Vasodilators in myocardial infarction: rationale and current status.
While digitalis and diuretics constitute conventional therapy of congestive heart failure due to acute myocardial infarction, systemic vasodilator drugs offer an innovative approach of decreasing left ventricular systolic wall tension (afterload) by reducing aortic impedance and/or by reducing cardic venous return. Thus, vasodilators increase lowered cardiac output by diminishing peripheral vascular resistance and/or decreasing increased left ventricular end-diastolic pressure (ventricular preload) by reducing venous tone. Concomitantly, there is a reduction of myocardial oxygen demand thereby potentially limiting infarct size and ischaemia. The vasodilators produce disparate modifications of cardiac function depending on their differing alterations of preload versus impedance: nitrates principally cause venodilatation (decrease left ventricular end-diastolic pressure); sodium nitroprusside, phentolamine and prazosin produced relatively balanced arterial and venous dilatation (decrease left ventricular end-diastolic pressure while increasing cardiac output, provided upper limits of normal left ventricular end-diastolic pressure are maintained); and hydrallazine solely effects arteriolar dilatation (increases cardiac output). Combined sodium nitroprusside and dopamine therapy synergistically enhances cardiac output and decreases left ventricular end diastolic pressure. In addition, sodium nitroprusside is aided by mechanical counterpulsation which sustains myocardial perfusion pressure in acute myocardial infarction.


Predictive and Preventive Potential of Preoperative Gut Microbiota in Chronic Postoperative Pain in Breast Cancer Survivors.
Evidence suggests a potential relationship between gut microbiota and chronic postoperative pain (CPP). This study aimed to explore the predictive and preventive potential of preoperative gut microbiota in CPP in breast cancer survivors. In the clinical experiments, we designed a nested case-control study to compared preoperative gut microbiota of breast cancer survivors with and without CPP using 16s rRNA sequencing. The primary outcome was clinically meaningful pain in or around the operative area 3 months after surgery. Logistic prediction models based on previously identified risk factors for CPP in breast cancer survivors were tested with and without differential bacteria to evaluate the model's potential for improvement with the addition of gut microbiota information. In the animal experiments, preoperative fecal microbiota was transplanted from patients with and without CPP to mice, and a spared nerve injury (SNI) model was used to mimic neuropathic pain in CPP. Mechanical hyperalgesia and the expression of markers of spinal microglia and peroxisome proliferator-activated receptor-γ (PPAR-γ) were assessed. Sixty-six CPP patients and 66 matched controls were analyzed. Preoperative gut microbiota composition was significantly different in the 2 groups at phylus, family, and genera levels. The discrimination of the clinical prediction model (determined by area under the receiver operating characteristic curve) improved by 0.039 and 0.099 after the involvement of differential gut microbiota at the family and genus levels, respectively. After fecal microbiota transplantation (FMT), "CPP microbiota" recipient mice exhibited significantly increased mechanical hyperalgesia and decreased expression of Ppar-γ and arginase-1 (Arg-1) in the spinal cord. Preoperative gut microbiota has the potential to predict and prevent the development of CPP and plays a causal role in its development via the PPAR-γ-microglia pathway in the spinal cord. Thus, it could be targeted to develop a prevention strategy for CPP in breast cancer survivors.


Biomechanical interpretation of a free-breathing lung motion model.
The purpose of this paper is to develop a biomechanical model for free-breathing motion and compare it to a published heuristic five-dimensional (5D) free-breathing lung motion model. An ab initio biomechanical model was developed to describe the motion of lung tissue during free breathing by analyzing the stress-strain relationship inside lung tissue. The first-order approximation of the biomechanical model was equivalent to a heuristic 5D free-breathing lung motion model proposed by Low et al in 2005 (Int. J. Radiat. Oncol. Biol. Phys. 63 921-9), in which the motion was broken down to a linear expansion component and a hysteresis component. To test the biomechanical model, parameters that characterize expansion, hysteresis and angles between the two motion components were reported independently and compared between two models. The biomechanical model agreed well with the heuristic model within 5.5% in the left lungs and 1.5% in the right lungs for patients without lung cancer. The biomechanical model predicted that a histogram of angles between the two motion components should have two peaks at 39.8° and 140.2° in the left lungs and 37.1° and 142.9° in the right lungs. The data from the 5D model verified the existence of those peaks at 41.2° and 148.2° in the left lungs and 40.1° and 140° in the right lungs for patients without lung cancer. Similar results were also observed for the patients with lung cancer, but with greater discrepancies. The maximum-likelihood estimation of hysteresis magnitude was reported to be 2.6 mm for the lung cancer patients. The first-order approximation of the biomechanical model fit the heuristic 5D model very well. The biomechanical model provided new insights into breathing motion with specific focus on motion trajectory hysteresis.


A bacterial clone synthesizing proinsulin.
We have cloned double-stranded cDNA copies of a rat preproinsulin messenger RNA in Escherichia coli chi1776, using the unique Pst endonuclease site of plasmid pBR322 that lies in the region encoding amino acids 181-182 of penicillinase. This site was reconstructed by inserting the cDNA with an oligo(dG)-oligo(dC) joining procedure. One of the clones expresses a fused protein bearing both insulin and penicillinase antigenic determinants. The DNA sequence of this plasmid shows that the insulin region is read in phase; a stretch of six glycine residues connects the alanine at position 182 of penicillinase to the fourth amino acid, glutamine, of rat proinsulin.


Effect of deprotonation on absorption and emission spectra of Ru(II)-bpy complexes functionalized with carboxyl groups.
Changes in the ground and excited state electronic structure of the [Ru(bpy)(3)](2+) (bpy = 2,2'-bipyridine) complex induced by functionalization of bpy ligands with carboxyl and methyl groups in their protonated and deprotonated forms are studied experimentally using absorption and emission spectroscopy and theoretically using density functional theory (DFT) and time dependent DFT (TDDFT). The introduction of the carboxyl groups shifts the metal-to-ligand-charge-transfer (MLCT) absorption and emission bands to lower energies in functionalized complexes. Our calculations show that this red-shift is due to the stabilization of the lowest unoccupied orbitals localized on the substituted ligands, while the energies of the highest occupied orbitals localized on the Ru-center are not significantly affected. Consistent with previously observed trends in optical spectra of related Ru(II) complexes, deprotonation of the carboxyl groups results in a blue shift in the absorption and phosphorescence spectra. The effect originates from interplay of positive and negative solvatochromism in the protonated and deprotonated complexes, respectively. This results in more delocalized character of the electron transition orbitals in the deprotonated species and a strong destabilization of the three lowest unoccupied orbitals localized on the substituted and unsubstituted ligands, all of which contribute to the lowest-energy optical transitions. We also found that owing to the complexity of the excited state potential energy surfaces, the calculated lowest triplet excited state can be either weakly optically allowed (3)MLCT or optically forbidden Ru (3)d-d transition depending on the initial wavefunction guess used in TDDFT calculations.


Effect of erenumab on functional outcomes in patients with episodic migraine in whom 2-4 preventives were not useful: results from the LIBERTY study.
To evaluate the effect of erenumab on patient-reported, functional outcomes in patients with episodic migraine (EM) in whom 2-4 preventives were not useful from the Phase 3b LIBERTY study. As previously reported, 246 patients with EM with 2-4 prior failed preventives were randomised 1:1 to subcutaneous erenumab 140 mg or placebo every 4 weeks for 12 weeks. This analysis evaluated Migraine Physical Function Impact Diary (MPFID), Headache Impact Test (HIT-6) and Work Productivity and Activity Impairment (WPAI) scores at Week 12. P values were nominal without multiplicity adjustment. Erenumab significantly improved MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores versus placebo (treatment difference (TD) (95% CI) MPFID-PI: -3.5 (-5.7 to -1.2) (p=0.003); MPFID-EA: -3.9 (-6.1 to -1.7)) (p<0.001) at 12 weeks. Patients on erenumab were more likely to have a ≥5-point reduction in MPFID score (OR vs placebo (95% CI) MPFID-EA: 2.1 (1.2 to 3.6); MPFID-PI: 2.5 (1.4 to 4.5)). A similar trend was observed for HIT-6 (TD: -3.0; p<0.001); significantly higher proportions of patients on erenumab reported a ≥5-point reduction (OR (95% CI): 2.4 (1.4 to 4.1)). In three out of four WPAI domains, erenumab showed improvement versus placebo. At 12 weeks, erenumab was efficacious on functional outcomes in patients with EM in whom 2-4 preventives were not useful. ClinicalTrials.gov identifier: NCT03096834.


Dosage suppressors of a benomyl-dependent tubulin mutant: evidence for a link between microtubule stability and cellular metabolism.
To identify factors important for the regulation of microtubule stability in yeast, dosage suppressors of the hyperstable microtubule phenotype of the budding yeast tub2-150 beta-tubulin mutation were isolated. Of the two suppressors reported here, one (JSN2) encodes a tRNAVal, and the other (JSN3) is an antimorphic allele of the methionine biosynthesis transcription factor Met4p. Furthermore, growth of tub2-150 mutants and suppression of tub2-150 mutants by JSN3 are sensitive to levels of methionine in the growth medium. We explore several possible explanations for these findings, including the potential involvement of the general amino acid control and the involvement of Cbflp, a component of yeast kinetochores that is also necessary for Met4p-mediated transcription.


Thermal face protection delays finger cooling and improves thermal comfort during cold air exposure.
When people dress for cold weather, the face often remains exposed. Facial cooling can decrease finger blood flow, reducing finger temperature (T (f)). This study examined whether thermal face protection limits finger cooling and thereby improves thermal comfort and manual dexterity during prolonged cold exposure. T (f) was measured in ten volunteers dressed in cold-weather clothing as they stood for 60 min facing the wind (-15°C, 3 m s(-1)), once while wearing a balaclava and goggles (BAL), and once with the balaclava pulled down and without goggles (CON). Subjects removed mitts, wearing only thin gloves to perform Purdue Pegboard (PP) tests at 15 and 50 min, and Minnesota Rate of Manipulation (MRM) tests at 30 and 55 min. Subjects rated their thermal sensation and comfort just before the dexterity tests. T (f) decreased (p < 0.05 for time × trial interaction) by 15 min of cold exposure during CON (33.6 ± 1.4-28.7 ± 2.0°C), but not during BAL (33.2 ± 1.4-30.6 ± 3.2°C); and after 30 min T (f) remained warmer during BAL (23.3 ± 5.9°C) than CON (19.2 ± 3.5); however, by 50 min, T (f) was no different between trials (14.1 ± 2.7°C). Performance on PP fell (p < 0.05) by 25% after 50 min in both trials; MRM performance was not altered by cold on either trial. Subjects felt colder (p < 0.05) and more uncomfortable (p < 0.05) during CON, compared to BAL. Thermal face protection was effective for maintaining warmer T (f) and thermal comfort during cold exposure; however, local cooling of the hands during manual dexterity tests reduced this physiological advantage, and performance was not improved.


Early Experience With COVID-19 and Solid Organ Transplantation at a US High-volume Transplant Center.
The novel coronavirus severe acute respiratory syndrome coronavirus 2 [coronavirus disease 2019 (COVID-19)] poses unique challenges for immunosuppressed patients. Solid organ transplant (SOT) recipients comprise a large proportion of this group, yet there is limited knowledge about the presentation, clinical course, and immunosuppression management of this novel infection among heart, lung, liver, pancreas, and kidney transplant recipients. We present 21 SOT recipients diagnosed with COVID-19 between January 1, 2020 and April 22, 2020 at a US high-volume transplant center. Diagnostic workup, clinical course, immunosuppression/antiviral management, and immediate outcomes are described. Twenty-one (15.9%) of 132 symptomatic patients tested were positive. Mean age at diagnosis was 54.8 ± 10.9 y. Median time from transplant was 5.58 y (interquartile range 2.25, 7.33). Median follow-up was 18 d (interquartile range 13, 30). Fourteen patients required inpatient management, with 7 (50%) placed in the intensive care unit (ICU). All transplant types were represented. Nearly 43% exhibited GI symptoms. Over half (56.2%) presented with elevated serum creatinine suggestive of acute kidney injury. The majority of patients (5/7) with concomitant infections at baseline required the ICU. Eighty percent received hydroxychloroquine ± azithromycin. Ten received toclizumab and/or ribavirin; 1 received remdesivir. Antimetabolites ± calcineurin inhibitors were held or reduced. Over half of hospitalized patients (8/14) were discharged home. Only 1 mortality (4.8%) to date, in a critically ill heart/kidney patient who had been in the ICU before diagnosis. COVID-19 positive SOT at our institution had favorable short-term outcomes. Those with concomitant infections had more severe illness. More data will be available to evaluate long-term outcomes and disease impact on graft function.


Influence of thermally processed carbohydrate/amino acid mixtures on the fermentation by Saccharomyces cerevisiae.
The production of alcoholic beverages such as Tequila, Mezcal, whiskey, or beer includes the fermentation of a mash containing Maillard reaction products. Because excessive heating of the mash can lead to complications during the following fermentation step, the impact of Maillard products on the metabolism of Saccharomyces cerevisiae was investigated. For this purpose, fermentation was carried out in a model system in the presence and absence of Maillard reaction products and formation of ethanol served as a marker for the progression of fermentation. We found that increasing amounts of Maillard products reduced the formation of ethanol up to 80%. This effect was dependent on the pH value during the Maillard reaction, reaction time, as well as the carbohydrate and amino acid component used for the generation of Maillard reaction products. Another important factor is the pH value during fermentation: The inhibitory effect of Maillard products was not detectable at a pH of 4 and increased with higher pH-values. These findings might be of relevance for the production of above-mentioned beverages.


Obesity and Migraine: Effect Modification by Gender and Perceived Stress.
The association between obesity and migraine has been established; however, it is unclear whether it varies by perceived stress within each gender. This cross-sectional study used data from the ongoing NutriNet-Santé e-cohort with enrollees from the general population. Anthropometric and migraine data were provided via self-report questionnaires (2013-2016). Migraine was defined using established criteria. Perceived stress was assessed with Cohen's Perceived Stress Scale-10. Associations were estimated via gender- and stress-stratified multivariable polytomous logistic regression models. Among 32,835 participants with complete data (75% women; mean age = 51.9 ± 13.8 years), 34% reported no headache, 44% non-migraine headache, and 22% migraine with or without aura during one's lifetime. In these groups, obesity was present in 8.6, 9.9, and 11.6%, respectively. Stress was a significant moderator of the obesity-migraine association only among women. The largest significant adjusted odds ratio (aOR) was found between obesity and migraine in women with high stress (aOR 1.61, 95% CI 1.35-1.91). We found support for gender- and stress-dependent associations between obesity and migraine using a large, heterogeneous adult sample. This underscores the need for evidence-based strategies for weight loss and stress reduction for female migraineurs.


Impact of prescriber's handwriting style and nurse's duty duration on the prevalence of transcription errors in public hospitals.
To investigate the prevalence of transcription errors in a main public hospital in Pakistan and to test the impact of medication name and dose writing styles and the nurse duty duration on the occurrence of transcription errors. Medication errors occur frequently in public hospitals. Errors occurring at the transcription stage have not been sufficiently investigated. Medications transcripts and dispensed item labels were prospectively reviewed. In the second stage, nurses (n=25) transcribed medication charts in a double-blind randomised cross-over design administered at one, six and 10 hours after the commencement of their duty. METHODS. Inpatient (n=1000), discharge patient (n=1000) medication transcripts and labels of dispensed items for (n=1000) transcripts were reviewed. On medication charts, orthographically similar medications (n=20) were written in lowercase and Tall Man, decimal doses were written covered and uncovered, and metric doses were written with and without trailing zeros. Of the 6583 and 5329 medications transcribed from inpatient and discharge patient charts, error rates were 16·9 and 13·8%, respectively. Labels for 6734 dispensed items were reviewed, and error rate was 6·1%. Tall Man, covered decimal points and avoiding trailing zeros with decimal units significantly reduced transcription errors. Errors increased with increasing nurse duty duration. Highlighting orthographically similar medications and the use of proper decimal and metric units reduce errors. Transcription errors are highly prevalent in Pakistan public hospitals; therefore, elimination of transcription stage is encouraged.


Anatomical correlates of the lateral hypothalamic influence on waking-sleep relationship in the rat.
Restricted electrolytic lesions of the lateral hypothalamus (LH) evoke sleeplessness in the rat. The present study was aimed to analyze a possible anatomical substrate of the LH hyposomnia within the hypothalamus. In a group of electrolytically lesioned LH rats the intensity of sleep disturbances, assessed on the basis of EEG records from the neocortex and the hippocampus, was confronted with the localization and the extent of destruction of the LH area and with the topography of known fiber systems of the medical forebrain bundle (MFB). In separate experiments the effects of the destruction of LH cell bodies by means of bilateral ibotenic acid (IBO) injections and inhibition of LH neuronal elements by bilateral muscimol (MUSC) administration were also tested. It was found that pronounced hyposomnia follows electrolytic but not IBO lesions of the LH/MFB area. The effective LH damage might have been localized at every level of its antero-posterior axis, from the preoptic area up to the posterior hypothalamus, suggesting involvement of fiber system(s) rather than a localized group of neuronal pericaria. The most effective lesions transsected projections descending from the preoptic/anterior hypothalamic area, olfactory structures, ventral striatum and the central amygdaloid nucleus as well as fibers connecting LH with the brainstem reticular formation, many of them using GABA as a neurotransmitter. Bilateral MUSC injections caused a dose-dependent, bicuculline-reversible, increase in waking time, most pronounced at a dose of 50 ng, which ressembled the effect of the electrolytic lesion. These results indicate that LH hyposomnia is not attributable to the damage to the intrahypothalamic neurons and suggest the participation of GABA-ergic transmission in LH in waking-sleep regulation.


Mapping reflexive shifts of attention in eye-centered and hand-centered coordinate systems.
Behavioral studies indicate that directional gaze and hand pointing are fundamental social signals that may capture spatial attention more powerfully than directional arrows. By using fMRI, we explored whether reflexive shifts of attention triggered by different distracters were influenced by the motor effector used for performing an overt response. In separate blocks, healthy participants performed a directional saccadic or a hand pointing movement. Color changes of a central black fixation point constituted the imperative instruction signal to make a leftward (red color) or a rightward (blue color) movement while ignoring distracting leftward or rightward oriented gaze, hand pointing, or arrow. Distracters that were directionally incongruent with the instruction cue impaired the saccadic and pointing-release RTs. The comparison of incongruent vs. congruent conditions showed an increase of BOLD signal in the frontal eye field (FEF), the intraparietal sulcus (IPS), and the posterior parietal cortex (PPC) bilaterally. Importantly, a specific relationship between distracter and effector used for the response was found in these frontal and parietal regions. In particular, higher activity in the FEF, for distracting gaze was found mainly during the saccadic response task. In the same vein, higher activity in the left and right IPS regions was found for the distracting hand mainly in the hand pointing task. The results suggest that reflexive shifts of attention triggered by social signals are coded in the fronto-parietal cortex according to effector-specific mapping rules.


Small RNA regulation of ovule development in the cotton plant, G. hirsutum L.
The involvement of small RNAs in cotton fiber development is under explored. The objective of this work was to directly clone, annotate, and analyze small RNAs of developing ovules to reveal the candidate small interfering RNA/microRNAs involved in cotton ovule and fiber development. We cloned small RNA sequences from 0-10 days post anthesis (DPA) developing cotton ovules. A total of 6691 individual colonies were sequenced from 11 ovule small RNA libraries that yielded 2482 candidate small RNAs with a total of 583 unique sequence signatures. The majority (362, 62.1%) of these 583 sequences were 24 nt long with an additional 145 sequences (24.9%) in the 21 nt to 23 nt size range. Among all small RNA sequence signatures only three mirBase-confirmed plant microRNAs (miR172, miR390 and ath-miR853-like) were identified and only two miRNA-containing clones were recovered beyond 4 DPA. Further, among all of the small RNA sequences obtained from the small RNA pools in developing ovules, only 15 groups of sequences were observed in more than one DPA period. Of these, only five were present in more than two DPA periods. Two of these were miR-172 and miR-390 and a third was identified as 5.8S rRNA sequence. Thus, the vast majority of sequence signatures were expressed in only one DPA period and this included nearly all of the 24 nt sequences. Finally, we observed a distinct DPA-specific expression pattern among our clones based upon sequence abundance. Sequences occurring only once were far more likely to be seen in the 0 to 2 DPA periods while those occurring five or more times were the majority in later periods. This initial survey of small RNA sequences present in developing ovules in cotton indicates that fiber development is under complex small RNA regulation. Taken together, the results of this initial small RNA screen of developing cotton ovules is most consistent with a model, proposed by Baulcombe, that there are networks of small RNAs that are induced in a cascade fashion by the action of miRNAs and that the nature of these cascades can change from tissue to tissue and developmental stage to developmental stage.


Assessment of cerebrovascular autoregulation: changes of highest modal frequency of cerebrovascular pressure transmission with cerebral perfusion pressure.
Development of a method to continuously assess cerebrovascular autoregulation of patients with traumatic brain injury would facilitate therapeutic intervention and thus reduce secondary complications. Changes in arterial blood pressure (ABP), intracranial pressure (ICP), cerebral blood flow velocity (CBFV), and pial arteriolar diameter (PAD) induced by acute pressor challenge (norepinephrine; 1 microg/[kg. min]) were evaluated in both uninjured and fluid percussion injured piglets equipped with cranial windows. The linear correlation coefficient and corresponding slope of the regression line of the relationship between highest modal frequency (HMF) of cerebrovascular pressure transmission of ABP to ICP and cerebral perfusion pressure (CPP) were determined for each challenge. For all uninjured piglets, pressor challenge resulted in an inverse relationship between HMF and CPP characterized by significant negative correlation values and negative corresponding regression line slopes with respective group mean values (+/-SD) of -0.50 (+/-0.14) and -0.6 (+/-0.44) Hz/mm Hg, respectively. Consistent with functional autoregulation of the uninjured preparations, pressor challenge resulted in a decrease of PAD, and CBFV remained relatively constant. For all injured piglets, pressor challenge resulted in direct relationship between HMF and CPP, characterized by positive correlation values and corresponding regression line slopes with group mean values of 0.48 (+/-0.21) and 1.13 (+/-2.08) Hz/mm Hg, respectively. Consistent with impaired autoregulation, PAD and CBFV increased during pressor challenge after brain injury. Evaluation of changes of the HMF of cerebrovascular pressure transmission with respect to CPP changes permits continuous monitoring of cerebral autoregulation.


Prostate specific antigen. Current clinical application and future prospects.
Prostate-specific antigen (PSA) is a glycoprotein produced by the prostate gland and its production can be enhanced in benign and malignant diseases. The introduction of PSA testing has greatly increased the detection of prostate cancer. However there is continuing controversy and confusion over the most appropriate application of the PSA test. PubMed and Web of Science databases were used to search original and review articles on the historical aspects, clinical utilization and possible future directions in PSA. After its discovery, PSA was quickly established as an exquisitely sensitive tumor marker for prostate cancer detection, assessment of treatment responses and follow-up among patients with prostate cancer. Nevertheless, controversy exists about the proper threshold for recommending prostate biopsy. If this limit is lowered to improve the sensitivity even more, patients with low-risk prostate cancer would be subsequently detected. Post-treatment PSA levels can certainly provide valuable information about the effectiveness of the therapy given. Recently introduced ultrasensitive PSA detection techniques are offering new insight into the changes in serum PSA at very low concentrations. This has resulted in identification of valuable postoperative prognostic variables together with the possibility of earlier cancer relapse detection. The development of assays that may show superior sensitivity and specificity in prostate cancer diagnosis is focused on proteins possibly complexed with PSA and other potential markers detectable both in serum and urine. The goal of newly discovered prostate cancer biomarkers is greater cancer specificity in order to reduce the overdiagnosis, overtreatment and financial cost.


Experimental realization of a one-atom laser in the regime of strong coupling.
Conventional lasers (from table-top systems to microscopic devices) typically operate in the so-called weak-coupling regime, involving large numbers of atoms and photons; individual quanta have a negligible impact on the system dynamics. However, this is no longer the case when the system approaches the regime of strong coupling for which the number of atoms and photons can become quite small. Indeed, the lasing properties of a single atom in a resonant cavity have been extensively investigated theoretically. Here we report the experimental realization of a one-atom laser operated in the regime of strong coupling. We exploit recent advances in cavity quantum electrodynamics that allow one atom to be isolated in an optical cavity in a regime for which one photon is sufficient to saturate the atomic transition. The observed characteristics of the atom-cavity system are qualitatively different from those of the familiar many-atom case. Specifically, our measurements of the intracavity photon number versus pump intensity indicate that there is no threshold for lasing, and we infer that the output flux from the cavity mode exceeds that from atomic fluorescence by more than tenfold. Observations of the second-order intensity correlation function demonstrate that our one-atom laser generates manifestly quantum (nonclassical) light, typified by photon anti-bunching and sub-poissonian photon statistics.


Administration of xenobiotics with anti-estrogenic effects results in mRNA induction of adult male-specific cytochrome P450 isozymes in the livers of adult female rats.
Cytochrome P450 (CYP) catalyzes the oxidation of many endogenous and xenobiotic compounds. The expression of CYP isozymes are modulated by endogenous hormones and xenobiotics. We found that, although CYP2C11 and CYP3A2 are adult male-specific isozymes, they are also expressed in prepubertal female Sprague Dawley (SD) rats. However, the mRNA levels for these isozymes in prepubertal female SD rats decreased over time and became undetectable at 7 weeks of age. On the other hand, ovariectomy, administration of ICI182780, a specific estrogen antagonist, or administration of lindane, which is a widely used pesticide with anti-estrogenic effects, induced these adult male-specific CYP mRNAs in adult female SD rats. These results suggest that estrogen is involved in suppression of both CYP2C11 and CYP3A2 in adult female rats. The expression of these CYP isozymes in female rats, therefore, is affected by sexual maturity and by disrupting adult female hormonal homeostasis. We also performed a field survey to examine whether the induction of CYP2C11 or CYP3A2 differs between adult female roof rats in rural and metropolitan districts. RT-PCR showed that the mRNAs for CYP2C11 and CYP3A2 were expressed in half of the adult female roof rats captured in Osaka (as a metropolitan area district) but not in those captured in Hokkaido (as a rural district). Thus, induction of the adult male-specific CYP isozymes in adult female roof rats captured in Osaka might be caused by consumption of xenobiotics with anti-estrogenic effects.


Treatment Options for Germline BRCA-Mutated Metastatic Pancreatic Adenocarcinoma.
Pancreatic cancer is the fourth leading cause of death from cancer in both men and women. Pancreatic cancer is typically diagnosed at an advanced stage and has an overall 5-year survival of approximately 9.3%. The National Comprehensive Cancer Network recommends both germline testing (testing cells such as blood or skin that do not have cancer) as well as somatic testing (testing cells with cancer) for pathogenic variants that may increase the risk of pancreatic cancer. In December 2019, the U.S. Food & Drug Administration approved the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib for maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma in individuals who have completed at least 16 weeks of progression-free treatment with first-line platinum-based chemotherapy. This new therapy option has implications not only for treatment but also for the role of the oncology advanced practitioner as genetic testing becomes more prevalent in the care of patients with cancer.


Sodium Ferrous Citrate and 5-Aminolevulinic Acid Exert a Therapeutic Effect on Endotoxin-Induced Uveitis in Rats.
The metabolism of 5-aminolevulinic acid (ALA) is more efficient when combined with sodium ferrous citrate (SFC). Our previous study revealed that oral administration of ALA, which has anti-inflammatory properties, and SFC (ALA/SFC) immediately before lipopolysaccharide (LPS) inoculation suppressed endotoxin-induced uveitis (EIU) in rats. However, the therapeutic effect of ALA/SFC post-administration remains unexplored. Hence, this study aimed to evaluate the therapeutic efficacy of ALA/SFC on EIU in rats, which were administered with a gastric gavage of ALA/SFC (100/157 mg/kg) or prednisolone (Pred, 10 mg/kg) after 4 h of LPS inoculation. The treatment groups showed ameliorated clinical scores, inflammatory cells, protein levels in the aqueous humor (AqH), and histopathologic evaluation 24 h after LPS inoculation. Furthermore, the treatment groups had reduced tumor necrosis factor-α, nitric oxide, prostaglandin E2, and interleukin-6 levels in the AqH. ALA/SFC demonstrated an anti-inflammatory effect equivalent to that demonstrated by Pred. These findings indicate that ALA/SFC exerts a therapeutic effect on EIU in rats, indicating its clinical usefulness in uveitis treatment.


Laparoscopic management of a full-thickness uterine niche with subsequent pregnancy outcome.
Uterine niche is the consequence of impaired healing of the myometrium following a lower segment transverse caesarean section (CS). Although there is conflicting evidence on the management of these cases, laparoscopic repair is a commonly used surgical treatment modality. To demonstrate the management and laparoscopic repair of the niche with subsequent pregnancy outcome. We report a case of a 33-year-old patient who had a significant haematoma in the niche. The haematoma resolved after conservative management however, she remained symptomatic. Therefore, she had a laparoscopic repair. The narrated surgical video article demonstrates the dissection of the uterovesical fold overlying the niche, followed by the excision of the scar tissue and its repair with laparoscopic suturing. Ultrasound and magnetic resonance imaging images of the uterus demonstrating the haematoma at the caesarean section site, the niche after resolution of the haematoma and post-repair imaging are also provided. Repair of the niche, symptomatic relief of abnormal uterine bleeding, spontaneous conception and live birth. Ultrasonographic images also demonstrate uterine wall continuity post laparoscopic repair. The patient recovered uneventfully. Full-thickness of myometrium was demonstrated with post-operative imaging and confirmed at the subsequent caesarean section. Gynaecological symptoms resolved following the repair. The patient conceived spontaneously after surgery and delivered at term by caesarean section without any complications. Laparoscopic management of the niche should be considered where there is a complete myometrial defect or significant thinning of the myometrium, especially in symptomatic women who desire future pregnancy.


Exercise intensity impacts the improvement of metabolic dysfunction-associated steatotic liver disease via variations of monoacylglycerol O-acyltransferase 1 expression.
The involvement of monoacylglycerol O-acyltransferase 1 (MOGAT1) in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) has been recognized. While exercise is recommended for the improvement of obesity and MASLD, the impact of exercise intensity remains unclear. This study aimed to examine the influence of exercise intensity on MOGAT1 expression in high-fat diet (HFD)-induced obese mice with MASLD. Male C57BL/6 mice aged 6 weeks were subjected to either a regular or HFD with 60% fat content for 8 weeks. The mice were categorized into 5 groups based on their diet and exercise intensity: normal diet group (ND), HFD group, low-intensity exercise with HFD group (HFD+LIE), moderate-intensity exercise with HFD group (HFD+MIE), and high-intensity exercise (HIE) with HFD group (HFD+HIE). The duration of running was adjusted to ensure uniform exercise load across groups (total distance = 900 m): HFD+LIE at 12 m/min for 75 min, HFD+MIE at 15 m/min for 60 min, and HFD+HIE at 18 m/min for 50 min. Lipid droplet size and MASLD activity score were significantly lower in the HFD+HIE group compared to other exercise-intensity groups (p < 0.05). Among the 3 intensity exercise groups, the lowest MOGAT1 protein expression was found in the HFD+HIE group (p < 0.05). This study reveals that high-intensity aerobic exercise has the potential to mitigate MASLD development, partly attributed to the downregulation of MOGAT1 expression.


Gaussian-mixture-model-based spatial neighborhood relationships for pixel labeling problem.
In this paper, we present a new algorithm for pixel labeling and image segmentation based on the standard Gaussian mixture model (GMM). Unlike the standard GMM where pixels themselves are considered independent of each other and the spatial relationship between neighboring pixels is not taken into account, the proposed method incorporates this spatial relationship into the standard GMM. Moreover, the proposed model requires fewer parameters compared with the models based on Markov random fields. In order to estimate model parameters from observations, instead of utilizing an expectation-maximization algorithm, we employ gradient method to minimize a higher bound on the data negative log-likelihood. The performance of the proposed model is compared with methods based on both standard GMM and Markov random fields, demonstrating the robustness, accuracy, and effectiveness of our method.


A neural network-based approximation method for discrete-time nonlinear servomechanism problem.
A feedback controller that solves the discrete-time nonlinear servomechanism problem relies on the solution of a set of nonlinear functional equations known as the discrete regulator equations. The exact solution of the discrete regulator equations is usually unavailable due to the nonlinearity of the system. The paper proposes to approximately solve the discrete regulator equations using a feedforward neural network. This approach leads to an effective way to practically solve the discrete nonlinear servomechanism problem. The approach has been illustrated using the well-known inverted pendulum on a cart system. The simulation shows that the control law designed by the proposed approach performs much better than the conventional linear control law.


Inflammatory bowel diseases patients suffer from significant low levels and barriers to physical activity: The "BE-FIT-IBD" study.
The place regular physical activity (PA) should occupy in managing patients with inflammatory bowel diseases (IBD) is unclear. To assess PA levels and barriers in a southern Italian IBD population. IBD patients with non-severe disease activity [assessed with partial Mayo score for ulcerative colitis (UC) and Harvey-Bradshaw index for Crohn's disease] were approached to receive an anonymous online questionnaire to assess PA levels using the International Physical Activity Questionnaire (IPAQ) and to assess disease activity as patient-reported outcomes 2 (PRO-2) and finally to assess habits, beliefs and barriers in conducting regular PA. Clinical, anthropometric and demographic data of patients were also collected. PA was expressed as continuous units of resting metabolic rate (Met) in min/wk. Three PA groups were identified: Inactive (< 700 Met min/wk), sufficiently active (700-2500 Met min/wk) and health enhancing PA (HEPA) (i.e., HEPA active, > 2500 Met min/wk) patients. Included patients (219) showed overall PA levels of 834.5 Met min/wk, with a large proportion (94, 42.9%) classified as inactive while only a minority (9, 4.1%) as health-enhancing PA. Patients without dyslipidaemia (P < 0.0001) or on biologics therapy (P = 0.022) showed better IPAQ scores in moderate activities. UC PRO-2 correlated negatively with IPAQ intense activities scores (τ = -0.156, P = 0.038). PRO-2 did not show notable sensitivity/specificity in predicting IPAQ inactivity (AUC < 0.6). IBD activity did not differ between active and inactive patients (P > 0.05). Active patients expressed the need to discuss PA with their gastroenterologist. Some barriers (e.g., diagnosis of IBD and fear of flare-ups after PA) are significantly more reported by inactive patients. A significant rate of physical inactivity was recorded in this setting. IPAQ showed good feasibility. PA should be an element of discussion in IBD visits assessed quickly with non-invasive questionnaires.


A somatic splice-site variant in PIK3R1 in a patient with vascular overgrowth and low immunoglobulin levels: A case report.
The PI3K/AKT pathway, extensively studied in cancer, is vital for regulating cell metabolism, differentiation, and proliferation. Pathogenic variants in the PIK3R1 gene, which encodes three regulatory units of class IA PI3Ks, have been found in affected tissue of individuals with vascular lesions. These variants predominantly occur in the iSH2 domain, disrupting inhibitory contacts with the catalytic unit and leading to PI3K activation. Germline variants in this gene are also linked to an immunological condition called Activated PI3K delta syndrome type 2 (APDS2). This is a case report and literature review. Clinical data were retrieved from medical records. A male patient presented with extensive vascular malformation covering over 90% of his body, along with complete 2-3 toe syndactyly, suggesting a vascular malformation syndrome called PROS. Low levels of IgA and IgG were detected. The patient achieved his developmental milestones and had above-average weight, height, and head circumference. Exome sequencing of skin and blood DNA revealed a de novo variant in PIK3R1 (c.1746-2A>G, p.?) in 9% of the patient's blood cells and 25% of cultured fibroblasts. Initially, classified as a variant of uncertain significance, this variant was later confirmed to be the cause. This is the first intronic SNV in a canonical splice site within iSH2 described, highlighting the importance of iSH2 in the regulation of the PI3K/AKT pathway and its involvement in the development of vascular overgrowth and antibody deficiency.


Four therapeutic diets: adherence and acceptability.
Many health conditions are treated, at least in part, by therapeutic diets. Although the success of any intervention depends on its acceptability to the patient, the acceptability of therapeutic diets and factors that influence it have been largely neglected in nutrition research. A working definition of acceptability is proposed and an examination and summary are provided of available data on the acceptability of common diet regimens used for medical conditions. The goal is to suggest ways to improve the success of therapeutic diets. The proposed working definition of "acceptability" refers to the user's judgment of the advantages and disadvantages of a therapeutic diet-in relation to palatability, costs, and effects on eating behaviour and health-that influence the likelihood of adherence. Very low-calorie, reduced-fat omnivorous, vegetarian and vegan, and low-carbohydrate diets all achieve acceptability among the majority of users in studies of up to one year, in terms of attrition and adherence rates and results of questionnaires assessing eating behaviours. Longer studies are fewer, but they suggest that vegetarian, vegan, and reduced-fat diets are acceptable, as indicated by sustained changes in nutrient intake. Few studies of this length have been published for very low-calorie or low-carbohydrate diets. Long-term studies of adherence and acceptability of these and other therapeutic diets are warranted.


Immunocytochemical demonstration of neuron-specific enolase for differential diagnosis of retroperitoneal tumours in children.
Six patients with malignant retroperitoneal tumours causing considerable diagnostic difficulties are reported. In a retrospective investigation the presence of neuron-specific enolase (NSE) was analysed immunocytochemically in specimens of these tumours. In all the patients who had finally got the definite diagnosis neuroblastoma, tumour specimens had a strong reaction for NSE whereas all other tumours did not react. An analysis of NSE already at the primary investigation could have led to an earlier definite diagnosis.


A review of transition experiences in perinatally and behaviourally acquired HIV-1 infection; same, same but different?
Despite sharing common psychosocial and developmental experiences, adolescents living with perinatally and behaviourally acquired HIV-1 infection are different in terms of timing of HIV infection and developmental stage at infection. Therefore, it is of interest to identify similarities and differences between these two groups of adolescents living with HIV in their experiences, facilitators and barriers during the transition process. A detailed literature search of peer-reviewed published papers was conducted on PubMed to identify relevant original research or viewpoints published up to September 2016. Conference abstracts and other unpublished data sources were not included. Existing published literature, mainly using qualitative methods, explores the transition from paediatric to adult healthcare provision, as experienced by these two groups of young people. Reports highlight the variation and similarities in their experiences and challenges of transition. Findings from the USA and Europe predominate, while experience from Africa and Asia is lacking, despite the importance of these regions in the global epidemic. Published transition data remain limited, and there are few studies focusing on behaviourally infected adolescents and key population groups (e.g. adolescents who use drugs, lesbian/gay/transgender individuals). Robust definitions of the transition process and standardized outcome measures are required to facilitate cross-study and geographic comparisons.


A multi-gene knockdown approach reveals a new role for Pax6 in controlling organ number in Drosophila.
Genetic screens are designed to target individual genes for the practical reason of establishing a clear association between a mutant phenotype and a single genetic locus. This allows for a developmental or physiological role to be assigned to the wild-type gene. We previously observed that the concurrent loss of Pax6 and Polycomb epigenetic repressors in Drosophila leads the eye to transform into a wing. This fate change is not seen when either factor is disrupted separately. An implication of this finding is that standard screens may miss the roles that combinations of genes play in development. Here, we show that this phenomenon is not limited to Pax6 and Polycomb but rather applies more generally. We demonstrate that in the Drosophila eye-antennal disc, the simultaneous downregulation of Pax6 with either the NURF nucleosome remodeling complex or the Pointed transcription factor transforms the head epidermis into an antenna. This is a previously unidentified fate change that is also not observed with the loss of individual genes. We propose that the use of multi-gene knockdowns is an essential tool for unraveling the complexity of development.


Sedentary behavior and mortality in older women: the Women's Health Initiative.
Although epidemiologic studies have shown associations between sedentary behavior and mortality, few have focused on older women with adequate minority representation and few have controlled for both physical activity and functional status. The objective of this study was to determine the relationship between sedentary time and total; cardiovascular disease (CVD); coronary heart disease (CHD); and cancer mortality in a prospective, multiethnic cohort of postmenopausal women. The study population included 92,234 women aged 50-79 years at baseline (1993-1998) who participated in the Women's Health Initiative Observational Study through September 2010. Self-reported sedentary time was assessed by questionnaire and examined in 4 categories (≤4, >4-8, ≥8-11, >11 hours). Mortality risks were examined using Cox proportional hazard models adjusting for confounders. Models were also stratified by age, race/ethnicity, body mass index, physical activity, physical function, and chronic disease to examine possible effect modification. Analyses were conducted in 2012-2013. The mean follow-up period was 12 years. Compared with women who reported the least sedentary time, women reporting the highest sedentary time had increased risk of all-cause mortality in the multivariate model (HR=1.12, 95% CI=1.05, 1.21). Results comparing the highest versus lowest categories for CVD, CHD, and cancer mortality were as follows: HR=1.13, 95% CI=0.99, 1.29; HR=1.27, 95% CI=1.04, 1.55; and HR=1.21, 95% CI=1.07, 1.37, respectively. For all mortality outcomes, there were significant linear tests for trend. There was a linear relationship between greater amounts of sedentary time and mortality risk after controlling for multiple potential confounders.


Experimental warming shows that decomposition temperature sensitivity increases with soil organic matter recalcitrance.
Soil C decomposition is sensitive to changes in temperature, and even small increases in temperature may prompt large releases of C from soils. But much of what we know about soil C responses to global change is based on short-term incubation data and model output that implicitly assumes soil C pools are composed of organic matter fractions with uniform temperature sensitivities. In contrast, kinetic theory based on chemical reactions suggests that older, more-resistant C fractions may be more temperature sensitive. Recent research on the subject is inconclusive, indicating that the temperature sensitivity of labile soil organic matter (OM) decomposition could either be greater than, less than, or equivalent to that of resistant soil OM. We incubated soils at constant temperature to deplete them of labile soil OM and then successively assessed the CO2-C efflux in response to warming. We found that the decomposition response to experimental warming early during soil incubation (when more labile C remained) was less than that later when labile C was depleted. These results suggest that the temperature sensitivity of resistant soil OM pools is greater than that for labile soil OM and that global change-driven soil C losses may be greater than previously estimated.


Reactivity of rhodium(I) complexes bearing nitrogen-containing ligands toward CH3I: synthesis and full characterization of neutral cis-[RhX(CO)2(L)] and acetyl [RhI(μ-I)(COMe)(CO)(L)]2 complexes.
The neutral rhodium(I) square-planar complexes [RhX(CO)(2)(L)] [X = Cl (3), I (4)] bearing a nitrogen-containing ligand L [diethylamine (a), triethylamine (b), imidazole (c), 1-methylimidazole (d), pyrazole (e), 1-methylpyrazole (f), 3,5-dimethylpyrazole (g)] are straightforwardly obtained from L and [Rh(μ-X)(CO)(2)](2) [X = Cl (1), I (2)] precursors. The synthesis is extended to the diethylsulfide ligand h for 3h and 4h. According to the CO stretching frequency of 3 and 4, the ranking of the electronic density on the rhodium center follows the order b > a ≈ d > c > g > f ≈ h > e. The X-ray molecular structures of 3a, 3d-3f, 4a, and 4d-4f were determined. Results from variable-temperature (1)H and (13)C{(1)H} NMR experiments suggest a fluxional associative ligand exchange for 4c-4h and a supplementary hydrogen-exchange process in 4e and 4g. The oxidative addition reaction of CH(3)I to complexes 4c-4g affords the neutral dimeric iodo-bridged acetylrhodium(III) complexes [RhI(μ-I)(COCH(3))(CO)(L)](2) (6c-6g) in very good isolated yields, whereas 4a gives a mixture of neutral 6a and dianionic [RhI(2)(μ-I)(COCH(3))(CO)][NHMeEt(2)](2) and 4h exclusively provides the analogue dianionic complex with [SMeEt(2)](+) as the counterion. X-ray molecular structures for 6d(2) and 6e reveal that the two apical CO ligands are in mutual cis positions, as are the two apical d and e ligands, whereas isomer 6d(1) is centrosymmetric. Further reactions of 6d and 6e with CO or ligand e gave quantitatively the monomeric complexes [RhI(2)(COCH(3))(CO)(2)(d)] (7d) and [RhI(2)(COCH(3))(CO)(e)(2)] (8e), respectively, as confirmed by their X-ray structures. The initial rate of CH(3)I oxidative addition to 4 as determined by IR monitoring is dependent on the nature of the nitrogen-containing ligand. For 4a and 4h, reaction rates similar to those of the well-known rhodium anionic [RhI(2)(CO)(2)](-) species are observed and are consistent with the formation of this intermediate species through methylation of the a and h ligands. The reaction rates are reduced significantly when using imidazole and pyrazole ligands and involve the direct oxidative addition of CH(3)I to the neutral complexes 4c-4g. Complexes 4c and 4d react around 5-10 times faster than 4e-4g mainly because of electronic effects. The lowest reactivity of 4f toward CH(3)I is attributed to the steric effect of the coordinated ligand, as supported by the X-ray structure.


Characterization of the Drosophila atlastin interactome reveals VCP as a functionally related interactor.
At least 25 genes, many involved in trafficking, localisation or shaping of membrane organelles, have been identified as causative genes for the neurodegenerative disorder hereditary spastic paraplegia (HSP). One of the most commonly mutated HSP genes, atlastin-1, encodes a dynamin-like GTPase that mediates homotypic fusion of endoplasmic reticulum (ER) membranes. However, the molecular mechanisms of atlastin-1-related membrane fusion and axonopathy remain unclear. To better understand its mode of action, we used affinity purification coupled with mass spectrometry to identify protein interactors of atlastin in Drosophila. Analysis of 72 identified proteins revealed that the atlastin interactome contains many proteins involved in protein processing and transport, in addition to proteins with roles in mRNA binding, metabolism and mitochondrial proteins. The highest confidence interactor from mass spectrometry analysis, the ubiquitin-selective AAA-ATPase valosin-containing protein (VCP), was validated as an atlastin-interacting protein, and VCP and atlastin showed overlapping subcellular distributions. Furthermore, VCP acted as a genetic modifier of atlastin: loss of VCP partially suppressed an eye phenotype caused by atlastin overexpression, whereas overexpression of VCP enhanced this phenotype. These interactions between atlastin and VCP suggest a functional relationship between these two proteins, and point to potential shared mechanisms between HSP and other forms of neurodegeneration.


L-leucine or its keto acid potentiate but do not initiate insulin release in chicken.
In the isolated perfused chicken pancreas, 20 and 40 mM L-leucine or 10-40 mM alpha-ketoisocaproic acid (alpha-KIC) did not initiate insulin release. In the presence of 14 mM glucose (a noninsulinotropic concentration), 20 mM L-leucine and 10 mM alpha-KIC evoked a slight biphasic insulin release. The response to 20 mM L-leucine was further increased when 14 mM glucose was combined with 10 mM L-glutamine (10 mM glutamine alone did not induce insulin release and did not potentiate the response to 10 mM L-leucine). At 1 mM, 8-bromo-adenosine 3',5'-cyclic monophosphate (8-BrcAMP) alone caused a slight and progressive increase in insulin secretion but did not sensitize the pancreas to either 20 mM L-leucine or 10 mM alpha-KIC, whereas it facilitated a marked insulin release in response to 14 mM glucose. On the other hand, 10-40 mM K+ or 20 mM L-arginine induced a rapid monophasic insulin output. In conclusion, L-leucine or alpha-KIC, which do not initiate insulin release alone and are not potentiated by 8-BrcAMP, may not be regarded as primary insulinotropic agents in the chicken. This result, together with the previously documented resistance of the chicken pancreas to glucose alone or to D-glyceraldehyde, strongly suggests that the mechanisms initiating insulin secretion are different in chickens and mammals, whereas potentiating mechanisms (low glucose concentration, arginine, acetylcholine, and cAMP) and membrane depolarization events (K+ and arginine) are present in both chickens and mammals.


Theoretical infrared and terahertz spectra of an RDX/aluminum complex.
Density functional theory is employed to characterize the infrared and terahertz spectra of an explosive molecular species, RDX, deposited over an aluminum surface, modeled as a planar cluster of Al(16). Changes in the inter- and intramolecular vibrational modes are systematically analyzed starting from the isolated monomer, dimer, and tetramer and then considering the interactions of the monomer with an Al plate. The results are compared to available experimental information for RDX films on Al surfaces. It is found that the RDX molecule changes conformation because of the interaction with the model Al surface, becoming closer to an AAA conformation with the three NO(2) groups in nearly axial positions. The calculated spectra serve as an initial guideline to interpret the main peaks of previously reported RDX films on Al.


Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study.
We assessed tumor cell DNA content (ploidy) and N-myc gene copy number as predictors of long-term disease-free survival in 298 children with neuroblastoma. Diploid tumor stem lines were identified in 101 patients (34%), clonal hyperdiploid abnormalities in 194 (65%), and hypodiploid stem lines in three (1%). In children with widely disseminated tumors at diagnosis (stage D), ploidy had a highly age-dependent influence on prognosis. Among infants (less than 12 months) treated with cyclophosphamide-doxorubicin, hyperdiploidy was closely associated with long-term disease-free survival (greater than 90% of cases), while diploidy invariably predicted early treatment failure (P less than .001). Similarly, in children 12 to 24 months of age who were treated with cisplatin-teniposide and cyclophosphamide-doxorubicin, diploidy uniformly predicted early failure, whereas half of the children with hyperdiploidy achieved long-term disease-free survival (P less than .001). There was no relationship between ploidy and treatment outcome in children older than 24 months with stage D tumors who had a very low probability of long-term disease-free survival (less than 10%). N-myc gene amplification was detected in 37 (25%) of the 147 tumors tested, with the remainder showing single-copy levels of the gene. N-myc gene amplification was more frequent in diploid than in hyperdiploid tumors (23 of 57 v 14 of 87, P = .001) and predicted a high likelihood of early treatment failure. In children younger than 2 years with disseminated neuroblastoma, tumor cell ploidy and N-myc gene copy number provide complementary prognostic information that will distinguish patients who can be cured on current regimens from those who require new treatment strategies.


Impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction a randomized, double-blind, placebo-controlled clinical trial.
Our purpose was to evaluate the impact of nesiritide on renal function in patients with acute decompensated heart failure and baseline renal dysfunction. Although nesiritide is approved for the treatment of acute decompensated heart failure, retrospective analyses have raised concerns that it may cause worsened renal function. To date, no randomized clinical trials have prospectively evaluated this issue. Consecutive patients with acute decompensated heart failure and baseline renal dysfunction were enrolled in this randomized, double-blind, placebo-controlled clinical trial. Subjects were randomized to receive nesiritide (0.01 microg/kg/min with or without a 2-microg/kg bolus) or placebo (5% dextrose in water) for 48 h in addition to their usual care. Predefined primary end points of the trial were a rise in serum creatinine by > or =20% and change in serum creatinine. Seventy-five patients were enrolled (39 nesiritide, 36 placebo). The groups had similar baseline age (74.9 vs. 75.5 years, respectively), blood pressure (123/64 vs. 125/64 mm Hg) and serum creatinine (1.82 vs. 1.86 mg/dl). There were no significant differences in the incidence of a 20% creatinine rise (23% vs. 25%) or in the change in serum creatinine (-0.05 vs. +0.05 mg/dl). There were no significant differences in the secondary end points of change in weight (-2.19 vs. -1.58 kg), intravenous furosemide (125 vs. 107 mg), discontinuation of the infusion due to hypotension (13% vs. 6%), or 30-day death/hospital readmission (33% vs. 25%). In this randomized, double-blind, placebo-controlled clinical trial, nesiritide had no impact on renal function in patients with acute decompensated heart failure. (BNP-CARDS trial; http://www.clinicaltrials.gov/ct/show/NCT00186329?order=1; NCT00186329).


Interleukin 10 treatment of patients with rheumatoid arthritis enhances Fc gamma receptor expression on monocytes and responsiveness to immune complex stimulation.
Several clinical studies performed with human recombinant interleukin 10 (IL-10) in patients with rheumatoid arthritis (RA) have shown little efficacy. We investigated potentially proinflammatory in vivo effects of IL-10 in humans. We evaluated the upregulation of Fc gamma receptor (Fc gamma R) expression on monocytes/macrophages (and granulocytes) in patients with RA receiving different dosages of IL-10. Together with changes in disease activity and several cell markers, the expression of Fc gamma RI, Fc gamma RIIa, and Fc gamma RIII was determined on granulocytes and monocytes/macrophages from the peripheral blood of 6 patients with active RA before and after treatment with recombinant human IL-10. In addition, the in vitro effect of IL-10 on Fc gamma R expression on monocytes/macrophages in combination with their susceptibility to immune complex induced production of tumor necrosis factor-alpha(TNF-alpha) was assessed. Clinical improvement was not observed in the IL-10 treated patients (based on ACR20 criteria). Significant decreases in thrombocyte numbers were observed in patients receiving IL-10. No changes in cell markers such as CD14 were found. On the other hand, expression of Fc gamma RI and Fc gamma RIIa on monocytes/macrophages was increased upon high dose IL-10 treatment. Interestingly, increases in expression of Fc gamma RI and Fc gamma RIIa correlated with a decrease in thrombocyte numbers. In vitro, IL-10 similarly upregulated Fc gamma RI and Fc gamma RIIa expression on monocytes/macrophages from RA patients. This was accompanied by increased TNF-a production after immune complex stimulation. These findings indicate that upregulation of Fc gamma R expression in RA with IL-10 treatment may counteract the otherwise antiinflammatory effects of IL-10 by potentiating immune complex mediated proinflammatory responses.


Causality in acute encephalitis: defining aetiologies.
Defining the causal relationship between a microbe and encephalitis is complex. Over 100 different infectious agents may cause encephalitis, often as one of the rarer manifestations of infection. The gold-standard techniques to detect causative infectious agents in encephalitis in life depend on the study of brain biopsy material; however, in most cases this is not possible. We present the UK perspective on aetiological case definitions for acute encephalitis and extend them to include immune-mediated causes. Expert opinion was primarily used and was supplemented by literature-based methods. Wide usage of these definitions will facilitate comparison between studies and result in a better understanding of the causes of this devastating condition. They provide a framework for regular review and updating as the knowledge base increases both clinically and through improvements in diagnostic methods. The importance of new and emerging pathogens as causes of encephalitis can be assessed against the principles laid out here.


Tension decline during isometric contractions without visual cues.
Subjects tried to maintain 15%, 30% and 50% maximum voluntary contraction (MVC) of their handgrip for 60 sec and 70% MVC for 30 sec. When the subjects watched the tension record, they could maintain the contraction for the required time. However, without visual cues (uncued), the tests resulted in a tension decline. Ae-alpha t described the tension decline in the 15% tests, Be-beta t the 70% test, while the form in the 30% and 50% tests was Ae-alpha t + Be-beta t. In all cases alpha and/or beta were found to be dependent on the starting tension. The electrical activity obtained from surface electromyograms did not increase during the uncued tests which would be expected if muscle fatigue were involved in the tension decline. Instead the electrical activity was directly proportional to the decline in tension suggesting that the fall in tension was not due entirely to muscle fatigue. 15% MVC uncued tests in which fatigue is known not to be a factor also showed a tension decline. Precooling the hand in an attempt to alter sensory input produced no systematic change from the original uncued tests, indicating that sensory information from the hand was probably not a major factor in the tension decline. It is suggested that during the uncued tests the fast component of the tension decline may be related to a sensory adaptation involving the Golgi tendon organs. The slow component is due to forearm muscle fatigue which is related to the ischemia produced during the isometric contractions.


Parkinsonian Patients with Striatal Cribriform State Present Rapidly Progressive Axial Parkinsonism.
To define the significance of striatal cribriform state (SCS) observed in patients with primary progressive parkinsonism. We reviewed medical records and brain magnetic resonance imaging studies of 1,260 patients with primary progressive parkinsonism. We identified 23 patients with SCS and analyzed their clinical features. All 23 patients had rapidly progressive parkinsonism predominated by postural instability and gait disturbance. Clinical features of 18 of the 23 patients were compatible with progressive supranuclear palsy (PSP); 2 patients were compatible with parkinsonian type multiple system atrophy; 2 patients were compatible with mixed clinical features of both; and 1 patient had PSP-like clinical features. Most parkinsonian patients with SCS present rapidly progressive parkinsonism predominated by postural instability and gait disturbance. SCS observed in patients with parkinsonism does not seem to be a coincidental finding associated with the generalized cerebrovascular process.


The fetal origins hypothesis: placental insufficiency and inheritance versus maternal malnutrition in well-nourished populations.
The 'Fetal origins hypothesis' states that individuals born small because of malnutrition are predisposed to adult diseases. Fetal malnutrition has two main causes, poor maternal nutrition and placental insufficiency. A distinction between these causes is important because it is likely that maternal nutrition has been sufficient in the majority of populations in which the fetal origins hypothesis has been tested. Thus, placental insufficiency is a more reasonable cause of reduced fetal growth in adequately nourished populations. Placental insufficiency is mainly due to inadequate vascular adaptation at the uteroplacental interface ('poor placentation'). Among women with placental insufficiency syndromes such as pre-eclampsia and 'idiopathic' intrauterine growth retardation, there is an increased prevalence of risk factors for cardiovascular diseases. Maternal cardiovascular risk factors may therefore increase the risk of adult diseases in the offspring both through direct inheritance and by interfering with uteroplacental vascular adaptation. The latter may result in placental insufficiency and fetal growth retardation that by itself could cause adult disease (as the Fetal origins hypothesis states). Alternatively, the association between low birth weight for gestational and adult disease could be an epiphenomenon, leaving inheritance as the main explanation for the fetal origins hypothesis, in adequately nourished populations.


Comparison of urea treatment with established methods of sorghum grain preservation and processing on site and extent of starch digestion by cattle.
To determine the effect of dry (D); reconstituted and ensiled (R); reconstituted and acid-treated (A); and urea-treated, high-moisture (U) sorghum grain on starch digestibility, four Angus x Hereford steers (means BW = 350 kg) with duodenal and ileal cannulas were used in a 4 x 4 Latin square design. Diets consisting of 69% ground sorghum grain were fed every 2 h in equal portions (8.2 kg/d). Diets averaged 46.5% starch and 12% CP, except for U, which averaged 14% CP due to urea treatment. Ytterbium attached to sorghum was used as a particulate marker. Duodenal, ileal, and fecal samples were taken 1 h postfeeding after a 14-d adaption to diets. Whole samples were analyzed. Preduodenal starch digestion (%) was 89, 83, 76, and 70, and starch digestion over the total tract was 99, 97, 95 and 91 for R, U, A, and D, respectively. Starch digestion proximal to each site (duodenum and ileum) was enhanced (P less than .05) by R and U compared with D. Within the small intestine, there was a linear relationship (P less than .003) between starch digestion and daily starch supply. However, digestibility of starch in the small intestine (mean = 45%) was not different among diets. Apparent digestibility of starch in the large intestine was not significantly different from digestibility in the small intestine. Urea-treated sorghum grain was equivalent to reconstituted, ensiled sorghum in digestion characteristics and was superior to dry sorghum.


Crosstalk between replicative and translesional DNA polymerases: PDIP38 interacts directly with Poleta.
Replicative DNA polymerases duplicate genomes in a very efficient and accurate mode. However their progression can be blocked by DNA lesions since they are unable to accommodate bulky damaged bases in their active site. In response to replication blockage, monoubiquitination of PCNA promotes the switch between replicative and specialized polymerases proficient to overcome the obstacle. In this study, we characterize novel connections between proteins involved in replication and TransLesion Synthesis (TLS). We demonstrate that PDIP38 (Poldelta interacting protein of 38kDa) directly interacts with the TLS polymerase Poleta. Interestingly, the region of Poleta interacting with PDIP38 is found to be located within the ubiquitin-binding zinc finger domain (UBZ) of Poleta. We show that the depletion of PDIP38 increases the number of cells with Poleta foci in the absence of DNA damage and diminishes cell survival after UV irradiation. In addition, PDIP38 is able to interact directly not only with Poleta but also with the specialized polymerases Rev1 and Polzeta (via Rev7). We thus suggest that PDIP38 serves as a mediator protein helping TLS Pols to transiently replace replicative polymerases at damaged sites.


Major T cell progenitor activity in bone marrow-derived spleen colonies.
Common lymphoid progenitors (CLP) are generated in adult bone marrow (BM), but the intermediate steps leading to T cell commitment are unknown, and so is the site at which this commitment occurs. Here, we show that colonies arising in the spleen 12 days after BM injection harbor T cell precursors that are undetectable in BM. These precursors did not generate myeloid cells in vivo but repopulated the thymus and the peripheral T cell compartment much faster than did CLP. Two lineage negative (Lin(-)) subpopulations were distinguished, namely CD44(+) Thy1(-) cells still capable of natural killer generation and transient low-level B cell generation, and T cell-restricted CD44(-) Thy1(+) cells. At a molecular level, frequency of CD3epsilon and preTalpha mRNA was very different in each subset. Furthermore, only the CD44(-) Thy1(+) subset have initiated rearrangements in the T cell receptor beta locus. Thus, this study identifies extramedullary T cell progenitors and will allow easy approach to T cell commitment studies.


Atrial natriuretic factor in maternal and fetal sheep.
To determine atrial natriuretic factor (ANF) concentrations in the circulation and body fluids of adult pregnant sheep and their fetuses, pregnant ewes were anesthetized with pentobarbital sodium, and the fetuses were exteriorized for sampling. ANF concentration, as measured by radioimmunoassay, was 47 +/- 6 (SE) pg/ml in maternal plasma, which was significantly higher than the 15 +/- 3 pg/ml in maternal urine. In the fetus, plasma ANF concentration was 265 +/- 49 pg/ml, 5.6 times that in maternal plasma. No umbilical arterial and venous difference in ANF concentration was observed. Fetal urine ANF concentration (13 +/- 2 pg/ml) was significantly lower than that in fetal plasma, and was similar to that measured in amniotic and allantoic fluid. In chronically catheterized maternal and fetal sheep, fetal plasma ANF was again 5.1 times that in maternal plasma, and these levels were not different from those measured in acutely anesthetized animals. These results demonstrate that immunoreactive ANF is present in the fetal circulation at levels higher than those found in the mother. The low concentration of ANF in fetal urine suggests that ANF is probably metabolized and/or reabsorbed by the fetal kidney.


II.2. Electrical safety.
Correct use of medical equipment within the clinical environment is of prime importance. This includes awareness of the safety issues regarding equipment, particular when it is an electrically powered device. Incidents can occur in the clinic in which a medical device is suspected of contributing to patient or staff injury. It is important that one can identify in advance any potential hazards which may arise with electrical equipment due to technical or environmental factors. This paper gives an overview of electrical safety.


Multidimensional Neuroanatomical Subtyping of Autism Spectrum Disorder.
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with multiple biological etiologies and highly variable symptoms. Using a novel analytical framework that integrates cortex-wide MRI markers of vertical (i.e., thickness, tissue contrast) and horizontal (i.e., surface area, geodesic distance) cortical organization, we could show that a large multi-centric cohort of individuals with ASD falls into 3 distinctive anatomical subtypes (ASD-I: cortical thickening, increased surface area, tissue blurring; ASD-II: cortical thinning, decreased distance; ASD-III: increased distance). Bootstrap analysis indicated a high consistency of these biotypes across thousands of simulations, while analysis of behavioral phenotypes and resting-state fMRI showed differential symptom load (i.e., Autism Diagnostic Observation Schedule; ADOS) and instrinsic connectivity anomalies in communication and social-cognition networks. Notably, subtyping improved supervised learning approaches predicting ADOS score in single subjects, with significantly increased performance compared to a subtype-blind approach. The existence of different subtypes may reconcile previous results so far not converging on a consistent pattern of anatomical anomalies in autism, and possibly relate the presence of diverging corticogenic and maturational anomalies. The high accuracy for symptom severity prediction indicates benefits of MRI biotyping for personalized diagnostics and may guide the development of targeted therapeutic strategies.


Morphologic and immunocytochemical performances of effusion cell blocks prepared using 3 different methods.
With increased use of the ThinPrep method for nongynecologic specimens, cell blocks are more commonly prepared by harvesting cells that are fixed in CytoLyt solution. The current study compared morphologic and immunocytochemical performance of effusion cell blocks prepared using CytoLyt-prefixed thrombin clot (CTC) with plasma thrombin clot (PT) and HistoGel (HG) preparation. The study included a total of 25 malignant or benign serous fluids. Three individual cell block materials were simultaneously prepared from each of the 25 effusion specimens using the CTC, PT, or HG method. H&E staining and immunostaining for pancytokeratin (pan-CK), carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), B72.3, HBME-1, estrogen receptor (ER), progesterone receptor (PR), CD45, CD20, and CD3 were then performed. The CTC preparation revealed compatible cellularity and good cellular details. In addition, CTC cell blocks revealed a similar percentage of cells with positive immunostaining along with the strongest intensity and the least background staining. The CTC method can be used reliably as an adjunct to other preparation techniques.


Proteomic characterization of histone variants in the mouse testis by mass spectrometry-based top-down analysis.
Various histones, including testis-specific histones, exist during spermatogenesis and some of them have been reported to play a key role in chromatin remodeling. Mass spectrometry (MS)-based characterization has become the important step to understand histone structures. Although individual histones or partial histone variant groups have been characterized, the comprehensive analysis of histone variants has not yet been conducted in the mouse testis. Here, we present the comprehensive separation and characterization of histone variants from mouse testes by a top-down approach using MS. Histone variants were successfully separated on a reversed phase column using high performance liquid chromatography (HPLC) with an ion-pairing reagent. Increasing concentrations of testis-specific histones were observed in the mouse testis and some somatic histones increased in the epididymis. Specifically, the increase of mass abundance in H3.2 in the epididymis was inversely proportional to the decrease in H3t in the testis, which was approximately 80%. The top-down characterization of intact histone variants in the mouse testis was performed using LC-MS/MS. The masses of separated histone variants and their expected post-translation modifications were calculated by performing deconvolution with information taken from the database. TH2A, TH2B and H3t were characterized by MS/MS fragmentation. Our approach provides comprehensive knowledge for identification of histone variants in the mouse testis that will contribute to the structural and functional research of histone variants during spermatogenesis.


The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and disease.
The liver has long been known to respond to exposure to certain chemicals with hyperplasia and proliferation of the peroxisomal compartment. This response is now known to be mediated by specific receptors. The peroxisome proliferator-activated receptors (PPARs) were cloned 10 years ago, and in that interval, have been found to serve as receptors for a number of endogenous lipid compounds, in addition to the peroxisome proliferators that originally led to their study. Three receptors, designated the alpha, delta, and gamma receptors, have been found in mammals. PPARalpha: is the most abundant form found in the liver, with smaller amounts of the delta and gamma forms also expressed there. Kupffer cells, like other macrophages, appear to express the alpha and gamma isoforms. Hepatic stellate cells are reported to express the gamma isoform. PPARalpha knock-out mice fail to undergo peroxisome proliferation when challenged with the proliferators. Moreover, they have severe derangements of lipid metabolism, particularly during fasting, indicating that normal function of the alpha receptors is needed for lipid homeostasis. This in turn suggests that inadequate PPAR-mediated responses may contribute to abnormal fatty acid metabolism in alcoholic and non-alcoholic steatohepatitis. Recent information suggests that PPARgamma receptors may be important in control of the activation state of the stellate cells, and their repression or inactivation may predispose to hepatic fibrosis. The first approved drug that specifically activates PPARgamma, troglitazone, has rarely been found to cause serious liver injury. Although this is likely to represent an idiosyncratic reaction, the medical community will need to be alert to the possibility that activation or blockade of these receptors may cause hepatic dysfunction.


Validation of the adjusted global antiphospholipid syndrome score in a single centre cohort of APS patients from Turkey.
The adjusted global antiphospholipid syndrome score (aGAPSS) is a recently developed thrombotic risk assessment score that considers the antiphospholipid antibody (aPL) profile and conventional cardiovascular risk factors. In this retrospective study, we aimed to evaluate the validity of the aGAPSS in predicting clinical manifestations (criteria and extra-criteria) of antiphospholipid syndrome (APS) in a single centre cohort of patients. Ninety-eight patients with APS ± systemic lupus erythematosus (SLE) were classified according to clinical manifestations as vascular thrombosis (VT), pregnancy morbidity (PM) or both (VT + PM). The aGAPSS was calculated for each patient as previously defined. Mean aGAPSS of the cohort was calculated as 10.2 ± 3.8. Significantly higher aGAPSS values were seen in VT (n = 58) and VT + PM (n = 29) groups when compared to PM (n = 11) group (10.6 ± 3.7 vs 7.4 ± 2.9, P = 0.005; 10.7 ± 4 vs 7.4 ± 2.9, P = 0.008, respectively), mainly due to lower frequencies of cardiovascular risk factors in PM. Higher aGAPPS values were also associated with recurrent thrombosis (11.6 ± 3.7 vs 9.9 ± 3.6, P = 0.04). Regarding extra-criteria manifestations, patients with livedo reticularis (n = 11) and APS nephropathy (n = 9) had significantly higher aGAPSS values (12.9 ± 3.4 vs 9.9 ± 3.7, P = 0.02; 12.4 ± 2.9 vs 10 ± 3.8, P = 0.04, respectively). The computed AUC demonstrated that aGAPSS values ≥10 had the best diagnostic accuracy for thrombosis. Our results suggest that patients with higher aGAPSS values are at higher risk for developing vascular thrombosis (either first event or recurrence) and extra-criteria manifestations, especially livedo reticularis and APS nephropathy.


Responses of butter leaf lettuce to mixed red and blue light with extended light/dark cycle period.
To investigate the effects of extended light/dark (L/D) cycle period (relative to the diurnal L/D cycle) on lettuce and explore potential advantages of abnormal L/D cycles, butter leaf lettuce were grown in a plant factory with artificial light (PFAL) and exposed to mixed red (R) and blue (B) LED light with different L/D cycles that were respectively 16 h light/8 h dark (L16/D8, as control), L24/D12, L48/D24, L96/D48 and L120/D60. The results showed that, all the abnormal L/D cycles increased shoot dry weight (DW) of lettuce (by 34-83%) compared with the control, and lettuce DW increased with the L/D cycle period prolonged. The contents of soluble sugar and crude fiber in lettuce showed an overall upward trend with the length of L/D cycle extended, and the highest vitamin C content as well as low nitrate content were both detected in lettuce treated with L120/D60. The light use efficiency (LUE) and electric use efficiency (EUE) of lettuce reached the maximum (respectively 5.37% and 1.76%) under L120/D60 treatment and so were DW, Assimilation rate (A), RC/CS, ABS/CS, TRo/CS and DIo/CS, indicating that longer L/D cycle period was beneficial for the assimilation efficiency and dry matter accumulation in lettuce leaves. The highest shoot fresh weight (FW) and nitrate content detected in lettuce subjected to L24/D12 may be related to the vigorous growth of root, specific L/D cycle seemed to strengthen root growth and water absorption of lettuce. The openness level of RC in PSII (Ψo), ETo/CS, and PIabs were all the highest in lettuce treated with L24/D12, implying that slightly extending the L/D cycle period might promote the energy flowing to the final electron transfer chain. In general, irradiation modes with extended L/D cycle period had the potential to improve energy use efficiency and biomass of lettuce in PFAL. No obvious stress or injury was detected in lettuce subjected to prolonged L/D cycles in terms of plant growth and production. From the perspective of shoot FW, the optimal treatment in this study was L24/D12, while L120/D60 was the recommended treatment as regards of the energy use efficiency and nutritional quality.


Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating beta1 integrin.
We have shown previously that treatment of human aortic endothelial cells (HAECs) with minimally modified low-density lipoprotein (MM-LDL) induces monocyte but not neutrophil binding. This monocyte binding was not mediated by endothelial E-selectin, P-selectin, vascular cell adhesion molecule-I, or intercellular adhesion molecule-I, suggesting an alternative monocyte-specific adhesion molecule. We now show that moncytic alpha4beta1 integrins mediate binding to MM-LDL-treated endothelial cells. We present data suggesting that the expression of the connecting segment-1 (CS-1) domain of fibronectin (FN) is induced on the apical surface of HAEC by MM-LDL and is the endothelial alpha4beta1 ligand in MM-LDL-treated cells. Although the levels of CS-1 mRNA and protein were not increased, we show that MM-LDL treatment causes deposition of FN on the apical surface by activation of beta1integrins, particularly those associated with alpha5 integrins. Activation of beta1 by antibody 8A2 also induced CS-1-mediated monocyte binding. Confocal microscopy demonstrated the activated beta1 and CS-1colocalize in concentrated filamentous patches on the apical surface of HAEC. Both anti-CS-1 and an antibody to activated beta1 showed increased staining on the luminal endothelium of human coronary lesions with active monocyte entry. These results suggest the importance of these integrin ligand interactions in human atherosclerosis.


Actions speak louder than words in socially foraging human groups.
SOCIAL FORAGING IN HUMANS HAS A DEEP EVOLUTIONARY HISTORY: early hominids searched for dispersed food sources in a patchy, uncertain environment. A fundamental assumption is that social foragers benefit by exchanging information about food sources, in order to make collective decisions based on pooled information. We conducted the first experimental test of this assumption, and showed that, as predicted, communication significantly enhanced group performance. A further, unexpected result was that physical communication through gesturing, rather than verbal communication, appeared to play a crucial role in the early stages of group interaction, facilitating consensus decision making by groups. The importance of gestures in human interactions may therefore be underestimated, and this has important implications for modern human societies, where communications are becoming increasingly dominated by virtual modes of communication that preclude the use of gestures.


Self-rated health, multimorbidity and depression in Mexican older adults: Proposal and evaluation of a simple conceptual model.
Self-rated health is an individual and subjective conceptualization involving the intersection of biological, social and psychological factors. It provides an invaluable and unique evaluation of a person's general health status. To propose and evaluate a simple conceptual model to understand self-rated health and its relationship to multimorbidity, disability and depressive symptoms in Mexican older adults. We conducted a cross-sectional study based on a national representative sample of 8,874 adults of 60 years of age and older. Self-perception of a positive health status was determined according to a Likert-type scale based on the question: "What do you think is your current health status?" Intermediate variables included multimorbidity, disability and depressive symptoms, as well as dichotomous exogenous variables (sex, having a partner, participation in decision-making and poverty). The proposed conceptual model was validated using a general structural equation model with a logit link function for positive self-rated health. A direct association was found between multimorbidity and positive self-rated health (OR=0.48; 95% CI: 0.42-0.55), disability and positive self-rated health (OR=0.35; 95% CI: 0.30-0.40), depressive symptoms and positive self-rated health (OR=0.38; 95% CI: 0.34-0.43). The model also validated indirect associations between disability and depressive symptoms (OR=2.25; 95% CI: 2.01- 2.52), multimorbidity and depressive symptoms (OR=1.79; 95% CI: 1.61-2.00) and multimorbidity and disability (OR=1.98; 95% CI: 1.78-2.20). A parsimonious theoretical model was empirically evaluated, which enabled identifying direct and indirect associations with positive self-rated health.


Bacteroides fragilis resistance to clindamycin in vitro.
Clindamycin resistance in Bacteroides fragilis was examined in 507 strains isolated from 1973 to 1981. Three groups were recognized: highly susceptible (minimum inhibitory concentration [MIC] less than or equal to 0.125 microgram/ml), intermediately susceptible (MIC = 0.25 to 4 micrograms/ml), and highly resistant to (MIC greater than or equal to 8 microgram/ml). The incidence of high-level resistance (1.8%) had not changed during this period. Only 8 of 17 isolates reputed to be highly clindamycin resistant that were referred to our laboratory proved to be highly resistant (MICs greater than or equal to 32 microgram/ml), whereas the other 9 were intermediately susceptible. Analysis of 2- and 10-microgram clindamycin disks for determining the susceptibility of B. fragilis revealed a high false-resistance rate with the 2-microgram disk, most errors occurring with the intermediate group. There was no false resistance with the 10-microgram disk. When disk diffusion susceptibility of B. fragilis is employed, we recommend the 10-microgram disk to predict accurately the susceptibility of B. fragilis to clindamycin.


Peripheral and central somatosensory nerve conduction defects in Friedreich's ataxia.
Somatosensory evoked potentials were recorded over the clavicle, cervical spine, mastoid processes and the hand area of the contralateral somatosensory cortex to median nerve stimulation in 22 cases of Friedreich's ataxia. There was a marked attenuation of the clavicular potential, but little evidence of delay of this or the major cervical component. A dispersed and delayed cortical response was therefore suggestive of slowed conduction in central pathways. The cortical response was shown to be mediated by peripheral fibres with normal conduction velocity between stimulation sites at the wrist and the elbow.


Evolutionary dynamics of complete Campylobacter pan-genomes and the bacterial species concept.
Defining bacterial species and understanding the relative cohesiveness of different components of their genomes remains a fundamental problem in microbiology. Bacterial species tend to be comprised of both a set of core and dispensable genes, with the sum of these two components forming the species pan-genome. The role of the core and dispensable genes in defining bacterial species and the question of whether pan-genomes are finite or infinite remain unclear. Here we demonstrate, through the analysis of 96 genome sequences derived from two closely related sympatric sister species of pathogenic bacteria (Campylobacter coli and C. jejuni), that their pan-genome is indeed finite and that there are unique and cohesive features to each of their genomes defining their genomic identity. The two species have a similar pan-genome size; however, C. coli has acquired a larger core genome and each species has evolved a number of species-specific core genes, possibly reflecting different adaptive strategies. Genome-wide assessment of the level of lateral gene transfer within and between the two sister species, as well as within the core and non-core genes, demonstrates a resistance to interspecies recombination in the core genome of the two species and therefore provides persuasive support for the core genome hypothesis for bacterial species.


Investigation of AID, Dicer, and Drosha Expressions in Patients with Chronic Lymphocytic Leukemia.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries. Cytogenetic lesions such as del13q14, del11q22.3, and del17p13 are identified in 50-60% of patients. Activation-induced cytidine deaminase (AID) plays a central role in somatic hyper mutation (SHM) and class switch recombination (CSR) and functions on Ig genes, but also target non-Ig genes, and over-expression of AID can lead to point mutations or translocations in non-Ig genes such as IgH/Myc translocation. Dicer and Drosha, which have a role in activation process of miRNA, also act in a double-strand DNA break (DSB) repair mechanism. In this study, whether the changes of AID, Dicer and Drosha expressions may be associated with both deletions and clinical outcomes in patients with CLL were investigated. AID expressions were increased in patients with CLL. However, cell lysate AID protein levels were only increased in patients with del17p or del11q who have poor prognosis. Decreased Dicer expressions were found in patients with deletion, whereas increased Drosha expressions were found in patients without deletion and with del13q. According to Rai and Binet staging systems, advanced-stage patients showed increased AID protein levels, decreased Dicer and Drosha expressions. Our findings may suggest that high AID expression and lower Dicer expression were observed in patients with CLL especially del17p and del11q and might associated with deletions such as del17p and del11q. AID, Dicer, and Drosha expressions might be used as an indicator of prognosis for CLL.


Birth weight, infant growth and insulin resistance.
Size at birth and early postnatal growth rates are important determinants of human perinatal survival; they also predict the tempo of growth, adult height and long-term risks for obesity, type 2 diabetes and cardiovascular disease. Results from the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC) show that fetal growth is influenced by both fetal genes and maternal-uterine-placental factors. Important maternal-placental factors include parity, smoking and weight gain, but also maternal genetic factors in the mother or fetal placenta, including the mitochondrial DNA 16189 variant and H19. These maternal genetic factors particularly influence smaller, growth-restrained infants, as in first pregnancies. Fetal genes include the insulin gene (INS) VNTR (variable number of tandem repeat), which we recently confirmed to be associated with birth size and cord blood IGF-II levels; these fetal gene effects are more evident in the absence of maternal-uterine growth restraint. During postnatal life, the INS VNTR III/III genotype remains associated with body size, including body mass index and waist circumference, and also lower insulin sensitivity among girls. However, as at birth, significant gene-environment interactions are seen. Rapid 'catch-up' early postnatal weight gain follows maternal-uterine restraint, and strongly predicts later childhood obesity and insulin resistance; among these children, those with INS VNTR class I alleles are more obese. Genetic factors that influence early growth may have conferred some early survival advantage in human history during times of undernutrition. With abundant nutrition and rising obesity rates, these genetic factors and their interactions with maternal and childhood environmental factors that influence childhood growth may now contribute to the early development of adult disease risk. Their recognition may help the development of targeted early interventions to prevent the progression towards adult disease.