Cyclic neutropenia: an unusual disorder of granulopoiesis effectively treated with recombinant granulocyte colony-stimulating factor.
Cyclic neutropenia (CN) is a rare hematologic disorder characterized by regular cycling of the absolute neutrophil count and a symptom complex presenting during the neutropenic nadirs. Despite the profound cyclic neutropenia, most patients have a benign course of recurrent fever, malaise, oral ulceration, and minor skin and upper respiratory tract infections. Recurrent infections, inflammation, and ulcers can lead to significant chronic morbidity. Severe dental disease is common, pregnancy complications are increased, and overwhelming infections, bowel necrosis, and mortality, although rare, are potential sequelae. We report a 10-year-old boy with a classical presentation of CN that had remained undiagnosed for 10 years. The difficulty in diagnosing this unusual disorder is highlighted. Treatment with daily recombinant granulocyte colony-stimulating factor (rG-CSF) resulted in a complete clearing of symptoms and a significant increase in quality of life. The excellent clinical response of CN to rG-CSF, in the absence of major adverse effects, is strongly demonstrated by this case and supports rG-CSF as a first-line therapy for CN. The physiologic and adverse effects of rG-CSF use in CN and other neutropenic disorders, including potential leukemic induction, are reviewed. The need for long-term follow-up to investigate the effects of chronic hematopoietic stimulation by rG-CSF is emphasized.


Characterization of an ATP-driven H+ pump in human placental brush-border membrane vesicles.
The presence of an ATP-driven H+ pump as measured by H+ uptake upon addition of ATP was not demonstrable in human placental brush-border membrane vesicles when used in their native form, owing to their right-side-out orientation. However, the presence of the H+ pump in these membranes became evident when the membrane vesicles were transiently exposed to 1% cholate, with subsequent removal of the detergent to re-form the vesicles. Apparently, cholate pretreatment reoriented the H+ pump from an inward-facing configuration to outward-facing. Consequently, H+ uptake in response to externally added ATP was easily demonstrable in these cholate-pretreated vesicles by using the delta pH indicator Acridine Orange. In addition, bafilomycin A1-sensitive ATPase activity was measurable in cholate-pretreated vesicles, but not in native intact vesicles, indicating reorientation of the H+ pump. The reoriented H+ pump was electrogenic because H+ uptake was stimulated by an inside-negative anion-diffusion potential or when the vesicles were voltage-clamped. ATP supported H+ uptake with an apparent Km of 260 microM. ITP and GTP supported the pump activity partially, whereas CTP and UTP did not. Mg2+ and Mn2+ were the most preferred bivalent cations. Co2+ and Zn2+ showed partial activity, whereas Ca2+ and Ba2+ showed little or no activity. The pump was inhibited by nanomolar concentrations of bafilomycin A1 and micromolar concentrations of N-ethylmaleimide, p-chloromercuribenzenesulphonate, NN-dicyclohexylcarbodi-imide and 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole, but was relatively insensitive to oligomycin, vanadate and NaN3. The inhibition by N-ethylmaleimide was protectable by ATP. It is concluded that human placental brush-border membranes possess an ATP-driven H+ pump and that, on the basis of its characteristics, it belongs to the class of vacuolar (V-type) H+ pumps.


Isolated oculomotor nerve palsy due to dural cavernous sinus fistula.
Two patients with a dural carotid-cavernous sinus fistula presented with unilateral oculomotor nerve palsies without signs of ocular congestion or proptosis. According to this, dural carotid-cavernous sinus fistula should be included in the differential diagnosis of any case of painful ophthalmoplegia, even in the absence of other ocular signs.


Rescue of pituitary function in a mouse model of isolated growth hormone deficiency type II by RNA interference.
Splicing mutations in the human GH (hGH) gene (GH-1) that cause skipping of exon 3 result in a form of GH deficiency termed isolated GH deficiency type II (IGHD II). The GH-1 gene contains five exons; constitutive splicing produces the wild-type 22-kDa hormone, whereas skipping of exon 3 results in transcripts encoding a 17.5-kDa isoform that acts as a dominant-negative to block secretion of the wild-type hormone. Common characteristics of IGHD II include short stature due to impaired bone elongation, growth, and, in severe cases, anterior pituitary hypoplasia. Typically, IGHD II is treated by sc delivery of hGH, which can rescue stature but, unfortunately, does not inhibit pituitary hypoplasia. Direct destruction of transcripts encoding the dominant-negative 17.5-kDa isoform should both rescue stature and prevent hypoplasia. Here, we have used delivery of short hairpin RNAs to rescue a murine model of IGHD II by specifically targeting transcripts encoding the 17.5-kDa isoform using RNA interference. To our knowledge, this is the first example where a short hairpin RNA has been expressed to specifically degrade an incorrectly spliced transcript and rescue a dominant-negative disease phenotype in vivo.


Regional differences in baseline disease activity and remission rates following golimumab treatment for RA: results from the GO-MORE trial.
GO-MORE (NCT00975130) was a large open-label, multinational, multicenter, prospective phase 3 trial evaluating add-on therapy with golimumab in biologic-naïve patients with active rheumatoid arthritis (RA). The objective of this post hoc analysis was to examine regional differences in baseline disease activity and remission rates following golimumab treatment for RA. This was a planned, descriptive post hoc analysis of data from the GO-MORE trial. Baseline disease activity and remission were defined as moderate or severe based on EULAR criteria. This analysis included 3280 participants from the GO-MORE trial. All participants included in this analysis had high or moderate disease activity at baseline. At baseline, high disease activity was least common in Europe (71.0%), Canada (77.0%), and the Middle East (78.2%) and most common in Latin America (90.7%), South Africa (91.5%), and Asia (92.5%). Month 6 remission rates were highest in South Africa (29.1%), Europe (27.9%), and the Middle East (27.3%) and lowest in Canada (19.7%), Latin America (17.2%), and Asia (15.0%). Higher rates of remission in each geographical region generally corresponded with lower baseline disease activity. We suspect that access to care and implementation of the treat-to-target strategy were the most important determinants, but this apparent relationship needs to be confirmed in further studies that include a statistical analysis of prognostic indicators.


Medication adherence, healthcare costs and utilization associated with acne drugs in Medicaid enrollees with acne vulgaris.
Acne vulgaris is a common chronic disease that may require long-term treatment. Medication adherence is critical to acne management; non-adherence is a common reason for treatment failure and can lead to poor quality of life. The aim of the study was to examine medication adherence, healthcare costs, and utilization associated with acne drugs among acne patients in the USA. This was a retrospective cohort study from January 2004 to December 2007 using the Marketscan Medicaid Database, a national healthcare claims database. The study followed acne patients aged 0-64 years for 90 days after the first acne drug prescription to measure acne medication adherence, acne-related outpatient visits, and total acne-related healthcare costs. Adherence was measured among different acne drug classes using medication possession ratio (MPR). Multivariate regression analyses were conducted to assess the outcomes. The study included 24,438 eligible patients, of whom 89.39 % were under 18 years old. The average adherence rate to acne drugs (MPR) was 0.34, and only 11.74 % of the patients were adherent (MPR ≥0.80). Patients with drug refills had a higher adherence rate (MPR = 0.74) than who those without refills (MPR = 0.27). Factors significantly associated with adherence were age, comorbidity, gender, number of drug refills and number of drug classes used. Patients were more adherent to oral retinoids than any other acne drug classes (MPR = 0.78, 57 % adherent). Patients were less adherent to oral antibiotics (MPR = 0.21) and topical retinoids (MPR = 0.31). After controlling for medication use behavior, the use of oral antibiotics decreased the number of acne-related outpatient visits by 50.9 % (p < 0.001) and lowered acne-related total costs by 51.7 % (p < 0.001). Medication non-adherence is generally prevalent among young acne patients enrolled in Medicaid. The combination of a topical retinoid and an antibiotic agent may be a good choice given their associated healthcare outcomes and costs. However, adherence to these agents is not satisfactory. Therefore, developing specific strategies to improve adherence to these drugs among teenage acne patients is warranted.


Beta-catenin is elevated in human benign prostatic hyperplasia specimens compared to histologically normal prostate tissue.
Benign prostatic hyperplasia (BPH) is linked to lower urinary tract symptoms (LUTS) such as incomplete bladder emptying, urinary frequency and urgency. Mechanisms responsible for BPH are not fully known. Here, we tested whether beta-catenin (CTNNB1) immunostaining intensity and distribution differ in human glandular BPH tissue specimens compared to normal prostate tissue. Multiplex immunostaining of CTNNB1, its putative transcriptional target gene lymphoid enhancer binding factor 1 (LEF1), and the epithelial marker E-cadherin were examined in clinical human prostate specimens with or without histological BPH (pure epithelial or mixed stromal-epithelial nodules). BPH specimens were obtained from 24 men who experienced LUTS and underwent transurethral resection of the prostate surgery. Control specimens were tumor-adjacent histologically normal prostate tissue from 48 patients who underwent radical prostatectomy. The resulting multispectral images were unmixed and optical densities recorded to quantify staining abundance, cellular (membranous, cytoplasmic, and nuclear) and tissue localization (stromal versus epithelial), and determination of percentage of CTNNB1-positive cells. The following CTNNB1 indices were significantly higher in BPH compared to normal prostate tissue: overall staining intensity, staining intensity in prostate stromal cell membranes, cytoplasm and nuclei, and prostate epithelial cell nuclei. The following LEF1 indices were significantly lower in BPH compared to tumor-adjacent normal prostate tissue: stromal LEF1 staining intensity, percentage of LEF1-positive stromal cells, and intensity of LEF1 staining in stromal cell membranes, cytoplasm, and nuclei. The percentage of stromal cells with CTNNB1(+)/LEF1(-) nuclei was higher and percentage of stromal cells with CTNNB1(-)/LEF1(+) nuclei was lower in BPH compared to tumor-adjacent normal prostate tissues. These results support the hypothesis that CTNNB1 expression increases in specific BPH tissue compartments. Further, since nuclear LEF1 staining does not coincide with cytoplasmic or nuclear CTNNB1 staining, it does not appear to be a reliable index of CTNNB1 activity in adult human prostate.


The Effect of High-frequency Repetitive Transcranial Magnetic Stimulation on Reducing Depression and Anxiety in Methamphetamine Users.
Methamphetamine use has been associated with higher rates of depression and anxiety. The mesocorticolimbic dopaminergic reward system seems to play a crucial role in inducing depression and anxiety in methamphetamine users. High-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to alter dopaminergic neurotransmission considering the acute rewarding and reinforcing effects in the subcortical structure. The aim of this study was to investigate the efficacy of rTMS in reducing depression and anxiety symptoms in methamphetamine users. In a single-subject method with concurrent multiple baseline designs, in 2017, in Iran, eight methamphetamine users were included, which compared 15 days of active versus placebo stimulation and control group. Two subjects received rTMS on the right dorsolateral prefrontal cortex (DLPFC) and two subjects received rTMS on the left DLPFC. We carried out the measurement using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) before, during, and after 15 and 30 days of the procedure. Right and left DLPFC stimulation significantly reduced depression and anxiety, but the reduction of depression and anxiety by the right DLPFC stimulation was noticeable in this study. High-frequency rTMS is useful for the treatment of depression and anxiety in methamphetamine users.


Species redistribution creates unequal outcomes for multispecies fisheries under projected climate change.
Climate change drives species distribution shifts, affecting the availability of resources people rely upon for food and livelihoods. These impacts are complex, manifest at local scales, and have diverse effects across multiple species. However, for wild capture fisheries, current understanding is dominated by predictions for individual species at coarse spatial scales. We show that species-specific responses to localized environmental changes will alter the collection of co-occurring species within established fishing footprints along the U.S. West Coast. We demonstrate that availability of the most economically valuable, primary target species is highly likely to decline coastwide in response to warming and reduced oxygen concentrations, while availability of the most abundant, secondary target species will potentially increase. A spatial reshuffling of primary and secondary target species suggests regionally heterogeneous opportunities for fishers to adapt by changing where or what they fish. Developing foresight into the collective responses of species at local scales will enable more effective and tangible adaptation pathways for fishing communities.


Species-dependent enantioselective glucuronidation of three 2-arylpropionic acids. Naproxen, ibuprofen, and benoxaprofen.
The enantioselective glucuronidation of several racemic 2-arylproprionic acids (naproxen, ibuprofen, and benoxaprofen) was investigated in vitro with immobilized microsomal protein from human, rhesus monkey, and rabbit liver as the source of UDP-glucuronyl-transferases. Human microsomes, solubilized microsomal protein, and immobilized protein all gave comparable enantioselectivity. The diastereomeric glucuronides were separated and quantitated by HPLC and characterized stereochemically by co-elution with glucuronides formed from authentic resolved enantiomers. Conjugation of the carboxylic acid moieties occurred stereoselectively with all three substrates. However, enantioselectivity varied qualitatively and quantitatively with substrate as well as with species. The glucuronidation of (S)-naproxen by human liver enzymes was inhibited in the presence of (R)-naproxen and vice versa. The ratio of the glucuronides of (S)-benoxaprofen to that of (R)-benoxaprofen in rhesus monkey urine varied between individual animals and appeared to change through time as dosing continued. Hydrolysis of the diasteriomeric glucuronides of (R)- and (S)-naproxen was differentially inhibited by addition of 1,4-saccharolactone.


Rickettsial diseases and ectoparasites from military bases in Japan.
Ectoparasitic arthropods are often vectors of rickettsiosis. We conducted a survey of ectoparasites on U.S. military facilities throughout Japan with the use of specimens submitted by pest control, public health, and veterinary personnel. Over 1,600 individual ectoparasites were collected. Fifteen species were identified, including several significant vectors of human diseases such as scrub typhus and rickettsial spotted fevers. These ectoparasites included Ctenocephalides felis , Haemaphysalis longicornis, Ixodes persulcatus , Leptotrombidium fuji, Leptotrombidium pallidum, and Rhipicephalus sanguineus . Rickettsial agents were detected by PCR and DNA sequencing. These included Bartonella henselae , Bartonella japonica, a novel Bartonella, Coxiella burnetii , an unnamed Coxiella, Ehrlichia canis , Orientia tsutsugamushi , Rickettsia typhi , and "Rickettsia Rf2125"/"Rickettsia cf1and5".


A "scientific luxury".
In the lay press, the New York Times has long been a leading advocate and defender of federal support for basic research. On 16 July, however, the Times departed from this pattern to question the advisability of proceeding at this time with the construction of the Weston accelerator. Leading off with an editorial on last week's riots in Newark, New Jersey, titled, "The Gravest Responsibility . . .," the Times followed with an editorial on the 200-Bev accelerator, titled ". . . Vs. Scientific Luxury."


Incidence and clinical importance of cardiac tumors in China--review of the literature.
The first successful excision of a left atrial myxoma in China was performed in 1962. Till October 1988, 656 surgical cases of cardiac tumors have been reported in the Chinese literature. The diagnosis of all excised tumors was confirmed by pathologic studies. The age of patients ranged from 46 days to 72 years. Among these 656 cases, 647 tumors were benign (97%) and 9 tumors were malignant (3%). 633 myxomas (97.8%) represented the vast majority of the benign cardiac tumors. In 26 cases, myxomas were found multilocalized. Before 1975, echocardiography could not be performed universally in our country, and diagnosis often failed. At present, echocardiography is the most used and the most reliable examination method for cardiac tumors in China. The majority of the patients presented clinical symptoms of congestive heart failure with palpitation, dyspnoe, syncope, and hemoptysis. In 99% the main abnormality was an atypical and frequently variable heart murmur. Arterial embolization occurred in 15%. In all patients the myxomas was removed as a whole with its attachment to the interatrial septum or the atrial wall to prevent recurrence. Examination of all heart chambers should be performed to exclude multilocalized tumors. The operative mortality ranged between 5.8 to 13%. The recurrence rate of myxomas in China was reported to amount to 3%.


Fatty acid composition and preservation of the Tyrolean Iceman and other mummies.
In anthropology, objective parameters to adequately describe storage conditions and the preservation of mummies have yet to be identified. Considering that fatty acids degrade to stable products, we analysed their profile in human mummies and in control samples by gas chromatography coupled to mass spectrometry (GC/MS). Originating from different epochs and civilizations, samples of the Tyrolean Iceman, other glacier corpses, a freeze dried mummy, corpses from a permafrost region, a corpse mummified immersed in water, and a desert mummy were evaluated. Chemometric analysis based on the concentrations of 16 fatty acids revealed the degree of similarity between anthropologic and fresh corpse samples, which was mainly influenced by the content of palmitic acid, oleic acid, and 10-hydroxystearic acid. The presence of 10-hydroxystearic acid was associated with immersion in water, whereas dry mummification was accompanied by high contents of oleic acid. Samples of the Tyrolean Iceman clustered between fresh tissue and those of other glacier corpses indicating the good preservation of this mummy. Thus, environmental post-mortem conditions were associated with characteristic fatty acid patterns suggesting that chemometric analysis of fatty acid contents may add to our knowledge about post-mortem storage conditions and the preservation of human corpses.


A study of preceptor roles in clinical teaching.
Acknowledging the continuing use of preceptors for clinical teaching in undergraduate nursing programs, this study examined the role of preceptors, criteria for selection, and knowledge and skills they require to undertake clinical teaching in baccalaureate (BSN) programs. All National League for Nursing (NLN)-accredited BSN programs in the Midwest were surveyed (N = 142) using an instrument developed by the investigator; 84 instruments were returned, for a response rate of 59.2%. Most nursing programs (74.7%) used preceptors from affiliating clinical settings for teaching senior-year clinical courses (90.9%) such as leadership and management, community health nursing, and critical care. Across the majority of nursing programs two important responsibilities of the preceptor were selecting patients for care by students and teaching students in the clinical setting. Findings also revealed that certain responsibilities were shared by faculty and preceptors, including assessing students' learning needs and evaluating learning in the clinical settings. Although preceptors played an important role in teaching students, only half of the programs had a written position statement that described the role. Selection criteria for preceptors were educational preparation at the BSN level (75.8%) and experience as a staff nurse (59.7%). Respondents also identified the knowledge and skills required by preceptors to undertake clinical teaching and content included in preceptor-preparation programs, providing a framework for faculty to use when preparing preceptors for this important role.


A synthetic RNA-mediated evolution system in yeast.
Laboratory evolution is a powerful approach to search for genetic adaptations to new or improved phenotypes, yet either relies on labour-intensive human-guided iterative rounds of mutagenesis and selection, or prolonged adaptation regimes based on naturally evolving cell populations. Here we present CRISPR- and RNA-assisted in vivo directed evolution (CRAIDE) of genomic loci using evolving chimeric donor gRNAs continuously delivered from an error-prone T7 RNA polymerase, and directly introduced as RNA repair donors into genomic targets under either Cas9 or dCas9 guidance. We validate CRAIDE by evolving novel functional variants of an auxotrophic marker gene, and by conferring resistance to a toxic amino acid analogue in baker's yeast Saccharomyces cerevisiae with a mutation rate >3,000-fold higher compared to spontaneous native rate, thus enabling the first demonstrations of in vivo delivery and information transfer from long evolving RNA donor templates into genomic context without the use of in vitro supplied and pre-programmed repair donors.


Temporal dynamics of memory trace formation in the human prefrontal cortex.
Event-related repetitive transcranial magnetic stimulation (rTMS) can dynamically interfere with the memory encoding of complex visual scenes. Here, we investigated the critical time elapsing from stimulus presentation to the formation of an effective memory trace by delivering rTMS (900 ms at 20 Hz) during the encoding of visual scenes at different poststimulus delays (from 100 to 500 ms) in 28 healthy volunteers. The stimulation delay showed a robust inverse correlation with the correct retrieval of encoded images. In particular, rTMS stimulation delivered with a delay of 500 ms and lasting for 400 ms after stimulus offset resulted in a huge drop in retrieval accuracy. Such a timing suggests that rTMS affects the formation of long-term memory through interference with postperceptual executive processes, rather than with perceptual analysis of the stimuli. The effect was specific for stimulation of the left dorsolateral prefrontal cortex (DLPFC), whereas rTMS applied to the right DLPFC, vertex (active control site), as well as sham stimulation (placebo) did not affect accuracy. These results confirm the crucial role of the left DLPFC in encoding and provide novel information about the critical timing of its engagement in the formation, consolidation, and maintenance of the memory trace.


Assessing the reliability and validity of the John Henry Active Coping Scale in an urban sample of African Americans and white Americans.
The primary focus of this study was to examine the psychometric properties of the John Henry Active Coping scale (JHAC12) among an urban middle-aged sample of African Americans and white Americans. The sample consisted of 75 African Americans and 129 white Americans from South Florida ranging in age from 25 to 54 years. Subjects completed the JHAC12, the Life Orientation Test (LOT), Coping Orientation to Problems Encountered (COPE) subscales, and the Marlowe-Crowne Social Desirability scale. Major findings supported the validity and reliability of the JHAC12 among both African Americans and white Americans. For both the African American and white American subsamples, the JHAC12 was correlated with the active coping and suppression of competing activities subscales of the COPE and negatively correlated with the Marlowe-Crowne Social Desirability scale. In the African American subsample the JHAC12 was positively correlated with the LOT. The JHAC12 was also negatively associated with the behavioral disengagement subscale of the COPE among white Americans. Multiple regression analyses revealed that the proportion of variance in the JHAC12 explained by the various subscales of the COPE, Marlowe-Crowne, and the LOT was 43% for African Americans and 20% for white Americans. Factor analyses suggested two similar and meaningful factors among the African American and white American subsamples. Finally, Cronbach alpha reliabilities revealed similar subsample coefficients. The implications of the findings are discussed in terms of the JHAC12's ability to assess the construct of active coping among African Americans and white Americans.


Syncytial mutations in the herpes simplex virus type 1 gK (UL53) gene occur in two distinct domains.
Syncytial (syn) mutants of herpes simplex virus cause cell fusion. Many syn mutations map to the syn1 locus, which has been identified with the gK (UL53) gene. In this work, the gK genes of eight syn mutants derived from the KOS strain were sequenced to identify residues and, possibly, domains important for the fusion activity of mutant gK. DNA sequencing showed that six mutants (syn30, syn31, syn32, syn102, syn103, and syn105) had single missense mutations in the gK gene. Two of these, syn31 and syn32, had identical mutations that caused the introduction of a potential site for N-linked glycosylation. syn31 gK was analyzed by in vitro translation and found to utilize the novel glycosylation site. Two other mutants, syn8 and syn33, had three mutations each, resulting in three amino acid substitutions in syn8 and two substitutions in syn33. Of the 10 gK syn mutant sequences known, 8 have mutations in the N-terminal domain of gK, suggesting that this domain, which is likely to be an ectodomain, is important for the function of the protein. The other two mutants, syn30 and syn103, have mutations near the C terminus of gK.


Atypical carcinoid localized at the bronchus accompanied by diffuse idiopathic pulmonary neuroendocrine cell hyperplasia in the distal lung: a rare case report.
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is hyperplasia of noninvasive neuroendocrine cells originating from Kultchitsky cells. This is a rare pathological condition, suspected to be a precursor lesion of carcinoid, together with tumorlet. In the WHO histological classification (4th edition) revised in 2015, DIPNECH was added to the category that includes neuroendocrine tumors. Our patient was a 77-year-old woman who initially visited another doctor because of coughing. Chest CT revealed a mass occluding the right intermediate bronchial trunk, and bronchial carcinoid was suspected from biopsy findings, leading to referral of this patient to our department. The tumor was excised under a rigid bronchoscope for the purpose of making a definitive histological diagnosis and determining the extent of spread. The stalk portion of the tumor extended from the bifurcation of the middle and lower lobe bronchi in the membranous part of the intermediate trunk to the central side. The airway appeared to be almost completely occluded under bronchoscopy, but aeration from the periphery was maintained. Histopathologically, there was hyperplasia of oval atypical cells with relatively poor cytoplasm beneath the bronchial mucosa on HE staining, suggesting neuroendocrine tumor. Immunostaining revealed that these cells were positive for CD56, chromogranin A, and synaptophysin, and that there was moderate mitosis, leading to a diagnosis of atypical carcinoid. At a later date, radical surgery comprised of right pulmonary middle and lower lobectomy and lymph node dissection was performed. The final histopathological diagnosis was atypical carcinoid of the bronchus (pT1aN0M0, stage IA). There were multiple aggregations of atypical cells, measuring approximately 1-3 mm, along the airway around the bronchioles in the excised lung, indicating concomitant DIPNECH. The patient currently has no evidence of either recurrence or metastasis at 12 months after surgery, but we will continue meticulous follow-up.


Shyness, Self-regulation, and Cognitive Problem Solving in Typically Developing 4-year-olds: A Pilot Study.
Because shy children are at risk for poor academic achievement, it is important to examine factors that contribute to variability in the relation between individual differences in shyness and cognitive functioning before school entry. The authors examined whether on-task facilitative private speech-a proxy of self-regulation-moderated the association between individual differences in shyness and performance on an executive function (EF) task in 52 typically developing 4-year-olds. They found that private speech interacted with shyness to predict performance on the EF task in girls but not in boys. More specifically, shyness was inversely related to EF task performance when girls used low amounts of regulatory private speech, but was positively related to performance when girls used high amounts of regulatory private speech. These preliminary findings are discussed in the context of implications for shy children in educational settings.


Value of Head CT Scan in the Emergency Department in Patients with Vertigo without Focal Neurological Abnormalities.
Vertigo is a common symptom and reason for admission to the emergency department (ED). This research aimed to determine the incidence of clinically significant findings on computed tomography (CT) in patients with vertigo without focal neurological abnormalities in the ED. The results of the native CT scans in the ED were retrospectively analysed. Exclusion criteria included: focal neurological abnormalities, underlying malignancy, brain metastasis, previous brain operation, headache, fever, nausea, vomiting, head trauma, coagulopathy. As a clinically significant finding, we took into an account tumour, haemorrhage and acute ischemic lesion. 72 patients fulfilled the set criteria, present vertigo, without focal neurological abnormalities. Out of 72 patients with a median age of 62 (23-87) years old, 54% of the patients were female, and 46% were male. Normal CT findings were found in 44 patients (61.1%), 28 patients (38.9%) had pathological findings, out of that number 23 (31.9%) findings were clinically irrelevant and 5 (6.9%) were clinically significant. Out of the 5 clinically significant findings, tumour process was found in 3 (4.2%) patients, haemorrhage was found in 1 (1.4%) patient, and the ischemic lesion was found in 1 (1.4%) patient. Additional evaluation of five clinically significant findings showed a change of initial diagnosis in one case, but the significance of the finding remained the same. Our study demonstrates a low diagnostic yield of head CT examination with 6.9% of clinically significant findings in patients with vertigo without focal neurological abnormalities.


Temporal Associations Between Social Activity and Mood, Fatigue, and Pain in Older Adults With HIV: An Ecological Momentary Assessment Study.
Social isolation is associated with an increased risk for mental and physical health problems, especially among older persons living with HIV (PLWH). Thus, there is a need to better understand real-time temporal associations between social activity and mood- and health-related factors in this population to inform possible future interventions. This study aims to examine real-time relationships between social activity and mood, fatigue, and pain in a sample of older PLWH. A total of 20 older PLWH, recruited from the University of California, San Diego HIV Neurobehavioral Research Program in 2016, completed smartphone-based ecological momentary assessment (EMA) surveys 5 times per day for 1 week. Participants reported their current social activity (alone vs not alone and number of social interactions) and levels of mood (sadness, happiness, and stress), fatigue, and pain. Mixed-effects regression models were used to analyze concurrent and lagged associations among social activity, mood, fatigue, and pain. Participants (mean age 58.8, SD 4.3 years) reported being alone 63% of the time, on average, (SD 31.5%) during waking hours. Being alone was related to lower concurrent happiness (beta=-.300; 95% CI -.525 to -.079; P=.008). In lagged analyses, social activity predicted higher levels of fatigue later in the day (beta=-1.089; 95% CI -1.780 to -0.396; P=.002), and higher pain levels predicted being alone in the morning with a reduced likelihood of being alone as the day progressed (odds ratio 0.945, 95% CI 0.901-0.992; P=.02). The use of EMA elucidated a high rate of time spent alone among older PLWH. Promoting social activity despite the presence of pain or fatigue may improve happiness and psychological well-being in this population.


[Utilization++ of statistical analysis in original articles published in the Revista Clínica Española (1992-1993)].
To report the types of statistical analysis performed and to quantitate statistical accessibility in the originals of Revista Clínica Española from 1992 to 1992. Ninety-one originals were reviewed. Statistical analysis were classified according to 18 categories and statistical accessibility was evaluated from the same categorization. Seventy-four percent of originals used inferential methods. The most frequently used categories were Bivariable tables (46%) and t and z test (42%). Thirty-six percent of originals used some multivariable analysis and particularly the Analysis of survival (12%). Considering the high frequency of use of multivariable techniques, investigators need to have some knowledge on statistics beyond a basic course.


Improved fixation for immunofluorescence microscopy using light-activated 1,3,5-triazido-2,4,6-trinitrobenzene (TTB).
A new fixation method has been developed for immunofluorescent microscopy using the photosensitive compound 1,3,5-triazido-2,4,6-trinitrobenzene (TTB). Our results show that TTB-fixed cells are well preserved morphologically and that the cellular antigens are better preserved than conventionally fixed cells. By altering one condition at a time in the TTB fixation procedure and analyzing resulting fluorescent antitubulin staining patterns in mammalian tissue culture cells, an optimal procedure was developed. Cells fixed with TTB and stained with antitubulin, antiprekeratin, anti-intermediate filament, anti-alpha-actinin, anti-myosin, antiactin, or anticlathrin were compared with cells fixed by conventional methods and stained with the same antibody. The quality of immunofluorescence images of TTB fixed cells was the same as or better than that of conventionally fixed cells. The most dramatic improvement in image quality was seen when using antiprekeratin or antitubulin. In dividing cells, particularly in metaphase, fluorescent staining with antiactin and anti-alpha-actinin was relatively excluded from the spindle. Antimyosin, on the other hand, stained the spindle and surrounding area more heavily than the subcortical region. We suggest that after TTB fixation, the immunofluorescent patterns of these contractile proteins more closely reflect their relative concentrations in living cells. The exact mechanism for fixation by TTB is not yet known. However, our studies indicated that TTB fixation was not caused by the typical fast photoinduced nitrene diradical mechanism, but rather by some slower, temperature-dependent reaction of a photoactivation product of TTB with the cell.


Evaluation of biofield treatment dose and distance in a model of cancer cell death.
This study assessed the potential influence of biofield treatment on cultured human cancer cells and whether such influence was affected by varying the duration of the treatment (dose) or the distance between the biofield practitioner and the target cells. Biofield treatment dosage was assessed from a short distance (0.25 meters) in three independent experiments involving 1, 2, or 5 treatments, along with another set of three independent and comparable mock experiments. Biofield treatment distance was assessed at 0.25, 25, and ∼ 2000 meters involving two treatments in three independent experiments along with another set of three mock experiments. Biofield treatments were delivered by a highly acclaimed biofield practitioner with the intention of diminishing growth of the cells or inducing cancer-cell death. Cell viability was quantified 20 hours after treatments, using a spectrophotometric assay for live-cell counting. The dependent measure for each experiment was the log ratio of the cell viability values of treated samples (biofield or mock) over the values of untreated control samples. A trend of decreasing cell viability with increasing biofield dose was evident in the first set of experiments assessing dose-response; however, no such effect was evident in the second set of experiments evaluating biofield treatment distance. Mock experiments yielded relatively stable viability ratios in both sets of experiments. Linear regression analysis and hypothesis testing of the data taken as a whole did not yield statistical significance at p<0.05. These results represent the first indication of a biofield treatment dose-response in a controlled laboratory setting. The data are inconclusive because of the inability of reproduce the cellular response in a replicate experiment.


Knowledge discovery in metabolomics: an overview of MS data handling.
While metabolomics attempts to comprehensively analyse the small molecules characterising a biological system, MS has been promoted as the gold standard to study the wide chemical diversity and range of concentrations of the metabolome. On the other hand, extracting the relevant information from the overwhelming amount of data generated by modern analytical platforms has become an important issue for knowledge discovery in this research field. The appropriate treatment of such data is therefore of crucial importance in order, for the data, to provide valuable information. The aim of this review is to provide a broad overview of the methodologies developed to handle and process MS metabolomic data, compare the samples and highlight the relevant metabolites, starting from the raw data to the biomarker discovery. As data handling can be further separated into data processing, data pre-treatment and data analysis, recent advances in each of these steps are detailed separately.


Differences in mortality and incidence for major sites of cancer by education level in a Japanese population.
We aimed to examine the relationships between education and mortality and incidence for major sites of cancer in a Japanese population. Subjects were 32,883 respondents of questionnaire survey in 1978 with ages younger than 75 years. Cancer cases were ascertained through 2001, and causes of deaths were identified through 2003. Hazard ratios of deaths from cancer or developing cancers were compared among those with 9 or less, 10-12, and 13 years or more of education using Cox proportional hazard models. As for cancer mortality of all sites combined, a statistically significantly decreasing trend was observed in age-adjusted models in both men and women, but no significant differences were observed in multivariate-adjusted (age, body mass index, smoking, radiation dose, and city) models. Among major cancer sites (stomach, colon/rectum, liver, lung, and female breast) examined, a significantly decreasing trend was observed for male liver cancer in a multivariate-adjusted model. As for incidence, a significantly decreasing trend was observed for cancer of all sites combined in men, and for male liver and prostate cancer and female lung cancer in a multivariate-adjusted model. Educational differences in cancer incidence and mortality were generally rather small, but were significant for incidence for male all-site, male liver, prostate, and female lung cancers.


Crossover phenomena in epileptic syndromes of childhood.
Benign Rolandic epilepsy (BRE) and primary generalized epilepsy (PGE) are found at about the same period of childhood. Crossover from PGE to BRE and vice versa may occur; two short case reports provide further evidence for this development. Hence, transitions from a primarily generalized to a focal (partial) epileptic seizure disorder and vice versa is a possibility. Both PGE and BRE are based upon states of hyperexcitability, i.e. dysfunctional rather than structural abnormalities that are capable of changing their spatial distribution.


"Recovery" from the diagnosis of autism - and then?
The aim of this study was to follow up the 17 children, from a total group of 208 children with autism spectrum disorder (ASD), who "recovered from autism". They had been clinically diagnosed with ASD at or under the age of 4 years. For 2 years thereafter they received intervention based on applied behavior analysis. These 17 children were all of average or borderline intellectual functioning. On the 2-year follow-up assessment, they no longer met criteria for ASD. At about 10 years of age they were targeted for a new follow-up. Parents were given a semistructured interview regarding the child's daily functioning, school situation, and need of support, and were interviewed using the Vineland Adaptive Behavior Scales (VABS) and the Autism - Tics, Attention-deficit/hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC) telephone interview. The vast majority of the children had moderate-to-severe problems with attention/activity regulation, speech and language, behavior, and/or social interaction. A majority of the children had declined in their VABS scores. Most of the 14 children whose parents were A-TAC-interviewed had problems within many behavioral A-TAC domains, and four (29%) had symptom levels corresponding to a clinical diagnosis of ASD, AD/HD, or both. Another seven children (50%) had pronounced subthreshold indicators of ASD, AD/HD, or both. Children diagnosed at 2-4 years of age as suffering from ASD and who, after appropriate intervention for 2 years, no longer met diagnostic criteria for the disorder, clearly needed to be followed up longer. About 3-4 years later, they still had major problems diagnosable under the umbrella term of ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations). They continued to be in need of support, educationally, from a neurodevelopmental and a medical point of view. According to parent interview data, a substantial minority of these children again met diagnostic criteria for ASD.


1,25-dihydroxyvitamin D3 stimulates vesicular transport within 5 s in polarized intestinal epithelial cells.
Controversy remains regarding whether the seco-steroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) enhances calcium and phosphate movement across the intestinal epithelial cell by facilitated diffusion or a vesicular transport mechanism. In this study we investigated whether membrane trafficking, as judged by confocal microscopy, was sufficiently rapid in comparison to hormone-stimulated uptake of phosphate (32P). Primary cultures of chick intestinal cells were established overnight either in Petri dishes (uptake studies) or chambered coverslips (confocal microscopy). Addition of 130 pM 1,25(OH)2D3 resulted in an apparent increase in 32P uptake within 1 min, relative to controls, that was statistically significant from 3-10 min of incubation. Using the endocytic marker dye, FM1-43, confocal microscopy revealed a profound decrease in membrane-associated fluorescence (apical> basal) within 10 s of hormone treatment, a return of fluorescence at 15-65 s, followed by another round of decreasing and increasing fluorescence. Between 3-9 min of incubation, fluorescence intensity increased 50% (apical region) and 20% (basal region) over control conditions. An antibody (Ab 099) directed against a putative membrane receptor for 1,25(OH)2D3 (1,25D3-MARRS) inhibited both 32P uptake, and changes in fluorescence. In addition, the protein kinase C (PKC) inhibitor, calphostin C, inhibited both 32P uptake and the observed 1,25(OH)2D3-mediated changes in fluorescence. At the microscopic level, calphostin C pretreatment abolished the very rapid redistribution of the endocytic marker dye, although a slight increase in fluorescence was still observed. We conclude that 1,25(OH)2D3-stimulated vesicular trafficking is mediated by the 1,25D3-MARRS protein, implicates a PKC signaling mechanism, and occurs in a time frame that is commensurate with a role in ion transport.


Major trauma and acceleration of the ageing process.
It is well established that numerous factors can affect the rate at which we age biologically. Diet, physical activity, lifestyle and our genes all play a major role in influencing the ageing trajectory and longevity. Major trauma affects millions globally, is the major cause of death in young adults and could influence ageing processes but has largely been ignored by biogenterologists. The long-term health consequences of physical trauma are well known in the medical community, how trauma effects the ageing process at a molecular level is not. It has long been difficult to assess ageing trajectories due to the absence of a biomarker of biological rather than chronological age. Recent advances in epigenetics have helped by identifying specific DNA methylation sites as good indicators of biological age. Recent investigations into the impact of psychological trauma and the associated physical stress on accelerating ageing as measured by epigenetic drift are promising. The physical and metabolic stress which is synonymous with physical trauma may also accelerate the ageing process. We suggest that long term epigenetic profiling is required to understand to what degree the ageing trajectory is altered by trauma, which will in turn add support for the development of novel therapies to improve health outcomes for survivors of traumatic injury.


Rapid measurement of deuterium content of breath following oral ingestion to determine body water.
The ability to measure total body water accurately, non-invasively and rapidly with results that are immediately available would represent an important advance in body composition research. Flowing afterglow mass spectrometry (FA-MS) has been developed to enable immediate measurement of deuterium content in breath water from single exhalations, which when combined with oral D2O loading enables measurement of total body water. We report here its first use in normal subjects, demonstrating the dispersal kinetics of deuterium in the body by monitoring deuterium in breath water following ingestion. Ten studies were performed in six normal subjects. After obtaining baseline samples, each subject ingested 0.3 g x kg(-1) of 99.9% pure D2O. Subsequently, breath samples were obtained every 3-5 minutes until equilibration had occurred. Three distinct phases in breath deuterium content were observed: an initial immediate peak due to HDO remaining in the oral cavity, a secondary peak reflecting gastrointestinal absorption and finally equilibration with the body water. The incremental increase in breath deuterium abundance between baseline and equilibration was used to calculate the total body water. Mathematical fitting of this final equilibration phase demonstrated that the measured deuterium abundance was within 0.2% of the ideal (asymptotic) value within 2 hours in all cases. We conclude that FA-MS is a powerful new method that, when combined with oral D2O loading, enables measurement of the dispersal kinetics of HDO and the calculation of total body water within 2 hours.


Prevalence And Impact of Medical Comorbidities in A Real-World Lung Cancer Screening Population.
Lung cancer screening trials generally enroll motivated, relatively healthy, and adherent populations. We therefore evaluated the prevalence and effects of comorbidities in a real-world population undergoing low-dose computed tomography (LDCT) scans. We calculated the Charlson Comorbidity Index (CCI) of patients for whom an initial low-dose computed tomography (LDCT) for lung cancer screening was ordered between February 2017 and February 2019 in an integrated safety-net healthcare system. We examined the association between CCI and initial LDCT completion using multivariable logistic regression, assessed the association between specific medical comorbidity and LDCT completion using Chi-square test or Fisher's exact test as appropriate, and examined the association between CCI and LDCT Lung-RADS results using Fisher's exact test. A total of 1358 patients were included in the analysis. Mean age was 63 years, 57% were women, and 50% were Black. Patients had moderate comorbidity burden (median CCI 3) with chronic pulmonary disease the most common comorbidity. Overall, 943 LDCT (70%) were completed. There was no difference in 30-day, 90-day, or 1-year completion rates of initial LDCT according to CCI. However, 30-day LDCT completion rates did increase over time (P < .001). Lung-RADS scores were not associated with CCI. In a real-world setting, patients undergoing lung cancer screening have moderate comorbidity burden. The degree and type of medical comorbidity are not associated with initial screening completion or results. Timeliness of LDCT completion may improve as program experience increases.


Initial pain and disability characteristics can assist the prediction of the centralization phenomenon on initial assessment of patients with low back pain.
Determine whether the achievement of the centralization phenomenon on initial assessment of patients with low back pain (LBP) can be predicted by history and physical examination variables. Ninety patients referred to physical therapy due to LBP completed pain, disability, and fear-avoidance questionnaires, followed by a complete history and a physical examination based on mechanical diagnosis and therapy principles. Patients were subsequently classified as centralizers or noncentralizers. Univariate, followed by multivariate analysis was performed to identify history and physical examination variables that predicted the occurrence of the CP. Factors retained in the multivariate analysis were used to develop a clinical prediction rule (CPR). Twenty-eight patients (31%) were classified as centralizers immediately following assessment. Three predictors were retained in the multivariate analysis: (1) modified Oswestry Disability Index score lower than 33%; (2) intensity of the most distal symptom lower than 6/10; and (3) back pain equal to or greater than leg pain. The resultant CPR indicated the presence of all three variables increased the post-test likelihood of the CP to 57%. The findings of this study suggest the CP may be considerably more likely in less severe cases of LBP characterized by lower disability, lower intensity of distal symptoms, and a greater back-versus-leg pain intensity. Pending future validation, the CPR developed in this study may aide decision making regarding the initial management strategy of patients with LBP.


Multiple imputation with multivariate imputation by chained equation (MICE) package.
Multiple imputation (MI) is an advanced technique for handing missing values. It is superior to single imputation in that it takes into account uncertainty in missing value imputation. However, MI is underutilized in medical literature due to lack of familiarity and computational challenges. The article provides a step-by-step approach to perform MI by using R multivariate imputation by chained equation (MICE) package. The procedure firstly imputed m sets of complete dataset by calling mice() function. Then statistical analysis such as univariate analysis and regression model can be performed within each dataset by calling with() function. This function sets the environment for statistical analysis. Lastly, the results obtained from each analysis are combined by using pool() function.


[Compulsory hospitalization of non-compliant patients with tuberculosis].
The procedure and results of forced treatment per curiam were analyzed in 584 bacteria-discharging persons registered as Group 1 patients to be examined in the tuberculosis facilities of the Kemerovo Region in 2004 to 2007. If a package of measures for forcing the patient to be treated is ineffective, a phthisiatrician draws up documents for court. By the decision of the court, the patient is conveyed by justice officers to a tuberculosis hospital. Judicial practice provides a means of substantially enhancing the efficiency of treatment in this socially compromised group of patients with predominantly destructive processes. Among those who had voluntarily come to the hospital just before or after sentence pronouncement, bacterial discharge cessation and decay cavity closure were achieved in almost 90% of cases; clinical resolution was observed in two thirds. At the same time, there is a group of patients, in whom the existing system of measures has proven to be ineffective. There are serious gaps in the legislation of the Russian Federation, which impede the bringing of patients with tuberculosis, the homeless in particular, to compulsory hospitalization. Legislation should be perfected in this area.


Microtubules in Pancreatic β Cells: Convoluted Roadways Toward Precision.
Pancreatic islet β cells regulate glucose homeostasis via glucose-stimulated insulin secretion (GSIS). Cytoskeletal polymers microtubules (MTs) serve as tracks for the transport and positioning of secretory insulin granules. MT network in β cells has unique morphology with several distinct features, which support granule biogenesis (via Golgi-derived MT array), net non-directional transport (via interlocked MT mesh), and control availability of granules at secretion sites (via submembrane MT bundle). The submembrane MT array, which is parallel to the plasma membrane and serves to withdraw excessive granules from the secretion hot spots, is destabilized and fragmented downstream of high glucose stimulation, allowing for regulated secretion. The origin of such an unusual MT network, the features that define its functionality, and metabolic pathways that regulate it are still to a large extent elusive and are a matter of active investigation and debate. Besides the MT network itself, it is important to consider the interplay of molecular motors that drive and fine-tune insulin granule transport. Importantly, activity of kinesin-1, which is the major MT-dependent motor in β cells, transports insulin granules, and has a capacity to remodel MT network, is also regulated by glucose. We discuss yet unknown potential avenues toward understanding how MT network and motor proteins provide control for secretion in coordination with other GSIS-regulating mechanisms.


Giant spontaneous exchange bias obtained by tuning magnetic compensation in samarium ferrite single crystals.
Spontaneous exchange bias (SEB) under zero field cooling (ZFC) has recently attracted lots of attention due to its underlying physics and potential applications. Here we report the giant SEB (GSEB) of SmFeO3 single crystals by tuning magnetic compensation by temperature, which is rather convenient. A SEB field of up to 1 T at 3.9 K after ZFC (-1.4 T at 3.9 K after field cooling) was obtained. The SEB shows reciprocal relationship with remnant magnetization.


Should operations be regionalized? The empirical relation between surgical volume and mortality.
This study examines mortality rates for 12 surgical procedures of varying complexity in 1498 hospitals to determine whether there is a relation between a hospital's surgical volume and its surgical mortality. The mortality of open-heart surgery, vascular surgery, transurethral resection of the prostate, and coronary bypass decreased with increasing number of operations. Hospitals in which 200 or more of these operations were done annually had death rates, adjusted for case mix, 25 to 41 per cent lower than hospitals with lower volumes. For other procedures, the mortality curve flattened at lower volumes. For example, hospitals doing 50 to 100 total hip replacements attained a mortality rate for this procedure almost as low as that of hospitals doing 200 or more. Some procedures, such as cholecystectomy, showed no relation between volume and mortality. The results may reflect the effect of volume or experience on mortality, or referrals to institutions with better outcomes, as well as a number of other factors, such as patient selection. Regardless of the explanation, these data support the value of regionalization for certain operations.


Routine pre-cesarean Staphylococcus aureus screening and decolonization: a cost-effectiveness analysis.
To estimate the economic value of screening pregnant women for Staphylococcus aureus carriage before cesarean delivery. Computer simulation model. We used computer simulation to assess the cost-effectiveness, from the third-party payer perspective, of routine screening for S aureus (and subsequent decolonization of carriers) before planned cesarean delivery. Sensitivity analyses explored the effects of varying S aureus colonization prevalence, decolonization treatment success rate (for the extent of the puerperal period), and the laboratory technique (agar culture vs polymerase chain reaction [PCR]) utilized for screening and pathogen identification from wound isolates. Pre-cesarean screening and decolonization were only cost-effective when agar was used for both screening and wound cultures when the probability of decolonization success was ≥ 50% and colonization prevalence was ≥ 40%, or decolonization was ≥ 75% successful and colonization prevalence was ≥ 20%. The intervention was never cost-effective using PCR-based laboratory methods. The cost of agar versus PCR and their respective sensitivities and specificities, as well as the probability of successful decolonization, were important drivers of the economic and health impacts of preoperative screening and decolonization of pregnant women. The number needed to screen ranged from 21 to 2294, depending on colonization prevalence, laboratory techniques used, and the probability of successful decolonization. Despite high rates of cesarean delivery, presurgical screening of pregnant women for S aureus and decolonization of carriers is unlikely to be cost-effective under prevailing epidemiologic circumstances.


Postnephrectomy arteriovenous fistula: a case report.
We report a 57-yr-old woman with severe cardiac failure secondary to postnephrectomy arteriovenous fistula which was successfully removed. A review of the literature shows the rarity of this complication; only 72 cases have been reported in the world literature including 6 cases (including the present case) from Japan. Surgical intervention is generally the treatment of choice from a fistula and provides satisfactory results for cardiac failure which is the major complication of this fistula. A characteristic bruit was observed in all reported cases. Therefore, nonsurgical closure by percutaneous embolization for a small sized shunt may be possible if early diagnosis is obtained by careful auscultation of the loin.


Nephelometry of acute-phase glycoproteins by binding to concanavalin A.
Nephelometry of serum acute-phase glycoproteins by binding to concanavalin A (con-A) was compared with assays for haptoglobin and alpha 1-acid glycoprotein, and for C-reactive protein. The cutoff points for positive reactions were determined on the basis of results for a random sample (n = 130) from a middle-aged population. The sensitivity of the con-A binding assay compared favorably with that of individual acute-phase glycoproteins in a follow-up cohort of 198 patients with inflammatory joint diseases. Unlike the case in many individual acute-phase glycoprotein assays, the distribution of con-A binding values in healthy subjects is remarkably symmetrical, allowing an easy distinction between abnormal and normal values.


Substantial induction of a new serum protein by growth hormone: physiochemical and physiological characterization.
Serum from GH-treated hypophysectomized rats was examined by two-dimensional gel electrophoresis followed by silver staining to screen a large number of serum proteins for GH responsiveness. A distinctive, highly acidic protein of 60,000 mol wt was clearly responsive to GH administration, increasing 7-fold over levels observed in hypophysectomized controls. Administration of T4, corticosterone, and 5 alpha-dihydrotestosterone failed to induce this protein; however, addition of GH to this regimen resulted in a 60-fold increase in its concentration. Examination of proteins synthesized by isolated hepatocytes in the presence of [35S]methionine showed that this protein is of hepatic origin. Physiological and physiochemical evidence suggest that this protein is unlikely to be one of the other well documented GH-responsive serum proteins: somatomedin-C, alpha 2U-globulin, or the somatomedin-binding protein. The protein demonstrates a remarkable ontogeny, increasing 135-fold over newborn levels by 35 days of age. This is qualitatively similar to changes observed in somatomedin-C, however, the quantitative change is much more striking. Examination of the protein in an altered physiological state which limits growth (uremia) reveals a 30-fold diminution of levels of the protein after 3 weeks of renal failure. In contrast, pair-fed animals demonstrated only a 2-fold decrease. This suggests that there is a profound inhibition of GH action which is not accounted for by poor nutritional intake. This protein may be useful in the investigation of the GH-hepatic axis.


Effects of hypoxia on anabolic and catabolic gene expression and DNA methylation in OA chondrocytes.
Cartilage is an avascular and aneural tissue. Chondrocytes thrive in this restricted environment of low oxygen tension and poor nutrient availability which has led to suggestions that hypoxia may be a protective mechanism against the development of osteoarthritis (OA). There is also a growing body of evidence to support the role of epigenetic factors in the pathogenesis of OA. However, few studies have investigated the epigenetic-OA process within a hypoxic environment. The current study has investigated the effects of hypoxia on gene expression and DNA methylation of anabolic and catabolic genes involved in the pathogenesis of OA. Chondrocytes extracted from OA femoral heads were incubated in normoxia and hypoxia (20% and 2% oxygen concentrations respectively). Interleukin 1-beta (IL-1β) plus oncostatin M (OSM), 5-azadeoxycytidine (5-aza-dC) or media alone (control) were added twice weekly to the incubated samples. After 5 weeks, levels of Collagen type IX (COL9A1), IL1B, and matrix metalloproteinase-13 (MMP13) gene expression were measured using SYBR Green-based qRT-PCR and were correlated with methylation status analysed by pyrosequencing methodology. Hypoxia resulted in a >50-fold and >10-fold increase in relative expression of COL9A1 and IL1B respectively. This was inversely correlated to the DNA methylation status of these genes. Expression of MMP13 was reduced at 2% oxygen tension in control cells. Relative expression of MMP13 increased in cells stimulated with IL-1β and 5-aza-dC in normoxic conditions, and this effect was eliminated at low oxygen tension although no correlation with methylation status was observed. These findings demonstrate a role for hypoxia in the regulation of anabolic and catabolic gene expression and the influence of changes in DNA methylation. These results further support the role of epigenetics in OA and, critically, highlight the complex relationship between the physiological environment of cartilaginous cells and the osteoarthritic process with implications for therapeutic intervention and our understanding of OA pathophysiology.


Growth performance, blood profiles and carcass traits of Barbary partridge (Alectoris barbara) fed two different insect larvae meals (Tenebrio molitor and Hermetia illucens).
To investigate the effect of two insect meals (from Hermetia illucens, HI and Tenebrio molitor, TM larvae) on productive performance and blood profiles of Barbary partridge, ninety, seven days old partridges were divided into 5 groups (6 replicates, 3 partridges/replicate). Up to 64d, the groups fed 5 isoproteic and isoenergetic diets: the control fed a corn-soybean meal diet (SBM group); in TM25 and TM50 groups the 25 and 50% of SBM proteins were substituted by the protein from TM, respectively; in HI25 and HI50 groups the 25 and 50% of SBM were substituted by the protein from HI, respectively. The birds fed TM25 and both the HI levels reached a higher (P<0.01) live weight at 64d than the control. Considering the entire experimental period the TM groups had a more favorable FCR than SBM. The carcass weights of all the insect groups were higher (P<0.01) than the control. The weight of the full digestive tract in SBM group was the highest (P<0.01). The caecal weight, the intestinal and caecal length were the highest (P<0.01) in the SBM group. The SBM group the highest value of albumin/globulin (P<0.01) and creatinine (P<0.05). TM seems to be more effective than HI in improving FCR. The reduced albumin/globulin ratio in the insect meal fed groups could be ascribed to the chitin content and this result was not affected by the amount of chitin intake, suggesting that also the lowest values are able to express their potential effects in partridges.


Strong, Multifaceted Guanidinium-Based Adhesion of Bioorganic Nanoparticles to Wet Biological Tissue.
Gluing dynamic, wet biological tissue is important in injury treatment yet difficult to achieve. Polymeric adhesives are inconvenient to handle due to rapid cross-linking and can raise biocompatibility concerns. Inorganic nanoparticles adhere weakly to wet surfaces. Herein, an aqueous suspension of guanidinium-functionalized chitin nanoparticles as a biomedical adhesive with biocompatible, hemostatic, and antibacterial properties is developed. It glues porcine skin up to 3000-fold more strongly (30 kPa) than inorganic nanoparticles at the same concentration and adheres at neutral pH, which is unachievable with mussel-inspired adhesives alone. The glue exhibits an instant adhesion (2 min) to fully wet surfaces, and the glued assembly endures one-week underwater immersion. The suspension is lowly viscous and stable, hence sprayable and convenient to store. A nanomechanic study reveals that guanidinium moieties are chaotropic, creating strong, multifaceted noncovalent bonds with proteins: salt bridges comprising ionic attraction and bidentate hydrogen bonding with acidic moieties, cation-π interactions with aromatic moieties, and hydrophobic interactions. The adhesion mechanism provides a blueprint for advanced tissue adhesives.


Suture-button suspensionplasty for thumb carpometacarpal arthritis: a minimum 2-year follow-up.
To retrospectively review the results at a minimum of 2 years of suture-button plasty with partial or full trapeziectomy and suture-button suspensionplasty. We evaluated 21 patients who received suture-button suspensionplasty at least 2 years after surgery. We measured postoperative pinch strength, grip strength, range of motion, and metacarpal height. All patients also completed the Quick Disabilities of the Arm, Shoulder, and Hand questionnaire. At an average follow-up of 2.8 ± 0.7 years, the mean Quick Disabilities of the Arm, Shoulder, and Hand score was 10 ± 9. Pinch and grip strengths were 86% and 89% of the contralateral limb, respectively. Average first trapezial height was 74% of the contralateral trapezial height. There were no major complications. The favorable results of the suture-button suspensionplasty procedure confirm its usefulness in treating thumb carpometacarpal arthritis with minimal risk of complications, ineffective fixation, or loss of function. Subjective and objective outcomes measures are similar to previously described techniques. The benefit of this technique results from the implanted nature of the suspensionplasty elements that require no time to heal, so rehabilitation is begun as early as 10 days postoperatively. Therapeutic IV.


Polarity-Differentiated Dielectric Materials in Monolayer Graphene Charge-Regulated Field-Effect Transistors for an Artificial Reflex Arc and Pain-Modulation System of the Spinal Cord.
The nervous system is a vital part of organisms to survive and it endows them with remarkable abilities, such as perception, recognition, regulation, learning, and decision-making, by intertwining myriad neurons. To realize such outstanding efficacies and functions, many artificial devices and systems have been investigated to emulate the operating principles of the nervous system. Here, an artificial reflex arc (ARA) and artificial pain modulation system (APMS) are proposed to imitate the unconscious behaviors of the spinal cord. Gdx Oy - and Alx Oy -based charge-regulated field-effect transistors (CRFETs) with a monolayer graphene channel are fabricated and adopted as inhibitory and excitatory synapses, respectively, under the same pulse signals to mimic the biological reflex arc through a connection with a poly(vinylidene fluoride-co-trifluoroethylene)-based actuator. Additionally, a memristor is integrated with a CRFET as the interneuron to regulate the Dirac point by controlling the voltage drop on the graphene channel, analogous to the descending pain-inhibition system in the spinal cord, to prevent excessive pain perception. The proposed ARA and APMS provide a significant step forward to realizing the functions of the nervous system, giving promising potential for developing future intelligent alarm systems, neuroprosthetics, and neurorobotics.


Early Palliative Care Services and End-of-Life Care in Medicare Beneficiaries with Hematologic Malignancies: A Population-Based Retrospective Cohort Study.
Background: Patients with hematologic malignancies (HM) often receive aggressive care at the end of life (EOL). Early palliative care (PC) has been shown to improve EOL care outcomes, but its benefits are less established in HM than in solid tumors. Objectives: We sought to describe the use of billed PC services among Medicare beneficiaries with HM. We hypothesized that receipt of early PC services (rendered >30 days before death) may be associated with less aggressive EOL care. Design: Retrospective cohort analysis Setting/Subjects: Using the Surveillance, Epidemiology, and End Results-Medicare registry, we studied patients with leukemia, lymphoma, myeloma, myelodysplastic syndrome, or myeloproliferative neoplasm who died between 2001 and 2015. Measurements: We described trends in the use of PC services and evaluated the association between early PC services and metrics of EOL care aggressiveness. Results: Among 139,191 decedents, the proportion receiving PC services increased from 0.4% in 2001 to 13.3% in 2015. Median time from first encounter to death was 10 days and 84.3% of encounters occurred during hospitalizations. In patients who survived >30 days from diagnosis (N = 120,741), the use of early PC services was more frequent in acute leukemia, women, and black patients, among other characteristics. Early PC services were associated with increased hospice use and decreased health care utilization at the EOL. Conclusion: Among patients with HM, there was an upward trend in PC services, and early PC services were associated with less aggressive EOL care. Our results support the need for prospective trials of early PC in HM.


[Biology of lysogenic strains of Streptococcus bovis and virulent mutants of their temperate phages].
Three lysogenic streptococcal strains and four virulent mutants of temperate phages were studied. The bacterial strains proved to be close to the type strain of Streptococcus bovis in their morphological, cultural, physiological, and biochemical properties. Investigation into the interaction of the lysogenic cultures with virulent mutants of temperate phages showed that the culture age optimal for infecting was 3-5 h; intense lysis began in the second hour after infection and was virtually completed by the end of the third hour, i.e., the procedure of obtaining phages in HMT medium took 7-8 h. Phage titers in phage lysates varied from 3.93 x 10(10) to 11.25 x 10(10) active phage particles per ml; residual amounts of viable bacteria varied from 0.7 x 10(6) to 34.0 x 10(6) cells per ml. In liquid HMT medium, phage production by lysogenic cultures was not limited by 0.3% glucose or maltose, 0.5% peptone, or casein hydrolysate. Descriptions of virulent mutants VM 6/6, VM 32/6, VM 28/28, and VM 54/54 of temperate phages of Str. bovis are presented.


Comparison of complement dependent lytic, hemagglutination inhibition and microneutralization antibody responses in influenza vaccinated individuals.
Virus specific, non-neutralizing antibodies such as complement dependent lytic (CDL) antibodies may reduce morbidity following infection through the clearance of infectious virus particles and infected cells. We examined hemagglutination inhibition (HAI), microneutralization (MN) and CDL antibody titers to influenza A H1 and H3 virus strains in 23 healthy young adults who received the 2005-2006 trivalent inactivated influenza vaccine. Post vaccination, we detected statistically significant increases in MN and CDL antibodies but not in HAI antibodies. Statistically significantly higher fold increases in CDL antibodies post vaccination were seen compared with MN and HAI antibodies post vaccination. However, the overall fold increases were modest, likely related to the fact that most of the subjects had received influenza vaccination previously. This study showed that influenza vaccination is not only capable of increasing the level of antibodies that neutralize virus but also antibodies that can cause lysis of infected cells. The biological significance of these CDL antibodies merits further investigation in clinical studies.


Defensive medicine among antibiotic stewards: the international ESCMID AntibioLegalMap survey.
To investigate fear of legal claims and defensive behaviours among specialists in infectious diseases (ID) and clinical microbiology (CM) and to identify associated demographic and professional characteristics. AntibioLegalMap was an international cross-sectional internet-based survey targeting specialists in ID and CM. Three variables were explored: fear of legal liability in antibiotic prescribing/advising on antibiotic prescription; defensive behaviours in antibiotic prescribing; and defensive behaviours in advising. A multivariable logistic regression analysis was performed to identify factors significantly associated with each of the three variables. Eight hundred and thirty individuals from 74 countries participated. Only 0.4% (3/779) had any kind of condemnation for malpractice related to antibiotic prescription. Concerning the fear of liability, 21.2% (164/774) of respondents said they never worried, 45.1% (349/774) sometimes worried and 28.6% (221/774) frequently worried when prescribing/advising on antibiotic prescription. Being female, younger than or equal to 35 years and aware of previous cases of litigation were independently associated with fear. Most respondents (85.0%, 525/618) reported some defensive behaviour in antibiotic prescribing. These behaviours were independently associated with being younger than or equal to 35 years and sometimes or often worried about liability. Similarly, 76.4% (505/661) reported defensive behaviours in advising. These behaviours were associated with being sometimes or often worried about liability. The preferred measures to reduce fear and defensive behaviours were having local guidelines and sharing decisions through teamwork. A significant proportion of specialists in ID and CM reported some form of defensive behaviour in prescribing or advising to prescribe antibiotics. Defensive medicine should be considered when implementing antibiotic stewardship programmes.


microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD).
The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration. These include ~18 different viral-induced encephalopathies for which data are available, at least ~10 known prion diseases (PrD) of animals and humans, Alzheimer's disease (AD) and other sporadic and progressive age-related neurological disorders. Despite the apparent lack of nucleic acids in prions, both DNA- and RNA-containing viruses along with prions significantly induce miRNA-146a in the infected host, but whether this represents part of the host's adaptive immunity, innate-immune response or a mechanism to enable the invading prion or virus a successful infection is not well understood. Current findings suggest an early and highly interactive role for miRNA-146a: (i) as a major small noncoding RNA (sncRNA) regulator of innate-immune responses and inflammatory signaling in cells of the human brain and CNS; (ii) as a critical component of the complement system and immune-related neurological dysfunction; (iii) as an inducible sncRNA of the brain and CNS that lies at a critical intersection of several important neurobiological adaptive immune response processes with highly interactive associations involving complement factor H (CFH), Toll-like receptor pathways, the innate-immunity, cytokine production, apoptosis and neural cell decline; and (iv) as a potential biomarker for viral infection, TSE and AD and other neurological diseases in both animals and humans. In this report, we review the recent data supporting the idea that miRNA-146a may represent a novel and unique sncRNA-based biomarker for inflammatory neurodegeneration in multiple species. This paper further reviews the current state of knowledge regarding the nature and mechanism of miRNA-146a in viral and prion infection of the human brain and CNS with reference to AD wherever possible.


Sibling advocates of people with intellectual disabilities.
The aim of this study was to examine the experience of the first generation of sibling advocates in Hong Kong. A qualitative approach was adopted and six sibling advocates of people with intellectual disabilities from one non-government organization were interviewed. Data were analyzed using a constant comparative method and content analysis. Findings revealed that the six participants were reactive in the process of taking up the caregiver responsibility and they performed three functions: to advocate for more service provision, to improve service quality, and to facilitate communication between individual service units and family members of people with intellectual disabilities. All of the participants expressed that they needed support from service providers when they tried to function as the sibling advocates. Strategies to promote the involvement of siblings of people with intellectual disabilities as advocates are discussed and it is expected that more siblings of people with intellectual disabilities will be supported to have a higher level of involvement in advocacy.


Three- and 4-Level Lumbar Arthrodesis Using Adjunctive Pulsed Electromagnetic Field Stimulation: A Multicenter Retrospective Evaluation of Fusion Rates and a Review of the Literature.
The incidence of 3- and 4-level lumbar arthrodesis is rising due to an aging population, and fusion rates affect clinical success in this population. Pulsed electromagnetic field (PEMF) stimulation is used as an adjunct to increase fusion rates following multilevel arthrodesis. The purpose of the study was to evaluate the fusion rates for subjects who underwent 3- and 4-level lumbar interbody arthrodesis following PEMF treatment. In this retrospective, multicenter study, patient charts that listed 3- or 4-level lumbar arthrodesis with adjunctive use of a PEMF device were evaluated. Inclusion criteria included patients who were diagnosed with lumbar degenerative disease, spinal stenosis, and/or spondylolisthesis (grade 1 or 2). A radiographic evaluation of fusion status was performed at 12 months by the treating physicians. Fusion rates were stratified by graft material, surgical interbody approach, and certain clinical risk factors for pseudoarthrosis. A total of 55 patients were identified who had a 12-month follow-up. The radiographic fusion rate was 92.7% (51 patients) at 12 months. There were no significant differences in fusion rates for patients treated with allograft or autograft, for patients with different interbody approaches, or for those with or without certain clinical risk factors. With modern fusion techniques and PEMF, the overall fusion rate was high following 3- and 4-level lumbar arthrodesis. 4. PEMF may be a useful adjunct for treatment of patients with surgical risk factors, such as multilevel arthrodesis, and clinical risk factors.


Clinical and functional characteristics of young adults living in single room occupancy housing: preliminary findings from a 10-year longitudinal study.
Young adults living in single room occupancy (SRO) hotels, a form of low-income housing, are known to have complex health and substance problems compared to their peers in the general population. The objective of this study is to comprehensively describe the mental, physical, and social health profile of young adults living in SROs. This study reports baseline data from young adults aged 18-29 years, as part of a prospective cohort study of adults living in SROs in Vancouver, British Columbia, Canada. Baseline and follow-up data were collected from 101 young adults (median follow-up period 1.9 years [IQR 1.0-3.1]). The comprehensive assessment included laboratory tests, neuroimaging, and clinician- and patient-reported measures of mental, physical, and social health and functioning. Three youth died during the preliminary follow-up period, translating into a higher than average mortality rate (18.6, 95% CI 6.0, 57.2) compared to age- and sex-matched Canadians. High prevalence of interactions with the health, social, and justice systems was reported. Participants were living with median two co-occurring illnesses, including mental, neurological, and infectious diseases. Greater number of multimorbid illnesses was associated with poorer real-world functioning (ρ = - 0.373, p < 0.001). All participants reported lifetime alcohol and cannabis use, with pervasive use of stimulants and opioids. This study reports high mortality rates, multimorbid illnesses, poor functioning, poverty, and ongoing unmet mental health needs among young adults living in SROs. Frequent interactions with the health, social, and justice systems suggest important points of intervention to improve health and functional trajectories of this vulnerable population.


Neutrophil elastase augments acute edematous injury in isolated rat lungs perfused with neutrophil cytoplasts.
To assess the contribution of neutrophil elastase to neutrophil-mediated acute edematous lung injury, isolated rat lungs were perfused with human neutrophil cytoplasts that produce O2 metabolites normally but contain little of the neutrophil elastase usually found in neutrophils. We found that addition of neutrophil cytoplasts and phorbol myristate acetate (PMA) caused less edematous injury in isolated lungs than addition of neutrophils and PMA. However, addition of neutrophil elastase along with neutrophil cytoplasts and PMA increased the amounts of lung injury found in lungs perfused with neutrophil cytoplasts and PMA to levels that equaled the amount of lung injury found after addition of normal neutrophils and PMA. By comparison, addition of purified neutrophil elastase, PMA alone, or human neutrophils alone did not cause lung injury. The results indicate that neutrophil elastase is a necessary component for the maximal development of acute edematous injury in isolated lungs perfused with neutrophils and PMA.


Phosphorus-containing metabolites in anthracycline-resistant murine leukemia P388 cells.
The method of 31P nuclear magnetic resonance was used to study in vivo the level of phosphorus-containing metabolites in P388 leukemia cells sensitive or resistant to rubomycin (daunomycin) and its nitroxyl analog-emoxyl. It was shown that decreased content of phosphomonoesters (PME) is characteristic of the resistant strains in comparison with the parent cells. Rubomycin and emoxyl were established not to affect practically the pool of phosphorus-containing metabolites in the cells of the resistant strains, but caused considerable increase of PME level in the cells of the parent strain.


The 'good mother'--a comparative study of Swedish, Italian and American maternal behavior and goals.
This paper is based on a comparative, psychologically informed ethnographic study of maternal goals and infant care during the first year of life for 20 mothers and infants in each of three Western settings: Stockholm, Sweden, outside Rome, Italy, and suburban Boston, in the United States. Two research questions were posed to consider cultural ideas and ideals about mothering; How was the 'good mother' defined? How did sample women themselves, mother? Research hypotheses were that definitions of a good mother would be culture-specific with minimal within-culture variance. Furthermore, the frequency of maternal behaviors would also exhibit culture specific patterns. Research methods included event based behavioral observations of infant-caregiver interactions in the home, daily routine questionnaires, maternal attitude interviews, and ethnographic observations of community and family life. Research hypothesis were confirmed. Results revealed culture-specific variation in conceptions of the 'good mother'. Cultural differences were reflected in the short- and long-term goals which the sample women described for their children. Patterns of infant care, in turn, were consistent with the cultural values expressed, as well as the cultural norms of social interaction.


Leveraging transformers-based language models in proteome bioinformatics.
In recent years, the rapid growth of biological data has increased interest in using bioinformatics to analyze and interpret this data. Proteomics, which studies the structure, function, and interactions of proteins, is a crucial area of bioinformatics. Using natural language processing (NLP) techniques in proteomics is an emerging field that combines machine learning and text mining to analyze biological data. Recently, transformer-based NLP models have gained significant attention for their ability to process variable-length input sequences in parallel, using self-attention mechanisms to capture long-range dependencies. In this review paper, we discuss the recent advancements in transformer-based NLP models in proteome bioinformatics and examine their advantages, limitations, and potential applications to improve the accuracy and efficiency of various tasks. Additionally, we highlight the challenges and future directions of using these models in proteome bioinformatics research. Overall, this review provides valuable insights into the potential of transformer-based NLP models to revolutionize proteome bioinformatics.


An Update on Temporomandibular Disorders (TMDs) and Headache.
To provide an overview and highlight recent updates in temporomandibular disorders (TMDs) and their comorbidity with headache disorders regarding pathophysiology and management. In the last decade, there have been great advancements in the understanding of TMDs and their relationship with neurovascular pains such as headaches. Understanding of TMDs is necessary for the context of its comorbidity with primary headache disorders. The literature regarding management of these comorbidities is scarce but points to combination therapy including pharmacological and non-pharmacological approaches to optimize management. The use of CGRP receptor-targeted monoclonal antibodies or CGRP receptor antagonists should be explored for the management of chronic TMDs. It could also be used as a novel monotherapy or in combination with non-pharmacological approaches for TMDs' comorbidity with headache, particularly migraine. Research is needed to support evidence-based management protocols. A team involving neurology (headache medicine) and dentistry (orofacial pain) is critical for optimal management.


Effect of feeding and sludge age on acclimated bacterial community and fate of slowly biodegradable substrate.
The study investigated the effect of feeding regime and sludge age on starch utilization. For this purpose, parallel sequencing batch reactors were operated with pulse and continuous feeding of soluble starch at sludge ages of 8 and 2 days. Pulse feeding induced almost complete conversion of starch to glycogen, while storage was lowered and accompanied with direct growth under continuous feeding, regardless of sludge age. Low sludge age did not alter simultaneous storage and utilization for direct growth but it slightly favoured direct utilization due to faster growing biomass. Experimental results suggested adsorption of starch onto biomass as a preliminary removal mechanism prior to hydrolysis at sludge age of 8 days. Adsorption was not noticeable as substrate removal, glycogen generation and dissolved oxygen decrease were synchronous at sludge age of 2 days. Bacterial community always included fractions storing glycogen although sludge age only affected the relative magnitude of filamentous growth.


Pesticide use negatively affects bumble bees across European landscapes.
Sustainable agriculture requires balancing crop yields with the effects of pesticides on non-target organisms, such as bees and other crop pollinators. Field studies demonstrated that agricultural use of neonicotinoid insecticides can negatively affect wild bee species1,2, leading to restrictions on these compounds3. However, besides neonicotinoids, field-based evidence of the effects of landscape pesticide exposure on wild bees is lacking. Bees encounter many pesticides in agricultural landscapes4-9 and the effects of this landscape exposure on colony growth and development of any bee species remains unknown. Here we show that the many pesticides found in bumble bee-collected pollen are associated with reduced colony performance during crop bloom, especially in simplified landscapes with intensive agricultural practices. Our results from 316 Bombus terrestris colonies at 106 agricultural sites across eight European countries confirm that the regulatory system fails to sufficiently prevent pesticide-related impacts on non-target organisms, even for a eusocial pollinator species in which colony size may buffer against such impacts10,11. These findings support the need for postapproval monitoring of both pesticide exposure and effects to confirm that the regulatory process is sufficiently protective in limiting the collateral environmental damage of agricultural pesticide use.


VGLUT3 does not synergize GABA/glycine release during functional refinement of an inhibitory auditory circuit.
The vesicular glutamate transporter 3 (VGLUT3) is expressed at several locations not normally associated with glutamate release. Although the function of this protein has been generally elusive, when expressed in non-glutamatergic synaptic terminals, VGLUT3 can not only allow glutamate co-transmission but also synergize the action of non-glutamate vesicular transporters. Interestingly, in the immature glycinergic projection between the medial nucleus of the trapezoid body (MNTB) and the lateral superior olive (LSO) of auditory brainstem, the transient early expression of VGLUT3 is required for normal developmental refinement. It has however been unknown whether the primary function of VGLUT3 in development of these inhibitory synapses is to enable glutamate release or to promote loading of inhibitory neurotransmitter through vesicular synergy. Using tissue from young mice in which Vglut3 had been genetically deleted, we evaluated inhibitory neurotransmission in the MNTB-LSO pathway. Our results show, in contrast to what has been seen at adult synapses, that VGLUT3 expression has little or no effect on vesicular synergy at the immature glycinergic synapse of brainstem. This finding supports the model that the primary function of increased VGLUT3 expression in the immature auditory brainstem is to enable glutamate release in a developing inhibitory circuit.


Seroprevalence of HBV and HCV in blood donors: A study from regional blood transfusion services of Nepal.
Hepatitis B and hepatitis C are significant health problems that might involve the late sequel of liver cirrhosis and hepatocellular carcinoma. A high prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) in blood donors poses an increased risk of window period transmission through blood transfusion. The present study aimed to know the seroprevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) among blood donors in regional blood transfusion services of Nepal. This was a retrospective study conducted among blood donors in Banke (5,211), Morang (5,351), and Kaski (5,995) blood transfusion services. Serum samples were tested for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies using rapid enzyme immunoassays. The donors information was collected via the donor record register through their respective blood transfusion services. The software "Winpepi ver 3.8" was used for statistical analysis. The seroprevalence rate of HBV was highest in the Banke (1.2%) followed by Biratnagar (0.87%) and Kaski (0.35%) (P < 0.0001). The seroprevalence of HCV was highest in the Morang (0.26%) followed by Kaski (0.16%) and Banke (0.11%) (P > 0.05). The seroprevalence of HBV was significantly higher than HCV in all three blood transfusion services. The burden of HBV as well as HCV seems to be higher in male donors (P > 0.05). The study revealed that the seroprevalence of HBV was alarmingly higher in two of the three blood transfusion services. Implementation of community-based preventive measures and improved strategies for safe blood supply might prove useful to decrease the seroprevalence.


Estimation of penetrance from twin data.
A simple method for estimating the gene frequency p and the penetrance value K from data on polymorphic monogenic characteristics on monozygotic twin pairs is presented. In spite of the method here presented having limited value because the results it yields cannot be evaluated on their own, the estimates of p and K it provides can be indirectly tested by comparing them to the ones obtained in familial aggregates through classical segregation analysis or by using the latter to calculate the expected proportions of dominant-dominant, dominant-recessive and recessive-recessive monozygotic twin pairs. When the method is applied to data on tongue-rolling ability published in the literature, a good agreement is observed between twin and familial estimates, thus indicating that the method is reliable and that it can be used as an ancillary way of corroborating or otherwise evidence of monogenic autosomal dominant mechanism inferred from the analysis of familial data.


Usefulness of the DL in ME with NBI for determining the expanded area of early-stage differentiated gastric carcinoma.
To investigate whether magnifying endoscopy with narrow band imaging (ME-NBI) is useful for evaluating the area of superficial, depressed- or flat-type differentiated adenocarcinoma of the stomach. This procedure was performed in Saitama Medical University International Medical Center, Japanese Red Cross Kumamoto Hospital and Kitakyushu Municipal Medical Center. The subjects were 31 patients in whom biopsy findings, from superficial, depressed- or flat-type gastric lesion, suggested differentiated adenocarcinoma in the above 3 hospitals between January and December 2009. Biopsy was performed on the lesion and non-lesion sides of a boundary (imaginary boundary) visualized on ME-NBI. The results were pathologically investigated. We evaluated the accuracy of estimating a demarcation line (DL) on ME-NBI in comparison with biopsy findings as a gold standard. The DL that could be recognized at 2 points on the orifice and anal sides of each lesion during ME-NBI was consistent with the pathological findings in 22 patients with 0-IIc lesions, 7 with 0-IIb lesions, and 2 with 0-IIb + IIc lesions, showing an accuracy of 100%. The results suggest the usefulness of ME-NBI for evaluating the area of superficial, depressed- and flat-type differentiated adenocarcinoma of the stomach.


Early evaluation of myocardial injury by means of high-sensitivity methods for cardiac troponins after strenuous and prolonged exercise.
All the latest international guidelines recommend that cardiac troponin (cTn) I and T should be considered the preferred biomarkers for diagnosis of acute myocardial infarction. However, only in the last 5 years, a progressive improvement in analytical performance of immunometric assays has allowed the measurement of circulating levels of cTnI and cTnT in the large part of apparently healthy adult subjects. The routine use of these high-sensitivity methods for cardiac troponin (hs-cTn) assay has in a short time demonstrated that cardiac troponin concentrations frequently increase after strenuous prolonged exercise in healthy athletes. This acute response of hs-cTn assay following exercise was at first considered to be physiological and without long-term adverse consequences. More recent studies have suggested that exercise-induced increases in hs-cTn values may not be always a physiological response to exercise, but, conversely, it should sometimes be considered as an early cardiovascular risk marker. The aim of this review is to provide an overview of acute and chronic effects of strenuous physical exercise on hs-cTn circulating levels and also to discuss the potential pathophysiological and clinical implications of biomarker responses.