Aspirin in polycythemia vera and essential thrombocythemia: current facts and perspectives.
The role of aspirin in the antithrombotic strategy of patients with polycythemia vera (PV) and essential thrombocythemia (ET) is highly controversial. Long considered unsafe on the basis of a single clinical trial testing very high doses in PV patients, aspirin is being increasingly used at lower dosage. The rationale for the use of aspirin in patients with PV and ET is provided by the efficacy of this agent in the treatment of microcirculatory disturbances of thrombocythemic states associated with myeloproliferative disorders and by recent evidence that asymptomatic PV and ET patients have persistently increased thromboxane (TX) A2-biosynthesis. This increase, which most likely reflects enhanced platelet activation in vivo, is independent of the platelet mass and blood viscosity and largely supressed by a short term low-dose aspirin regimen (50 mg/day for 7 days). Since enhanced TXA2 biosynthesis may play a role in transducing the increased thrombotic risk associated with PV and ET, long-term low-dose aspirin administration has been proposed as a possible antithombotic strategy in these subjects. The safety of this treatment in PV patients has been recently reassessed by the Gruppo Italiano per lo Studio della Policitemia Vera (GISP) which has followed for over one year 112 patients randomized to receive 40 mg/day aspirin or placebo. In the same study, serum TXB2 measurements provided evidence that the low-dose aspirin regimen tested was fully effective in inhibiting platelet cyclooxygenase activity. On this basis, a large scale trial aimed at assessing the antithrombotic efficacy of this approach is currently being organized. In patients with ET both the minimal aspirin dose required for complete inhibition of platelet cyclooxygenase and the safety of long-term aspirin administration need to be established prior to extensive clinical evaluation of this strategy.


Comparison of reversal of rat pulmonary fibrosis of nintedanib, pirfenidone, and human umbilical mesenchymal stem cells from Wharton's jelly.
The present study compared the effects of antifibrotic medications, pirfenidone, and nintedanib, with transplantation of human umbilical mesenchymal stem cells (HUMSCs) in restoring rat pulmonary fibrosis (PF). A stable animal model was established via an intratracheal injection of 5 mg bleomycin (BLM). One single transplantation of 2.5× 107 HUMSCs or initiation of daily oral nintedanib/pirfenidone administration was performed on day 21 following BLM damage. Pulmonary function examination revealed that BLM rats exhibited a significant decrease in blood oxygen saturation and an increase in respiratory rates. While no significant improvements were found in BLM rats receiving nintedanib or pirfenidone, those who transplanted with HUMSCs showed a statistical amelioration in blood oxygen saturation and significant alleviation in respiratory rates. Quantification results revealed that a significant reduction in alveolar space and marked increases in substantial cell infiltration and collagen deposition in the left lungs of BLM rats. No significant alteration was observed in BLM rats administered nintedanib or pirfenidone. However, BLM rats transplanted with HUMSCs had a significant recovery in alveolar space and noticeable decreases in cell infiltration and collagen deposition. The inflammatory cell numbers in the bronchoalveolar lavage was increased in the BLM group. While the rats treated with nintedanib or pirfenidone had a lower cell number than the BLM group, a higher cell number was found as compared with the Normal group. In rats transplanted with HUMSCs, the cell number did not differ from the Normal group. Transplantation of HUMSCs could effectively treat PF as opposed to the administration of anti-fibrotic drugs with nintedanib or pirfenidone with a significant better result in lung volume, pathological changes, lung function, and blood oxygen saturation.


Technetium-99m-MIBI scintimammography by planar and SPECT imaging in the diagnosis of breast carcinoma and axillary lymph node involvement.
We compared SPECT and planar (99m)Tc-MIBI scintimammography (SMM) in the detection of primary breast cancer and metastatic axillary lymph node involvement, and the scintigraphic results with the histopathological/cytological findings. 303 consecutive patients with 308 suspicious or indeterminate lesions observed in mammographies were entered in this study. After an intravenous injection of 740 MBq of (99m)Tc-MIBI, anterior supine, right and left lateral planar images in a prone position and a SPECT study were acquired. 85 malignant and 223 benign breast lesions were confirmed by histopathology/cytology. The overall sensitivity in the detection of breast cancer was 92% (78/85) for SPECT and 82% (70/85) for planar imaging (p = NS), respectively; overall specificity was 91% (204/223) for SPECT and 91% (202/223) for planar scans (p = NS), respectively. Metastatic axillary lymph node involvement was seen in 35 patients; per-axilla overall sensitivity was 66% (23/35) for SPECT and 54% (19/35) for planar images (NS), respectively; overall specificity was 76% (38/50) and 86% (43/50), respectively (NS). Our results confirm the high diagnostic accuracy of (99m)Tc-MIBI scintimammography in the diagnosis of breast cancer, and show SPECT to be slightly more sensitive than planar imaging, especially in detecting malignant breast lesions. We found the sensitivity of both imaging modalities to be quite low in the detection of metastatic axillary lymph node involvement. SPECT provides additional information to planar SMM with respect to the localization of (99m)Tc-MIBI uptake and tumour extent and improves diagnostic certainty. Our experience suggests that SPECT combined with planar SMM should be used more widely.


Nationwide survey of subjectively reported adverse drug reactions in Sweden.
Adverse drug reactions (ADRs) and the safety of drugs continue to be widely discussed. However, information on the prevalence of subjectively experienced ADRs (SADRs) and their subsequent burden in the general population is largely lacking. To analyze, from an epidemiologic perspective, SADRs with respect to occurrence and health status. A cross-sectional mail survey to a random national sample in Sweden of inhabitants aged 18-84 years was conducted; 61% (N = 4875) of the sample answered the questionnaire. Self-reported SADRs occurring during a 2-week period of using prescription, over-the-counter (OTC), or herbal drugs were classified according to Meyler's classification of ADRs. Self-perceived health status was assessed with a visual analog scale graded from 0 (worst possible health/death) to 1 (perfect health). SADRs were reported by 6.4% of the total study sample, 10.2% of the 2851 users of prescription drugs, 1.0% of the 2862 users of OTC drugs, and 0.1% of the 1352 users of herbal drugs. Of the total sample, 3.3% reported SADRs of the nervous system, 2.6% of the gastrointestinal system, and 0.6% of the cardiovascular system. Users of prescription drugs with SADRs reported a mean health status score of 0.655, while those who did not report SADRs scored 0.744. Among users of OTC and herbal drugs, the corresponding scores were 0.720 and 0.818, respectively. Those in the population who did not use any drugs rated their health status as 0.846. Both the prevalence of SADRs and the magnitude of the decrease in subjective health status in respondents experiencing them reflect the importance of individual subjective perceptions for public health. However, in a cross-sectional study like this, causal relationships cannot be firmly established. Further, other factors, such as comorbidity or disappointment with treatment outcomes, could be associated with the decrease in health status.


[Is microalbuminuria, an early marker of clinical nephropathy, also a cardiovascular risk factor?].
Microalbuminuria is not only a predictor of diabetic nephropathy in type 1 diabetes, but also a potent marker of cardiovascular risk, especially in type 2 diabetes. Microalbuminuria also predicts cardiovascular morbidity in the general population. We describe semi-quantitative and quantitative methods for determination of low urinary excretion of albumin. Pathogenetic hypotheses common to both renal and endothelial dysfunction are discussed, suggesting that microalbuminuria may be a link between micro- and macroangiopathy. Improved glycemic control and antihypertensive treatment postpone and potentially prevent development of nephropathy in diabetic patients with microalbuminuria. These interventions must be instituted early in the development of diabetic nephropathy. In type 2 diabetes, prospective studies are needed to evaluate the precise impact of such a therapy on the cardiovascular risk.


Electrochemical Injection Oxygen Vacancies in Layered Ca2Mn3O8 for Boosting Zinc-Ion Storage.
Manganese-based compounds have emerged as attractive cathode materials for zinc-ion batteries owing to their high operating voltage, large specific capacity, and no pollution. However, the structural collapse and sluggish kinetics of manganese-based compounds are major obstacles that hinder their practical applications. Here, a kind of novel layered Ca2Mn3O8 with a low ion diffusion barrier and high structural stability has been achieved through an electrochemical charging process with in situ injecting oxygen vacancies. This greatly increases the electrochemical active area and improves the Zn ions diffusion coefficient by 2 orders of magnitude, which significantly enhances the reaction kinetics, pseudocapacitance properties, and capacity. As a result, the cathode containing oxygen vacancies present an impressive reversible capacity of 368 mAh g-1, an unprecedented energy density of 512 Wh kg-1, and superior capacity retention of 92.3% at a high current density of 5 A g-1 after 3000 cycles. This work unveils an effective method for vacancy regulation of electrode materials, paving a new way to improve the electrochemical performance of zinc-ion batteries.


New perspectives in the management of osteoarthritis. structure modification: facts or fantasy?
Several entities have been carefully investigated for the symptomatic and structural management of osteoarthritis (OA). The most compelling evidence of a potential for inhibiting the structural progression of OA has been obtained with glucosamine sulfate, while some preliminary results also suggest that other compounds could be used in the same indication. At any rate, several medications have clearly demonstrated a symptomatic action, mainly in OA of the lower limbs, including pain relief and improvement of functional disability. An important issue is that all conclusive studies with such chemical entities resulted from the use of prescription medicines and not over-the-counter or nutriceutical supplements.


Application of functional principal component analysis in race walking: an emerging methodology.
This study considered the problem of identifying and evaluating the factors of individual performance during race walking. In particular, the study explored the use of functional principal component analysis (f-PCA), a multivariate data analysis, for assessing and classifying the kinematics and kinetics of the knee joint in competitive race walkers. Seven race walkers of international and national level participated to the study. An optoelectronic system and a force platform were used to capture three-dimensional kinematics and kinetics of lower limbs during the race walking cycle. Functional principal component analysis was applied bilaterally to the sagittal knee angle and net moment data, because knee joint motion is fundamental to race walking technique. Scatterplots of principal component scores provided evidence of athletes' technical differences and asymmetries even when traditional analysis (mean +/- s curves) was not effective. Principal components provided indications for race walkers' classification and identified potentially important technical differences between higher and lower skilled athletes. Therefore, f-PCA might represent a future aid for the fine analysis of sports movements, if consistently applied to performance monitoring.


[Interphase analysis of X-aneuploidy using fluorescent in situ hybridization in various tissues of healthy individuals].
The frequency of spontaneous X-chromosome hypo- and hyperploidy was studied in interphase nuclei of cultured and uncultured blood lymphocytes and oral epithelium of 21 healthy individuals by means of fluorescence in situ hybridization of the centromere-specific DNA probe. In women, the frequencies of haploid epithelial cells and cultured and uncultured lymphocytes were 0.84%, 1.59%, and 0.73%, respectively, while the frequency of hyperploid cells was 0.29%, 0.28%, and 0.12% respectively. In men, the X-chromosome spontaneous hyperploidy of epithelial cells, cultured and uncultured lymphocytes was 0.14%, 0.57%, and 0.11% respectively. The upper frequency limit of the spontaneous aneuploidy of various cell types was determined for the purpose of being used for the diagnosis of X-mono- and trisomy mosaicism in women and the disomy in men. In the latter, the frequency of hypoploidy in the cultured lymphocytes was significantly higher than in uncultured lymphocytes. Under conditions of intense cell proliferation in FHA-stimulated cultures, more severe disturbances in chromosome segregation are proposed to occur than in resting cells.


The efficacy of bromides, stiripentol and levetiracetam in two patients with malignant migrating partial seizures in infancy.
The syndrome of malignant migrating partial seizures in infancy is a devastating, age-specific, epileptic encephalopathy, which still presents an aetiological, pathophysiological and therapeutic problem. In this study, we present two patients who were diagnosed with the disease, based on electroclinical symptoms. The patients were treated with a combination of sodium bromide, stiripentol and levetiracetam. The first patient unequivocally responded, following a course of ineffective conventional drugs, and the second, who was diagnosed and treated immediately, showed a more significant therapeutic response. Antiepileptic drugs, previously reported to be beneficial in case reports, when given concomitantly, may substantially reduce the number and severity of seizures, without influence on psychomotor development. [Published with video sequences].


An investigation into the effects of metal primer and surface topography on the tensile bond strength between cobalt chromium alloy and composite resin.
This study examined the influence of surface preparation and metal primer on the tensile bond strength between cobalt chromium alloy and composite resin. The bond strength between 168 cobalt chromium alloy dumb-bells with one of three test surfaces (beaded, machined or sandblasted) to composite resin were tested. Half of each group were treated with metal primer. The weakest bond strength was produced by the unprimed machined surface, many specimens failing before testing. The metal primer increased the bond strengths of all groups tested. The greatest bond strengths were achieved with the primed beaded and sandblasted surfaces. Within the limits of the study it has been shown that the surface preparation of the cobalt-chromium alloy did influence tensile bond strengths with composite resin and Metal Primer II increased the tensile bond strengths for all groups tested. The sandblasted surface treated with Metal Primer II is recommended for the bonding of composite resin to cobalt chromium alloy.


Caring for relatives with lung cancer in Europe: an evaluation of caregivers' experience.
Informal caregiving for cancer patients is associated with substantial costs and negative health impact. This study investigated the health, humanistic and economic consequences of caring for lung cancer patients in five European Union (EU) countries. The study included respondents to the 2010/2011 EU National Health and Wellness Survey from France, Germany, Italy, Spain and the United Kingdom who self-reported being caregivers of a relative with lung cancer (n = 107) or non-caregivers (n = 103,868). Bivariate and multivariable analyses tested the association of caregiving with stress-related comorbidities; health-related quality of life (HRQoL), using the Short Form-12; healthcare resource use; and work productivity/activity impairment, using the Work Productivity and Activity Impairment (WPAI) questionnaire. Costs were based on absenteeism and presenteeism rates. Caregivers versus non-caregivers had significantly higher odds of depression, insomnia, headache and gastrointestinal symptoms, and worse HRQoL. Caregivers reported significantly higher rates of presenteeism-related, overall work and activity impairment; higher odds of impairment across WPAI measures; and higher annual indirect costs with presenteeism and overall work impairment. Caregiving for lung cancer patients is associated with significant health/work impairments and costs, highlighting a need for increased, personalized caregiver support.


Metal induction of a Paxillus involutus metallothionein and its heterologous expression in Hebeloma cylindrosporum.
* Metallothioneins are small polypeptides involved in metal tolerance of many eukaryotes. Here we characterized the Pimt1 gene, coding for a metallothionein from the ectomycorrhizal fungus Paxillus involutus. * Expression of Pimt1 in P. involutus under metal stress conditions was measured by northern blot and RT-PCR analyses. The full-length cDNA was used to perform functional complementation in yeast mutant strains and agrotransformation of Hebeloma cylindrosporum. * Heterologous expression in yeast showed that PiMT1 was able to complement the hypersensitivity of mutant strains to cadmium (Cd) and copper (Cu), but not to zinc (Zn). Transcripts were almost undetectable under control conditions, whereas Cu and Cd, but not Zn, strongly induced Pimt1 expression in P. involutus. Constitutive overexpression of Pimt1 in H. cylindrosporum conferred a higher copper tolerance. * The present study identified PiMT1 as a potential determinant in the response of mycorrhizal fungi to Cu and Cd stress. Additionally, we demonstrated the usefulness of mycorrhizal fungi transformation using Agrobacterium technology to approach gene function.


Inequality in uptake of bowel cancer screening by deprivation, ethnicity and smoking status: cross-sectional study in 86 850 citizens.
Survival from colorectal cancer depends on stage at detection. In England, bowel cancer mortality has historically been highest in deprived areas. During the initial stages of the COVID-19 pandemic, it was necessary to temporarily halt many screening programmes, which may have led to inequalities in uptake since screening restarted. Cross-sectional data from the Bristol, North Somerset and South Gloucestershire Systemwide Dataset were analyzed. Associations of baseline characteristics with uptake of bowel screening were examined using logistic regression. Amongst 86 850 eligible adults aged 60-74 years, 5261 had no screening record. There was little evidence of association between no screening and sex (adjusted odds ratio 0.95 (95% confidence interval 0.90, 1.02)). Absence of screening record was associated with deprivation (1.26 (1.14, 1.40) for the most compared with the least deprived groups), smoking (1.11 (1.04, 1.18)) compared with no smoking record and black (1.36 (1.09, 1.70)) and mixed (1.08 (1.01, 1.15)) ethnicity compared with white ethnicity. In a data set covering a whole NHS Integrated Care Board, there was evidence of lower uptake of bowel cancer screening in adults living in more deprived areas, of minority ethnic groups and who smoked. These findings may help focus community engagement work and inform research aimed at reducing inequalities.


Anthocyanins increase low-density lipoprotein and plasma cholesterol and do not reduce atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits.
Anthocyanin-rich beverages have shown beneficial effects on coronary heart disease in epidemiological and intervention studies. In the present study, we investigated the effect of black currant anthocyanins on atherosclerosis. Watanabe Heritable Hyperlipidemic rabbits (n = 61) were fed either a purified anthocyanin fraction from black currants, a black currant juice, probucol or control diet for 16 weeks. Purified anthocyanins significantly increased plasma cholesterol and low-density lipoprotein (LDL) cholesterol. Intake of black currant juice had no effect on total plasma cholesterol, but lowered very-low-density lipoprotein (VLDL) cholesterol significantly. There were no significant effects of either purified anthocyanins or black currant juice on aortic cholesterol or development of atherosclerosis after 16 weeks. Probucol had no effect on plasma cholesterol but significantly lowered VLDL-cholesterol and decreased aortic cholesterol accumulation. The erythrocyte antioxidant enzyme glutathione peroxidase was significantly increased by purified anthocyanins and superoxide dismutase was increased by both anthocyanin-containing treatments. Other markers of plasma antioxidant capacity, antioxidant enzymes, protein and lipid oxidation were not affected by any of the anthocyanin treatments. Adverse effects of purified anthocyanins were observed on plasma- and LDL-cholesterol. These effects were not observed with black currant juice, suggesting that black currants may contain components reducing the adverse effects of anthocyanins.


Enterobacter asburiae sp. nov., a new species found in clinical specimens, and reassignment of Erwinia dissolvens and Erwinia nimipressuralis to the genus Enterobacter as Enterobacter dissolvens comb. nov. and Enterobacter nimipressuralis comb. nov.
Enterobacter asburiae sp. nov. is a new species that was formerly referred to as Enteric Group 17 and that consists of 71 strains, 70 of which were isolated from humans. Enterobacter asburiae sp. nov. strains gave positive reactions in tests for methyl red, citrate utilization (Simmons and Christensen's), urea hydrolysis, L-ornithine decarboxylase, growth in KCN, acid and gas production from D-glucose, and acid production from L-arabinose, cellobiose, glycerol (negative in 1 to 2 days, positive in 3 to 7 days), lactose, D-mannitol, alpha-methyl-D-glucoside, salicin, D-sorbitol, sucrose, trehalose, and D-xylose. They gave negative reactions in the Voges-Proskauer test and in tests for indole, H2S production, phenylalanine, L-lysine decarboxylase, motility, gelatin, utilization of malonate, lipase, DNase, tyrosine clearing, acid production from adonitol, D-arabitol, dulcitol, erythritol, i(myo)-inositol, melibiose, and L-rhamnose. They gave variable reactions in tests for L-arginine dihydrolase (25% positive after 2 days) and acid production from raffinose (69% positive after 2 days). Thirty-four Enterobacter asburiae sp. nov. strains were tested for DNA relatedness by the hydroxyapatite method with 32PO4-labeled DNA from the designated type strain (1497-78, ATCC 35953). The strains were 69 to 100% related in 60 degrees C reactions and 63 to 100% related in 75 degrees C reactions. Divergence within related sequences was 0 to 2.5%. Relatedness of Enterobacter asburiae sp. nov. to 84 strains of members of the Enterobacteriaceae was 5 to 63%, with closest relatedness to strains of Enterobacter cloacae, Erwinia dissolvens, Enterobacter taylorae, Enterobacter agglomerans, Erwinia nimipressuralis, and Enterobacter gergoviae. All strains tested were susceptible to gentamicin and sulfdiazine, and most were susceptible to chloramphenicol, colistin, kanamycin, nalidixic acid, carbenicillin and streptomycin. All strains were resistant to ampicillan, cephalothin, and penicillin, and most were resistant or moderately resistant to tetracycline. Enterobacter asburiae sp. nov strains were isolated from a variety of human sources, most prevalent of which were urine (16 strains), respiratory sources (15 strains), stools (12 strains), wounds (11 strains), and blood (7 strains). The clinical significance of Enterobacter aburiae is not known. As a result of this and previous studies, proposals are made to transfer Erwinia dissolvens and Erwinia nimipressuralis to the genus Enterobacter as Enterobacter dissolvens comb. nov. and Enterobacter nimipressuralis comb. nov., respectively.


Interventions to help external cephalic version for breech presentation at term.
Breech presentation places a fetus at increased risk. The outcome for the baby is improved by planned caesarean section compared with planned vaginal delivery. External cephalic version attempt reduces the chance of breech presentation at birth, but is not always successful. Tocolytic drugs to relax the uterus as well as other methods have been also used in an attempt to facilitate external cephalic version at term. The objective of this review is to assess the effects of routine tocolysis, fetal acoustic stimulation, epidural or spinal analgesia and transabdominal amnioinfusion for external cephalic version at term on successful version and measures of pregnancy outcome. The Cochrane Pregnancy and Childbirth Group Trials Register (searched December 2001) and the Cochrane Controlled Trials Register (The Cochrane Library, Issue 4, 2001) were searched. Randomised and quasi-randomised trials comparing routine versus selective or no tocolysis; fetal acoustic stimulation in midline fetal spine positions versus dummy or no stimulation; epidural or spinal analgesia versus no regional analgesia; or transabdominal amnioinfusion versus no amnioinfusion for external cephalic version at term. Eligibility and trial quality were assessed by the reviewer. In six trials, routine tocolysis was associated with fewer failures of external cephalic version (relative risk 0.74, 95% confidence interval 0.64 to 0.87). The reduction in non-cephalic presentations at birth was not statistically significant. Caesarean sections were reduced (relative risk 0.85, 95% confidence interval 0.72 to 0.99). Fetal acoustic stimulation in midline fetal spine positions was associated with fewer failures of external cephalic version at term (relative risk 0.17, 95% confidence interval 0.05 to 0.60). With epidural or spinal analgesia, external cephalic version failure, non-cephalic births and caesarean sections were reduced in two trials but not the other. The overall differences were not statistically significant. No randomised trials of transabdominal amnioinfusion for external cephalic version at term were located. Routine tocolysis appears to reduce the failure rate of external cephalic version at term. Although promising, there is not enough evidence to evaluate the use of fetal acoustic stimulation in midline fetal spine positions, nor of epidural or spinal analgesia. Large volume intravenous preloading may have contributed to the effectiveness demonstrated in two of the latter trials. No randomised trials of transabdominal amnioinfusion for external cephalic version at term were found.


Limited value of the urinary phenytoin metabolic ratio for the assessment of cytochrome P4502C9 activity in vivo.
Relationships between the ratio of p-hydroxyphenytoin (p-HPPH), the major metabolite of phenytoin, to unchanged phenytoin excreted in urine (the urinary metabolic ratio or MR) were compared with a number of indices of the metabolic clearances of phenytoin and tolbutamide published previously for seventeen subjects separately administered these known cytochrome P4502C9 (CYP2C9) substrates. Significant correlations (rs = 0.50-0.60, P < 0.05) were observed between the phenytoin MR, derived from either 0-24 or 24-48 h urine collections, and inverse areas under the plasma unbound concentration-time curves (measured over various time intervals) of phenytoin and with plasma unbound tolbutamide clearance. Significant correlations (rs = 0.59-0.74) were also observed between the phenytoin MRs and metabolic unbound clearances for p-hydroxyphenytoin formation. Despite the significant correlations, variability in tolbutamide and phenytoin metabolic clearance parameters tended to account for < 50% of the variability in phenytoin MR. Correlations between the renal clearance of phenytoin and the phenytoin MRs suggest that variability in the renal clearance of unchanged drug limits the usefulness of the phenytoin MR for the investigation of factors influencing CYP2C9 activity in vivo.


Neonatal syncytial giant cell hepatitis with paramyxoviral-like inclusions.
Syncytial giant cell hepatitis in the neonatal period has been associated with many different etiologic agents and may present initially as cholestasis. Infectious causes are most common and include: (1 ) generalized bacterial sepsis, (2) viral agents, (3) toxoplasmosis, (4) syphilis, (5) listeriosis, and (6) tuberculosis. Viral hepatitis may be due to cytomegalovirus, rubella virus, herpes simplex, HHV-6, varicella, coxsackievirus, echovirus, reovirus 3, parvovirus B19, HIV, enteroviruses, paramyxovirus, and hepatitis A, B, or C (rare). Giant cell hepatitis may result in fulminant liver failure with massive hepatocyte necrosis and severe liver dysfunction leading to death, resolution with severely compromised liver function, or liver transplantation. The authors report a 6-week-old male who had an unremarkable perinatal period, became jaundiced after developing diarrhea, and subsequently developed liver dysfunction with massively increased liver enzymes and a coagulopathy. Open wedge and core liver biopsies were performed to determine if the patient should be listed for liver transplantation. Giant cell hepatitis with a significant mixed lymphocytic and neutrophilic infiltrate was present on both the wedge and core biopsies. The residual 60% of hepatocytes had ballooning degeneration and many possessed pyknotic nuclei. The hepatocytes were arranged in a pseudoacinar pattern. Electron microscopy showed paramyxoviral-like inclusions in the giant cells, characterized as large inclusions with fine filamentous, beaded substructures (18-20 nm). Paramyxoviridae are nonsegmented, negative-sense, single-stranded RNA viruses. This family is divided into the Paramyxovirinae subfamily containing respirovirus (Sendai virus, parainfluenza virus type 3), rubulavirus (mumps, parainfluenza virus type 2), and morbillivirus genera (measles); and Pneumovirinae subfamily (pneumovirus genus [respiratory syncytial virus]). Supportive care to determine if hepatic function resolves following the viral episode, liver transplantation with fulminant liver failure, and ongoing evaluation in those who recover to assess chronic liver disease are necessary. Ultrastructural evaluation may unmask the etiologic agent for hepatitis and direct therapy.


A major T-cell-inducing cytosolic 23 kDa protein antigen of the vaccine candidate Mycobacterium habana is superoxide dismutase.
This study describes the purification and immunochemical characterization of a major 23 kDa cytosolic protein antigen of the vaccine candidate Mycobacterium habana (TMC 5135). The 23 kDa protein alone was salted out from the cytosol at an ammonium sulfate saturation of 80-95%. It represented about 1.5% of the total cytosolic protein, appeared glycosylated by staining with periodic acid/Schiff's reagent, and showed a pl of approximately 5.3. Its native molecular mass was determined as approximately 48 kDa, suggesting a homodimeric configuration. Immunoblotting with the WHO-IMMLEP/IMMTUB mAbs mc5041 and IT61 and activity staining after native PAGE established its identity as a mycobacterial superoxide dismutase (SOD) of the Fe/Mn type. The sequence of the 18 N-terminal amino acids, which also contained the binding site for mc5041, showed a close resemblance, not only with the reported deduced sequences of Mycobacterium leprae and Mycobacterium tuberculosis Fe/MnSODs, but also with human MnSOD. In order to study its immunopathological relevance, the protein was subjected to in vivo and in vitro assays for T cell activation. It induced, in a dose-related manner, skin delayed hypersensitivity in guinea-pigs and lymphocyte proliferation in BALB/c mice primed with M. habana. Most significantly, it also induced lymphocyte proliferative responses, in a manner analogous to M. Ieprae, in human subjects comprising tuberculoid leprosy patients and healthy contacts.


Modification and Initial Psychometric Evaluation of the Physical Health Attitude Scale for Use in the Canadian Mental Health and Addictions Context.
The Physical Health Attitude Scale (PHASe) tool was developed to better understand mental health nurses' attitudes towards their involvement and confidence in physical health care. This tool has been used in the United Kingdom and Australia; however, it has not been used in Canada. This study aims to modify and provide an initial psychometric evaluation of the PHASe tool for use in a Canadian mental health and addictions context. In Phase 1, clinical experts (n = 8) were consulted to provide feedback on the content and face validity of the PHASe tool. In Phase 2, the PHASe tool was piloted with nurses at a large urban mental health and addiction organization in Ontario, Canada (n = 77). In Phase 1, 4 items were added and 5 items were removed from the tool based on feedback provided by experts. In Phase 2, 12 poorly correlated items were removed. A two-factor solution was identified, with subscales "confidence" and "barriers and attitudes". Initial psychometric evaluation suggests that a revised 15-item version of the PHASe tool is valid and reliable in a Canadian mental health and addictions context; however, more testing is recommended in larger, more diverse samples.


Predictors of diabetes relapse after metabolic surgery in Asia.
Limited studies have focused on diabetes relapse after metabolic surgery, especially among Asians. To identify the predictors of diabetes relapse following initial postoperative remission in Asia. Four tertiary hospitals METHODS: We assessed 342 patients (age, 41.0 ± 10.8 yr; body mass index [BMI], 39.6 ± 7.3 kg/m2) with complete diabetes data before and 1 and 3 years after metabolic surgery. A total of 290 (84.8%) and 277 (81.0%) patients had diabetes remission at 1 and 3 years after surgery. Logistic regressions were performed to identify the independent predictors of diabetes relapse. Two published predictive models for diabetes remission were also tested for relapse. Of the 290 patients with 1-year diabetes remission, 29 (10%) experienced a relapse at 3 years after surgery. The area under the receiver operating characteristic curve of the ABCD score in predicting 1-year remission, 3-year remission, and 3-year relapse were .814, .793, and .795, while those of the DiaRem2 score were .823, .774, and .701, respectively. The baseline age, BMI, and insulin use were independent predictors for relapse. The most powerful predictive model for relapse was composed of preoperative insulin use, 1-year A1C, and a change in BMI between the first and third year (C-statistic: .919). The ABCD score predicted both mid-term postoperative diabetes remission and relapse in Asians. Initial older age, lower BMI, insulin use, higher 1-year A1C, and weight regain were independent predictors of relapse. Personalized strategies should be proposed for those at risk of relapse to optimize diabetes outcomes after surgery.


Cost-effective scalable synthesis of mesoporous germanium particles via a redox-transmetalation reaction for high-performance energy storage devices.
Nanostructured germanium is a promising material for high-performance energy storage devices. However, synthesizing it in a cost-effective and simple manner on a large scale remains a significant challenge. Herein, we report a redox-transmetalation reaction-based route for the large-scale synthesis of mesoporous germanium particles from germanium oxide at temperatures of 420-600 °C. We could confirm that a unique redox-transmetalation reaction occurs between Zn(0) and Ge(4+) at approximately 420 °C using temperature-dependent in situ X-ray absorption fine structure analysis. This reaction has several advantages, which include (i) the successful synthesis of germanium particles at a low temperature (∼450 °C), (ii) the accommodation of large volume changes, owing to the mesoporous structure of the germanium particles, and (iii) the ability to synthesize the particles in a cost-effective and scalable manner, as inexpensive metal oxides are used as the starting materials. The optimized mesoporous germanium anode exhibits a reversible capacity of ∼1400 mA h g(-1) after 300 cycles at a rate of 0.5 C (corresponding to the capacity retention of 99.5%), as well as stable cycling in a full cell containing a LiCoO2 cathode with a high energy density (charge capacity = 286.62 mA h cm(-3)).


A New Spin on Spatial Cognition in ADHD: A Diffusion Model Decomposition of Mental Rotation.
Multiple studies have found evidence of task non-specific slow drift rate in ADHD, and slow drift rate has rapidly become one of the most visible cognitive hallmarks of the disorder. In this study, we use the diffusion model to determine whether atypicalities in visuospatial cognitive processing exist independently of slow drift rate. Eight- to twelve-year-old children with (n = 207) and without ADHD (n = 99) completed a 144-trial mental rotation task. Performance of children with ADHD was less accurate and more variable than non-ADHD controls, but there were no group differences in mean response time. Drift rate was slower, but nondecision time was faster for children with ADHD. A Rotation × ADHD interaction for boundary separation was also found in which children with ADHD did not strategically adjust their response thresholds to the same degree as non-ADHD controls. However, the Rotation × ADHD interaction was not significant for nondecision time, which would have been the primary indicator of a specific deficit in mental rotation per se. Poorer performance on the mental rotation task was due to slow rate of evidence accumulation, as well as relative inflexibility in adjusting boundary separation, but not to impaired visuospatial processing specifically. We discuss the implications of these findings for future cognitive research in ADHD.


Microglia Are Irrelevant for Neuronal Degeneration and Axon Regeneration after Acute Injury.
The role of microglia in degenerative and regenerative processes after damage of the nervous system remains ambiguous, partially due to the paucity of appropriate investigative methods. Here, we show that treatment with the pharmacological colony stimulating factor 1 receptor inhibitor PLX5622 specifically eliminated microglia in murine retinae and optic nerves with high efficiency. Interestingly, time course and extent of retinal ganglion cell (RGC) degeneration after optic nerve crush remained unaffected upon microglia depletion, although remnants of prelabeled apoptotic RGCs were not cleared from the retina in these animals. In addition, microglia depletion neither affected the induction of regeneration associated genes upon optic nerve injury nor the increased regenerative potential of RGCs upon lens injury (LI). However, although the repopulation of the optic nerve lesion site by astrocytes was significantly delayed upon microglia depletion, spontaneous and LI-induced axon regeneration were unaffected by PLX5622 treatment or peripheral macrophage depletion by clodronate liposome treatment. Only concurrent double depletion of microglia and infiltrated macrophages slightly, but significantly, compromised optic nerve regeneration. Therefore, microglia are not essentially involved in RGC degeneration or axonal regeneration after acute CNS injury.SIGNIFICANCE STATEMENT The roles of microglia, the phagocytosing cells of the CNS, and invading macrophages in degenerative and regenerative processes after injury are still controversial and insufficiently characterized. Here, we show that application of a CSF1R inhibitor eliminated virtually all microglia from the visual system, whereas macrophages were spared. Specific microglia depletion impaired the removal of dead labeled retinal ganglion cells after optic nerve crush, but remarkable had no influence on their degeneration. Similarly, optic nerve regeneration was completely unaffected, although repopulation of the lesion site by astrocytes was delayed significantly. Therefore, contrary to previous reports, this experimental approach revealed that microglia seemingly neither promote nor inhibit neuronal degeneration or axonal regrowth within the injured visual system.


Inhibition of rat liver cathepsins B and L by the peptide aldehyde benzyloxycarbonyl-leucyl-leucyl-leucinal and its analogues.
Cathepsins B and L belong to the papain superfamily of cysteine proteases and play important roles in various physiological and pathological processes. In the course of studies on their inhibitors, we examined the inhibitory effects of the peptide aldehyde benzyloxycarbonyl-leucyl-leucyl-leucinal (ZLLLal) and its analogues. As a result, rat liver cathepsins B and L were shown to be strongly inhibited by them. The concentration required for 50% inhibition (IC(50)) by ZLLLal was 88 nM for cathepsin B and 163 nM for cathepsin L. Moreover, various analogues of ZLLLal, including 2-furancarbonyl-, nicotinyl-, isonicotinyl- and 4-morpholinylsuccinyl-LLLals, and some acetyl-Pro (AcP)-containing analogues, AcPLLLal and AcPPLLLal, were shown to inhibit both enzymes more strongly than ZLLLal. Among them, isonicotinyl-LLLal was most inhibitory against both cathepsins B (IC(50), 12 nM) and L (IC(50), 20 nM). Several of these inhibitors were indicated to be somewhat more soluble in aqueous media than ZLLLal.


Pharmacoinformatics-based identification of potential bioactive compounds against Ebola virus protein VP24.
The impact of Ebola virus disease (EVD) is devastating with concomitant high fatalities. Currently, various drugs and vaccines are at different stages of development, corroborating the need to identify new therapeutic molecules. The VP24 protein of the Ebola virus (EBOV) plays a key role in the pathology and replication of the EVD. The VP24 protein interferes with the host immune response to viral infections and promotes nucleocapsid formation, thus making it a viable drug target. This study sought to identify putative lead compounds from the African flora with potential to inhibit the activity of the EBOV VP24 protein using pharmacoinformatics and molecular docking. An integrated library of 7675 natural products originating from Africa obtained from the AfroDB and NANPDB databases, as well as known inhibitors were screened against VP24 (PDB ID: 4M0Q) utilising AutoDock Vina after energy minimization using GROMACS. The top 19 compounds were physicochemically and pharmacologically profiled using ADMET Predictor™, SwissADME and DataWarrior. The mechanisms of binding between the molecules and EBOV VP24 were characterised using LigPlot+. The performance of the molecular docking was evaluated by generating a receiver operating characteristic (ROC) by screening known inhibitors and decoys against EBOV VP24. The prediction of activity spectra for substances (PASS) and machine learning-based Open Bayesian models were used to predict the anti-viral and anti-Ebola activity of the molecules, respectively. Four natural products, namely, ZINC000095486070, ZINC000003594643, ZINC000095486008 and sarcophine were found to be potential EBOV VP24-inhibitiory molecules. The molecular docking results showed that ZINC000095486070 had high binding affinity of -9.7 kcal/mol with EBOV VP24, which was greater than those of the known VP24-inhibitors used as standards in the study including Ouabain, Nilotinib, Clomiphene, Torimefene, Miglustat and BCX4430. The area under the curve of the generated ROC for evaluating the performance of the molecular docking was 0.77, which was considered acceptable. The predicted promising molecules were also validated using induced-fit docking with the receptor using Schrödinger and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The molecules had better binding mechanisms and were pharmacologically profiled to have plausible efficacies, negligible toxicity as well as suitable for designing anti-Ebola scaffolds. ZINC000095486008 and sarcophine (NANPDB135) were predicted to possess anti-viral activity, while ZINC000095486070 and ZINC000003594643 to be anti-Ebola compounds. The identified compounds are potential inhibitors worthy of further development as EBOV biotherapeutic agents. The scaffolds of the compounds could also serve as building blocks for designing novel Ebola inhibitors.


A novel multisystem disease associated with recessive mutations in the tyrosyl-tRNA synthetase (YARS) gene.
Aminoacyl-tRNA synthetases (ARSs) are a group of ubiquitously expressed enzymes that are best known for their function in the first step of protein translation but have been increasingly associated with secondary functions including transcription and translation control and extracellular signaling. Mutations in numerous ARSs have been linked to a growing number of both autosomal dominant and autosomal recessive human diseases. The tyrosyl-tRNA synthetase (YARS) links the amino acid tyrosine to its cognate tRNA. We report two siblings who presented with failure to thrive (FTT), hypertriglyceridemia, developmental delay, liver dysfunction, lung cysts, and abnormal subcortical white matter. Using exome sequencing the siblings were found to harbor bi-allelic pathogenic-appearing variants within the YARS gene (NM_003680.3):c.638C>T p.(Pro213Leu) and c.1573G>A p.(Gly525Arg). These YARS variants occur in the catalytic domain and the C-terminal domain, respectively. Mutations in YARS have been previously associated with an autosomal dominant form of Charcot-Marie-Tooth (CMT); our findings suggest the disease spectrum associated with YARS dysregulation is broader than peripheral neuropathy. © 2016 Wiley Periodicals, Inc.


Phosphorylation of complement component C3 after synthesis in U937 cells by a putative protein kinase, casein kinase 2, which is regulated by CD11b: evidence that membrane-bound proteases preferentially cleave phosphorylated C3.
It was our aim in this study to investigate the possibility that the third component of complement (C3) is phosphorylated during synthesis and secretion in U937 cells. Labelling of U937 cells with [32P]Pi, followed by immunoprecipitation of C3 from cell lysates and culture supernatants at different time points, showed that C3 was phosphorylated intracellularly immediately before release into the medium, which initiated cleavage of the protein into an iC3b-like fragment. Stimulation of CD11b/CD18 increased phosphorylation 7-fold, from a basal level of 2%. The phosphorylation sites in C3 did not resemble those described previously for casein kinase (CK) 1, cAMP-dependent protein kinase A or calcium- and phospholipid-dependent protein kinase C. Instead, protein kinase CK2 was suggested inasmuch as: (1) CK2 was detected both on the cell surface and on shed microparticles; (2) phosphorylation of purified C3 by microparticles was abolished by a monoclonal antibody, anti-CK2; (3) the [32P]Pi tag of both phosphorylated C3 (secreted from U937 cells) and of microparticle-phosphorylated C3, which was cleaved either by membrane proteases or by leucocyte elastase, was found in a 40 and a 70 kDa polypeptide; (4) both secreted C3 and C3 phosphorylated in vitro were much more susceptible to cleavage by proteases. Generation of C3 fragments provides a means by which U937 cells can stimulate nearby cells which are expressing complement receptors. The present study demonstrates that the cleavage of C3 is controlled by an intracellular phosphorylation event regulated by CD11b/CD18.


Biomedicine. Staying slim with insulin in mind.
Striking the delicate balance between energy intake in the form of food and energy expenditure in the form of metabolic activity keeps the body extremely busy. As Schwartz explains in his enlightening Perspective, the finding that insulin signals the brain to promote weight loss (Brüning et al.) flies in the face of the notion that insulin is involved solely in glucose storage, its conversion to fat, and weight gain.


Arthroscopic Capsular Plication and Labral Seal Restoration in Borderline Hip Dysplasia: 2-Year Clinical Outcomes in 55 Cases.
To report clinical outcomes in patients with borderline dysplasia undergoing an arthroscopic technique of labral seal restoration with minimal acetabular rim resection and capsular plication. Patients younger than 40 years with a lateral center-edge angle of 18° greater and 25° or less and 2-year follow-up after undergoing an arthroscopic technique of labral seal restoration with minimal rim resection (≤2 mm) and capsular plication (3-5 sutures placed in an oblique orientation to create an imbrication and inferior shift) were included. Patients underwent arthroscopy for symptoms that had marginal improvement with a minimum 6-week structured physical therapy program. Patients with a Tönnis grade of 1 or greater, a center-edge angle of 17° or less, and Legg-Calvé-Perthes disease were excluded. The following patient-reported outcomes (PROs) were recorded prospectively but retrospectively reviewed: modified Harris Hip Score, Non-Arthritic Hip Score, Hip Outcome Score-Sports-Specific Subscale, and Hip Outcome Score-Activities of Daily Living. The visual analog scale score, patient satisfaction score, complications, and revision procedures were also recorded. A 2-tailed paired t test was used to analyze change in preoperative to postoperative PRO scores. Significance was defined as P < .05. During the study period, 232 hip arthroscopies were performed in patients with a lateral center-edge angle between 18° and 25°. The inclusion criteria were met by 59 procedures. Of these procedures, 55 (93.2%) were available for follow-up. The labrum was repaired, debrided, and reconstructed in 37 procedures, 17 procedures, and 1 procedure, respectively. The iliopsoas was released in 34 procedures, the ligamentum teres was debrided in 29, and femoral osteoplasty was performed in 32. At 2-year follow-up, there was significant improvement in the mean scores of all PROs compared with baseline. Mean improvements for the modified Harris Hip Score, Hip Outcome Score-Activities of Daily Living, Hip Outcome Score-Sports-Specific Subscale, and Non-Arthritic Hip Score were 20.7, 17.5, 27.6, and 20.0, respectively. There was significant improvement in the visual analog scale score at 2 years, decreasing by 3.16 compared with baseline, and the mean patient satisfaction score was 8.09, with 83.6% of patients achieving a good to excellent result (patient satisfaction score ≥7). No complications were related to the procedure, and 6 patients (11%) required revision procedures (4 for labral retear, 1 for painful iliopsoas internal snapping, and 1 for removal of a symptomatic loose body). Arthroscopic intervention that encompasses minimal rim resection, restoration of labral function, and capsular plication significantly improves outcomes in patients with borderline dysplasia who do not warrant a periacetabular osteotomy. Level IV, therapeutic case series.


The phagocytic system in host defense.
In response to microbial invasion, an inflammatory response is stimulated, polymorphonuclear cells accumulate, and the infection is localized. Active factors released by microbes or from activation of complement attract neutrophils in a unidirectional fashion toward the highest concentration of factors in the center of an inflammatory process. Opsonins increase the affinity of microbes for phagocytic cells by neutralizing antiphagocytic factors on the microbial surface and binding to the surface of phagocytes. Enzymes responsible for the respiratory oxidative metabolism during phagocytosis reside in the neutrophil plasma membrane. Perturbation of membrane receptors stimulate the metabolic machinery required for engulfment of particles and for oxidative metabolism of the phagocytic cell. Highly reactive oxygen radicals, superoxide and singlet oxygen, and hydrogen peroxide are produced during the oxidative response to phagocytosis. These and factors released from azurophilic and specific granules are critical factors determining microbial death within phagocytic vacuoles.


Neurofilaments and tau proteins in cerebrospinal fluid and serum in dementias and neuroinflammation.
The aim of this study was to evaluate the diagnostic potential of cerebrospinal fluid (CSF) and serum levels of neurocytoskeletal proteins and their ratios for the diagnosis of dementias and to assess the differences in neurocytoskeletal proteins between neurodegeneration and neuroinflammation. CSF and serum levels of neurofilament light subunits (NFL) and neurofilament heavy subunits (NFH) as well as CSF levels of total tau (t-tau) and phosphorylated tau (p-tau) proteins were determined using ELISA in 20 Alzheimer's disease patients (AD group), 13 patients with other dementias (OD group), 17 patients with inflammatory aseptic neuro-infections (IP), and 20 aged-matched cognitively normal elderly persons (NC group). The ratio CSF p-tau/t-tau was significantly higher in the NC group than that in the AD or OD groups (P<0.0005 for each group). The CSF NFH/p-tau and CSF NFL/p-tau ratios were significantly lower in AD patients than OD patients (P≤0.003). Serum and CSF NFL and CSF NFH levels were significantly higher in OD patients than AD patients (P≤0.03). The lowest values of the CSF NFL/NFH ratio were found in the IP group and they significantly differed from those in normal controls (P<0.0001) and any dementia group (IP vs. AD P<0.0001; IP vs. OD P=0.03). CSF tau proteins and their index differentiated between AD or OD patients and cognitively normal subjects, while CSF levels of neurofilaments expressed as their index seem to contribute to the discrimination between patients with neuroinflammation and normal controls or AD patients.


Infections and risk of epilepsy in children and young adults: A nationwide study.
The development of epilepsy has been linked to infections of the central nervous system, but recently also to infections and inflammation outside of the central nervous system. Thus we investigated the association between infections and the risk of subsequent epilepsy. This was a Danish nationwide population-based cohort study comprising a total of 1 938 555 individuals born between 1982 and 2012. Individuals were followed from birth until December 31, 2012, death, disappearance, emigration, or epilepsy diagnosis, whichever came first (28 512 666 person-years of follow-up). The exposure was hospital contacts for infection and the outcome was a diagnosis of epilepsy as recorded in the Danish National Hospital Register. Hazard ratios were calculated using Cox proportional hazards models adjusted for age, sex, calendar period, Apgar score, gestational age, birth weight, and parental history of epilepsy. A total of 25 825 individuals received an epilepsy diagnosis during the study period, among whom 8235 (32%) had a previous hospital contact for infection. A hospital contact for infection was associated with a 78% increase in the risk of subsequently receiving an epilepsy diagnosis (hazard ratio 1.78, 95% confidence interval [CI] 1.73-1.83) compared with those without infection. The highest risk was observed after central nervous system infections (hazard ratio 4.97, 95% CI 4.42-5.59), but increased risks were identified across all infected organ systems and types of pathogens. The risk of receiving an epilepsy diagnosis was correlated with the temporal proximity of the infection (P < 0.001) and increased with the number of hospital contacts for infection (P < 0.001) and with the severity of infection (P < 0.001). The risk of receiving an epilepsy diagnosis was increased after a wide range of infections, suggesting that systemic inflammatory processes may be involved in the development of epilepsy.


Modification by adoptive humoral immunity of murine cytomegalovirus infection.
The effects of specific antiviral antibody on several aspects of infection with murine cytomegalovirus (CMV) were examined. Administration of immune serum 24 hr before subcutaneous inoculation of 10(5) plaque-forming units of murine CMV prevented detectable viral replication in the tissues of 92% of animals. Protection was associated with the immune globulin fraction and not with normal serum or heterologous antiviral serum. However, the development of latent murine CMV infection was not prevented by prior administration of antibody since immunosuppression with antilymphocyte serum and cortisone 16 weeks later unmasked dormant virus in 17 of 20 animals. In normal animals murine CMV-immune serum administered six days after acute virus infection had been initiated did not influence the outcome; however, in immunosuppressed mice, virus dissemination during acute infection was substantially reduced by specific antibody. These results demonstrate a significant effect of humoral immunity on the course of experimental CMV infection.


Intercellular communication and cell-cell adhesion.
In developmental biology, binary cell-cell interactions often determine the fate of one or both cell partners. The two cells must adhere to one another to allow chemical signals to be transmitted in one or both directions across the regions of cell-cell contact. The molecular mechanisms of cell-cell adhesion and intercellular communication, even if they are mediated by different cell surface components, may be functionally integrated in several different ways. Studies of helper T cells with antigen-presenting B cells in culture have illuminated such binary interactions. The possible application of similar mechanisms to other binary developmental systems is briefly explored.


Comparative clinical outcomes of Taiwanese patients with resected buccal and tongue squamous cell carcinomas.
Although patients with buccal squamous cell carcinoma (SCC) usually show acceptable outcomes, local control and survival rates are generally lower than those observed for tongue SCC. This study was designed to compare the clinical outcomes of Taiwanese patients with these two common oral cavity malignancies. Patients with first primary buccal or tongue SCC who were included in the Taiwanese Cancer Registry Database between 2004 and 2012 were eligible. The study sample consisted of 16,379 patients (7870 buccal SCC and 8509 tongue SCC) who received surgery with or without adjuvant therapy. The 5-year disease-specific survival (DSS) and overall survival (OS) rates served as the outcome measures. Compared with tongue SCC, patients with buccal SCC had a higher prevalence of males (95.7% vs. 86.4%, p<0.0001), pT4 disease (21.4% vs. 12.7%, p<0.0001), and p-Stage IV (30.4% vs. 24.8%, p<0.0001) but a lower frequency of pN2 disease (15.2% vs. 18.5%, p<0.0001). The 5-year DSS and OS rates of buccal SCC patients were slightly higher than those of tongue SCC (78% vs. 77%, p=0.0297; and 71% vs. 69%, p=0.0231, respectively). Multivariate analysis identified tumor site (tongue vs. buccal SCC), sex (male vs. female), age (≥65 vs. <65years), pT classification (T4/T3/T2 vs. T1), and pN classification (N3/N2/N1vs. N0) as independent prognostic factors in the entire study cohort. The survival advantage of buccal SCC over tongue SCC appears significant in large clinical samples, despite a higher prevalence of p-Stage IV disease in the former.


When conflicts get heated, so does the planet: coupled social-climate dynamics under inequality.
Climate dynamics are inextricably linked to processes in social systems that are highly unequal. This suggests a need for coupled social-climate models that capture pervasive real-world asymmetries in the population distribution of the consequences of anthropogenic climate change and climate (in)action. Here, we use evolutionary game theory to develop a social-climate model with group structure to investigate how anthropogenic climate change and population heterogeneity coevolve. We find that greater homophily and resource inequality cause an increase in the global peak temperature anomaly by as much as 0.7°C. Also, climate change can structure human populations by driving opinion polarization. Finally, climate mitigation achieved by reducing the cost of mitigation measures paid by individuals tends to be contingent upon socio-economic conditions, whereas policies that achieve communication between different strata of society show climate mitigation benefits across a broad socio-economic regime. We conclude that advancing climate change mitigation efforts can benefit from a social-climate systems perspective.


Treatment of a Child With Submassive Pulmonary Embolism Associated With Hereditary Spherocytosis Using Ultrasound-Assisted Catheter-Directed Thrombolysis.
Background: The clinical presentation of hereditary spherocytosis varies from no symptoms to severe hemolytic anemia requiring splenectomy. Splenectomy imposes the risk of hypercoagulability and acute pulmonary embolism. Catheter-directed thrombolysis is an established treatment for submassive pulmonary embolism in adults. However, the literature regarding its use in children is limited. Case Report: We present the case of a 12-year-old male with hereditary spherocytosis who was diagnosed with pulmonary embolism and successfully treated with catheter-directed thrombolysis. The patient was initially treated with 10.5 mg of recombinant tissue plasminogen activator (r-tPA) delivered over 8 hours. However, because of minimal clinical and hemodynamic improvement, a second course of thrombolytic was administered for an additional 24 hours (25 mg of r-tPA), and the treatment resulted in marked clinical and hemodynamic improvement. Clot resolution was confirmed via angiography. The patient was discharged on enoxaparin and with regular follow-up. One year later, the patient was asymptomatic on enoxaparin. Conclusion: This case demonstrates that catheter-based treatment of submassive pulmonary embolism restores hemodynamic stability and thus is an alternative to surgery or systemic thrombolysis, even in the pediatric setting. While catheter-directed thrombolysis is a safe and effective alternative to systemic thrombolysis, further research is needed to establish appropriate dosing and indications in the adolescent population.


Influence of bone marrow on osseointegration in long bones: an experimental study in sheep.
To evaluate the influence of yellow bone marrow on osseointegration of titanium oral implants using a long bone model. The two tibiae of eight sheep were used as experimental sites. Two osteotomies for implant installation were prepared in each tibia. At the control sites, no further treatments were performed while, at the test sites, bone marrow was removed from the osteotomy site with a curette to an extent that exceeded the implant dimensions. As a result, the apical portion of the implants at the control sites was in contact with bone marrow while, at the test sites, it was in contact with the blood clot. After 2 months, the same procedures were performed in the contralateral side. After another month, the animal was sacrificed. Ground sections were obtained for histological analysis. After 1 month of healing, no differences between test and control sites were found in the apical extension of osseointegration and the percentage of new bone-to-implant contact. However, after 3 months of healing, a higher percentage of new bone-to-implant contact was found at the test compared to the control sites in the marrow compartment. The apical extension of osseointegration, however, was similar to that found at the 1-month healing period both for test and control sites. Osseointegration appeared to be favored by the presence of a blood clot when compared to the presence of yellow fatty bone marrow. Moreover, the contact with cortical bone appeared to be a prerequisite for the osseointegration process in the long bone model.


Critical pathway effectiveness: assessing the impact of patient, hospital care, and pathway characteristics using qualitative comparative analysis.
To qualitatively describe patient, hospital care, and critical pathway characteristics that may be associated with pathway effectiveness in reducing length of stay. Administrative data and review of pathway documentation and a sample of medical records for each of 26 surgical critical pathways in a tertiary care center's department of surgery, 1988-1998. Retrospective qualitative study. DATA COLLECTION/ABSTRACTION METHODS: Using information from a literature review and consultation with experts, we developed a list of characteristics that might impact critical pathway effectiveness. We used hypothesis-driven qualitative comparative analysis to describe key primary and secondary characteristics that might differentiate effective from ineffective critical pathways. " All 7 of the 26 pathways associated with a reduced length of stay had at least one of the following characteristics: (1) no preexisting trend toward lower length of stay for the procedure (71 percent), and/or (2) it was the first pathway implemented in its surgical service (71 percent). In addition, pathways effective in reducing length of stay tended to be for procedures with lower patient severity of illness, as indicated by fewer intensive care days and lower mortality. Effective pathways tended to be used more frequently than ineffective pathways (77 versus 59 percent of medical records with pathway documents present), but high rates of documented pathway use were not necessary for pathway effectiveness. Critical pathway programs may have limited effectiveness, and may be effective only in certain situations. Because pathway utilization was not a strong predictor of pathway effectiveness, the mechanism by which critical pathways may reduce length of stay is unclear.


Rare coagulation disorders.
The type of hemorrhagic manifestations that occur in patients with recessively transmitted coagulation disorders and their optimal treatment are not well established as for hemophilia A and B and von Willebrand disease, due to the rarity of these disorders. In a Muslim country like Iran where consanguineous marriages are frequent these disorders are less rare. We chose to evaluate the pattern of bleeding symptoms in 237 Iranian patients with the inherited deficiencies of fibrinogen, factor II, combined factor V and factor VIII, factor V, factor VII and factor X. Considering "severe" life-endangering hemorrhages such as those in the CNS, gastrointestinal tract and from the umbilical cord and those potentially handicapping such as hematomas and hemarthroses; and "mild" epistaxis, menorrhagia, hematuria, oral and postsurgical bleeding, it would appear the most severe diseases are factor X and factor II deficiencies. For the remaining defects only a minority of patients, even those with unmeasurable plasma levels, had life-endangering hemorrhages or musculoskeletal disabilities as a consequence of hemarthroses and hematomas. The relatively mild severity of clinical manifestations in recessive coagulation disorders commands safety as the primary criterion in the choice of replacement material for treatment. Hence, virally inactivated plasma and factor concentrates should be the products of choice.


Form and function of mental health authorities at Robert Wood Johnson Foundation Program sites: preliminary observations.
The Robert Wood Johnson Foundation Program on Chronic Mental Illness provides support for broad change in the organization, financing, and delivery of services in public systems of care for chronic mentally ill persons. To address the lack of an organizational locus of responsibility in these systems, the foundation proposed that each of the nine cities participating in the program create a mental health authority that would centralize administrative, clinical, and fiscal oversight. The authors present site-by-site observations of the developing mental health authorities at the end of the program's two-and-a-half-year planning phase. They conclude that although the Robert Wood Johnson Foundation grant represented a significant incentive for innovation, at this relatively early stage in the demonstration authorities at only a few sites had achieved direct clinical responsibility for chronic mentally ill persons. Although services had expanded, no site had yet developed a comprehensive system of care that included inpatient services as well as a full range of ambulatory, housing, and social welfare services.


Analysis of resistant starches in rat cecal contents using Fourier transform infrared photoacoustic spectroscopy.
Fourier transform infrared photoacoustic spectroscopy (FTIR-PAS) qualitatively and quantitatively measured resistant starch (RS) in rat cecal contents. Fisher 344 rats were fed diets of 55% (w/w, dry basis) starch for 8 weeks. Cecal contents were collected from sacrificed rats. A corn starch control was compared against three RS diets. The RS diets were high-amylose corn starch (HA7), HA7 chemically modified with octenyl succinic anhydride, and stearic-acid-complexed HA7 starch. To calibrate the FTIR-PAS analysis, samples from each diet were analyzed using an enzymatic assay. A partial least-squares cross-validation plot generated from the enzymatic assay and FTIR-PAS spectral results for starch fit the ideal curve with a R(2) of 0.997. A principal component analysis plot of components 1 and 2 showed that spectra from diets clustered significantly from each other. This study clearly showed that FTIR-PAS can accurately quantify starch content and identify the form of starch in complex matrices.


Political orientation and adherence to social distancing during the COVID-19 pandemic in Italy.
Many governments have implemented social distancing and lockdown measures to curb the spread of the novel coronavirus (COVID-19). Using province-level geolocation data from Italy, we document that political disbelief can limit government policy effectiveness. Residents in provinces leaning towards extreme right-wing parties show lower rates of compliance with social distancing order. We also find that, during the Italian lockdown, provinces with high protest votes virtually disregarded all social distancing orders. On the contrary, in provinces with higher political support for the current political legislation, we found a higher degree of social distancing compliance. These results are robust to controlling for other factors, including time, geography, local COVID-19 cases and deaths, healthcare hospital beds, and other sociodemographic and economic characteristics. Our research shows that bipartisan support and national responsibility are essential to implement and manage social distancing efficiently. From a broader perspective, our findings suggest that partisan politics and discontent with the political class (i.e., protest voting) might significantly affect human health and the economy.


Neuropeptides and peptide hormones in syncope and orthostatic intolerance.
Syncope and orthostatic intolerance (OI) are common clinical syndromes often requiring medical attention. The former is defined as transient loss of consciousness and postural tone due to self-limited cerebral hypoperfusion, while the latter consists of inappropriate cardiovascular responses to upright posture such as occur with orthostatic hypotension (OH) or postural orthostatic tachycardia syndrome. The most frequent causes of syncope and OI are conditions that temporarily disrupt essential moment-to-moment interaction between the autonomic nervous system and cardiovascular system. In this regard, many neuropeptides (NPs) or peptide hormones (PH) exert cardioactive effects that might contribute to the pathophysiology of certain forms of syncope or OI. To date, the principal peptides that have been studied in this context are: atrial and B-type-neuropeptides, adrenomedullin, endothelin-1 (ET-1), galanin, and vasopressin. While definitive conclusions cannot yet be drawn, the intrinsic vasoconstrictor ET-1 appears to be elevated in OH, presumably to compensate for vasodilation and hypotension of other etiologies. As such elevated ET-1 may become a marker for OH. Further, elevated NT-proBNP may play a role in causing vasodilation and hypotension in some forms of OH of previously unknown cause, and may be a marker in other patients of a cardiovascular cause of syncope and OI. In the end, the study of the role of NPs and PHs in syncope and OI syndromes is at an early stage, and considerable further future effort is needed.


Demographic predictors of central sensitization in patients of knee osteoarthritis.
Evidence suggests that central sensitization (CS) may contribute to pain in osteoarthritis (OA) knee patients, which cannot be treated by locally directed treatment strategies. The aim of this study was to examine differences in demographic profile of patients with and without central sensitization in osteoarthritis knee. Observational cross-sectional study at tertiary care hospital. The study was conducted in the Department of Physical Medicine and Rehabilitation, VMMC and Safdarjung Hospital in 345 OA knee patients. Demographic profiles including age, gender, education, occupations, type of family, marital and socioeconomic status and central sensitization were assessed. The association between CS and various demographic parameters was investigated. Statistical Package for Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, version 21.0. For statistical significance, P value of less than 0.05 was considered statistically significant. Ninety out of 345 (26%) of study subjects had CS; out of which 96% were females. Younger homemaker and those with unskilled/semiskilled type of job had higher chances of having CS in comparison with those with skilled and professional job (P < .001). Elicitation of specific demographic factors that can predict CS in people with knee OA may help in early identification and management of CS in OA knee patients.


Imaging perturbed shock propagation in powders.
A novel experimental methodology is presented to study the deviatoric response of powders in shock regimes. The powders are confined to a cylindrical wedge volume, and a projectile-driven shock wave with a sinusoidally varying front propagates through the powder. The perturbed shock wave exhibits a damping behavior due to irreversible processes of viscosity and strength (deviatoric) of the powder with propagation through increasing powder thicknesses. The inclined surface of the wedge is polished and coated to establish a diffuse surface suitable for reflecting incident laser light into a high-speed camera imaging at 5 MHz. Images of the contrast loss upon shock wave arrival at the observation surface are post-processed for qualitative and quantitative information. New data of shock damping behavior with parameters of perturbation wavelength and initial shock strength are presented for powders of copper, tantalum, and tungsten carbide as well as their mixtures. We present the first full-field images showing additional spatial disturbances on the perturbed shock front that appear dependent on particle material and morphology.


Chronic critical illness after hypothermia in trauma patients.
Chronic critical illness (CCI) is a phenotype that occurs frequently in patients with severe injury. Previous work has suggested that inflammatory changes leading to CCI occur early following injury. However, the modifiable factors associated with CCI are unknown. We hypothesized that hypothermia, an early modifiable factor, is associated with CCI. To determine the association of hypothermia and CCI, a secondary analysis of the Inflammation and Host Response to Injury database was performed, and subsequently validated on a similar cohort of patients from a single level 1 trauma center from January 2015 to December 2019. Hypothermia was defined as initial body temperature ≤34.5°C. CCI was defined as death or sustained multiorgan failure ≥14 days after injury. Data were analyzed using univariable analyses with Student's t-test and Pearson's χ2 test, and logistic regression. An arrayed genomic analysis of the transcriptome of circulating immune cells was performed in these patients. Of the initial 1675 patients, 254 had hypothermia and 1421 did not. On univariable analysis, 120/254 (47.2%) of patients with hypothermia had CCI, compared with 520/1421 (36.6%) without hypothermia who had CCI, p<0.001. On multivariable logistic regression, hypothermia was independently associated with CCI, OR 1.61 (95% CI 1.17 to 2.21) but not mortality. Subsequent validation in 1264 patients of which 172 (13.6%) were hypothermic, verified that hypothermia was independently associated with CCI on multivariable logistic regression, OR 1.84 (95% CI 1.21 to 2.41). Transcriptomic analysis in hypothermic and non-hypothermic patients revealed unique cellular-specific genomic changes to only circulating monocytes, without any distinct effect on neutrophils or lymphocytes. Hypothermia is associated with the development of CCI in severely injured patients. There are transcriptomic changes which indicate that the changes induced by hypothermia may be associated with persistent CCI. Thus, early reversal of hypothermia following injury may prevent the CCI. III.


Corneal confocal microscopy identifies small fibre damage and progression of diabetic neuropathy.
Accurately quantifying the progression of diabetic peripheral neuropathy is key to identify individuals who will progress to foot ulceration and to power clinical intervention trials. We have undertaken detailed neuropathy phenotyping to assess the longitudinal utility of different measures of neuropathy in patients with diabetes. Nineteen patients with diabetes (age 52.5 ± 14.7 years, duration of diabetes 26.0 ± 13.8 years) and 19 healthy controls underwent assessment of symptoms and signs of neuropathy, quantitative sensory testing, autonomic nerve function, neurophysiology, intra-epidermal nerve fibre density (IENFD) and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), branch density (CNBD) and fibre length (CNFL). Mean follow-up was 6.5 years. Glycated haemoglobin (p = 0.04), low-density lipoprotein-cholesterol (LDL-C) (p = 0.0009) and urinary albumin creatinine ratio (p < 0.0001) improved. Neuropathy symptom profile (p = 0.03), neuropathy disability score (p = 0.04), vibration perception threshold (p = 0.02), cold perception threshold (p = 0.006), CNFD (p = 0.03), CNBD (p < 0.0001), CNFL (p < 0.0001), IENFD (p = 0.04), sural (p = 0.02) and peroneal motor nerve conduction velocity (p = 0.03) deteriorated significantly. Change (∆) in CNFL correlated with ∆CPT (p = 0.006) and ∆Expiration/Inspiration ratio (p = 0.002) and ∆IENFD correlated with ∆CNFD (p = 0.005), ∆CNBD (p = 0.02) and ∆CNFL (p = 0.01). This study shows worsening of diabetic neuropathy across a range of neuropathy measures, especially CCM, despite an improvement in HbA1c and LDL-C. It further supports the utility of CCM as a rapid, non-invasive surrogate measure of diabetic neuropathy.


Pragmatic abilities of children with hearing loss using cochlear implants or hearing AIDS compared to hearing children.
This study characterized the profile of pragmatic abilities among 24 children with hearing loss (HL) aged 6.3-9.4 years, 13 using hearing aids (HAs) and 11 using cochlear implants (CIs), in comparison to those of 13 hearing children with similar chronological and language ages. All the children with HL used spoken language, attended regular schools, and received communication therapy twice a week. They had no disabilities other than the HL. We assessed pragmatic abilities using the pragmatic protocol of C. A. Prutting & D. M. Kirchner (1987. A clinical appraisal of the pragmatic aspects of language. Journal of Speech and Hearing Disorders, 52, 105-119), which includes verbal, nonverbal, and paralinguistic aspects. Findings showed that children with HL used varied pragmatic functions but revealed more incidents of inappropriate use of the different abilities, compared to hearing children. Intergroup differences were significant only for verbal parameters. No differences emerged between children who used CIs vs. HAs. It seems that the CI group had the same pragmatic abilities as severe HA children. The different or less effective pragmatic abilities of children with HL may be explained by less flexible use of language structures, difficulties in theory of mind, difficulties in auditory perception of spoken language, and less exposure to varied pragmatic situations and strategies. Results indicated the need to incorporate pragmatic communication abilities into rehabilitation programs.


An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection.
The CD4(+)CD25(+) regulatory T lymphocytes have been implicated in suppressing T cell immune responses. Our aim was to characterize the frequency, phenotype, function, and specificity of CD4(+)CD25(+) T cells in hepatitis C virus (HCV) infection. Peripheral CD4(+)CD25(+) cells from recovered (n = 15), chronic infected (n = 30), and normal control (n = 15) subjects were analyzed ex vivo for quantitation, phenotype, and effect on HCV-specific interferon gamma production and proliferation. CD4(+)CD25(+) specificity was determined by intracellular cytokine staining for interleukin 10 (IL-10). A higher proportion of CD4(+)CD25(+) were found in chronic infection (mean, 3.02%) when compared with recovered (1.64%, P = .001) and normal controls (2.27%, P = .02). CD4(+)CD25(+) cells display CD45RO(high), CD45RA(low), CD28(high), CD62L(high), and CD95(high) phenotype. HCV-specific interferon gamma activity was enhanced in peripheral blood mononuclear cells depleted of CD4(+)CD25(+) and suppressed in peripheral blood mononuclear cells enriched with CD4(+)CD25(+). Depletion of CD4(+)CD25(+) cells also enhanced HCV-specific CD4(+) and CD8(+) T cell proliferation. Cytokine analysis suggested CD4(+)CD25(+) cells secrete transforming growth factor beta (TGF-beta(1)) and IL-10. The inhibitory role for TGF-beta(1) was confirmed by anti-TGF-beta(1). Transwell studies showed CD4(+)CD25(+) mediated suppression to be dose dependent and requiring cell contact. CD4(+)CD25(+) cells showed HCV-specificity through IL-10 production, with a frequency ranging from 1.9% to 5.3%. A positive correlation was detected between CD4(+)CD25(+) T cell frequency and HCV RNA titer, whereas an inverse relation was found with liver inflammatory activity. In conclusion, CD4(+)CD25(+) T lymphocytes constitute a highly differentiated population and appear to play a role in viral persistence by suppressing HCV-specific T cell responses in a cell-cell contact manner.


A review of nail gun suicides and an atypical case report.
The nail gun was designed as a powerful industrial tool to drive nails into various hard surfaces with ease. Serious injuries associated with the tool are uncommon and deaths are rare. Unintentional injuries normally occur from misuse of the tool or from ricocheting nails. The intentional use of a nail gun to commit suicide is unusual. This paper will review successful and unsuccessful suicide attempts by use of a nail gun. We will present an atypical case of suicide committed with a nail gun by a 46-year-old depressed male investigated by the Allegheny County Coroner's Office in Allegheny County, Pennsylvania in April 2002. This case reports for the first time a unique pathological finding of a ring of bone traveling with the nail, which has not been seen in wounds of the head caused by other types of projectiles.


Ankylosing Spondylitis Increases Perioperative and Postoperative Complications After Total Hip Arthroplasty.
Ankylosing spondylitis (AS) is a chronic autoimmune spondyloarthropathy that primarily affects the axial spine and hips. Progressive disease leads to pronounced spinal kyphosis, positive sagittal balance, and altered biomechanics. The purpose of this study is to determine the complication profile of patients with AS undergoing total hip arthroplasty (THA). The Medicare sample was searched from 2005 to 2012 yielding 1006 patients with AS who subsequently underwent THA. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for 90-day, 2-year, and the final postoperative follow-up for complications including hip dislocation, periprosthetic fracture, wound complication, revision THA, and postoperative infection. Compared to controls, AS patients had an RR of 2.50 (CI, 1.04-5.99) of THA component breakage at 90-days post-operatively and 1.99 (CI, 1.10-3.59) at 2-years. The RR of periprosthetic hip dislocation was elevated at 90 days (1.44; CI, 0.93-2.22) and significantly increased at 2-years (1.67; CI, 1.25-2.23) and overall follow-up (1.49; CI, 1.14-1.93). Similarly, the RR for THA revision was elevated at 90-days (1.46; CI, 0.97-2.18) and significantly increased at 2-years (1.69; CI, 1.33-2.14) and overall follow-up (1.51; CI, 1.23-1.85). Patients with AS are at increased risk for complications after THA. Altered biomechanics from a rigid, kyphotic spine place increased demand on the hip joints. The elevated perioperative and postoperative risks should be discussed preoperatively, and these patients may require increased preoperative medical optimization as well as possible changes in component selection and position to compensate for altered spinopelvic biomechanics.


EMG-based detection of muscle fatigue during low-level isometric contraction by recurrence quantification analysis and monopolar configuration.
The center frequency (CF) of the power spectral density of a bipolar-configured surface electromyogram is typically used as an index of muscle fatigue. However, this index may be inadequate for measuring wave slowing due to muscle fatigue during low-level contractions. A previous study in which strong muscle fatigue was mimicked by compressing the proximal region of the forearm during isometric contractions showed that the differences in the degree of fatigue under compression and non-compression conditions were undetectable. The purpose of this study was to improve detection sensitivity of surface EMG variation caused by muscle fatigue using two approaches. The first approach employed recurrence quantification analysis (RQA) instead of traditional frequency analysis (FA) to compute the muscle fatigue index. The second approach employed a monopolar configuration for measuring surface EMG. We measured the surface EMG signal by using monopolar and bipolar configurations simultaneously during low-level isometric contractions under blood flow-restricted (BFR) and unrestricted (CON) conditions, and then compared and evaluated the detected differences in muscle fatigue. The results showed that the effect of BFR was better detected by RQA than by FA, and that the fatigability change was larger in the monopolar configuration than in the bipolar configuration.


Changing infants' sleep position increases risk of sudden infant death syndrome. New Zealand Cot Death Study.
To examine whether the prone sleeping position may increase the risk for sudden infant death syndrome (SIDS), particularly in infants unused to prone sleep. A 3-year (1987-1990) case-control study. Nationwide study in New Zealand. Four hundred eighty-five infants who died of SIDS and 1800 controls. Infants were classified as unaccustomed to prone if their usual sleep position was nonprone and they were placed prone for the last sleep. Secondary prone was used to describe infants placed nonprone but found prone. Infants usually and last placed nonprone were at the lowest risk for SIDS (odds ratio [OR], 1.0); those usually and last placed prone were at increased risk (adjusted OR, 4.6; 95% confidence interval, 3.4-6.3). Risk was greatly increased among infants unaccustomed to the prone position (adjusted OR, 19.3; 95% confidence interval, 8.2-44.8). These infants accounted for 8% (31/ 386) of all SIDS deaths. Ninety percent (28/ 31) of infants in this group were found prone, and 71% (20/28) of those found prone were found with their faces turned down into bedding-a position in which asphyxia has been implicated as a mechanism of death. In addition, 138 infants who died of SIDS were last placed nonprone. Forty-seven infants (34%) in this group were found prone (secondary prone), and 60% (28/47) of those found prone were found with their faces turned down into the bedding. This group accounted for 12% of all SIDS deaths. Most of these infants (91% [43/47]) were usually placed nonprone. Infants placed supine to sleep were at the lowest risk of SIDS, which supports the recommendation that this is the preferred sleeping position for healthy infants. In New Zealand, 20% of SIDS deaths involved lack of experience with the prone sleeping position. Our findings suggest the possibility that an infant's competence in escaping from potentially lethal situations during prone sleep (eg, the face-down position) may be impaired by inexperience in prone sleeping. Great caution should be exercised in placing infants unaccustomed to the prone sleeping position in the prone position.


Real-time tracking of protein unfolding with time-resolved x-ray solution scattering.
The correct folding of proteins is of paramount importance for their function, and protein misfolding is believed to be the primary cause of a wide range of diseases. Protein folding has been investigated with time-averaged methods and time-resolved spectroscopy, but observing the structural dynamics of the unfolding process in real-time is challenging. Here, we demonstrate an approach to directly reveal the structural changes in the unfolding reaction. We use nano- to millisecond time-resolved x-ray solution scattering to probe the unfolding of apomyoglobin. The unfolding reaction was triggered using a temperature jump, which was induced by a nanosecond laser pulse. We demonstrate a new strategy to interpret time-resolved x-ray solution scattering data, which evaluates ensembles of structures obtained from molecular dynamics simulations. We find that apomyoglobin passes three states when unfolding, which we characterize as native, molten globule, and unfolded. The molten globule dominates the population under the conditions investigated herein, whereas native and unfolded structures primarily contribute before the laser jump and 30 μs after it, respectively. The molten globule retains much of the native structure but shows a dynamic pattern of inter-residue contacts. Our study demonstrates a new strategy to directly observe structural changes over the cause of the unfolding reaction, providing time- and spatially resolved atomic details of the folding mechanism of globular proteins.


Coordinated mapping of Li+ flux and electron transfer reactivity during solid-electrolyte interphase formation at a graphene electrode.
Interphases formed at battery electrodes are key to enabling energy dense charge storage by acting as protection layers and gatekeeping ion flux into and out of the electrodes. However, our current understanding of these structures and how to control their properties is still limited due to their heterogenous structure, dynamic nature, and lack of analytical techniques to probe their electronic and ionic properties in situ. In this study, we used a multi-functional scanning electrochemical microscopy (SECM) technique based on an amperometric ion-selective mercury disc-well (HgDW) probe for spatially-resolving changes in interfacial Li+ during solid electrolyte interphase (SEI) formation and for tracking its relationship to the electronic passivation of the interphase. We focused on multi-layer graphene (MLG) as a model graphitic system and developed a method for ion-flux mapping based on pulsing the substrate at multiple potentials with distinct behavior (e.g. insertion-deinsertion). By using a pulsed protocol, we captured the localized uptake of Li+ at the forming SEI and during intercalation, creating activity maps along the edge of the MLG electrode. On the other hand, a redox probe showed passivation by the interphase at the same locations, thus enabling correlations between ion and electron transfer. Our analytical method provided direct insight into the interphase formation process and could be used for evaluating dynamic interfacial phenomena and improving future energy storage technologies.


Amphetamine-induced incentive sensitization of sign-tracking behavior in adolescent and adult female rats.
Age-specific behavioral and neural characteristics may predispose adolescents to initiate and escalate use of alcohol and drugs. Adolescents may avidly seek novel experiences, including drugs of abuse, because of enhanced incentive motivation for drugs and natural rewards, perhaps especially when that incentive motivation is sensitized by prior drug exposure. Using a Pavlovian conditioned approach (PCA) procedure, sign-tracking (ST) and goal-tracking (GT) behavior was examined in amphetamine-sensitized and control adolescent and adult female Sprague-Dawley rats, with expression of elevated ST behavior used to index enhanced incentive motivation for reward-associated cues. Rats were first exposed to a sensitizing regimen of amphetamine injections (3.0 mg/kg/ml d-amphetamine per day) or given saline (0.9% wt/vol) once daily for 4 days. Expression of ST and GT was then examined over 8 days of PCA training consisting of 25 pairings of an 8-s presentation of an illuminated lever immediately followed by response-independent delivery of a banana-flavored food pellet. Results showed that adults clearly displayed more ST behavior than adolescents, reflected via both more contacts with, and shorter latencies to approach, the lever. Prior amphetamine sensitization increased ST (but not GT) behaviors regardless of age. Thus, when indexed via ST, incentive motivation was found to be greater in adults than adolescents, with a prior history of amphetamine exposure generally sensitizing incentive motivation for cues predicting a food reward regardless of age.


Disubstituted 2-phenyl-benzopyranopyrimidine derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA.
A series of 2-phenyl-benzopyranopyrimidine (PBPP) derivatives with alkylamino side chains were synthesized and found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, and their biological properties were reported for the first time. Their interactions with telomeric G-quadruplex DNA were studied with FRET melting, surface plasmon resonance, CD spectroscopy, and molecular modeling. Our results showed that the disubstituted PBPP derivatives could strongly bind to and effectively stabilize the telomeric G-quadruplex structure, and had significant selectivity for G-quadruplex over duplex DNA. In comparison, the mono substituted derivatives had much less effect on the G-quadruplex, suggesting that the disubstitution of PBPP is essential for its interaction with the G-quadruplex. Furthermore, telomerase inhibition of the PBPP derivatives and their cellular effects were studied, and compound 11b was found to be the most promising compound as a telomerase inhibitor and telomeric G-quadruplex binding ligand for further development for cancer treatment.


Risk factors for seropositivity to bovine coronavirus and bovine respiratory syncytial virus in dairy herds.
A cross-sectional study was conducted to evaluate the association between herd-level characteristics, management routines and farm-level antibody status of bovine coronavirus (BCV) and bovine respiratory syncytial virus (BRSV) in 257 Swedish dairy herds. The possible spatial clustering of positive herds compared with negative herds was also investigated. For each herd, a pooled milk sample from five primiparous cows was analysed for the presence of antibodies to BCV and BRSV. Herd-level information was obtained by a questionnaire. Logistic regression was used to evaluate the association between predictors and antibody status to BCV and BRSV. Large herd size, being located in southern Sweden, and not providing boots for visitors were found to be associated with being antibody-positive to BCV and BRSV. A short distance to the nearest cattle herd was an additional risk factor for BCV. One of the studied areas was suitable for spatial analysis. Positive herds were not spatially autocorrelated when compared with negative herds as estimated by the K-function regarding both BCV and BRSV. This indicates that local factors such as daily visiting milk trucks and wild animals were unlikely to be important sources of infection in this area. Moran's I statistics and semi-variogram showed no evidence of spatial autocorrelation in the residuals, indicating that remaining unidentified factors are not spatially dependent in the areas under study.


Sporadic hereditary pancreatic desmoid tumor: a new entity?
Deeply seated aggressive fibromatosis also termed as desmoid tumors are rare tumors that invade surrounding structures. Although they never metastasize mortality rate may be as high as 10% due to their aggressive local behavior. Intraabdominal desmoid tumors are usually associated with familial poliposis coli and have a high recurrence rate regardless of the therapy instituted. Sporadic cases are very rare and generous surgical excision may be of benefit. We hereby report 2 siblings with sporadic pancreatic desmoid tumors who also harbor additional fibrotic masses in the pelvis. Although in previously reported cases there is usually a triggering event such as trauma, in the present cases there was no inciting event. Furthermore, the cases are without an associated FAP history, which provides the first clinical clue of a possible genetic determinant in this rare disorder.