter has increased remarkably, leading to the development of new restorative techniques and materials that may help minimize this problem.


Adipose gene expression response of lean and obese mice to short-term dietary restriction.
Overweight and obesity lead to higher morbidity risks, which are alleviated even by mild weight loss. To gain insight in the molecular effects of weight loss in adipose tissue, we analyzed the effects of short-term dietary restriction (DR) on mice fed a low-fat diet (lean mice) or a high-fat diet (obese mice). Female C57Bl6/J mice on both diets were on DR until an average body weight loss of 20%, which was achieved in 8 to 12 days depending on body weight at the start of DR. Plasma free fatty acids and blood glucose levels decreased significantly on DR. In the (restricted) low-fat diet groups, gene expression analysis using adipose-enriched cDNA microarrays revealed only two transcripts to be significant differentially expressed by DR: up-regulation of malic enzyme (Mod1) and down-regulation of major urinary protein 1 (Mup1). Real-time polymerase chain reaction analysis confirmed these findings and showed, for the high-fat diet groups, an identical expression pattern for Mup1, whereas Mod1 showed an opposed gene expression pattern for the high-fat diet groups. In conclusion, initial weight loss induces transcriptional changes only in a very small number of adipose genes, which also depends on the (restricted) diet used.


Endocrine function and morphological findings in patients with disorders of the hypothalamo-pituitary area: a study with magnetic resonance.
Evaluation of the sellar area was performed with magnetic resonance imaging in 101 patients (age range 0.8-27 years) with hypopituitarism, isolated diabetes insipidus, hypogonadotrophic hypogonadism, and central precocious puberty. The hypopituitary patients (n = 70) included multiple pituitary deficiency (n = 23), pituitary deficiency with diabetes insipidus (n = 5), and isolated growth hormone deficiency (n = 42). The patients with multiple pituitary deficiency showed pathological morphological findings in all cases, with stalk and posterior lobe always involved. The group with associated diabetes insipidus had abnormal stalk in four of five cases and posterior lobe not visible in all cases. Only five of 42 (12%) patients with isolated growth hormone deficiency had abnormalities of the sellar area. In two out of four patients with isolated diabetes insipidus posterior lobe was not seen. All patients with hypogonadotrophic hypogonadism (three with Kallmann's syndrome, one Prader-Willi syndrome, and two idiopathic hypogonadism) appeared normal. In precocious puberty (n = 21) the three patients with onset of symptoms before age 2 years exhibited a hypothalamic hamartoma, whereas in the others with onset of puberty between age 2 and 7 the magnetic resonance image was normal in 17 of 18 patients. The probability of finding a pathological magnetic resonance image was considerably high in our patients with multiple pituitary deficiency, isolated diabetes insipidus, and precocious puberty with very early onset of symptoms. On the contrary, purely functional abnormality is suggested in most patients with isolated growth hormone deficiency, hypogonadotrophic hypogonadism, and precocious puberty with later onset of symptoms.


Effective second-order nonlinearity in acentric optical crystals with low symmetry.
We derive explicit expressions in the frame of the optical indicatrix for the second-order effective nonlinearity in biaxial crystals with point groups 2, m, and 1, governing the conversion efficiency in three-wave nonlinear optical interactions. The tabulated expressions for the monoclinic symmetry classes 2 and m are valid for all possible orientations of the optical indicatrix relative to the crystallographic frame and for propagation along an arbitrary direction outside the principal planes. They can be used for direct estimation of the effective nonlinearity in the same frame where the phase-matching loci are calculated. The relevant properties and conventions used for the newly emerging acentric monoclinic crystals belonging to the borate family are summarized and tabulated. The derivations are expected to help establish adherence to uniform nomenclature and conventions for these novel inorganic nonlinear crystals, and to eliminate ambiguity and increasing confusion in the literature and in the industrial specifications. The general expressions for the effective nonlinearity are reduced for triclinic crystals of point group 1 to simplified forms in the principal planes.


THz Dynamic Nuclear Polarization NMR.
Dynamic nuclear polarization (DNP) increases the sensitivity of nuclear magnetic resonance (NMR) spectroscopy by using high frequency microwaves to transfer the polarization of the electrons to the nuclear spins. The enhancement in NMR sensitivity can amount to a factor of well above 100, enabling faster data acquisition and greatly improved NMR measurements. With the increasing magnetic fields (up to 23 T) used in NMR research, the required frequency for DNP falls into the THz band (140-600 GHz). Gyrotrons have been developed to meet the demanding specifications for DNP NMR, including power levels of tens of watts; frequency stability of a few megahertz; and power stability of 1% over runs that last for several days to weeks. Continuous gyrotron frequency tuning of over 1 GHz has also been demonstrated. The complete DNP NMR system must include a low loss transmission line; an optimized antenna; and a holder for efficient coupling of the THz radiation to the sample. This paper describes the DNP NMR process and illustrates the THz systems needed for this demanding spectroscopic application. THz DNP NMR is a rapidly developing, exciting area of THz science and technology.


Early life predictors of midlife allostatic load: A prospective cohort study.
Allostatic load has been suggested as a pathway through which experiences become biologically embedded to influence health. Research on childhood predictors of allostatic load has focused on socioeconomic and psychosocial exposures, while few studies include prospective measures of biomedical exposures. Further, findings on sex differences in the association of childhood predictors with various health outcomes related to allostatic load are ambiguous. To examine the influence of early life biomedical and social factors in the first year of life on midlife allostatic load, assessing potential sex differences. This prospective cohort study includes early life information collected at birth and a one year examination for 1,648 members of the Copenhagen Perinatal Cohort who also participated in the Copenhagen Aging and Midlife Biobank study (aged 49-52 years, 56% women). Allostatic load based on 14 biomarkers was selected as a measure of midlife health status. Early life factors were categorized as predominantly biomedical or social, and their associations with midlife allostatic load were examined in domain-specific and combined sex-stratified multiple regression models. The biomedical factors model explained 6.6% of the variance in midlife allostatic load in men and 6.7% in women, while the social model explained 4.1% of the variance in men and 7.3% in women. For both sexes, parental socioeconomic position at one year and maternal BMI significantly predicted midlife allostatic load in a model containing all early life factors. For women, additional significant predictors were complications at birth, birth weight and not living with parents at one year. The results confirm an association of lower childhood socioeconomic position with higher adult allostatic load while demonstrating the importance of other prenatal and early life exposures and highlighting potential sex differences.


Lack of PGC-1α exacerbates high glucose-induced apoptosis in human umbilical vein endothelial cells through activation of VADC1.
Endothelial cells (ECs) apoptosis induced by hyperglycemia is intimately involved in the pathophysiology of diabetes and its complication. Although PGC-1α is known for its role in glucose metabolism, its role in ECs injury caused by high glucose milieu is still unclear. Therefore, this study aims to investigate whether PGC-1α participates in ECs apoptosis under high glucose condition. Human umbilical vein endothelial cells (HUVECs) were down-regulated PGC-1α expression by adenovirus-mediated PGC-1α specific siRNA (Ad-shPGC-1α) and exposed to high glucose. Cell viability, apoptosis, mitochondrial membrane permeability, apoptotic marker, reactive oxygen species (ROS), and expression of PGC-1α and VDAC isoforms were studied. Our results showed that high glucose-induced cell apoptosis was associated with an obvious decrease in PGC-1α expression. Lack of PGC-1α exacerbated high glucose-induced cell apoptosis, inner mitochondrial membrane permeabilization, mitochondrial cytochrome c release into cytoplasm and caspases activation; while further decreased cell viability and mitochondrial membrane potential. Analysis of apoptotic markers (Bcl-2, Bax), intracellular ROS and endoplasmic reticulum stress revealed that these mechanisms were not accounted for the effects of Ad-shPGC-1α on apoptosis. However, we found silencing PGC-1α further increased high glucose-induced VDAC1 expression. The pharmacological inhibition of VDAC1 with 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) inhibited the increased apoptosis in high glucose-treated PGC-1α knockdown cells. These findings strongly suggest that PGC-1α defect is one of the major mechanisms for ECs apoptosis under high glucose condition, and provide a novel strategy to prevent endothelial dysfunction in diabetes.


Hammer for Coq: Automation for Dependent Type Theory.
Hammers provide most powerful general purpose automation for proof assistants based on HOL and set theory today. Despite the gaining popularity of the more advanced versions of type theory, such as those based on the Calculus of Inductive Constructions, the construction of hammers for such foundations has been hindered so far by the lack of translation and reconstruction components. In this paper, we present an architecture of a full hammer for dependent type theory together with its implementation for the Coq proof assistant. A key component of the hammer is a proposed translation from the Calculus of Inductive Constructions, with certain extensions introduced by Coq, to untyped first-order logic. The translation is "sufficiently" sound and complete to be of practical use for automated theorem provers. We also introduce a proof reconstruction mechanism based on an eauto-type algorithm combined with limited rewriting, congruence closure and some forward reasoning. The algorithm is able to re-prove in the Coq logic most of the theorems established by the ATPs. Together with machine-learning based selection of relevant premises this constitutes a full hammer system. The performance of the whole procedure is evaluated in a bootstrapping scenario emulating the development of the Coq standard library. For each theorem in the library only the previous theorems and proofs can be used. We show that 40.8% of the theorems can be proved in a push-button mode in about 40 s of real time on a 8-CPU system.


N-terminal pro-atrial natriuretic peptide (N-ANP) and N-terminal pro-B-type natriuretic peptide (N-BNP) in the prediction of death and heart failure in unselected patients following acute myocardial infarction.
Elevated plasma natriuretic peptide levels after AMI (acute myocardial infarction) are associated with adverse outcome. The aim of the present study was to examine the relationship of plasma N-ANP (N-terminal pro-atrial natriuretic peptide) and N-BNP (N-terminal pro-B-type natriuretic peptide) with mortality and heart failure following AMI. We studied 403 patients with AMI. Blood was sampled for measurement of N-ANP and N-BNP on a single occasion between 72 and 96 h after symptom onset. Natriuretic peptide levels were related to all-cause mortality and heart failure episodes. During follow up (median, 462 days; range 5-764), 43 (10.7%), 25 (6.2%) and 49 (12.2%) patients suffered death, heart failure hospitalization and outpatient heart failure respectively. Only N-BNP (P < 0.0005), N-ANP (P = 0.005) and previous AMI (P = 0.016) were independently predictive of death. N-BNP, but not N-ANP, predicted 30-day mortality. N-ANP, but not N-BNP, predicted mortality after 30 days. N-BNP was the better predictor of heart failure. N-ANP and N-BNP were above the median in 35 and 38 respectively, of 43 patients who later died. N-ANP, N-BNP, or both were above the median in 41 out of 43 patients. Of 25 patients hospitalized with heart failure, N-ANP and N-BNP was above the median in 20 and 24 respectively, and one or other was elevated in all cases. Above-median N-ANP predicted 36 and N-BNP predicted 41 out of 49 episodes of outpatient heart failure. One or other peptide was above the median in 45 out of 49 patients. Our results indicate that N-BNP predicts 30-day and N-ANP >30-day mortality. We conclude that consideration of both N-ANP and N-BNP identifies a greater number of patients at risk of death or heart failure than either peptide alone.


High-altitude illnesses: physiology, risk factors, prevention, and treatment.
High-altitude illnesses encompass the pulmonary and cerebral syndromes that occur in non-acclimatized individuals after rapid ascent to high altitude. The most common syndrome is acute mountain sickness (AMS) which usually begins within a few hours of ascent and typically consists of headache variably accompanied by loss of appetite, nausea, vomiting, disturbed sleep, fatigue, and dizziness. With millions of travelers journeying to high altitudes every year and sleeping above 2,500 m, acute mountain sickness is a wide-spread clinical condition. Risk factors include home elevation, maximum altitude, sleeping altitude, rate of ascent, latitude, age, gender, physical condition, intensity of exercise, pre-acclimatization, genetic make-up, and pre-existing diseases. At higher altitudes, sleep disturbances may become more profound, mental performance is impaired, and weight loss may occur. If ascent is rapid, acetazolamide can reduce the risk of developing AMS, although a number of high-altitude travelers taking acetazolamide will still develop symptoms. Ibuprofen can be effective for headache. Symptoms can be rapidly relieved by descent, and descent is mandatory, if at all possible, for the management of the potentially fatal syndromes of high-altitude pulmonary and cerebral edema. The purpose of this review is to combine a discussion of specific risk factors, prevention, and treatment options with a summary of the basic physiologic responses to the hypoxia of altitude to provide a context for managing high-altitude illnesses and advising the non-acclimatized high-altitude traveler.


Facile and clean release of vertical Si nanowires by wet chemical etching based on alkali hydroxides.
A simple method to release Si nanowires (SiNWs) from a substrate, with their original length almost intact, is demonstrated. By exploiting the unique chemistry involved for the fabrication of vertical arrays of SiNWs in metal-assisted chemical etching (MaCE) based either on HF/AgNO3 or HF/H2O2 chemistries, wet etching with alkali hydroxides such as NaOH or KOH preferentially attacks the bottom part of the vertical SiNWs. A protective layer of Si oxide is found to exist on the outer wall of the SiNWs and to play the key role of etch mask during the release-etching by alkali hydroxides. The clean release of SiNWs also enables the repeated use of the Si substrate for the fabrication of vertical SiNW arrays by MaCE. The released SiNWs are further used for the fabrication of field-effect transistors on a flexible plastic substrate. The method developed here, when combined with a suitable assembling technique, can be very useful in implementing flexible electronics, or in the fabrication of SiNW composites with other functional materials.


Engraftment and activity of anti-CD3-activated human peripheral blood lymphocytes transferred into mice with severe combined immune deficiency.
Human PBL (huPBL) were activated with anti-CD3 mAb in vitro and then were transferred into mice with severe combined immune deficiency (SCID) to determine the effect of activation on engraftment and to determine if the engrafted human cells could provide antitumor effects in mice. Some mice were also treated with human rIL-2 after huPBL transfer. Mice were analyzed 6 to 8 wk after cell transfer and the number of human cells in the peripheral lymphoid organs was determined. Mice receiving anti-CD3-activated huPBL demonstrated a significant increase in the incidence of human T cell engraftment in the periphery as assessed by flow cytometry. Human cells were also detected in the murine thymus after anti-CD3 stimulation indicating that human T cells can migrate to the murine thymus provided that they are activated before the transfer. The transfer of anti-CD3-activated huPBL also resulted in an xenogeneic graft-vs-host reaction manifested primarily by proliferation of murine splenic hemopoietic cells. When SCID mice received the human colon carcinoma HT29, the concurrent transfer of anti-CD3-activated human cells resulted in a significant increase in survival. However, the human cells displayed low cytolytic activity toward human tumor targets when they were recovered from the lymphoid organs of the SCID recipients. Supernatants from the anti-CD3-activated cells were able to inhibit the growth of HT29 in vitro, partly because of the presence of IFN-gamma, suggesting that the human T cells are producing cytokines in vivo that have antitumor effects. Thus, the use of anti-CD3-activated huPBL in SCID mice may be of value for optimizing human cell engraftment in the human/mouse lymphoid chimeras and may be used to evaluate potential anti-neoplastic therapies that employ human effector cells.


Current status and perspectives of patient-derived xenograft models in cancer research.
Cancers remain a major public health problem worldwide, which still require profound research in both the basic and preclinical fields. Patient-derived xenograft (PDX) models are created when cancerous cells or tissues from patients' primary tumors are implanted into immunodeficient mice to simulate human tumor biology in vivo, which have been extensively used in cancer research. The routes of implantation appeared to affect the outcome of PDX research, and there has been increasing applications of patient-derived orthotopic xenograft (PDOX) models. In this review, we firstly summarize the methodology to establish PDX models and then go over recent application and function of PDX models in basic cancer research on the areas of cancer characterization, initiation, proliferation, metastasis, and tumor microenvironment and in preclinical explorations of anti-cancer targets, drugs, and therapeutic strategies and finally give our perspectives on the future prospects of PDX models.


Painting place: Re-imagining landscapes for older people's subjective wellbeing.
This study provides insights into how a participatory painting activity impacts older people's subjective wellbeing. The study uses qualitative methods to analyze the findings, and employs qualitative data collection methods to examine how creativity conducted in an environment of relational connectivity is beneficial to wellbeing. The findings demonstrate that processes of re-imagining landscape contribute to participants' retaining significant places in the mind when physical engagement is limited. The study reveals how the activity of re-imagining landscape provokes emotions and memories that help participants connect the past with the present, and to connect their older and younger-age selves, positively to reaffirm their older age identity. The paper reflects on the intervention as a form of encounter with landscape whose benefits are potentially therapeutic for different groups, particularly those for whom engagement with memories may assist with processes of adaptation or transition.


Suppression of keratoepithelin and myocilin by small interfering RNAs (siRNA) in vitro.
Mutations of keratoepithelin (KE) and myocilin (MYOC) have been linked to certain types of inherited corneal stromal dystrophy and open-angle glaucoma, respectively. We investigated the potential use of small interfering RNAs (siRNAs) to suppress the expression of KE and MYOC and the related cytotoxicity of mutant myocilins in vitro. cDNAs of the human keratoepithelin (KE) gene and myocilin (MYOC) gene were amplified by polymerase chain reaction and subcloned into pEGFP-N1 to construct respective plasmids, KEpEGFP and MYOCpEGFP, to produce fluorescence-generating fusion proteins. Short hairpin RNAs (shRNAs) were generated from an RNA polymerase III promoter-driven vector (pH1-RNA). Transformed HEK293 and trabecular meshwork (TM) cells were cotransfected via liposomes with either KEpEGFP or MYOCpEGFP and respective shRNA-generating plasmids to evaluate the suppression efficacy of shRNAs. Suppression of KE-EGFP fusion protein by KE-specific shRNAs was evaluated by fluorescence microscopy and western blotting. Suppression of MYOC-EGFP fusion protein by myocilin-specific shRNAs was quantified with UN-SCAN-IT software on digitized protein bands of western blots. The cellular stress response of TM cells induced by misfolded mutant myocilins was evaluated with a BiP promoter-driven luciferase reporter assay. One shRNA (targeting the coding sequence starting at 1,528 bp of KE) reduced the expression of KE-EGFP in HEK293 cells approximately by 50% whereas the other shRNA (targeting the 3'-UTR region of KE) suppressed more than 80% of the expression of fusion protein. Cotransfection of MYOCpEGFP and various shRNA-generating plasmids targeting different regions of MYOC (containing amino acid residues R76, E352, K423, or N480 associated with inherited glaucoma) showed effective reduction of MYOC-EGFP fusion protein, ranged from 78% to 90% on average. The activation of the BiP gene (a cellular stress response induced by mutant myocilins) in transformed TM cells was significantly reduced when mutant myocilin proteins were suppressed by myocilin-specific shRNAs. KE-specific or MYOC-specific shRNAs effectively suppressed the expression of recombinant KE or myocilin proteins and the related cytotoxicity of mutant myocilins in vitro. RNA interference may have future therapeutic implications in suppressing these genes.


An open trial of adjunctive escitalopram in bipolar depression.
This study was designed to evaluate the efficacy and safety of a highly potent and selective serotonergic antidepressant, escitalopram, in the treatment of bipolar depression. Twenty outpatients with DSM-IV bipolar depression types I and II were enrolled in a 12-week open trial of escitalopram, 10 mg daily, adjunctive to their ongoing mood stabilizer. Assessments were carried out using the Hamilton Rating Scale for Depression (HAM-D), the Young Mania Rating Scale (YMRS), and the Clinical Global Impressions for Severity (CGI-S) and Improvement (CGI-I) scales. The study was conducted from August 2003 to February 2004. Escitalopram was associated with significant improvement as measured by the HAM-D total score, which showed a mean reduction from baseline (mean = 20.9, SD = 4.2) to endpoint (mean = 8.9, SD = 3.6; p < .001) of 12 points. The mean CGI-S score decreased by 3.3 points (baseline: mean = 4.8, SD = 0.7; week 12: mean = 1.5, SD = 0.6; p < .001). Adverse events emerged in 75% of the patients (N = 15), usually of mild-to-moderate severity. Four dropouts took place due to manic switch (N = 1), hypomanic symptoms (N = 2), and hospitalization due to the emergence of suicidal ideation and psychosis (N = 1). These findings suggest that escitalopram in association with mood stabilizers may be an effective and reasonably well-tolerated treatment for patients with moderate-to-severe bipolar depression. The switch rate was similar to what is described in the literature for the selective serotonin reuptake inhibitors. Randomized controlled trials of escitalopram in bipolar depression are warranted.


Global stressors and the global decline of amphibians: tipping the stress immunocompetency axis.
There is a widespread consensus that the earth is experiencing a mass extinction event and at the forefront are amphibians, the most threatened of all vertebrate taxa. A recent assessment found that nearly one-third (32%, 1,856 species) of the world's amphibian species are threatened. Amphibians have existed on the earth for over 300 million years, yet in just the last two decades there have been an alarming number of extinctions, nearly 168 species are believed to have gone extinct and at least 2,469 (43%) more have populations that are declining. Infectious diseases have been recognized as one major cause of worldwide amphibian population declines. This could be the result of the appearance of novel pathogens, or it could be that exposure to environmental stressors is increasing the susceptibility of amphibians to opportunistic pathogens. Here I review the potential effects of stressors on disease susceptibility in amphibians and relate this to disease emergence in human and other wildlife populations. I will present a series of case studies that illustrate the role of stress in disease outbreaks that have resulted in amphibian declines. First, I will examine how elevated sea-surface temperatures in the tropical Pacific since the mid-1970s have affected climate over much of the world and could be setting the stage for pathogen-mediated amphibian declines in many regions. Finally, I will discuss how the apparently rapid increase in the prevalence of amphibian limb deformities is linked to the synergistic effects of trematode infection and exposure to chemical contaminants.


GETPrime: a gene- or transcript-specific primer database for quantitative real-time PCR.
The vast majority of genes in humans and other organisms undergo alternative splicing, yet the biological function of splice variants is still very poorly understood in large part because of the lack of simple tools that can map the expression profiles and patterns of these variants with high sensitivity. High-throughput quantitative real-time polymerase chain reaction (qPCR) is an ideal technique to accurately quantify nucleic acid sequences including splice variants. However, currently available primer design programs do not distinguish between splice variants and also differ substantially in overall quality, functionality or throughput mode. Here, we present GETPrime, a primer database supported by a novel platform that uniquely combines and automates several features critical for optimal qPCR primer design. These include the consideration of all gene splice variants to enable either gene-specific (covering the majority of splice variants) or transcript-specific (covering one splice variant) expression profiling, primer specificity validation, automated best primer pair selection according to strict criteria and graphical visualization of the latter primer pairs within their genomic context. GETPrime primers have been extensively validated experimentally, demonstrating high transcript specificity in complex samples. Thus, the free-access, user-friendly GETPrime database allows fast primer retrieval and visualization for genes or groups of genes of most common model organisms, and is available at http://updepla1srv1.epfl.ch/getprime/. Database URL: http://deplanckelab.epfl.ch.


An empirical evaluation of proposed changes for gambling diagnosis in the DSM-5.
Recommendations related to pathological gambling for the fifth edition of the Diagnostic and statistic manual for mental disorders (DSM) are to eliminate the criterion related to committing illegal acts and reduce the threshold for diagnosis from five to four criteria. This study evaluated the impact of these changes on prevalence rates and classification accuracy. Data were analyzed from five samples, varying in severity of gambling problems. Surveys of randomly selected household residents in the United States (US) (n = 2417), gambling patrons (n = 450), individuals in brief intervention studies (n = 375), patients in community-based gambling treatment programs (n = 149) and participants in randomized intervention studies (n = 319). The national opinion research center DSM-IV screen for gambling problems (NODS) was administered to all participants. Internal consistency and factor structure were evaluated using both 10 and nine criteria. Base rates, hit rates, sensitivity, specificity and overall agreement were compared across classification systems, using DSM-IV classification as the standard. Eliminating the illegal acts criterion did not impact internal consistency and modestly improved variance accounted for in the factor structure. In comparing a classification system using four of 10 criteria versus one using four of nine, the four of nine system yielded equal or slightly better classification accuracy in all comparisons and across all samples. The inclusion of the illegal acts criterion in the proposed DSM-V pathological gambling diagnosis does not appear necessary for diagnosis of pathological gambling and, if it is eliminated, reducing the cut-point to four results in more consistent diagnoses relative to the current classification system.


A case of exceptional reading accuracy in a child with Down syndrome: Underlying skills and the relation to reading comprehension.
We report on a case of a girl with Down syndrome (DS), K.S., whose reading accuracy is exceptional. This ability is associated with robust phonological skills and relative strengths in visual and verbal short-term memory, articulation, and speech fluency. Although her reading comprehension is age appropriate when it comes to the retention of literal information, K.S. has some difficulties in using knowledge-based inferences in reading comprehension. Reading comprehension in that sense is at a level commensurate with her oral language skills. Her reading performance parallels that of children with reading comprehension difficulties who do not have DS. This reading profile is in contrast with claims that individuals with DS mainly use sight-word strategies in reading and shows that the phonological pathway can be highly proficient in a child with DS. However, even in a case such as K.S. where reading accuracy is good, functional literacy is constrained by limited comprehension skills.


OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset.
Congenitally athymic rats injected with CD45RBhigh CD4+ T cells from congenic euthymic donors developed a severe wasting disease with inflammatory infiltrates in liver, lung, stomach, thyroid, and pancreas. In contrast, recipients of CD45RBlow CD4+ T cells remained well and continued to gain weight. Animals given unfractionated CD4+ T cells, i.e., a mixture of approximately two-thirds CD45RBhigh and one-third CD45RBlow, were protected from the wasting disease, and the incidence of organ-specific inflammation was much reduced compared with that found in recipients of CD45RBhigh cells alone. The data suggest that this latter subset of CD4+ T cells has autoaggressive potential that is inhibited in normal animals by cells of the CD45RBlow CD4+ phenotype. The possible consequences of a breakdown in this immunoregulatory mechanism are briefly discussed.


Alternate options to hormone replacement therapy for osteoporosis.
This presentation, developed from a symposium lecture at the 40th Annual Convention of the American College of Osteopathic Family Physicians on March 22, 2003, in Nashville, Tenn, highlights three pivotal studies that have altered the preferred option for the treatment and prevention of osteoporosis in post-menopausal women. The Heart Estrogen/progestin Replacement Study (HERS), the HERS II, and the Women's Health Initiative provide evidence that the benefits (fewer colorectal cancers and hip fractures) of using hormone replacement therapy--conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) specifically--did not outweigh the risks (more CHD-related deaths, strokes, venous thromboembolisms, and invasive breast cancer). Treatment and prevention options for osteoporosis now include modification of risk factors, calcium and vitamin D supplementation, third-generation bisphosphonates (alendronate sodium and risedronate sodium), selective estrogen receptor modulators, and synthetic parathyroid hormone.


The mode of action of adenosine 3':5'-cyclic monophosphate in mammalian islets of Langerhans. Preparation and properties of islet-cell protein phosphokinase.
1. A protein was demonstrated in mammalian islets of Langerhans that after purification appeared as a single component possessing both cyclic-AMP (adenosine 3':5'-cyclic monophosphate)-binding and cyclic-AMP-dependent protein phosphokinase activities. 2. The protein had an intrinsic association constant for cyclic AMP of 1.15x10(-8)m, which was similar to the K(m) for cyclic AMP (1.11x10(-8)m) of the protein phosphokinase activity. 3. Incubation of the protein in the presence of cyclic AMP resulted in its dissociation into cyclic-AMP-independent protein phosphokinase (catalytic) and cyclic-AMP-binding (receptor) subunits, which could be separated on Sephadex G-200. 4. The cyclic-AMP-dependent protein phosphokinase was capable of phosphorylating a variety of proteins, the most readily phosphorylated being histone, casein and protein components of sub-cellular fractions prepared from islets of Langerhans. 5. The cyclic-AMP-dependent phosphorylation of histone had a K(m) for ATP of 1.1x10(-5)m. 6. The endogenous protein phosphokinase activity in rat islets incubated with agents that are known to alter the intracellular concentration of cyclic AMP was investigated. Theophylline and 3-isobutyl-1-methylxanthine, agents that raise cyclic AMP concentrations in islets, increased the activity of the protein phosphokinase, whereas adrenaline, which lowers islet cyclic AMP concentrations, decreased its activity. 7. It is suggested that cyclic AMP may exert its effects on insulin release by increasing the activity of a protein phosphokinase and may thereby promote the phosphorylation and activity of a rate-determining component of the secretory mechanism.


Gustducin couples fatty acid receptors to GLP-1 release in colon.
Sweet taste receptor subunits and α-gustducin found in enteroendocrine cells of the small intestine have been implicated in release of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in response to glucose and noncaloric sweeteners. α-Gustducin has also been found in colon, although its function there is unclear. We examined expression of α-gustducin, GLP-1, and GIP throughout the intestine. The number of α-gustducin-expressing cells and those coexpressing α-gustducin together with GLP-1 and/or GIP increased from small intestine to colon. α-Gustducin also was coexpressed with fatty acid G protein-coupled receptor (GPR) 40, GPR41, GPR43, GPR119, GPR120, and bile acid G protein-coupled receptor TGR5 in enteroendocrine cells of the colon. In colon, GPR43 was coexpressed with GPR119 and GPR120, but not with TGR5. Treatment of colonic mucosa isolated from wild-type mice with acetate, butyrate, oleic acid, oleoylethanolamide, or lithocholic acid stimulated GLP-1 secretion. However, GLP-1 release in response to these fatty acids was impaired in colonic tissue from α-gustducin knockout mice.


Early diagnosis of secondary progressive multiple sclerosis: focus on fluid and neurophysiological biomarkers.
Most patients with multiple sclerosis presenting with a relapsing-remitting disease course at diagnosis transition to secondary progressive multiple sclerosis (SPMS) 1-2 decades after onset. SPMS is characterized by predominant neurodegeneration and atrophy. These pathogenic hallmarks result in unsatisfactory treatment response in SPMS patients. Therefore, early diagnosis of SPMS is necessary for prompt treatment decisions. The aim of this review was to assess neurophysiological and fluid biomarkers that have the potential to monitor disease progression and support early SPMS diagnosis. We performed a systematic review of studies that analyzed the role of neurophysiological techniques and fluid biomarkers in supporting SPMS diagnosis using the preferred reporting items for systematic reviews and meta-analyses statement. From our initial search, we selected 24 relevant articles on neurophysiological biomarkers and 55 articles on fluid biomarkers. To date, no neurophysiological or fluid biomarker is sufficiently validated to support the early diagnosis of SPMS. Neurophysiological measurements, including short interval intracortical inhibition and somatosensory temporal discrimination threshold, and the neurofilament light chain fluid biomarker seem to be the most promising. Cross-sectional studies on an adequate number of patients followed by longitudinal studies are needed to confirm the diagnostic and prognostic value of these biomarkers. A combination of neurophysiological and fluid biomarkers may be more sensitive in detecting SPMS conversion.


A Combination with Probiotic Complex, Zinc, and Coenzyme Q10 Attenuates Autoimmune Arthritis by Regulation of Th17/Treg Balance.
Probiotic complex, zinc, and coenzyme Q10 (CoQ10) are recognized dietary supplements with an anti-inflammatory role. Although these supplementations are individually known to benefit rheumatoid arthritis (RA), there is no evidence suggesting any synergic effect. The primary goal of this study is to determine whether probiotic complex, zinc, and CoQ10 attenuate the development of collagen-induced arthritis (CIA). The combination of probiotic complex, zinc, and CoQ10 reduced CIA severity by downregulating the levels of IgG, IgG1, and IgG2a in serum. Joint inflammation, bone destruction, and cartilage damage were also improved by the complex. There was a decrease in the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17, and vascular endothelial growth factor (VEGF) in the joint synovium. The balance between helper T 17 (Th17) cells and regulatory T (Treg) cells was shown to be controlled reciprocally by the complex. These findings suggest that the combination of probiotic complex, zinc, and CoQ10 can ameliorate the development of CIA by inhibiting the expression of proinflammatory cytokines, and is thus an important therapeutic candidate for RA treatment.


Fermat photons in turbid media: an exact analytic solution for most favorable paths-a step toward optical tomography.
Photon propagation in a turbid medium characterized by highly forward-directed light scattering can be described by a generalized Fermat principle, a counterpart of the conventional Fermat principle for transparent media. An exact analytic solution for the most favorable photon paths (Fermat paths) has been found and is investigated. An analysis intended to encourage and facilitate experimental observation of Fermat photons is presented. The feasibility of using the theory in time-resolved optical tomography for the recognition of objects hidden in turbid media is discussed.


Control of skin circulation during exercise and heat stress.
At any given environmental and mean skin temperature, exercise brings about an increase in internal body temperature and skin blood flow. At high environmental temperatures, when skin temperature is elevated, skin blood flow at any given internal temperature reaches higher levels than at cooler skin temperatures. Increased cutaneous blood flow serves to deliver metabolic heat from the core to the skin, where the heat is lost to the environment by convective, radiative, and evaporative mechanisms. However, at high levels of skin blood flow, peripheral vascular pooling and fluid losses by filtration lead to reduced central venous pressure. This lowers cardiac stroke volume, and requires a higher heart rate to maintain a given cardiac output. Mechanisms which alleviate some of the cardiovascular strain produced by exercise in the heat include the following: acutely, reflexes which arise from receptors in working muscles produce vasoconstriction in a number of central and peripheral vascular beds. Other reflexes, arising from cardiac baroreceptors, produce additional peripheral vasoconstriction when cardiac filling is impaired. In the long term, physical conditioning and heat acclimation lead to increases in sweat output during thermal stress, leading to cooler skin and core temperature during exercise, and decreasing the level of skin blood flow needed for regulation of body temperature.


Effect of cereal test breakfasts differing in glycemic index and content of indigestible carbohydrates on daylong glucose tolerance in healthy subjects.
Frequent hyperglycemic episodes are increasingly being associated with an increased risk of type 2 diabetes and cardiovascular disease. We studied the extent to which acute glycemia and glycemia after subsequent meals can be modulated by the characteristics of cereal foods, such as glycemic index (GI) and content of indigestible carbohydrates. Twelve healthy subjects consumed test meals in a random order. In series 1, the test meals were consumed at breakfast, and postprandial blood glucose incremental areas under the curve (IAUCs) were calculated after the test breakfast, standardized lunch, and standardized dinner. In series 2, the subjects consumed test evening meals and IAUCs were calculated after a subsequent standardized breakfast. Breath hydrogen was measured as an indicator of colonic fermentation. Barley or rye kernel breakfasts lowered the blood glucose IAUC (0-120 min) at breakfast, at a subsequent lunch, and the cumulative IAUCs (breakfast+lunch+dinner) when compared with white-wheat bread (P < 0.05). The lunch blood glucose IAUCs were positively correlated with breakfast IAUCs (r = 0.30, P < 0.05). Breath hydrogen excretion was negatively correlated with blood glucose IAUCs after lunch (r = -0.33, P < 0.05) and dinner (r = -0.22, P < 0.05). A barley kernel evening meal resulted in lower IAUCs (P < 0.05) and higher breath hydrogen (P < 0.001) after a subsequent breakfast compared with white-wheat bread. Glucose tolerance at subsequent meals can be notably improved during the course of a whole day or overnight by choosing specific low-GI, whole-grain cereal products. A low GI may be sufficient to achieve a second-meal effect from breakfast to lunch. A specific indigestible carbohydrate mixture appears to be required to show benefits on glucose tolerance in a longer time frame (9.5 h), most likely mediated through colonic fermentation.