Past infectious events and disease evolution in multiple sclerosis.
A computerized study of past infectious events and neurological parameters revealed the existence of a history of repeated respiratory-tract infections (RRI) beginning in childhood, in 52% of 251 multiple sclerosis (MS) patients studied. The 251 MS patients were divided into two groups: those without a past history of RRI were designated as "MS type I", and those with a history of infectious problems before the onset of MS as "MS type II". Significant differences in the neurological symptoms, the treatment received and some general parameters were found between the groups, which suggested a correlation between the evolution of MS and the presence or not of RRI in these patients. When compared to the MS type I group, a significantly higher percentage of MS type II patients reported visual problems (P less than or equal to 0.01), paresthesia (P less than or equal to 0.01), loss of sensitivity (P less than or equal to 0.03), pain (P less than or equal to 0.004), motor problems (P less than or equal to 0.016) and sexual dysfunction in males (P less than or equal to 0.02). The mean number of attacks in the first 5 years of the disease was significantly more frequent in MS type II patients, 6.2 compared to 2.9 (P less than or equal to 0.02). A significantly higher percentage of MS type II patients also received oral corticosteroids (P less than or equal to 0.02) or ACTH (P less than or equal to 0.003). Although the age of onset of MS was the same for both groups, MS type II patients were significantly younger than MS type I patients, the mean age being 36 years compared to 41 years (P less than or equal to 0.001). Only 12% of patients in the MS type II group compared to 30% in the MS type I group had the disease for more than 15 years (P less than or equal to 0.001). As is usual with MS, the majority of the patients in both groups were females, 79.3% in the MS type II compared to 63.4% in the MS type I group. These findings suggest that MS patients with a past history of RRI (MS type II) have a different evolution of their disease from MS type I patients and that in general the disease is more severe. The past infectious history of patients would thus appear of putative value, in addition to neurological criteria, in assessing the probable future evolution of the disease.


Production of tetrodotoxin and its derivatives by Pseudomonas sp. isolated from the skin of a pufferfish.
Bacteria isolated from the skin of the pufferfish Fugu poecilonotus were screened for tetrodotoxin production. Tetrodotoxin and its derivatives were detected by HPLC analyses in broth cultures of a Pseudomonas sp. Upon alkali treatment the compounds yielded, as do tetrodotoxin and its derivatives, 2-amino-6-hydroxymethyl-8-hydroxyquinazoline, the identity of which was confirmed, after methylation or trimethylsilylation, by HPLC, mass spectrometry and gas chromatography - mass spectrometry.


Dorsal vascular network of the first web space. Anatomical bases of the kite flap.
Thirty dissections were performed on adult non embalmed cadavers, after vascular injection with MICROFIL or Methylene blue. In contrast to the classical descriptions of a single dorsal metacarpal artery, this study shows the existence of a vascular network with 1 or 2 vessels running over or under the deep aponeurosis. Direct cutaneous arteries provide blood supply to the kite flap when the only dorsal metacarpal vessel of the first web space is in a deep situation. The main source of blood supply to the kite flap is described in each anatomical variation of the dorsal network.


[Performance of uteroplacental perfusion in contrast to hormone-analytic investigations in intrauterine retardation and under the influence of intravenous long-term application of heparin (author's transl)].
The digital estimation of utero-placental circulation by means of nuclear-medical examinations with help of 113 m In-Cl and regarding to the "region of interest" gives no depositions in cases with an intrauterine retardation. This concerns the activity as well in the placenta as in the uterus too. Exceptions represents intrauterine retardations on the base of heaviness EPH-gestosis and placenta previa. Herewith the rise of activity corresponds with the thickness in the III. trimester of pregnancy. A treatment about several weeks with Hepain under bed conditions leads to no proofed influence of the uteroplacental circulation, on the contrary to a rise of estriol and HPL-values, meaning a improvement of placental performance. The estimation of the utero-placental circulation by means of nuclear-medical examinations is situated to the problem of fetal condition by EPH-gestosis, placenta previa and other.


A CDK-Dependent Phosphorylation of a Novel Domain of Rif1 Regulates its Function during Telomere Damage and Other Types of Stress.
Rif1 mediates telomere length, DNA replication, and DNA damage responses in budding yeast. Previous work identified several posttranslational modifications of Rif1, however none of these was shown to mediate the molecular or cellular responses to DNA damage, including telomere damage. We searched for such modifications using immunoblotting methods and the cdc13-1 and tlc1Δ models of telomere damage. We found that Rif1 is phosphorylated during telomere damage, and that serines 57 and 110 within a novel phospho-gate domain (PGD) of Rif1 are important for this modification, in cdc13-1 cells. The phosphorylation of Rif1 appeared to inhibit its accumulation on damaged chromosomes and the proliferation of cells with telomere damage. Moreover, we found that checkpoint kinases were upstream of this Rif1 phosphorylation and that the Cdk1 activity was essential for maintaining it. Apart from telomere damage, S57 and S110 were essential for Rif1 phosphorylation during the treatment of cells with genotoxic agents or during mitotic stress. We propose a speculative "Pliers" model to explain the role of the PGD phosphorylation during telomere and other types of damage.


Human papillomavirus types 2, 27, and 57 Identified in plantar verrucae from HIV-positive and HIV-negative individuals.
Although an increased prevalence of plantar verrucae has been associated with human immunodeficiency virus (HIV) infection, human papillomavirus (HPV) typing studies have not been published about this patient population. We sought to determine the prevalence of HPV types in plantar verrucae of HIV-positive (HIV+) and HIV-negative (HIV-) individuals. Thirty-nine plantar verruca lesions in 17 individuals were examined. Nine participants were HIV+ and eight were HIV-. Detection of HPV was performed by polymerase chain reaction using two sets of primers: MY09/MY11. The type of HPV was determined by hybridization to 38 different HPV types. Clinical types of verrucae were correlated to the HPV strain identified in each lesion. Of the 39 plantar verruca samples, 38 typed to HPV-2, HPV-27, and HPV-57 strains in HIV+ and HIV- individuals. Specifically, a large proportion of the samples from HIV- individuals typed as HPV-27 (87.5%), and HPV-2 was the predominant type identified in HIV+ individuals (50%). No rare or atypical HPV types were found in either group. We identified HPV-2 and HPV-27 in 96% of verruca plantaris clinical type. Mosaic warts typed to HPV-27 and HPV-57, and 80% of punctate verrucae typed to HPV-57. This study presents an increased prevalence of HPV-2, HPV-27, and HPV-57 in plantar verrucae in this study population and provides insight into the occurrence of these types in HIV+ and HIV- individuals.


Immunochemical similarity between a gastric mucosa non-pepsin acid proteinase and neutrophil cathepsin E of the rat.
Antiserum against a rat gastric mucosa non-pepsin acid proteinase precipitates rat neutrophil cathepsin E, with a precipitation curve essentially similar to that of the gastric enzyme. Taken together that the antiserum precipitates a cathepsin E-like acid proteinase from rat spleen (Muto, N., Yamamoto, M. and Tani, S. (1987) J. Biochem. (Tokyo) in press), the data indicate that the non-cathepsin D acid proteinases in rat neutrophils, gastric mucosa and spleen are immunochemically closely related. In contrast with the earlier data, cathepsin E from rabbit neutrophils exhibited a maximal activity at around pH 3.0-3.2 and preferred hemoglobin to albumin as substrate, which supports that the non-cathepsin D acid proteinases in the rat tissues are relevantly classified as cathepsin E.


Reinvestigating the clinical relevance of the m6A writer METTL3 in urothelial carcinoma of the bladder.
METTL3 is the major writer of N6-Methyladenosine (m6A) and has been associated with controversial roles in cancer. This is best illustrated in urothelial carcinoma of the bladder (UCB), where METTL3 was described to have both oncogenic and tumor-suppressive functions. Here, we reinvestigated the role of METTL3 in UCB. METTL3 knockout reduced the oncogenic phenotype and m6A levels of UCB cell lines. However, complete depletion of METTL3/m6A was not achieved due to selection of cells expressing alternative METTL3 isoforms. Systematic vulnerability and inhibitor response analyses suggested that uroepithelial cells depend on METTL3 for viability. Furthermore, expression and survival analyses of clinical data revealed a complex role for METTL3 in UCB, with decreased m6A mRNA levels in UCB tumors. Our results suggest that METTL3 expression may be a suitable diagnostic UCB biomarker, as the enzyme promotes UCB formation. However, the suitability of the enzyme as a therapeutic target should be evaluated carefully.


The deposition of hygroscopic phosphoric acid aerosols in ciliated airways of man.
The hygroscopic growth of phosphoric acid aerosol (Dc greater than 0.5 micron) within the human tracheobronchial tree is modeled to investigate changes in deposition characteristics when compared to nonhygroscopic aerosols of identical preinspired size. Phosphoric acid particles are assumed to grow in a stepwise fashion to 99% relative humidity (RH) within conducting airways of the lung, having initially reached equilibrium at 90% RH (T = 37 degrees C) in the trachea. Deposition efficiencies for growth and no growth are calculated from theoretical equations for inertial impaction, sedimentation and diffusion. The results show that neglecting the growth of an inhaled phosphoric acid aerosol may result in underestimation of the total deliverable dose by a factor of as much as 600-700%. Significant differences in regional deposition sites for hygroscopic or nonhygroscopic aerosols are predicted. Increased deposition efficiencies imply that measured physical properties (respirable fraction, aerodynamic diameter) of aerosols alone are not sufficient to assess deposition characteristics within the lung; hygroscopic growth must also be considered.


A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease.
A quantitative morphometric analysis was used to estimate neurone and synapse densities in cerebral cortical biopsy tissues from patients with dementia under 65 years of age and pathologically verified as suffering from Alzheimer's disease. Estimates of the numerical density of neurones and synapses were made in layers II-III and V of both frontal and temporal cortex. A greater loss of synapses than that of neurones was found in Alzheimer's disease, amounting to a minimum (uncorrected for atrophy) of 25% in layers II-III and 36% in layer V of the temporal cortex, and 27% in layer V of the frontal cortex. Values of synapse to neurone ratio also demonstrated this greater loss of synapses, there being on average 38% fewer synapses associated with each surviving neurone in layers II-III of the temporal cortex, 30% fewer in layer V, and a deficit of 14% in layer V of the frontal cortex. It is concluded that a major loss of synapses occurred in this group of patients with Alzheimer's disease, probably at an early stage of the disease, and that the loss is likely to form a fundamental part of the pathological process that underlies the cortical damage of this condition.


Stress, cortisol, and other appetite-related hormones: Prospective prediction of 6-month changes in food cravings and weight.
To examine whether baseline chronic stress, morning cortisol, and other appetite-related hormones (leptin, ghrelin, and insulin) predict future weight gain and food cravings in a naturalistic, longitudinal, 6-month follow-up study. A prospective community cohort of 339 adults (age 29.1 ± 9.0 years; BMI = 26.7 ± 5.4 kg/m2 ; 56.9% female; 70.2% white) completed assessments at baseline and 6-month follow-up. Fasting blood draws were used to assess cortisol and other appetite-related hormone levels at baseline. At baseline and follow-up, body weight was measured, and the Cumulative Adversity Interview and Food Craving Inventory were administered. Data were analyzed using linear mixed models adjusting for demographic and clinical covariates. Over the 6-month period, 49.9% of the sample gained weight. Food cravings and chronic stress decreased over 6 months (Ps < 0.05). However, after adjusting for covariates, individuals with higher baseline total ghrelin had significantly higher food cravings at 6 months (P = 0.04). Furthermore, higher cortisol, insulin, and chronic stress were each predictive of greater future weight gain (Ps < 0.05). These results suggest that ghrelin plays a role in increased food cravings and reward-driven eating behaviors. Studies are needed that examine the utility of stress reduction methods for normalizing disrupted cortisol responses and preventing future weight gain.


RBPJ is disrupted in a case of proximal 4p deletion syndrome with epilepsy.
Proximal 4p deletion syndrome is characterized clinically by mental retardation, minor dysmorphic facial features, and is occasionally complicated with epilepsy. More than 20 cases of proximal 4p deletion syndrome have been reported, but the causative gene(s) remain elusive. We describe here a 2-year-old female patient with a common manifestation of proximal 4p deletion syndrome and infantile epileptic encephalopathy possessing a de novo balanced translocation t(4;13)(p15.2;q12.13). The patient was diagnosed as infantile spasms at 9 months of age. She presented with dysmorphic facial features and global developmental delay, compatible with proximal 4p deletion syndrome. Using fluorescence in situ hybridization, we determined the translocation breakpoint at 4p15.2 to be within RBPJ. RBPJ is a transcription factor in the Notch/RBPJ signaling pathway, playing a crucial role in the developing human brain, and particularly telencephalon development. Our findings, combined with those of previous studies, strongly suggest that RBPJ is causative for proximal 4p deletion syndrome and epilepsy in this case.


Gaussian quantum states can be disentangled using symplectic rotations.
We show that every Gaussian mixed quantum state can be disentangled by conjugation with a passive symplectic transformation, that is a metaplectic operator associated with a symplectic rotation. The main tools we use are the Werner-Wolf condition on covariance matrices and the symplectic covariance of Weyl quantization. Our result therefore complements a recent study by Lami, Serafini, and Adesso.


Progamotaenia ruficola sp. n. (Cestoda: Anoplocephalidae) from the red kangaroo, Macropus rufus (Marsupialia).
Progamotaenia ruficola sp. n. is described from the red kangaroo (Macropus rufus) from New South Wales, Australia. It is distinguished from other similar species having paired, nondiverticulate uteri in each prolottis: Progamotaenia festiva (Rudolphi 1819), P. diaphana (Zschokke 1907), and P. macropodis Beveridge 1976, by the extremely broad, straight-edged velum, the lack of an external seminal vesicle, the cirrus armature, the number of testes, the lack of vaginal atrophy following insemination, and the morphology of the egg.


A fluorescence study of ligand-induced conformational changes in cytosolic fructose-1,6-bisphosphatase from germinating castor oil seeds.
The intrinsic fluorescence of homogeneous castor oil seed cytosolic fructose-1,6-bisphosphatase (FBPasec) was used as an indicator of conformational changes due to ligand binding. Binding of the substrate and the inhibitor fructose-2,6-bisphosphate (F-2,6-P2) was quantitatively compared to their respective kinetic effects on enzymatic activity. There are two distinct types of substrate interaction with FBPasec, corresponding to catalytic and inhibitory binding, respectively. Inhibitory substrate binding shares several characteristics with F-2,6-P2 binding which indicates that both ligands bind at the same site. However, F-2,6-P2 does not prevent fluorescence transitions attributed to catalytic substrate binding. The marked synergistic inhibition of FBPasec by AMP and F-2,6-P2 appears to arise via AMP's promotion of F-2,6-P2 binding. Based on the X-ray crystal structure of porcine kidney FBPase our modelling studies suggest the existence of a distinct F-1,6-P2/F-2,6-P2 inhibitory binding site which partially overlaps with the enzyme's catalytic site. We propose that a pronounced allosteric transition mediated by AMP binding increases access of F-1,6-P2 and F-2,6-P2 to this common inhibitory binding site.


Body mass index and the risk and prognosis of acute pancreatitis: a meta-analysis.
BMI has been indicated to be associated with prognosis of acute pancreatitis (AP). However, the relationship between BMI and the risk of AP development is still unresolved. We examined this association by conducting a detailed meta-analysis. We also assessed its prognostic role by including more researches. Studies were identified by searching MEDLINE and EMBASE through March 31, 2011. There were two end points in this meta-analysis: the risk of AP development and the outcome of AP (including severity, local complications, systemic complications, and mortality). Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. Compared with normal weight individuals, obese individuals (BMI>30 kg/m²) had an increased risk of AP development (SRRs 1.34, 95% CI: 1.07-1.68), with significant heterogeneity among these studies (P=0.002, I²=77.2%). In addition, compared with nonobese patients, obese patients developed significantly more severe AP (SRRs 1.82, 95% CI: 1.44-2.30), systemic complications (SRRs 1.71, 95% CI: 1.17-2.50), local complications (SRRs 2.32, 95%CI: 1.79-3.00), and mortality (SRRs 2.21, 95% CI: 1.28-3.83). There was no heterogeneity among these studies. Findings from this meta-analysis indicated that obesity is not only associated with an increased risk of AP development, but it is also a poor prognostic factor for AP.


Correction:Diagnostic Accuracy of Chest Computed Tomography Scans for Suspected Patients With COVID-19: Receiver Operating Characteristic Curve Analysis.
[This corrects the article DOI: 10.2196/19424.].


A comparison of human pharmaceutical concentrations in raw municipal wastewater and yellowwater.
Currently, many articles report on pharmaceutical residues detected in various compartments of the environment. A major pathway into the aquatic environment is municipal wastewater. This article discusses the relevance of yellowwater (urine) as pharmaceutical source within this wastewater stream. Literature data about concentrations of 28 pharmaceutical residues detected in raw wastewater are compared to their theoretically calculated concentrations in urine. The study shows that these pharmaceuticals and their metabolites are excreted predominantly via urine although some substances show reasonable excretion via faeces. It is demonstrated that the influence of pharmacokinetic activities is one important issue affecting the presence of pharmaceuticals in the aquatic environment. Nevertheless, only a weak correlation between concentrations of pharmaceuticals calculated in yellowwater and analysed in raw wastewater was observed. This is due to environmental effects taking place between the excretion of urine and the entrance of sewerage into the wastewater treatment plant. The data show that urine separation and separate handling/treatment of this wastewater stream represents a promising approach to protect the aquatic environment safely from human pharmaceuticals.


Frequency characteristics of the heart rate variability produced by Cheyne-Stokes respiration during 24-hr ambulatory electrocardiographic monitoring.
Spectral analysis of heart rates during 24-hr ambulatory electrocardiographic monitoring has been carried out to characterize the heart rate spectral components of Cheyne-Stokes respiration (CSR) by using fast Fourier transformation (FFT). Eight patients with congestive heart failure were selected for the study. FFT analyses have been performed for 614.4 sec. Out of the power spectrum, five parameters were extracted to characterize the CSR. The low peak frequencies in eight subjects were between 0.0179 Hz (56 sec) and 0.0081 Hz (123 sec). The algorithms used to detect CSR are the followings: (i) if the LFPA/ULFA ratios were above the absolute value of 1.0, and (ii) the LFPP/MLFP ratios were above the absolute values of 4.0, then the power spectrum is suggestive of CSR. We conclude that the automatic detection of CSR by heart rate spectral analysis during ambulatory ECG monitoring may afford a tool for the evaluation of the patients with congestive heart failure.


Hyperthermia as an early sign of intracranial hemorrhage in full-term neonates.
Intracranial hemorrhage (ICH) in full-term infants is uncommon and is a rare cause of neonatal fever. This study was conducted to estimate the incidences of ICH and fever in a hospital-based population, and to determine if the clinical features of neonatal ICH with and without hyperthermia differ. We selected 315 afebrile neonates who received cranial ultrasonography screening from 2003 to 2004 as the control group, and 153 neonates diagnosed with fever from 1998 to 2004 as the study group. During the same period, 28 full-term neonates with birth weights >2500g and ICH in the first week of life were enrolled retrospectively. They were divided into hyperthermia (n=11) and nonhyperthermia (n=17) groups. Three babies in the control group and 11 in the study group had ICH; the incidence of ICH in the hyperthermia group was significantly higher (3/315 vs. 11/153; p < 0.001). Compared with the nonhyperthermia group, the hyperthermia group had Less cyanosis (2/11 vs. 10/17; p = 0.04), Less lymphocyte predominance (33.7 vs. 80%; p = 0.032), higher neutrophil/lymphocyte ratio (1.9 vs. 0.3; p = 0.006), higher erythrocyte/leukocyte ratio (425 vs. 79.5; p = 0.05) in cerebrospinal fluid and an increased incidence of subarachnoid hemorrhage accompanied by intracerebral parenchymal hemorrhage (4/11 vs. 0/17; p = 0.016). The incidence of ICH was higher in febrile than in afebrile neonates. ICH presenting with hyperthermia might go unrecognized, because its other symptoms are subtle and a neutrophil predominance in the cerebrospinal fluid might result in a misdiagnosis of meningitis. ICH in the interior brain tended to manifest more commonly as hyperthermia than did ICH in the superficial brain. A cranial image examination should be considered in the evaluation of neonatal fever.


The impact of statistical properties of incremental monetary net benefit and incremental cost-effectiveness ratio on health economic modeling choices.
There is controversy on whether to use incremental monetary net benefit (INMB) or incremental cost-effectiveness ratio (ICER) in health economic evaluations alongside randomized controlled trials. We studied the impact of restricted mean survival time (RMST) on the long-term projection of INMB and ICER. We analyzed the unbiasedness and efficiency of ICER and INMB by (1) deriving the metrics' expected values and variances based on theoretical probability distributions, (2) simulating their 15-year post-trial projections based on between-arm-RMST-gained through a 2 × 4 × 2 factorial experiment of Markov 2-state microsimulations. Simulations and comparison were run on the data from the Cardiovascular Outcomes for People Using Anticoagulation Strategies Study (COMPASS). Our simulation findings using RMST showed that ICER was more efficient than INMB, regardless of disease populations, time horizon, modeling choices, and underlying probability distributions of incremental mean cost and effect. ICER had a small variance and thus showed its robustness to the choices of models. INMB's variance varies with a willingness-to-pay (WTP) threshold quadratically while ICER's variance with a WTP threshold value quadratically while ICER's variance with incremental-mean-cost quadratically. A simple and naïve model can sufficiently estimate ICER. Future metrics are expected to be health-economic-meaningful, unambiguous, unbiased, efficient, and statistical-inference-friendly.


Changes in lung morphology and cell number in radiation pneumonitis and fibrosis: a quantitative ultrastructural study.
We used stereologic-morphometric techniques to obtain a detailed quantitative picture of the changes in lung ultrastructure of rats at 12 and 26 weeks after unilateral thoracic irradiation with 3000 cGy. At 12 weeks post-radiation, the total number type 1 epithelial cells, type 2 epithelial cells and capillary endothelial cells were decreased 50-70%, total type 1 epithelial and capillary surface areas were decreased 55-60%, and the total volume of intracapillary blood was decreased 75%. The interstitial cells and matrix together accounted for more than 9% of the peripheral lung tissue volume including air, compared to 3% in controls. The numerical density of interstitial cells was increased to 3-fold the control value. The numerical density of interstitial cells was increased to 3-fold the control value. Although fibroblasts still comprised the largest interstitial cell subgroup, the numerical density of mast cells was increased over 150-fold and other inflammatory and immune cells were increased to a lesser extent. At 26 weeks post-radiation, the number, volume, and surface area of the type 1 epithelium and capillary endothelium had further decreased to only 5-10% of control values. The total number of type 2 epithelial cells was reduced by 75% but the volume density was actually increased because of a 4-fold increase in the mean cell volume. The interstitial cells and matrix now comprised over 77% of total peripheral lung tissue volume including air as compared to 6% in controls. Mast cells and plasma cells comprised 11% and 19% of all interstitial cells respectively and the densities of these cells were 540 and 180-fold the control value respectively. The relation of these morphometric findings to the results of previous morphologic studies is discussed.


On the stability of the Travelling Salesman Problem algorithm of Hopfield and Tank.
The application of the method of Hopfield and Tank to the Travelling Salesman Problem (1985) has been re-examined in an effort to find a procedure for scaling to system sizes of real interest. As this failed, methods were tried to improve the algorithm, recognizing the importance of a "silicon implementation". No satisfactory refinement was found, and the reasons for algorithm failure have been identified.


Lack of association between polymorphic copies of endogenous Jaagsiekte sheep retrovirus (enJSRVs) and Ovine Pulmonary Adenocarcinoma.
Ovine Pulmonary Adenocarcinoma (OPA) is a retrovirus-induced lung tumor of sheep, goat and mouflon, and its etiologic agent, Jaagsiekte sheep retrovirus (JSRV) is the only virus known to cause a naturally occurred lung adenocarcinoma. The oncogenic JSRV has several endogenous counterparts termed enJSRVs, some of which have been shown to interfere with JSRV replication at early and late stages of the retroviral cycle inhibiting JSRV exit from the cell, and thus, protecting sheep against the infection. In this work, Latxa sheep breed animals were classified depending on the presence/absence of OPA-characteristic clinical lesions in the lung. Using a PCR genotyping method and a logistic regression-based association study, five polymorphic enJSRV copies were analyzed in 49 OPA positive sheep and 124 control individuals. Our results showed that the frequency of the provirus enJSRV-16 is much higher in Latxa sheep breed than in other breeds, suggesting a recent proliferation of this provirus in the studied breed. However, no polymorphic enJSRV was found to be statistically associated with the susceptibility/resistance to OPA development.


Pharmacological evidence for glutamatergic pathway involvement in the antidepressant-like effects of 2-phenyl-3-(phenylselanyl)benzofuran in male Swiss mice.
Depression is a multifactorial and heterogeneous disease with several neurobiological mechanisms underlying its pathophysiology, including dysfunctional glutamatergic neurotransmission, which makes the exploration of the glutamate pathway an interesting strategy for developing novel rapid-acting antidepressant treatments. In the present study, we aimed to evaluate the possible glutamatergic pathway relation in the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) in Swiss mice employing the tail suspension test (TST). Male Swiss mice received drugs targeting glutamate receptors before acute SeBZF1 administration at effective (50 mg/kg) or subeffective (1 mg/kg) doses by intragastric route (ig). TST and the open-field test (OFT) were employed in all behavioral experiments. The pretreatment of mice with N-methyl-D-aspartate (NMDA) (0.1 pmol/site, intracerebroventricular, icv, a selective agonist of the NMDA receptors), D-serine (30 µg/site, icv, a co-agonist at the NMDA receptor), arcaine (1 mg/kg, intraperitoneal, ip, an antagonist of the polyamine-binding site at the NMDA receptor), and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (2,5 µg/site, icv, an antagonist of the AMPA/kainate type of glutamate receptors) inhibited the antidepressant-like effects of SeBZF1 (50 mg/kg, ig) in the TST. Coadministration of a subeffective dose of SeBZF1 with low doses of MK-801 (0.001 mg/kg, ip, a non-competitive NMDA receptor antagonist) or ketamine (0.1 mg/kg, ip, a non-selective antagonist of the NMDA receptors) produced significant antidepressant-like effects (synergistic action). These findings suggest the involvement of the glutamatergic system, probably through modulation of ionotropic glutamate receptors, in the antidepressant-like action of SeBZF1 in mice and contribute to a better understanding of the mechanisms underlying its pharmacological effects.


Synthesis, characterization and cellular mineral absorption of nanoemulsions of Rhododendron arboreum flower extracts stabilized with gum arabic.
To assess the cellular mineral uptake and oxidative stability of flower extract, a nanoscale gum arabic stabilized Rhododendron arboreum flower extract emulsion was formulated. Four different concentrations of flower extract (1-5%) were used for the optimization of the nanoemulsion. A significant (P < 0.05) difference was observed in average droplet size (43.51-55.87 nm) of the nanoemulsion. FTIR spectrum confirmed mainly C=C, aliphatic C-H, aliphatic and aromatic galacto-proteins, and polymeric-OH groups present in nanoemulsion. Smooth type of nanoemulsion was confirmed by inverted light microscopy. Ionic strength was evaluated and significant (P < 0.05) increase in particles size was attributed, whereas significant (P < 0.05) decrease in zeta potential was observed by increased NaCl concentration. Iron and calcium showed a non-significant difference in terms of mineral bioavailability. Calcium revealed significantly higher cellular uptake (52.11%) in comparison with iron (50.25%) and zinc (45.32%) during transwell assay. Higher cellular iron uptake unveiled a satisfactory amount of ferritin content.


Assessing mechanical vibration-altered wall shear stress in digital arteries.
The aim of this study is to implement and validate a method for assessing acute vibration-altered Wall Shear Stress (WSS) in the proper volar digital artery of the non-exposed left forefinger when subjecting the right hand to mechanical vibration. These changes of WSS may be involved in Vibration White Finger. Hence, an experimental device was set-up to link a vibration shaker and an ultra-high frequency ultrasound scanner. The Womersley-based WSS was computed by picking up the maximum velocity from pulse Wave Doppler measurements and extracting the artery diameter from B-mode images through an in-house image processing technique. The parameters of the former method were optimised on numerical ultrasound phantoms of cylindrical and lifelike arteries. These phantoms were computed with the FIELD II and FOCUS platforms which mimicked our true ultrasound device. The Womersley-based WSS were compared to full Fluid Structure Interaction (FSI) and rigid wall models built from resonance magnetic images of a volunteer-specific forefinger artery. Our FSI model took into account the artery's surrounding tissues. The diameter computing procedure led to a bias of 4%. The Womersley-based WSS resulted in misestimating the FSI model by roughly 10% to 20%. No difference was found between the rigid wall computational model and FSI simulations. Regarding the WSS measured on a group of 20 volunteers, the group-averaged basal value was 3 Pa, while the vibration-altered WSS was reduced to 1 Pa, possibly triggering intimal hyperplasia mechanisms and leading to the arterial stenoses encountered in patients suffering from vibration-induced Raynaud's syndrome.


Pharmacokinetics, mass balance, metabolism, and excretion of the liver-targeted acetyl-CoA carboxylase inhibitor PF-05221304 (clesacostat) in humans.
The disposition of the hepatoselective ACC inhibitor PF-05221304 (Clesacostat) was studied after a single 50-mg oral dose of [14C]-PF-05221304 to healthy human subjects.Mass balance was achieved with 89.9% of the administered dose recovered in urine and faeces, over the 11-day study period. The total administered radioactivity excreted in faeces and urine was 81.7 and 8.2%, respectively. Unchanged PF-05221304 accounted for 35.6% of the radioactive dose in faeces, suggesting ∼64% of the administered dose was absorbed.PF-05221304 was principally metabolised via oxidative and reductive pathways involving: (a) N-dealkylation, (b) isopropyl group monohydroxylation to yield enantiomeric metabolites (M2a and M2b), (c) hydroxylation on the 3-azaspiro[5.5]undecan-8-one moiety to metabolites M5 and 519c, and (d) carbonyl group reduction to enantiomeric alcohol metabolites M3, and M4. Secondary metabolites (521a, 521b, and 533), derived from a combination of oxidation and reduction of the primary metabolites accounted for ∼14.8% of the dose. In plasma, unchanged PF-05221304 represented 96.1% circulating radioactivity. Metabolites M1, M2b, and M2a represented 1.94, 1.76, and 0.18% of circulating radioactivity, respectively.Overall, these data suggest that PF-05221304 is well absorbed in humans and eliminated largely via phase I metabolism.


Na-K-2Cl cotransport in winter flounder intestine and bovine kidney outer medulla: [3H] bumetanide binding and effects of furosemide analogues.
The effects of several sulfamoyl benzoic acid derivatives on Na-K-Cl cotransport were investigated in winter flounder intestine. The relative efficacy (IC50 values) and order of potency of these derivatives were benzmetanide, 5 X 10(-8) M greater than bumetanide 3 X 10(-7) M greater than piretanide 3 X 10(-6) M greater than furosemide 7 X 10(-6) M greater than amino piretanide 1 X 10(-5) 3-amino-4-penoxy-5-sulfamoyl benzoic acid. Binding of [3H] bumetanide was studied in microsomal membranes from winter flounder intestine and compared to that in bovine kidney outer medulla. Binding was also studied in brush-border membranes from winter flounder intestine. The estimated values for Kd and number of binding sites (n) were: bovine kidney, Kd = 1.6 X 10(-7), n = 10.5 pmol/mg protein; winter flounder intestine, Kd 1.2 X 10(-7), n = 7.3 pmol/mg protein, and brush-border membranes from winter flounder, Kd = 5.3 X 10(-7), n = 20.4 pmol/mg protein. The estimated Kd for bumetanide binding to winter flounder brush-border membranes derived from association and dissociation kinetics was 6.8 X 10(-7) M. The similarity in magnitudes of IC50 and Kd for bumetanide suggests that the brush-border cotransporter is ordinarily rate-limiting for transmural salt absorption and that bumetanide specifically binds to the cotransporter. Measurement of bumetanide binding at various concentrations of Na, K and Cl showed that optimal binding required all three ions to be present at about 5 mM concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)


Rapid 40S scanning and its regulation by mRNA structure during eukaryotic translation initiation.
How the eukaryotic 43S preinitiation complex scans along the 5' untranslated region (5' UTR) of a capped mRNA to locate the correct start codon remains elusive. Here, we directly track yeast 43S-mRNA binding, scanning, and 60S subunit joining by real-time single-molecule fluorescence spectroscopy. 43S engagement with mRNA occurs through a slow, ATP-dependent process driven by multiple initiation factors including the helicase eIF4A. Once engaged, 43S scanning occurs rapidly and directionally at ∼100 nucleotides per second, independent of multiple cycles of ATP hydrolysis by RNA helicases post ribosomal loading. Scanning ribosomes can proceed through RNA secondary structures, but 5' UTR hairpin sequences near start codons drive scanning ribosomes at start codons backward in the 5' direction, requiring rescanning to arrive once more at a start codon. Direct observation of scanning ribosomes provides a mechanistic framework for translational regulation by 5' UTR structures and upstream near-cognate start codons.


A store-operated nonselective cation channel in human lymphocytes.
1. Agonist interaction with phospholipase C-linked receptors at the plasma membrane can elicit both Ca2+ and Na+ influxes in lymphocytes. While Ca2+ influx is mediated by Ca2+ release-activated Ca2+ (CRAC) channels, the pathway responsible for Na+ influx is largely unknown. 2. We show that thapsigargin, ionomycin, ADP-ribose and IP3 activated a nonselective cation channel in lymphocytes that had a slightly outwardly rectifying I-V relationship, and a single channel conductance of 23.1 pS. We termed this channel a Ca2+ release-activated nonselective cation (CRANC) channel. 3. On activation in cell-attached configuration, switching to an inside-out configuration abolished CRANC channel activity. 4. Transfection of Jurkat T cells with antisense oligonucleotides for LTRPC2 reduced capacitative Ca2+ entry. 5. These results suggest that CRANC channels are responsible for the Na+ influx as well as a portion of the Ca2+ influx in lymphocytes induced by store depletion, that sustained activation of CRANC channels requires some property of the environment of a cell depleted of its Ca2+ stores; and that LTRPC2 protein is a likely component of the CRANC channel.


Severe hypophosphatemia associated with diabetes mellitus in six dogs and one cat.
Severe hypophosphatemia was found in 6 diabetic dogs and in one diabetic cat. The cat suffered from hemolysis, and one dog had seizures, both apparently as a result of the severe hypophosphatemia. Clinical signs were not determined solely by the serum concentration of phosphorus, as seen in 5 other patients that did not have signs of disease despite similar serum phosphorus concentrations.


Cancer in developing countries: the next most preventable pandemic. The global problem of cancer.
Cancer is a global problem that accounts for almost 13% of deaths worldwide, a number similar to the 7 million deaths each year from HIV/AIDS, TB and malaria combined According to Globocan it is estimated that by 2020, there will be between 15 and 17 million new cases of cancer every year, 60% of which will be in developing countries. Moreover, the survival rates in these regions are often half those of developed countries. However, cancer is potentially the most preventable disease; with current resources, one-third of tumors could be preventable, and another one-third of newly diagnosed cancer patients could experience increased survival or early-stage detection. There have been proposed several strategies and programs to ameliorate cancer prevention and treatment in less developed countries. If all these proposed strategies are taken into consideration, worldwide cancer care, control and survival in low-income countries may improve in the years to come.


Lipid metabolism by muscle of diabetic rats.
This study was undertaken to ascertain whether enhanced oxidation of intracellular lipids could explain the impaired carbohydrate metabolism of diabetes. Pieces of diaphragms removed from diabetic (60--75 mg/kg streptozotocin i.v.) and control rats were incubated for 1 h with palmitate-1-14C. Tissue lipids from one piece were separated on silicic acid columns and the amount and specific activity of free fatty acids (FFA), triglycerides (TG) and phospholipids (PL) were measured. 14CO2 production was also assessed in some experiments. The other pieces of tissue were incubated for a subsequent hour (without radioactivity) at which time measurements of tissue lipid content and specific activity and 14CO2 production were again performed. FFA incorporation into CO2, tissue TG and PL was normal. TG content was moderately and PL content was slightly reduced in diabetic tissue. Changes in diaphragm TG and PL content and specific activity during the 2nd h of incubation strongly suggested that most of the 14CO2 produced during this period was derived from TG. Approximately 25% of tissue TG in both control and diabetic muscle was oxidized to CO2 during the 2nd h of incubation. In diaphragms from diabetic rats, (+)-octanoylcarnitine (an inhibitor of FFA oxidation) decreased TG oxidation considerably but had no effect on the impaired glucose uptake. Thus, these data do not support the hypothesis that the glucose-fatty acid cycle (utilizing either extra- or intracellular lipids) may account for the altered carbohydrate metabolism of diabetic muscle.


Validation and applicability of para-aortic lymph nodal contouring atlas in cervical cancer.
CTV delineation guidelines for the para-aortic nodal region for patients with cervical cancer have been proposed (Keenan et al., 2018). The purpose of this study was to validate these guidelines with the use of CT datasets of cervical cancer patients with macroscopic PALN treated with definitive (chemo)radiation (CTRT) at our center. Planning CT datasets of 71 cervical cancer patients with gross PA nodal disease treated with EFRT were used. Two hundred and two PALN were identified based on size and morphology on diagnostic CECT, PET CT, or histologically proven PALN. LN regions were divided into upper, middle, and lower and based on their relation to the aorta and IVC. Macroscopic PALN were contoured, and the CTV for PALN irradiation was generated based on the proposed guidelines on ECLIPSE (Version 13.5). The centre of mass (COMN) was calculated for each gross PALN. The evaluation was done to review the presence of COMN in relation to the CTV PALN. The most common location of PALN was Left para-aortic (105 LN-52%), Aortocaval (55 LN-27.2%), and Precaval (14 LN-6.9%). Lower PALN were the commonest (104 LN-51.5%). Ninety-three were middle PALN (46%), and 5 were upper PALN (2.5%). After excluding upper PALN, COMN for 11 PALN (5.5%) were outside the CTV while 20 were junctional. Our study shows that more than 95% of PALN in this patient cohort were covered using these guidelines with the addition of an extra 5 mm margin laterally on the left.


Column-switching high-performance liquid chromatographic (HPLC) determination of hydrochlorothiazide in rat, dog, and human plasma.
A fully automated HPLC assay for hydrochlorothiazide in plasma has been developed using a column-switching technique. The method involves direct injection of plasma to the extraction column for sample cleanup followed by switching onto the analytical column. Good precision, accuracy, and linearity were obtained over a range of 25 to 2000 ng/ml in rat, dog, and human plasma. The column-switching method has also been validated by comparison with a conventional HPLC method requiring a cumbersome plasma extraction procedure. Since the method is simple, rapid, and reproducible, it is useful for determination of hydrochlorothiazide levels in animal and human plasma.


Tissue-specific mechanisms of alternative polyadenylation: Testis, brain, and beyond (2018 update).
Alternative polyadenylation (APA) is how genes choose different sites for 3' end formation for mRNAs during transcription. APA often occurs in a tissue- or developmental stage-specific manner that can significantly affect gene activity by changing the protein product generated, the stability of the transcript, its localization within the cell, or its translatability. Despite the important regulatory effects that APA has on tissue-specific gene expression, only a few examples have been characterized mechanistically. In this 2018 update to our 2010 review, we examine mechanisms for the control of APA and update our understanding of the older mechanisms since 2010. We once postulated the existence of tissue-specific factors in APA. However, while a few tissue-specific polyadenylation factors are known, the emerging conclusion is that the majority of APA is accomplished by altering levels of core polyadenylation proteins. Examples of those core proteins include CSTF2, CPSF1, and subunits of mammalian cleavage factor I. But despite support for these mechanisms, no one has yet documented any of these proteins changing in either a tissue-specific or developmental manner. Given the profound effect that APA can have on gene expression and human health, improved understanding of tissue-specific APA could lead to numerous advances in gene activity control. This article is categorized under: RNA Processing > 3' End Processing RNA in Disease and Development > RNA in Development.


Bioinspired self-healing injectable nanocomposite hydrogels based on oxidized dextran and gelatin for growth-factor-free bone regeneration.
Hydrogels with great biocompatibility, biodegradability, and mechanical properties, combined with osteoconductivity, osteoinductivity, and osteointegration as biomaterials for bone regeneration without adding exogenous growth factors and cells are highly appealing but challenging. Here, inspired by organic-inorganic analogues of natural bone tissue and the adhesion chemistry of mussels, nanocomposite hydrogels with self-healing, injectable, adhesive, antioxidant, and osteoinductive properties (termed GO-PHA-CPs) were constructed by Schiff base cross-linking between dopamine-modified gelatin (Gel-DA) and oxidized dextran (ODex). Furthermore, the hydrogel network was enhanced by the introduction of polydopamine-functionalized nanohydroxyapatite (PHA) by improving the interfacial compatibility between the rigid inorganic particles and the flexible hydrogel matrix. Bioactive cod peptides (CPs) with osteogenic activity from Atlantic cod were further incorporated into the nanocomposite hydrogel. As a result, the multicomponent nanocomposite hydrogel favored the adhesion and spreading of MC3T3-E1 cells. The increased ALP activity suggested that GO-PHA-CPs hydrogels contributed to the osteogenic differentiation of MC3T3-E1 cells. The suitability of GO-PHA-CPs hydrogels for enhancing bone regeneration in vivo was further confirmed by the rat femoral defect model. Our results indicate that the multifunctional GO-PHA-CPs nanocomposite hydrogels without growth factors are a promising and effective candidate material for bone regeneration.


Efficacy and Safety of Interferon-Gamma in Chronic Granulomatous Disease: a Systematic Review and Meta-analysis.
Chronic granulomatous disease (CGD) is a primary immunodeficiency with increased susceptibility to several bacteria, fungi, and mycobacteria, caused by defective or null superoxide production by the NADPH oxidase enzymatic complex. Accepted treatment consists mainly of antimicrobial prophylaxis. The role of human recombinant subcutaneous interferon-gamma (IFNγ) is less clear since the available evidence on its efficacy derives mainly from a single clinical trial that has been challenged. We aimed to assess the efficacy and safety of IFNγ as an added treatment for CGD when compared to antimicrobial prophylaxis alone. A literature search was conducted using MeSH terms "Chronic granulomatous disease" AND ("interferon gamma" OR "interferon-gamma"), as well as antibiotics, placebo, no therapy, clinical trial, and trial, on MEDLINE, EMBASE, LILACS, WHOs, CENTRAL, KOREAMED, The Cochrane Library, clinicaltrials.gov, and abstracts from meetings, from 1976 to July 2022. We included clinical trials (CT) and prospective follow-up studies and registered the number of serious infections (requiring hospitalization and IV antibiotics) and deaths, adverse events, and autoimmune complications, in patients treated for CGD with antimicrobial prophylaxis plus IFN-γ, versus antimicrobial prophylaxis alone. We assessed the quality of the studies using risk of bias and STROBE. We performed a meta-analysis by calculating both Peto's odds ratio (OR) and risk reduction (RR) through the Mantel-Haenszel method with a fixed-effect model, using Review Manager 5.4, and we reported the number needed to treat (NNT). We identified 54 matches from databases and 4 from other sources. We excluded 12 duplicates, 7 titles, and 9 abstracts for relevance, after which we had 30 eligible studies. Twenty-four were then excluded after reading the full text. Six papers were included: one randomized CT and 5 follow-up studies. In total, 324 patients with Chronic granulomatous disease were followed for 319 months under treatment with antibiotic prophylaxis plus interferon-gamma or placebo (or antibiotic prophylaxis alone), reported between the years 1991 and 2016. Three of the studies included a control group, allowing for the aggregate analysis of efficacy (prevention of serious infections). The aggregate OR was 0.49, with a 95% confidence interval of 0.19 to 1.23. The risk ratio for serious infection was 0.56 (95%CI 0.35-0.90) under IFN-γ. The meta-analysis thus favors interferon-gamma for a risk reduction of serious infection. The results from this meta-analysis support the use of IFN-γ in the treatment of patients with CGD. However, we found insufficient clinical evidence and believe more clinical trials are needed to better assess the efficacy and long-term safety of IFN-γ.


Thin-film metallic glass: an effective diffusion barrier for Se-doped AgSbTe2 thermoelectric modules.
The thermal stability of joints in thermoelectric (TE) modules, which are degraded during interdiffusion between the TE material and the contacting metal, needs to be addressed in order to utilize TE technology for competitive, sustainable energy applications. Herein, we deposit a 200 nm-thick Zr-based thin-film metallic glass (TFMG), which acts as an effective diffusion barrier layer with low electrical contact resistivity, on a high-zT Se-doped AgSbTe2 substrate. The reaction couples structured with TFMG/TE are annealed at 673 K for 8-360 hours and analyzed by electron microscopy. No observable IMCs (intermetallic compounds) are formed at the TFMG/TE interface, suggesting the effective inhibition of atomic diffusion that may be attributed to the grain-boundary-free structure of TFMG. The minor amount of Se acts as a tracer species, and a homogeneous Se-rich region is found nearing the TFMG/TE interface, which guarantees satisfactory bonding at the joint. The diffusion of Se, which has the smallest atomic volume of all the elements from the TE substrate, is found to follow Fick's second law. The calculated diffusivity (D) of Se in TFMG falls in the range of D~10-20-10-23(m2/s), which is 106~107 and 1012~1013 times smaller than those of Ni [10-14-10-17(m2/s)] and Cu [10-8-10-11(m2/s)] in Bi2Te3, respectively.


SARS-CoV-2 intra-host diversity, antibody response, and disease severity after reinfection by the variant of concern Gamma in Brazil.
The rapid spread of the SARS-CoV-2 Variant of Concern (VOC) Gamma in Amazonas during early 2021 fueled a second large COVID-19 epidemic wave and raised concern about the potential role of reinfections. Very few cases of reinfection associated with the VOC Gamma have been reported to date, and their potential impact on clinical, immunological, and virological parameters remains largely unexplored. Here we describe 25 cases of SARS-CoV-2 reinfection in Brazil. SARS-CoV-2 genomic analysis confirmed that individuals were primo-infected with distinct viral lineages between March and December 2020 (B.1.1, B.1.1.28, B.1.1.33, B.1.195, and P.2) and reinfected with the VOC Gamma between 3 to 12 months after primo-infection. We found a similar mean cycle threshold (Ct) value and limited intra-host viral diversity in both primo-infection and reinfection samples. Sera of 14 patients tested 10-75 days after reinfection displayed detectable neutralizing antibodies (NAb) titers against SARS-CoV-2 variants that circulated before (B.1.*), during (Gamma), and after (Delta and Omicron) the second epidemic wave in Brazil. All individuals had milder or no symptoms after reinfection, and none required hospitalization. These findings demonstrate that individuals reinfected with the VOC Gamma may display relatively high RNA viral loads at the upper respiratory tract after reinfection, thus contributing to onward viral transmissions. Despite this, our study points to a low overall risk of severe Gamma reinfections, supporting that the abrupt increase in hospital admissions and deaths observed in Amazonas and other Brazilian states during the Gamma wave was mostly driven by primary infections. Our findings also indicate that most individuals analyzed developed a high anti-SARS-CoV-2 NAb response after reinfection that may provide some protection against reinfection or disease by different SARS-CoV-2 variants.


Nitrogen isotope signature evidences ammonium deprotonation as a common transport mechanism for the AMT-Mep-Rh protein superfamily.
Ammonium is an important nitrogen (N) source for living organisms, a key metabolite for pH control, and a potent cytotoxic compound. Ammonium is transported by the widespread AMT-Mep-Rh membrane proteins, and despite their significance in physiological processes, the nature of substrate translocation (NH3/NH4+) by the distinct members of this family is still a matter of controversy. Using Saccharomyces cerevisiae cells expressing representative AMT-Mep-Rh ammonium carriers and taking advantage of the natural chemical-physical property of the N isotopic signature linked to NH4+/NH3 conversion, this study shows that only cells expressing AMT-Mep-Rh proteins were depleted in 15N relative to 14N when compared to the external ammonium source. We observed 15N depletion over a wide range of external pH, indicating its independence of NH3 formation in solution. On the basis of inhibitor studies, ammonium transport by nonspecific cation channels did not show isotope fractionation but competition with K+. We propose that kinetic N isotope fractionation is a common feature of AMT-Mep-Rh-type proteins, which favor 14N over 15N, owing to the dissociation of NH4+ into NH3 + H+ in the protein, leading to 15N depletion in the cell and allowing NH3 passage or NH3/H+ cotransport. This deprotonation mechanism explains these proteins' essential functions in environments under a low NH4+/K+ ratio, allowing organisms to specifically scavenge NH4+. We show that 15N isotope fractionation may be used in vivo not only to determine the molecular species being transported by ammonium transport proteins, but also to track ammonium toxicity and associated amino acids excretion.


Cells in somatosensory areas show synchrony with beta oscillations in monkey motor cortex.
Oscillatory synchronization between somatosensory and motor cortex has previously been reported using field potential recordings, but interpretation of such results can be confounded by volume conduction. We examined coherence between single-unit discharge in somatosensory/parietal areas and local field potential from the same area as the unit, or from the motor cortex, in two macaque monkeys trained to perform a finger movement task. There were clear coherence peaks at approximately 17.5 Hz for cells in the primary somatosensory cortex (both proprioceptive and cutaneous areas) and posterior parietal cortex (area 5). The size of coherence in all areas was comparable to previous reports analysing motor cortical cells and M1 field potentials. Many coherence phases clustered around -pi/2 radians, indicating zero lag synchronization of parietal cells with M1 oscillatory activity. These results indicate that cells in somatosensory and parietal areas have information about the presence of oscillations in the motor system. Such oscillatory coupling across the central sulcus may play an important role in sensorimotor integration of both proprioceptive and cutaneous signals.


Autoimmune diseases during treatment with immunomodulatory drugs in multiple myeloma: selective occurrence after lenalidomide.
Immunomodulatory drugs (IMiDs) may favor autoimmune disease (AD) occurrence. We conducted a retrospective study to evaluate AD occurrence among IMiD-treated patients with myeloma. Patients were grouped into three classes depending on the type of IMiD engaged. The first group included patients treated with thalidomide (Thal) (n = 474), the second group with lenalidomide (Len) (n = 140) and patients in the third group were first treated with Thal followed by Len (Thal-Len) (n = 94). Absolute risk of AD was 0.4% for patients treated with Thal, 4.3% for Len and 1.1% for Thal-Len. ADs manifested prevalently as autoimmune cytopenias (55%), although we observed one vasculitis, one optic neuritis, one Graves' disease and one polymyositis. ADs occurred preferentially in the first months of IMiD treatment. A previous autologous transplant was shown to be a significant risk factor. All ADs were managed with IMiD discontinuation and steroids, resolving in a few weeks, except for Graves' disease and polymyositis.


Correction: Environmentally responsive hydrogel composites for dynamic body thermoregulation.
Correction for 'Environmentally responsive hydrogel composites for dynamic body thermoregulation' by M. Garzón Altamirano et al., Soft Matter, 2023, 19, 2360-2369, https://doi.org/10.1039/D2SM01548J.


Down to atomic-scale intracellular water dynamics.
Water constitutes the intracellular matrix in which biological molecules interact. Understanding its dynamic state is a main scientific challenge, which continues to provoke controversy after more than 50 years of study. We measured water dynamics in vivo in the cytoplasm of Escherichia coli by using neutron scattering and isotope labelling. Experimental timescales covered motions from pure water to interfacial water, on an atomic length scale. In contrast to the widespread opinion that water is 'tamed' by macromolecular confinement, the measurements established that water diffusion within the bacteria is similar to that of pure water at physiological temperature.


Repetitive transcranial magnetic stimulation protects hippocampal plasticity in an animal model of depression.
Despite its therapeutic success in treating mood-related disorders, little is known about the mechanism by which repetitive transcranial magnetic stimulation (rTMS) alters physiological responses of neurons. Using the forced swim test (FST) in rats as a model of depression, we tested the protective effect of rTMS on synaptic plasticity, specifically, on the induction of hippocampal long-term potentiation (LTP). Male Sprague-Dawley rats were subjected to FST to induce immobility, a behavioral symptom of depression. They were subsequently treated with one of the three conditions: rTMS (rTMS: 1000 stimuli at 10Hz), sham rTMS (SHAM: acoustic stimulation only), or an antidepressant drug, fluoxetine (FLX: 10mg/kg, i.p.) for 7 days. There was a significant difference in immobility time between rTMS and SHAM groups after 7 days of treatment, but not after a single day. Following the second swim test on day 7, they were anesthetized and LTP was induced in vivo in the perforant path-dentate gyrus synapses. Another group (NAIVE) that had received no prior treatment was used as a control for LTP. The SHAM or FLX group exhibited little signs of LTP induction. On the contrary, the rTMS and NAIVE group showed a significant increase in field excitatory postsynaptic potentials after LTP induction. These results show that rTMS has an antidepressant-like effect after a relatively short period of treatment, and this effect might be mediated by a cellular process that can potentially reverse the impaired synaptic efficacy caused by the forced swim procedure.


Efficacy and safety of topical brepocitinib for the treatment of mild-to-moderate atopic dermatitis: a phase IIb, randomized, double-blind, vehicle-controlled, dose-ranging and parallel-group study.
Atopic dermatitis (AD) is a prevalent inflammatory, pruritic skin disease. The Janus kinase (JAK) pathway is a treatment target. To assess the efficacy, safety and pharmacokinetics of topical cream brepocitinib, a small-molecule tyrosine kinase 2 (TYK2)/JAK1 inhibitor, in participants with mild-to-moderate AD. In this phase IIb, double-blind, dose-ranging study, participants were randomized to receive one of eight treatments for 6 weeks: brepocitinib 0·1% once daily (QD), 0·3% QD or twice daily (BID), 1·0% QD or BID, 3·0% QD, or vehicle QD or BID. The primary endpoint was the percentage change from baseline in the Eczema Area and Severity Index (EASI) total score at week 6. Adverse events (AEs) were monitored. Overall, 292 participants were enrolled and randomized. The brepocitinib 1% QD and 1% BID groups achieved statistically significantly greater (with multiplicity-adjusted P < 0·05 due to Hochberg's step-up method) percentage reductions from baseline in EASI total score at week 6 [least squares mean (90% confidence interval, CI): QD: -70·1 (-82·1 to -58·0); BID: -75·0 (-83·8 to -66·2)] compared with respective vehicle [QD: -44·4 (-57·3 to -31·6); BID: -47·6 (-57·5 to -37·7)]. There was not a dose-dependent trend in AE frequency, and there were no serious AEs or deaths. Topical brepocitinib is effective and well tolerated in participants with mild-to-moderate AD. What is already known about this topic? Janus kinase (JAK) inhibitors are in development for treatment of atopic dermatitis (AD). The tyrosine kinase 2 and JAK 1 inhibition by brepocitinib may bring a new profile for topical JAK inhibitors for treatment of mild-to-moderate AD. What does this study add? Topical brepocitinib can provide rapid, effective symptom reduction, and could offer a novel alternative to current topical treatments for mild-to-moderate AD.


The effect of towing a range of relative resistances on sprint performance.
The aim of this study was to compare sprint performance over 10 and 20 m when participants ran while towing resistances, weighing between 0 and 30% of body mass. The sample of 33 participants consisted of male rugby and soccer players (age 21.1 +/- 1.8 years, body mass 83.6 +/- 13.1 kg, height 1.82 +/- 0.1 m; mean +/- s). Each participant performed two sets of seven sprints over 20 m using a Latin rectangular design. The times were recorded at 10 and 20 m using electronic speed gates. The sprints of 13 players were video-recorded to allow calculation of stride length and frequency. For both sprints, a quadratic relationship was observed between sprint time and resistance as sprint time increased from 2.94 s to 3.80 s from 0 to 30% resistance. This relationship was statistically significant but considered not to be meaningful for performance because, over the range of resistances used in this study, the quadratic model was never more than 1% (in terms of sprint time) from the linear model. As resistance increased, the stride length shortened, with mean values of 1.63 +/- 0.13 m at 0% body mass and 1.33 +/- 0.13 m at 30% of body mass. There was no significant change in stride frequency with increasing resistance. The results show that in general there is an increase in sprint time with an increase in resistance. No particular resistance in the range tested (0 - 30%) can be recommended for practice.


Lymphocyte radiosensitivity correlated with pelvic radiotherapy morbidity.
To test the hypothesis that, before treatment, prostate cancer patients who demonstrate a high yield of ex vivo radiation-induced micronucleus (MN) in G(0) lymphocytes represent a patient population with a greater-than-average risk of developing radiotherapy (RT)-related morbidity. We prospectively conducted the cytokinesis-block MN assay of peripheral blood lymphocytes (PBLs) in 38 prostate cancer patients. Before the initiation of RT, PBLs from each patient were irradiated (1-4 Gy). The mean patient age +/- SEM was 68.7 +/- 1.0 years. The clinical stage was T1 in 17, T2 in 15, and T3 in 6. The preoperative prostate-specific antigen level was < or =4 ng/mL in 5, 4-10 ng/mL in 18, and >10 ng/mL in 15. All patients underwent standardized pelvic external beam radiotherapy (range 41.4-50.4 Gy) and boost (range 16-26 Gy). The mean follow-up +/- SEM was 32.8 +/- 4.6 months. At the end of follow-up, a radiation oncologist scored the GI or GU morbidity according to the Radiation Therapy Oncology Group criteria without knowledge of the MN data. We found that between the average reactors (n = 25; i.e., patients who had Grade 1 or less RT-related morbidity) and over reactors (n = 13; i.e., patients who developed Grade 2 or greater RT-related morbidity), the differences in the ex vivo radiation dose-response relationship of MN yield in PBLs were highly significant, especially at doses of > or =2 Gy. Also, the development of RT-related morbidity correlated with the radiation dose-response relationship of MN yield in PBLs before treatment, but did not correlate with any of the patients' clinical variables. Our findings suggest that the pre-RT ex vivo radiation dose-response relationship of MN yield in PBLs may be a significant predictive factor for the development of GI or GU morbidity in prostate cancer patients after pelvic RT.


The Association Between Cochlear and Retrocochlear Disorders with Tinnitus with Normal Hearing Thresholds.
Tinnitus is the perception of hearing the sound without any sound stimulus. It is a symptom of abnormality in a form of conductive disorder when it comes from the outer ear canal and middle ear. A tinnitus complaint has a normal hearing threshold but it has been not fully recognized its causes. Thus, an objective evaluation is needed to locate the abnormality by using OAE and BERA test. To analyze the association of TEOAE, DPOAE, and BERA to locate cochlear and retrocochlear disorders in tinnitus patients with normal hearing threshold. The study was conducted from August to November 2010 until the number of samples was fulfilled in Outpatient Clinic and Audiology Unit in Department of Otolaryngology-Head and Neck Surgery, Dr. Soetomo General Hospital Surabaya. The inclusion criteria in this study included: patients aged 20-50 years old, hearing threshold of ≤ 25 dB, type A tympanogram. The comparison and the association test of TEOAE, DPOAE and BERA in tinnitus group were: TEOAE-BERA analysis result using Mc Nemar obtained p = 0.006, Kappa p = 0.047, likelihood ratio p = 0.066, and the result of DPOAE-BERA analysis using Mc Nemar obtained p = 0.008, Kappa p = 0.439, likelihood ratio p = 0.336. There was a difference in the results of DPOAE examination between tinnitus patients with normal hearing threshold and the control group. There was no difference in TEOAE and BERA test results between tinnitus patients with normal hearing threshold and the control group. This indicates an abnormality in the cochlear.


Management of calcium pyrophosphate crystal deposition disease: A systematic review.
Calcium pyrophosphate crystal deposition disease (CPPD) is a common cause of acute and chronic arthritis, especially in the elderly population. There is a paucity of data regarding the management of CPPD disease, which is currently based on expert opinion and evidence derived from the treatment of gout. We conducted a systematic literature review in order to identify the available treatment options for CPPD, and describe their efficacy and safety. Online databases were searched from inception to May of 2020 using the search terms: (CPPD [Title/Abstract] OR CPDD [Title/Abstract] OR calcium pyrophosphate [Title/Abstract] OR chondrocalcinosis [Title/Abstract]) AND (treatment [Title/Abstract] OR management [Title/Abstract] OR therapy [Title/Abstract]). Articles evaluating the use of specific treatment agents for CPPD were eligible for inclusion. Case reports were excluded. A total of 22 eligible studies and 403 unique patients were selected. We identified only 3 randomized, double-blind, controlled trials (RCTs) evaluating the use of methotrexate, hydroxychloroquine, and magnesium carbonate in CPPD, and these therapeutic options, with the exception of methotrexate, have shown efficacy and reduction of pain intensity. Further, 10 case series and 9 cohort studies were included. Intramuscular and intra-articular glucocorticoids, ACTH, as well as the biologic agents anakinra and tocilizumab appear to be efficacious in CPPD. Intra-articular injections of glycosaminoglycan polysulphate, hyaluronic acid and yttrium, as well as synovial membrane destruction by laser irradiation were associated with symptomatic improvement. Due to significant study heterogenicity, direct comparison between studies was not possible. There are a limited number of studies evaluating the treatment of CPPD. High quality evidence is rather limited, while commonly administered agents such as NSAIDs, colchicine and corticosteroids have not been evaluated by RCTs. The need for high quality evidence supporting specific treatment modalities is urgent for this common yet neglected form of arthritis.


A quantitative method for assessing the quality of meibomian glands.
Meibomian gland dysfunction is a common cause of dry eye syndrome which can also lead to eyelid inflammation. Today, diagnostics of meibomian glands is not fully automatic yet and is based on a qualitative assessment made by an ophthalmologist. Therefore, this article proposes a new automatic analysis method which provides a quantitative assessment of meibomian gland dysfunction. The new algorithm involves a sequence of operations: image acquisition (acquisition of data from OCULUS Keratograph® 5M); image pre-processing (image conversion to gray levels, median filtering, removal of uneven lighting, normalization); main image processing (binarization, morphological opening, labeling, Gaussian filtering, skeletonization, distance transform, watersheds). The algorithm was implemented in Matlab with Image Processing Toolbox (Matlab: Version 22.214.171.1244, R2010b) on a PC running Windows 7 Professional, 64-bit with the Intel Core i7-4960X CPU @ 3.60GHz. The algorithm described in this article has the following features: it is fully automatic, provides fully reproducible results - sensitivity of 99.3% and specificity of 97.5% in the diagnosis of meibomian glands, and is insensitive to parameter changes. The time of image analysis for a single subject does not exceed 0.5s. Currently, the presented algorithm is tested in the Railway Hospital in Katowice, Poland.


Differences in cerebral reperfusion and oxidative injury after cardiac arrest in pigs.
An investigation of the free radical scavenger sodium 2-sulfophenyl-N-tert-butyl nitrone (S-PBN) and the weak vasodilatator Tris buffer mixture (TBM) on cerebral cortical blood flow (CCBF) and the jugular bulb concentration of two eicosanoids, indicators of oxidative stress and inflammation, was undertaken in 30 anaesthetized piglets during cardiopulmonary resuscitation (CPR) and after restoration of spontaneous circulation (ROSC). Thirty animals were subjected to 8 min of untreated circulatory arrest followed by 8 min of closed-chest CPR. During CPR, the animals were randomized to receive 60 mg/kg S-PBN, 1 mmol/kg TBM or 2 ml/kg normal saline (n = 10 in each group). Systemic haemodynamic variables, CCBF and jugular bulb plasma concentrations of 8-iso-PGF2alpha and 15-keto-dihydro-PGF2alpha were measured. The CCBF during reperfusion after ROSC was greater in the TBM group than in the S-PBN group, the regression coefficient between CCBF and mean arterial blood pressure being lower in the S-PBN group than in the TBM group. The jugular bulb plasma concentration of 8-iso-PGF2alpha during the first 30 min after ROSC was greater in the TBM group than in the S-PBN group. Administration of TBM after vasopressin did not attenuate the pressor effect of vasopressin. Administration of S-PBN during CPR results in less cerebral oxidative stress, possibly by promoting normal distribution of cerebral blood flow.


Reverse painting highlights the origin of chromosome aberrations.
Reverse chromosome painting, as the opposite of forward chromosome painting, means that an abnormal chromosome of interest is recovered by flow sorting or by chromosome microdissection, amplified and labelled by DOP-PCR and hybridized onto normal metaphases of optimal quality. This provides rapid and unequivocal information about the chromosomal origin on the aberrant chromosome in one hybridization. Not only will the specific chromosome(s) involved be identified, but also the subchromosomal origin, including the breakpoints. The method has been used for over 10 years and has proven to be very useful for resolving complex chromosome rearrangements in a variety of different applications, both as a research tool and for clinical purposes in pre- and postnatal diagnosis.


Long-term follow-up after intertrochanteric varus osteotomy for haemophilic arthropathy of the hip.
In view of an increasing tendency in prosthetic management of haemophilic arthropathy, we intended to evaluate the efficacy of corrective osteotomy of the hip, specifically taking long-term clinical and radiographic results into consideration. Eleven hips affected by haemarthropathy in nine patients suffering from severe haemophilia A were treated with an intertrochanteric varus osteotomy. The average follow-up period was 15 small middle dot4 years. The preoperative clinical score of the Advisory Committee of the World Federation of Haemophilia was 5 small middle dot3 points (range 4-7) and the Pettersson score was 6 small middle dot4 points (range 2-10). The average WFH score at follow-up had increased to 3 small middle dot6 points. Seven hips showed clinical improvement, two hips showed a postoperative deterioration while a further two hips remained unchanged. The Petterson score increased to an average of 7 small middle dot7 points. Here the radiographs of six patients indicated postoperative deterioration, three remained unaltered and two showed improvement. Our study cannot conclusively answer whether intertrochanteric varus osteotomy for haemophilic arthropathy of the hip is always a feasible alternative to joint arthroplasty. The decision for or against this procedure must be individually assessed and the patient must be thoroughly informed about the advantages and disadvantages of both procedures.


Distribution in spleen subcellular organelles of sialidase active towards natural sialogylcolipid and sialoglycoprotein substrates.
A procedure was devised for the preparation of enriched populations of subcellular organelles from homogenized bovine spleen. The fractions obtained were characterized for arylsulfatase, succinate dehydrogenase, UDPgalactosyltransferase and 5'-nucleotidase activities. The distribution of sialidase (acylneuraminyl hydrolase, EC 184.108.40.206) activity directed towards either endogenous substrate or exogenous ganglioside substrate suggests that it is enriched in the plasma membrane/microsomal fractions. Sialidase activity towards exogenous sialoglycoproteins, isolated from erythrocyte membrane, was enriched in the least dense of the plasma membrane/microsomal-containing fractions. The endogenous sialidase substrates were primarily the sialoglycolipids, hematoside and disialogangliosides. At the pH optimum, 3.8, and 37 degrees C, release of endogenous sialic acid was linear with time for 3 h. At the end of this time, 85% or more of the available endogenous substrate was hydrolyzed.


Outcomes and changes in code status of patients with acute myeloid leukemia undergoing induction chemotherapy who were transferred to the intensive care unit.
Patients with Acute Myeloid Leukemia (AML) have compromised marrow function and chemotherapy causes further suppression. As a result complications are frequent, and patients may require admission to the intensive care unit (ICU). How codes status changes when these events occur and how those changes influence outcome are largely unknown. Outcomes for adult patients with AML, undergoing induction chemotherapy, and transferred to the ICU between January 2000 and December 2013 were analyzed. 94 patients were included. Median survival was 1.3 months. At 3 and 6 months overall survival (OS) was 27% and 18% respectively. Respiratory failure was the most common reason for transfer to ICU (88%), with 63% requiring mechanical ventilation at transfer. Other reasons included: cardiac arrest (18%), septic shock (17%), hypotension (9%), and acute renal failure (9%). The most frequent interventions were mechanical ventilation in 85%, vasopressors in 62%, and hemodialysis in 30%. Following transfer 55 patients (58%) had a change in code status. Overall, 46 patients (49%) changed from Full Code (FC) to Comfort Care (CC), 7 (7%) from FC to Do Not Resuscitate (DNR), and 2 (2%) from DNR to CC. For the entire cohort, ICU mortality (IM) was 61% and hospital mortality (HM) was 71%. For FC or DNR patients, IM was 30% and HM was 41%. For CC patients, IM was 90% and HM was 100%. Overall, 27 patients (29%) survived to discharge. Of those discharged, 22 (81%) were alive at 3 months and 17 (63%) were alive at 6 months. In conclusion, patients that required ICU admission during induction chemotherapy have a poor prognosis. Code status changed during the ICU stay for the majority of patients and always to a less aggressive status.


The case of pulmonary tuberculosis with COVID-19 in an Indian male-a first of its type case ever reported from South Asia.
We report the first case of tuberculosis with COVID-19 from South Asia. The patient was a 43 years old Indian male. He reported to us in the outpatient department with chief complaints of cough with expectoration associated with fever, chest pain, and night sweats. The diagnosis of tuberculosis in the current pandemic of COVID-19 required a high degree of suspicion to rule out the SARS-CoV-2 infection along with the infection of Mycobacterium tuberculosis. The clinical presentations in the two diseases are quite similar and thus the present case will serve as a tool to help the clinicians handling cases of both the viral and bacterial infection across the globe.


Combined Orthodontic-Surgical Treatment May Be an Effective Choice to Improve Oral Health-Related Quality of Life for Individuals Affected With Severe Dentofacial Deformities.
Effect of conventional combined orthodontic-surgical treatment on oral health-related quality of life: A systematic review and meta-analysis. Yi J, Lu W, Xiao J, Li X, Li Y, Zhao Z. Am J Orthod Dentofacial Orthop 2019; 156:29-43. Government National Natural Science Foundation of China (grant 81801018) and Orthodontic National Key Clinical Specialty Program of China, West China Hospital of Stomatology, Sichuan University. Systematic review with meta-analysis.


A meta-analysis approach to the effects of fish farming on soft bottom polychaeta assemblages in temperate regions.
Marine fish farms could cause environmental disturbances on the sediment due to uneaten food and fish faeces that impact the marine benthos. Polychaete assemblages are considered good indicators of environmental perturbations. The present study aimed to establish groups of polychaetes as potential indicators of fish farm pollution. This study was carried out in ten fish farms along the Spanish coast. Changes in polychaete assemblage were analyzed with meta-analysis and multivariate techniques. Abundance, richness and diversity showed significant decreases under fish farm conditions. Distribution patterns of polychaetes responded to combinations of physicochemical variables. The main ones are sulfide concentration, silt and clays percentage, and stable nitrogen isotope ratio. The results showed that some families are tolerant, Capitellidae, Dorvilleidae, Glyceridae, Nereididae, Oweniidae and Spionidae; while others are sensitive to fish farm pollution, Magelonidae, Maldanidae, Nephtyidae, Onuphidae, Paralacydoniidae, Paraonide, Sabellidae and also Cirratulidae in spite of being reported as a tolerant family.


Rapid determination of DNA synthesis in adherent cells grown in microtiter plates.
A specific, rapid, and economical method for measuring the extent of DNA synthesis in adherent rat hepatoma H4-II-E cells grown in 96-well microtiter plates is described. The adherent cells were pulsed for 1 h with [methyl-3H]thymidine, released from the substratum by trypsinization, and collected on fiberglass filters with a MASH II cell harvester. The amount of radioactivity incorporated was directly proportional to the number of cells per well. Growth curves generated by measuring [methyl-3H]thymidine incorporation and counting the number of cells per well were identical. Experiments with inhibitors of DNA, protein, and RNA synthesis demonstrated that this method selectively measured DNA synthesis. In addition, [3H]thymidine uptake showed excellent correlation with autoradiographic assessment of DNA synthesis. This specific and sensitive method for determining DNA synthesis in microtiter cultures should facilitate studies of effects of various growth-controlling agents on epithelial, fibroblastic, and other cells which grow as adherent cells in culture.


Design, synthesis and biological evaluation of novel pyrimidine, 3-cyanopyridine and m-amino-N-phenylbenzamide based monocyclic EGFR tyrosine kinase inhibitors.
36 new compounds with the typical skeleton of 4-anilino-5-vinyl/ethynyl pyrimidine, 4-anilino-3-cyano-5-vinyl/ethynyl/phenyl pyridine, and m-amino-N-phenylbenzamide, are designed, synthesized and selectively tested on EGFR, ErbB-2 kinases, and A-549, HL60 cells growth inhibition. Results from the bioactivity and chemical structures yield preliminary structure-activity relationships (SARs). The most potent 5-ethynylpyrimidine derivative 20a has an IC50 value of 45 nM to EGFR kinase. Several compounds of other series also show IC50 values <1 μM for EGFR and <5 μM for A-549 and HL60 cells growth inhibition.


A Study on the Use of Radiation-Protective Apron among Interventionists in Radiology.
Radiation-protective aprons are commonly used by interventionists to protect against the harmful effects of ionizing radiation. Choice of appropriate aprons with respect to lead equivalence and weight is necessary for effective protection and reduced physical strain. This study evaluates the knowledge and practice of using radiation-protective aprons by interventionists. Ninety-one interventional radiologists who attended an annual interventional conference were provided with a questionnaire which included age, years of experience, area of expertise, type and weight of apron used, and physical strain caused due to the use of apron. About 14.3% of the interventionists practiced in an angiographic suite for less than an hour a day, 45% for 2-4 h, 21% for 4-6 h, 10% for 6-10 h, and the rest above 10 h/day. About 68% of the interventionists wore 0.5 mm lead-equivalent (Pbeq) aprons; 15.4% with 0.25 mm Pbeq; about 5.5% with 0.35 mm Pbeq aprons, and the remaining were not aware of the lead equivalence. About 47% reported that they had body aches due to wearing single-sided aprons. Interventionists working more than 10 h/day wearing single-sided lead apron predominantly complained of shoulder pain and back pain. A large fraction of interventionists reported that they had physical strain. It is suggestive for interventionists to wear correct fit and light-weight aprons with appropriate lead equivalence.


Tracking Protein S-Fatty Acylation with Proteomics.
Recently, Hang and co-workers developed "acyl-PEG exchange" (APE), which allows the investigation of protein S-fatty acylation with mass-tag labelling and gel electrophoresis, methods that are accessible to any biochemistry laboratory.


Day Type and Start Time May Influence Sleep in Adolescent Professional Football Players.
This study assessed whether scheduling (start time and day type) and workload variables influenced sleep markers (activity monitor) in professional academy footballers (n=11; 17.3±0.7 yrs) over a 10-week in-season period. Separate linear mixed regressions were used to describe the effect of start time on the previous nights sleep, and the effect of day type (match day, match day+1) and workload on subsequent sleep. Workload variables were modelled by day (day), 7-day (acute), and 28-day (chronic) periods. Sleep duration following match day+1 (400 mins; 95%CI:368-432) was significantly reduced compared to all other day types (p<0.001). Sleep onset time following match day (00:35; CI:00:04-01:12) and wake time on match day+1 (09:00; CI:08:37-09:23) were also significantly later compared to all other day types (p<0.001). Sleep duration (19.1 mins; CI:9.4-28.79), wake time (18 mins; CI:9.3-26.6), and time in bed (16.8 mins; CI:2.0-31.5) were significantly increased per hour delay in start time. When no activity was scheduled, sleep duration (37 mins; CI:18.1-55.9), sleep onset (42.1 mins; CI:28.8-56.2), and wake times (86 mins; CI:72-100) were significantly extended, relative to a 09:00 start time. Day, acute, and chronic workloads were associated with sleep onset and wake times only. Scheduled start times were associated with changes in sleep duration. Therefore, delaying start times may increase sleep in this population.


Associations of resilience and respiratory sinus arrhythmia with alienation among college students.
Although the sense of alienation is harmful and causes many developmental problems, very few studies have focused on its antecedent variables and when these variables are related to alienation. The purpose of this study was to examine the relationship between resilience and sense of alienation among college students, and the moderating role of baseline respiratory sinus arrhythmia (RSA) in this association. Physiological data were collected during a resting condition in the laboratory from 109 college students aged from 17 to 21 years (M = 18.94, SD = 0.92). Questionnaires that captured demographic information, resilience, and sense of alienation, were also completed. Results indicated that resilience was negatively related to the sense of alienation. Moreover, this negative relationship was moderated by baseline RSA such that it was significant only among students with low levels of baseline RSA. Our findings revealed that individuals with low resilience tend to have a higher level of alienation if their baseline RSA is relatively low. The current study sheds light on the psychological and biological characteristics of these individuals who tend to have higher levels of alienation, which may be useful for intervention program developers and practitioners.


Analysis of protein association networks regulating the neuroactive metabolites production in Lactobacillus species.
Human population is intensively suffering from mental disorders and stress. Microbial metabolites may alter the brain activity, which seems to be an effective approach in the treatment of psychological distress. Earlier, microbial neuroactive metabolites such as trimethylamine, imidazolone propionate and taurine have been shown to alter the brain activity. In the present study proteins regulating their production and activity were explored in Lactobacillus species with the help of STRING (11.5) as a bioinformatic tool. Dataset network of urocanate hydratase, glycine radical enzyme and taurine ABC transporter protein (ATP-dependent transporter) have been identified in Lactobacillus nodensis, Lactobacillus vini and Lactobacillus paraplantarum strains. Further, cluster analysis of network resulted with groups of homologous proteins that most likely related to reductive monocarboxylic acid cycle, pyruvate fermentation to acetate IV and L-histidine degradation I pathway. The findings emphasize on the use and evaluation of selected Lactobacillus strains as psychoactive bacteria for the prevention and treatment of certain neurological and neurophysiological conditions.


Treatment of posttraumatic stress disorder with relaxation and biofeedback training.
This study investigated the use of biofeedback and relaxation training on six patients with posttraumatic stress disorder (PTSD) referred routinely for biofeedback treatment in a VA medical center. Subjects received between 8 and 14 sessions of training overall, as well as concurrent individual and group therapy. Measures used to assess treatment outcome include pre- and posttreatment MMPI, State-Trait Anxiety Inventory, Beck Depression Inventory, and Multidimensional Health Locus of Control scores, as well as electromyographic and subjective measures of tension within each session. Additionally, an overall posttreatment clinical rating of change and 1- to 2-year follow-up data were obtained for each subject. Slight to marked improvements were demonstrated for each subject, as evidenced by improvements on the State Anxiety Inventory Scale and the Beck Depression Inventory, a decrease in overall MMPI scores, and lowered EMG and subjective tension ratings for all participants. Possible alternative explanations for improvement (situational demand characteristics, regression toward the mean, lack of independent subject evaluation) are described, along with other study limitations. This preliminary investigation suggests that the use of relaxation training and biofeedback may be a particularly useful component within a comprehensive treatment program for this disorder.


Variations in Metastasis Site by Primary Location in Colon Cancer.
The purpose of this paper is to determine whether sites of distant recurrence are associated with specific locations of primary disease in colon cancer. A cohort including all patients (n = 947) undergoing a segmental colonic resection for colon cancer at our center (2004-2011) comparing site-specific metastatic presentation and recurrence rates, as well as their respective multivariable American Joint Committee on Cancer (AJCC) stage-adjusted hazard ratios (mHR). Right-sided colectomies (n = 557) had a lower overall metastasis rate (24.8% vs. 31.8%; P = 0.017; mHR = 1.24 [95% CI: 0.96-1.60]; P = 0.011) due to significantly lower pulmonary metastasis in follow-up (2.7% vs. 9%; P < 0.001; mHR = 0.32 [95% CI: 0.17-0.58]; P = 0.001) and lower overall liver metastasis rate (15.6 vs. 22.1%; P = 0.012; mHR = 0.74 [95% CI: 0.55-0.99];P = 0.050). Left colectomies (n = 127) had higher rates of liver metastasis during follow-up (9.4% vs. 4.8%; P = 0.029; mHR = 1.64 [95% CI: 0.86-3.15]; P = 0.134). Sigmoid resections (n = 238) had higher baseline rates of liver metastasis (17.1% vs. 11.3%; P = 0.015) and higher cumulative rates of lung (12.2% vs. 5.4%; P < 0.001; mHR = 2.26 [95% CI: 1.41-3.63]; P = 0.001) and brain metastases (2.3% vs. 0.6%; P = 0.033; mHR = 4.03 [95% CI: 1.14-14.3]; P = 0.031). Other sites of metastasis, including the (retro) peritoneum, omentum, ovary, and bone, did not yield significant differences. Important variations in site-specific rates of metastatic disease exist within major resection regions of colon cancer. These variations may be important to consider when evaluating options for adjuvant treatment and surveillance after resection of the primary disease.


Controlled evaluation of allergoid in the immunotherapy of ragweed hay fever.
Immunotherapy with ragweed allergoid administered in a clustered regimen, placebos in a clustered regimen, and unaltered ragweed extract (allergen) in a weekly regimen were compared in three groups of hay fever patients carefully matched for ragweed sensitivity. The allergoid and placebo comparison was performed double-blind and the unaltered ragweed extract comparison was single-blind. In terms of antigen E (AgE) equivalents, doses were about 50 times higher in the allergoid-treated group than in the allergen-treated group. Whereas there was no immunologic response to placebos, the allergoid regimen produced a more rapid serum IgG antibody response, with significantly higher posttreatment levels than those in the allergen regimen. Initial IgE antibody rises and subsequent slow declines were similar. Symptom-medication scores were similar in the two specifically treated groups and significantly less than scores reported by the placebo group (p less than 0.01). Due to an overestimate of the initial allergoid doses, systemic reactions occurred mostly in the early visits with allergoid treatment, whereas systemic reactions appeared late in the allergen treatment. The overall incidence was similar. In a second year, after 8 mo of no injections, a preseasonal booster regimen with both materials produced virtually no untoward reactions. During the period of no injections, IgG antibody declines were modest and, after boosters, IgG antibody levels rose promptly. Clinical results in both groups were again excellent, with an advantage for allergoid.


Ancestral sequence reconstruction of ancient lipase from family I.3 bacterial lipolytic enzymes.
Family I.3 lipase is distinguished from other families by the amino acid sequence and secretion mechanism. Little is known about the evolutionary process driving these differences. This study attempt to understand how the diverse temperature stabilities of bacterial lipases from family I.3 evolved. To achieve that, eighty-three protein sequences sharing a minimum 30% sequence identity with Antarctic Pseudomonas sp. AMS8 lipase were used to infer phylogenetic tree. Using ancestral sequence reconstruction (ASR) technique, the last universal common ancestor (LUCA) sequence of family I.3 was reconstructed. A gene encoding LUCA was synthesized, cloned and expressed as inclusion bodies in E. coli system. Insoluble form of LUCA was refolded using urea dilution method and then purified using affinity chromatography. The purified LUCA exhibited an optimum temperature and pH at 70 ℃ and 10 respectively. Various metal ions increased or retained the activity of LUCA. LUCA also demonstrated tolerance towards various organic solvents in 25% v/v concentration. The finding from this study could support the understanding on temperature and environment during ancient time. In overall, reconstructed ancestral enzymes have improved physicochemical properties that make them suitable for industrial applications and ASR technique can be employed as a general technique for enzyme engineering.


Developments in novel breath tests for bacterial and fungal pulmonary infection.
Breath testing has developed over the last 20 years. New techniques that can identify fingerprints for specific diseases and specific markers of respiratory pathogens have been applied to breath analysis. This review discusses the recent advances in breath analysis for the diagnosis of bacterial and fungal lower respiratory tract infections. The current techniques continue to develop rapidly, but preconcentration techniques are needed to analyse many target volatile organic compounds for most systems. Breath testing with an electronic nose is promising for the diagnosis of tuberculosis (TB), and specific volatiles identifiable by gas chromatography with mass spectrometry have been identified in breath for Mycobacterium tuberculosis, Pseudomonas aeruginosa and Aspergillus fumigatus, but are found at very low concentrations in breath. Contamination from the environment is an ongoing confounding influence. Exhaled breath condensate (EBC) is disappointing as a diagnostic sample. Careful attention needs to be paid to the sensitivity and specificity of a technique and confounding from the environment. The role of technologies such as selected ion flow tube-mass spectrometry is emerging. The electronic nose requires further validation for TB. The identification of specific microbial biomarkers aids the quest for improved accuracy. EBC is currently of limited value.


Feeding jejunostomy for post-operative nutritional support.
Enteral feeding by tube jejunostomy, inserted during definitive surgery, was used in 19 adult patients operated upon in a 24 month period. Jejunostomy feeding was associated with a low rate of minor complications enabling delivery of adequate caloric and protein input shortly after major abdominal operations and up to 9 months later. We feel that the insertion of a regular size jejunostomy tube during surgery is a simple, brief and safe procedure which offers efficient and inexpensive nutritional support, and thus has an important role in the post-operative management of selected patients. It is also easily used in the home setting if needed.