Dysregulated intrathymic development in the IL-2-deficient mouse leads to colitis-inducing thymocytes.
Gene-targeted mice lacking the IL-2 gene (IL-2 -/- mice) develop various forms of autoimmunity as well as severe colitis, either spontaneously in a conventional environment or after immunization with 2,4,6-trinitrophenol (TNP)-conjugated keyhole limpet hemocyanin (KLH) in a specific pathogen-free environment. We show here that the induction of colitis with TNP-KLH induces a change in the thymocyte population characterized by decreased numbers of double positive (DP; CD4+CD8+) thymocytes (IL-2 +/+, 45.2 x 10(6) vs IL-2 -/-, 23.6 x 10(6)) and increased numbers of single positive (SP; CD4+CD8- or CD4-CD8+) thymocytes (IL-2 +/+, 5.3 x 10(6) vs IL-2 -/-, 20.9 x 10(6)). The latter also bear activation markers. In addition, thymocytes from TNP-KLH-immunized IL-2 -/- mice produce more IFN-gamma and less IL-4 than similarly immunized IL-2 +/+ mice. These defects in thymocyte maturation and lymphokine production are IL-12 driven, since they are prevented when immunized IL-2 -/- mice are coadministered with anti-lL-12. Furthermore, we demonstrate that IL-2 -/- mice exhibit decreased cortical apoptosis as determined by thymocyte numbers and detection of apoptotic cells in situ. Finally, we show that colitis-inducing thymocytes are generated in the immunized IL-2 -/- thymus, since IL-2 +/+ mice develop colitis following injection of small numbers of single positive thymocytes from immunized IL-2 -/- mice but not from IL-2 +/+ mice. Taken together, these data indicate that, in the absence of IL-2, thymocyte maturation is abnormally directed by IL-12 toward the generation of mature, activated Th1-type thymocytes that are capable of mediating colitis.


[Peri-ileostomic pyoderma gangrenosum. Report of one case].
We report a 39 years old woman with Ulcerative Colitis unresponsive to medical treatment. A total colectomy with Brooke ileostomy was performed, as the first operation. After six weeks she developed a peri-ileostomic Pyoderma Gangrenosum. She was treated by a multidisciplinary team, and after seven months with local treatment and systemic medication, the skin healed. Her bowel transit was reconstricted later with an ileoanal pouch and she was reinserted into her previous job.


cAMP modulates an S-type K+ channel coupled to GABAB receptors in mammalian respiratory neurons.
Premotor respiratory neurons from neonatal rats express a Ba(2+)-insensitive outward rectifying K+ channel (KOR) which is activated by gamma-aminobutyric acid acting at its beta receptor. The biophysical properties of KOR are similar to those described for the S-channel (KS) which underlies simple forms of non-associative learning in the marine mollusc Aplysia. We show here that KOR, like the S-channel, is inhibited by cAMP. In addition, we demonstrate that this inhibition is due to a change in closed time kinetics. Our data suggests that the ionic and biochemical substrates underlying synaptic plasticity in Aplysia have been phylogenetically conserved in mammalian motor circuits such as that controlling rhythmic breathing movements.


Detection of eubacteria in interstitial cystitis by 16S rDNA amplification.
To determine what role non-culturable microorganisms play in the etiology of interstitial cystitis (IC). Thirty patients fulfilling NIH criteria for the diagnosis of interstitial cystitis and sixteen control patients with culture negative urine gave written informed consent and underwent bladder biopsy. Polymerase chain reaction (PCR) using two sets of universal primers for bacterial 16S rDNA was performed on urine from the cystoscope and on a cold cup bladder biopsy specimen. Of the PCR positive bladder biopsies, three patients with interstitial cystitis and three controls were randomly selected and cloned. Ten clones from each were sequenced and putative taxonomic assignments made. 12/26 (46%) IC and 5/12 (42%) control urine specimens and 16/30 (53%) and 9/15 (60%) bladder biopsies were PCR positive, respectively. The bacterial populations in the two patient groups tested appeared to be different based upon analysis of the 16S rRNA sequences. Both IC and control patients had non-culturable bacteria in their bladders. A random sampling of the two populations revealed that the bacterial populations are different, suggesting a possible link between one or more bacterial species and IC.


Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina.
Ciliary neurotrophic factor (CNTF) rescues photoreceptors in several animal models of retinal degeneration and is currently being evaluated as a potential treatment for retinitis pigmentosa in humans. This study was conducted to test whether CNTF prevents photoreceptor cell loss in XLPRA2, an early onset canine model of X-linked retinitis pigmentosa caused by a frameshift mutation in RPGR exon ORF15. Four different treatment regimens of CNTF were tested in XLPRA2 dogs. Under anesthesia, the animals received at different ages an intravitreal injection of 12 microg of CNTF in the left eye. The right eye served as a control and was injected with a similar volume of phosphate buffered saline (PBS). Ocular examinations were performed regularly during the treatment periods. At termination, the dogs were euthanatized, eyes collected and the retinas were processed for embedding in optimal cutting temperature (OCT) medium. The outer nuclear layer (ONL) thickness was evaluated on H&E sections and values in both CNTF- and PBS-treated eyes were compared. Morphologic alterations in the peripheral retina were characterized by immunohistochemistry using cell-specific markers. Cell proliferation in the retinas was examined on semi-thin plastic sections, and by BrdU pulse-labeling and Ki67 immunohistochemistry on cryosections. All CNTF-treated eyes showed early clinical signs of corneal epitheliopathy, subcapsular cataracts and uveitis. No statistically significant difference in ONL thickness was seen between the CNTF- and PBS-injected eyes. Prominent retinal remodeling that consisted in an abnormal increase in the number of rods, and in misplacement of some rods, cones, bipolar and Müller cells, was observed in the peripheral retina of CNTF-treated eyes. This was only seen when CNTF was in injected before the age at which the canine retina reaches full maturation. In XLPRA2 dogs, intravitreal injections of CNTF failed to prevent photoreceptors from undergoing cell death in the central and mid-peripheral retina. CNTF also caused ocular side-effects and morphologic alterations in the periphery that were consistent with cell dedifferentiation and proliferation. Our findings suggest that some inherited forms of retinal degeneration may not respond to CNTF's neuroprotective effects.


Organocatalyzed synthesis of fluorinated poly(aryl thioethers).
The preparation of high-performance fluorinated poly(aryl thioethers) has received little attention compared to the corresponding poly(aryl ethers), despite the excellent physical properties displayed by many polysulfides. Herein, we report a highly efficient route to fluorinated poly(aryl thioethers) via an organocatalyzed nucleophilic aromatic substitution of silyl-protected dithiols. This approach requires low catalyst loadings, proceeds rapidly at room temperature, and is effective for many different perfluorinated or highly activated aryl monomers. Computational investigations of the reaction mechanism reveal an unexpected, concerted SNAr mechanism, with the organocatalyst playing a critical, dual-activation role in facilitating the process. Not only does this remarkable reactivity enable rapid access to fluorinated poly(aryl thioethers), but also opens new avenues for the processing, fabrication, and functionalization of fluorinated materials with easy removal of the volatile catalyst and TMSF byproducts.Fluorinated poly(aryl thioethers), unlike their poly(aryl ethers) counterparts, have received little attention despite excellent physical properties displayed by many polysulfides. Here the authors show a highly efficient route to fluorinated poly(aryl thioethers) via an organocatalyzed nucleophilic aromatic substitution of silyl-protected dithiols.


Fused multivariate empirical mode decomposition (MEMD) and inverse solution method for EEG source localization.
EEG source localization is determining possible cortical sources of brain activities with scalp EEG. Generally, every step of the data processing sequence affects the accuracy of EEG source localization. In this paper, we introduce a fused multivariate empirical mode decomposing (MEMD) and inverse solution algorithm with an embedded unsupervised eye blink remover in order to localize the epileptogenic zone accurately. For this purpose, we constructed realistic forward models using MRI and boundary element method (BEM) for each patient to obtain results that are more realistic. We also developed an unsupervised algorithm utilizing a wavelet method to remove eye blink artifacts. Additionally, we applied MEMD, which is one of the recent and suitable feature extraction methods for non-linear, non-stationary, and multivariate signals such as EEG, to extract the signal of interest. We examined the localization results using the two most reliable linear distributed inverse methods in the literature: weighted minimum norm estimation (wMN) and standardized low resolution tomography (sLORETA). Results affirm the success of the proposed algorithm with the highest agreement compared to MRI reference by a specialist. Fusion of MEMD and sLORETA results in approximately zero localization error in terms of spatial difference with the validated MRI reference. High accuracy results of proposed algorithm using non-invasive and low-resolution EEG provide the potential of using this work for pre-surgical evaluation towards epileptogenic zone localization in clinics.


Plasma noradrenaline and its deaminated metabolites in essential hypertension and pheochromocytoma.
Dihydroxyphenylglycol (DOPEG) is a metabolite of noradrenaline (NA) in the sympathetic nerve endings, and dihydroxymandelic acid (DOMA) is one in the extraneuronal tissues. The measurement of plasma DOPEG and DOMA were evaluated with NA as one of the clinical indices of sympathetic nerve activity. These were measured in essential hypertension and also applied for diagnosis of pheochromocytoma. Plasma DOPEG levels were correlated with NA. Plasma NA and DOPEG were decreased after oral administration of clonidine (150 micrograms) and plasma DOPEG levels were slowly increased after standing. Therefore, plasma DOPEG seemed to be useful as one of the rather stable indices of the sympathetic nerve activity. Plasma NA and DOPEG levels in WHO stage I essential hypertension were higher than those in normotensive controls. Observed normal plasma noradrenaline and DOPEG levels in stage II reflect the normalized sympathetic tone in this stage. The elevation of plasma NA and DOMA levels in stage III seemed to be at least partly explained by renal function disturbance. In patients with pheochromocytoma, despite of the marked elevation of plasma NA and DOMA, plasma DOPEG showed only three-fold elevation and the ratio DOPEG/NA was reduced. The simultaneous measurement of plasma NA, DOPEG and DOMA is useful to evaluate sympathetic nerve activity in essential hypertension and to differentiate pheochromocytoma in hypertension.


Gonadotropin-releasing hormone stimulation of luteinizing hormone release: A ligand-receptor-effector model.
A divalent antibody conjugate of a pure antagonist of gonadotropin-releasing hormone (GnRH) behaved as an agonist--i.e., released luteinizing hormone (LH) from pituitary cultures. Release was measured over a wide range of conjugate concentrations; it rose to a maximum of 66% of the LH released by the optimal concentration of GnRH and declined to basal levels at very high concentrations. This behavior was modeled on the assumption that the antibody conjugate, A, can react with a receptor, R, to form a complex, A . R2. This dimer then can react with a quiescent effector, E (e.g., a closed Ca2+ ion channel), to form A . R2 . E, which contains activated effector and leads to cellular responses. The equilibrium equations governing the behavior of this model were derived, solved, and found to yield a good fit to the experimental data. Consideration of our data in this model system, and of other available data describing the behavior of ligands in other cells, suggests that the present model may be of wide applicability.


Comparison of hemodynamic responses to laryngoscopy and intubation using Macintosh or McCoy or C-MAC laryngoscope during uniform depth of anesthesia monitored by entropy.
Laryngoscopy forms an important part of general anesthesia and endotracheal intubation. The aim of the present study was to compare the hemodynamic responses to Laryngoscopy and Intubation using Macintosh or McCoy or C-MAC Laryngoscope with M-Entropy module monitoring to ensure uniform and adequate depth of anesthesia, during and after intubation. A prospective, randomised, comparative study was done and patients included were of 18 to 60 years, ASA (American Society of Anesthesiologist) physical status I and II of both sexes undergoing elective surgery under general anesthesia. They were assigned to three groups using simple randomisation, after securing IV (intravenous) access, standard monitoring and Entropy leads were attached. General anesthesia was administered with glycopyrrolate 0.1 mg, fentanyl 2 ug/kg and intravenous thiopentone, 4 mg/kg. Adequate muscle relaxation was achieved with atracurium 0.6 mg/kg IV. By titrating isoflurane concentration, Entropy maintained between 40 and 60, orotracheal intubation done, with Macintosh or McCoy or C-MAC blades according to simple randomisation. Size of laryngoscope blade, time taken for laryngoscopy and intubation were noted. Heart rate, blood pressure, RE (Response Entropy) and SE (State Entropy) were noted before and during induction and laryngoscopy and post intubation up to 5 minutes. Statistical analysis done using NCSS 9 version 9.0.8 statistical software. Hemodynamic responses during laryngoscopy and intubation using Macintosh or McCoy or C-MAC laryngoscope were statistically insignificant (p > 0.05) between the three groups, provided the depth of anesthesia is maintained constant. It is the depth of anesthesia that decides the magnitude of hemodynamic responses and not the choice of laryngoscope.


Solvent and water retention in dental adhesive blends after evaporation.
This study examined the extent of organic solvent and water retention in comonomer blends with different hydrophilicity (Hoy's solubility parameter for hydrogen bonding, delta(h)) after solvent evaporation, and the extent of tracer penetration in polymerised films prepared from these resins. For each comonomer blend, adhesive/solvent mixtures were prepared by addition of (1) 50 wt% acetone, (2) 50 wt% ethanol, (3) 30 wt% acetone and 20 wt% water and (4) 30 wt% ethanol and 20 wt% water. The mixtures were placed in glass wells and evaporated for 30-60s for acetone-based resins, and 60-120 s for ethanol-based resins. The weight of the comonomer mixtures was measured before and after solvent evaporation. Resin films were prepared for transmission electron microscopy (TEM) after immersion in ammonical silver nitrate. The percentages of solvent and water retained in the comonomer mixtures, and between the acetone and ethanol groups were measured gravimetrically and were statistically compared. In comonomer-organic solvent mixtures, the percentage of solvent retained in acetone and ethanol-based mixtures increased significantly with hydrophilicity of the comonomer blends (P < 0.05). In resin-organic solvent-water mixtures, significantly more solvent and water were retained in the ethanol-based mixtures (P < 0.0001), when compared to acetone-based mixtures after 60s of air-drying. TEM revealed residual water being trapped as droplets in resin films containing acetone and water. Water-filled channels were seen along the film periphery of all groups and throughout the entire resin films containing ethanol and water. The addition of water to comonomer-ethanol mixtures results in increased retention of both ethanol and water because both solvents can hydrogen bond to the monomers.


Temperature-induced homeoviscous adaptation of Chinese hamster ovary cells.
Exponential and plateau phase Chinese hamster ovary cells were maintained for 3 days at 32, 37, 39 or 41 degrees C. The effect of growth temperature on the fluidity and composition of the cellular membranes, and on the ability of the cells to resist a subsequent heat treatment at 43 degrees C, was measured. Cells grown at temperatures above 37 degrees C displayed increased resistance or tolerance to a 43 degree C heat treatment, whereas cells grown at 32 degrees C were sensitized to heat. Extensive cell division was not required for expression of heat tolerance. Membrane fluidity, as determined by the degree of rotational mobility of the fluorescent probe diphenylhexatriene, decreased with increasing growth temperatures, but the relationship did not hold in exponential phase cells grown at 32 degrees C. The cholesterol : phospholipid molar ratio correlated with the fluorescence polarization values, suggesting that the cells are able to adjust membrane fluidity by varying the concentration of cholesterol. The results are compatible with the concept of homeoviscous adaptation: that organisms strive to maintain an optimal level of membrane fluidity and when grown at a different temperature will alter the lipid composition in order to maintain this level. Up until now, cholesterol has not been implicated in this process.


Twelve-month prevalence and correlates of psychiatric disorders in Iran: the Iranian Mental Health Survey, 2011.
No national information is available on the epidemiology of psychiatric disorders in Iran for the last decade. To estimate the 12-month prevalence of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) psychiatric disorders in Iranian population, and to investigate the severity and correlates of psychiatric disorders. The Iranian Mental Health Survey (IranMHS) was a nationally representative face-to-face household survey with a multistage, cluster sampling design that was carried out in 2011. A total of 7886 community dwelling residents aged 15-64 were recruited. 12-month diagnoses of DSM-IV psychiatric disorders including mood, anxiety, and substance use disorders were assessed using a validated Persian translation of the Composite International Diagnostic Interview (CIDI; version 2.1). The Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I) was administered by a psychiatrist on subjects screened positive for the presence of a psychotic disorder. The severity of psychiatric disorders was determined using criteria that included markers for disability, particular diagnoses and suicide attempts. The response rate was 86.2%. The 12-month weighted prevalence of "any psychiatric disorder" was 23.6% [95% confidence interval (CI): 22.4-24.8] with 26.5% of women and 20.8% of men having one or more psychiatric disorders. The most common category of psychiatric disorders was any anxiety disorder (15.6%) and the most prevalent particular disorder was major depressive disorder (12.7%), followed by generalized anxiety disorder (5.2%) and obsessive-compulsive disorder (5.1%). A 12-month psychotic disorder was observed in 0.5% of the population (95% CI: 0.33-0.66). Almost two-thirds (63.8%) of individuals with a mental disorder had moderate or serious illness. Unemployment, being widowed/divorced and urban living were associated with a greater likelihood of 12-month disorders; while, higher socioeconomic status and having a university degree were associated with a lower likelihood. The high prevalence of psychiatric disorders, particularly major depression, merits further attention in the country's mental health policy and program planning.


Infection prevention and control in pediatric ambulatory settings.
Since the American Academy of Pediatrics published a statement titled "Infection Control in Physicians' Offices" (Pediatrics. 2000;105[6]:1361-1369), there have been significant changes that prompted this updated statement. Infection prevention and control is an integral part of pediatric practice in ambulatory medical settings as well as in hospitals. Infection prevention and control practices should begin at the time the ambulatory visit is scheduled. All health care personnel should be educated regarding the routes of transmission and techniques used to prevent transmission of infectious agents. Policies for infection prevention and control should be written, readily available, updated annually, and enforced. The standard precautions for hospitalized patients from the Centers for Disease Control and Prevention, with a modification from the American Academy of Pediatrics exempting the use of gloves for routine diaper changes and wiping a well child's nose or tears, are appropriate for most patient encounters. As employers, pediatricians are required by the Occupational Safety and Health Administration to take precautions to identify and protect employees who are likely to be exposed to blood or other potentially infectious materials while on the job. Key principles of standard precautions include hand hygiene (ie, use of alcohol-based hand rub or hand-washing with soap [plain or antimicrobial] and water) before and after every patient contact; implementation of respiratory hygiene and cough-etiquette strategies for patients with suspected influenza or infection with another respiratory tract pathogen to the extent feasible; separation of infected, contagious children from uninfected children when feasible; safe handling and disposal of needles and other sharp medical devices and evaluation and implementation of needle-safety devices; appropriate use of personal protective equipment such as gloves, gowns, masks, and eye protection; and appropriate sterilization, disinfection, and antisepsis.


The short-term regulation of hepatic acetyl-CoA carboxylase during starvation and re-feeding in the rat.
Rapid inhibition of acetyl-CoA carboxylase (ACC) activity in rat liver in response to 6 h starvation and rapid re-activation in response to 2-6 h of re-feeding chow were shown to be due to changes in the expressed activity of existing enzyme. Decreases and increases in ACC concentration occurred at later stages of the transitions, i.e. 6-48 h starvation and 8-24 h re-feeding respectively. The decrease in expressed activity of ACC was due primarily to changes in its phosphorylation state, demonstrated by a significantly decreased Vmax. and significantly increased Ka for citrate of enzyme purified by avidin-Sepharose chromatography from 6 h- or 48 h-starved rats. These effects were totally reversed within 2-4 h of chow re-feeding. Changes in the activity of purified ACC closely correlated with reciprocal changes in the activity of AMP-activated protein kinase (AMP-PK) over the fed to starved to re-fed transition. Increases in the activity ratio of cyclic-AMP-dependent protein kinase in response to starvation lagged behind the increase in AMP-PK and the decrease in ACC activity. Changes in AMP-PK and ACC activities of rat liver closely correlated with changes in plasma insulin concentration in response to time courses of starvation and re-feeding.


Effects of auditory feedback on fricatives produced by cochlear-implanted adults and children: acoustic and perceptual evidence.
Acoustic analyses and perception experiments were conducted to determine the effects of brief deprivation of auditory feedback on fricatives produced by cochlear implant users. The words /si/ and /Si/ were recorded by four children and four adults with their cochlear implant speech processor turned on or off. In the processor-off condition, word durations increased significantly for a majority of talkers. These increases were greater for children compared to adults, suggesting that children may rely on auditory feedback to a greater extent than adults. Significant differences in spectral measures of /S/ were found between processor-on and processor-off conditions for two of the four children and for one of the four adults. These talkers also demonstrated a larger /s/-/S/ contrast in centroid values compared to the other talkers within their respective groups. This finding may indicate that talkers who produce fine spectral distinctions are able to perceive these distinctions through their implants and to use this feedback to fine tune their speech. Two listening experiments provided evidence that some of the acoustic changes were perceptible to normal-hearing listeners. Taken together, these experiments indicate that for certain cochlear-implant users the brief absence of auditory feedback may lead to perceptible modifications in fricative consonants.


Development of albuminuria and glomerular lesions in normoglycemic B6 recipients of db/db mice bone marrow: the role of mesangial cell progenitors.
The pathologic hallmarks of diabetic nephropathy are excess mesangial extracellular matrix (ECM) and mesangial cell proliferation. We previously showed that mesangial cell phenotypic changes play an important role in the pathogenesis of diabetic nephropathy. We concluded that phenotypic changes were present in bone marrow (BM)-derived mesangial cell progenitors, as transplantation of BM from db/db mice, a model of type 2 diabetic nephropathy, transferred the db genotype and a nephropathy phenotype to naive B6 mice recipients. The recipients did not develop diabetes; however, they did develop albuminuria and glomerular lesions mirroring those in the donors (i.e., glomerular hypertrophy, increased ECM, and increased cell number with cell proliferation). We found that matrix metalloproteinase 2 (MMP-2) facilitated invasion of the mesangial cells into ECM and proliferation in vitro. Thus, increased MMP-2 activity in db/db mesangial cell progenitors may partially explain increased mesangial cell repopulation and proliferation in B6 recipients of db/db BM. In summary, BM-derived mesangial cell progenitors may play a crucial role in the development and progression of ECM accumulation and mesangial cell proliferation in this model of diabetic nephropathy in type 2 diabetes.


Safety and accuracy of bedside external ventricular drain placement.
To study the safety and accuracy of ventriculostomy by neurosurgical trainees. Initial computed tomographic studies of 346 consecutive patients who underwent bedside ventriculostomy were reviewed retrospectively. Diagnosis, catheter tip location, midline shift, and procedural complications were tabulated. To analyze catheter placement, we used a new grading system: Grade 1, optimal placement in the ipsilateral frontal horn or third ventricle; Grade 2, functional placement in the contralateral lateral ventricle or noneloquent cortex; and Grade 3, suboptimal placement in the eloquent cortex or nontarget cerebrospinal fluid space, with or without functional drainage. Statistical analysis was performed using Fisher's exact test and a weighted kappa coefficient. Diagnoses included the following: subarachnoid hemorrhage, n = 153 (44%); trauma, n = 64 (18%); intracerebral hemorrhage/intraventricular hemorrhage, n = 63 (18%); and other, n = 66 (20%). There were 266 (77%) Grade 1, 34 (10%) Grade 2, and 46 (13%) Grade 3 catheter placements. Hemorrhagic complications occurred in 17 (5%). Four patients (1.2%) were symptomatic, with two (0.6%) requiring surgery. Inter- and intraobserver agreement was almost perfect (kappa = 0.846 and 0.922, respectively) as applied to our grading system. Rates of suboptimal placement were highest in patients with midline shift (P = 0.059) and trauma (P = 0.0001). Rates of optimal placement were highest in patients with subarachnoid hemorrhage (P = 0.003) and when the catheter was placed ipsilateral to the side of midline shift (P = 0.063). Neither the resident's training experience nor the side of placement seemed to affect accuracy. Bedside ventriculostomy is a safe and accurate procedure for intracranial pressure monitoring and cerebrospinal fluid drainage.


Immigration: a potential time bomb under the Integration of Conservation and Development.
Integrated Conservation and Development Projects (ICDPs) aim to stimulate conservation without the previous negative experiences for local people, but pay little attention to their long-term impact such as immigration. The rehabilitation of the Logone floodplain in North Cameroon, the core activity of the Waza-Logone ICDP, has led to a 34% increase of sedentary fishermen and a multiple number of temporary fishermen. Whereas livestock pressure tripled, kob antelopes, a key floodplain species, have not increased, reducing their competitiveness. The virtual disappearance of wildlife in nearby Kalamaloué National Park (NP), due to advanced human encroachment forms, is therefore a bleak perspective for Waza NP. Examples from the Central African Republic (CAR), Galapagos, Nigeria and Zimbabwe also showed that in open-access systems, improvement in living standards (development) may stimulate immigration, jeopardizing the stability necessary in protected areas (conservation). Most ICDPs lack demographic monitoring, masking its possible immigration risk. To counter the immigration risk in Waza, a policy was formulated based on local stakeholder categorization and subsequent privileges, resulting in the voluntarily displacement of a village out of Waza NP. It is further recommended that ICDPs should be involved in regional land-use planning and discourage development activities that stimulate immigration.


The complete sequence of the chicken alpha-cardiac actin gene: a highly conserved vertebrate gene.
We sequenced the entire chicken alpha-cardiac actin gene. A single intron was positioned 20 bp upstream from the initiation ATG codon in the 5' non-coding region while the coding region was interrupted by 5 introns at amino acid positions 41/42, 150, 204, 267, and 327/328. Sequencing allowed the first comparison of the alpha-cardiac and alpha-skeletal actin transcriptional promoters. These highly G+C rich promoters share two regions of homology which are found at position -134 (10 bp) and -296 (12 bp) in the alpha-cardiac actin promoter. A smaller 9 bp motif (CCGCGCCGG) homologous to the -134 sequence was detected before, between and after the TATA and CAAT boxes of the alpha-cardiac actin gene. The polyadenylation signal (AATAAA) was located 156 bp downstream from the translation termination codon. The complete length of the alpha-cardiac actin mRNA excluding the poly A tail is 1370 nucleotides. The 3' noncoding transcribed portion of the chicken alpha-cardiac actin gene was found to be extraordinarily conserved when compared to the human and rat alpha-cardiac actin mRNA sequences.


Blood pressure and sympathetic nerve tone relation during hemodialysis may reflect cardiovascular dysfunction.
The blood pressure response to the rapid removal of fluid during hemodialysis is complex and the pathophysiological mechanisms underlying intradialytic hypotension are not clear and sometimes these mechanisms render dialysis difficult to continue. We analyzed the changes in blood pressure and sympathetic nerve tone and attempted to clarify whether the dynamic pattern of this relationship reflects cardiovascular dysfunction. The dynamic pattern of sympathetic nerve activity throughout dialysis was analyzed by frequency analysis of RR intervals recorded by 24 hours Holter electrocardiography in 64 patients and 3 minutes ECG every 15 minutes during dialysis in 121 stable end-stage renal failure patients who underwent maintenance hemodialysis. Blood pressure and fluid volume removed was measured every 15-30 minutes during dialysis and the average value of the ratio of low to high frequency components (LF/HF) was calculated as an index of sympathetic nerve tone. The relationship between removed fluid volume, systolic blood pressure (Bp) and LF/HF was analyzed. The patients were classified into 3 groups based on the correlation between the LF/HF and Bp as follows: positive (52 cases), inverse (54 cases), and not significant (NS; 61 cases). Eighteen patients who showed multiple arrhythmias, atrial fibrillation and other artifacts or noises were eliminated as they were inadequate for frequency analysis of RR intervals. The positive group was characterized by a hypotension-resistant response with a low LF/HF, whereas the inverse group was characterized by a hypotension-prone response with high LF/HF. These results suggest that cardiovascular dysfunction is responsible for the inverse correlation. Analysis of the relationship between sympathetic nerve tone and Bp is effective in predicting the existing of cardiovascular dysfunction.


Coarse-grained versus atomistic simulations: realistic interaction free energies for real proteins.
To assess whether two proteins will interact under physiological conditions, information on the interaction free energy is needed. Statistical learning techniques and docking methods for predicting protein-protein interactions cannot quantitatively estimate binding free energies. Full atomistic molecular simulation methods do have this potential, but are completely unfeasible for large-scale applications in terms of computational cost required. Here we investigate whether applying coarse-grained (CG) molecular dynamics simulations is a viable alternative for complexes of known structure. We calculate the free energy barrier with respect to the bound state based on molecular dynamics simulations using both a full atomistic and a CG force field for the TCR-pMHC complex and the MP1-p14 scaffolding complex. We find that the free energy barriers from the CG simulations are of similar accuracy as those from the full atomistic ones, while achieving a speedup of >500-fold. We also observe that extensive sampling is extremely important to obtain accurate free energy barriers, which is only within reach for the CG models. Finally, we show that the CG model preserves biological relevance of the interactions: (i) we observe a strong correlation between evolutionary likelihood of mutations and the impact on the free energy barrier with respect to the bound state; and (ii) we confirm the dominant role of the interface core in these interactions. Therefore, our results suggest that CG molecular simulations can realistically be used for the accurate prediction of protein-protein interaction strength. The python analysis framework and data files are available for download at http://www.ibi.vu.nl/downloads/bioinformatics-2013-btt675.tgz.


First-onset mental disorders after cancer diagnosis and cancer-specific mortality: a nationwide cohort study.
The diagnosis of cancer is strongly associated with the risk of mental disorders even in patients with no previous history of mental disorders. Accumulating data suggest that mental distress may accelerate tumor progression. We hypothesized therefore that mental disorders after a cancer diagnosis may increase the risk of cancer-specific mortality. We conducted a nationwide cohort study including 244 261 cancer patients diagnosed in Sweden during 2004-2009 and followed them through 2010. Through the Swedish Patient Register, we obtained clinical diagnoses of all mental disorders and focused on mood-, anxiety-, and substance abuse disorders (ICD10: F10-F16, F18-F19, F32-F33, F40-F41, and F43-45) that are commonly diagnosed among patients with cancer. We further classified the studied mental disorders into first-onset or recurrent mental disorders. We used Cox regression to estimate multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) as a measure of the association between mental disorders after cancer diagnosis and cancer-specific mortality, adjusting for age, sex, calendar period, educational level, cancer stage, and cancer type at diagnosis. After cancer diagnosis, 11 457 patients were diagnosed with mood-, anxiety-, and substance abuse disorders; of which 7236 were first-onset mental disorders. Patients with a first-onset mental disorder were at increased risk of cancer-specific mortality (HR: 1.82, 95% CI: 1.71-1.92) while patients with a recurrent mental disorder had much lower risk elevation (HR: 1.14, 95% CI: 1.05-1.24). The increased cancer-specific mortality by first-onset mental disorders was observed for almost all cancer sites/groups and the association was stronger for localized cancers (HR: 2.00, 95% CI: 1.73-2.31) than for advanced cancers (HR: 1.49, 95% CI: 1.32-1.69). Patients with a first-onset common mood-, anxiety-, or substance abuse disorder after cancer diagnosis may be at increased risk of cancer-specific death.


Design considerations for plasmonic photovoltaics.
This paper reviews the recent research progress in the incorporation of plasmonic nanostructures with photovoltaic devices and the potential for surface plasmon enhanced absorption. We first outline a variety of cell architectures incorporating metal nanostructures. We then review the experimental fabrication methods and measurements to date, as well as systematic theoretical studies of the optimal nanostructure shapes. Finally we discuss photovoltaic absorber materials that could benefit from surface plasmon enhanced absorption.


[Salvage surgery for upper aerodigestive tract tumours].
Salvage surgeries of head and neck tumors are considered as poor satisfactory either for disease control results or for aesthetic and functional outcomes. Several improvements have been made possible since few years in all fields of oncologic treatments. A new approach must be initiated in that context, moreover since take in charge for head and neck region (exclusive initial medical treatment) let us consider an increasement of clinical situations for which a salvage therapy could be performed. The new surgery techniques have to be considered, reconstructive and guided by systems, which can improve surgical skills (navigation, robotic, sentinel node procedure, nervous detection and so on), the help of reirradiation techniques, the use of medical therapy during surgical procedure, the photodynamic therapy and all the help provided by new medical imaging and modern biology, which can determine more precisely the status of the cancer when it is taken in charge. The mastery of those techniques improvements must follow on an evolution of the concepts in the field of combined salvage treatments performed by multidisciplinary teams. Those treatments have to be realized in structures, which have the techniques and the multiple skills for allowing increasement of outcomes of those severe diseases.


Assessment of three-dimensional lumbar spine vertebral motion during gait with use of indwelling bone pins.
This study quantifies the three-dimensional motion of lumbar vertebrae during gait via direct in vivo measurement with the use of indwelling bone pins with retroreflective markers and motion capture. Two previous studies in which bone pins were used were limited to instrumentation of two vertebrae, and neither evaluated motions during gait. While several imaging-based studies of spinal motion have been reported, the restrictions in measurement volume that are inherent to imaging modalities are not conducive to gait applications. Eight healthy volunteers with a mean age of 25.1 years were screened to rule out pathology. Then, after local anesthesia was administered, two 1.6-mm Kirschner wires were inserted into the L1, L2, L3, L4, L5, and S1 spinous processes. The wires were clamped together, and reflective marker triads were attached to the end of each wire couple. Subjects underwent spinal computed tomography to anatomically register each vertebra to the attached triad. Subjects then walked several times in a calibrated measurement field at a self-selected speed while motion data were collected. Less than 4° of lumbar intersegmental motion was found in all planes. Motions were highly consistent between subjects, resulting in small group standard deviations. The largest motions were in the coronal plane, and the middle lumbar segments exhibited greater motions than the segments cephalad and caudad to them. Intersegmental lumbar flexion and axial rotation motions were both extremely small at all levels. The lumbar spine chiefly acts to contribute abduction during stance and adduction during swing to balance the relative motions between the trunk and pelvis. The lumbar spine acts in concert with the thoracic spine. While the lumbar spine chiefly contributes coronal plane motion, the thoracic spine contributes the majority of the transverse plane motion. Both contribute flexion motion in an offset phase pattern. This is a valid model for measuring the three-dimensional motion of the spine. Normative data were obtained to better understand the effects of spine disorders on vertebral motion over the gait cycle.


Qigong Exercise and Arthritis.
Background: Arthritis is a chronic condition resulting in considerable disability, particularly in later life. Aims: The first aim of this review was to summarize and synthesize the research base concerning the use of Qigong exercises as a possible adjunctive strategy for promoting well-being among adults with arthritis. A second was to provide related intervention directives for health professionals working or who are likely to work with this population in the future. Methods: Material specifically focusing on examining the nature of Qigong for minimizing arthritis disability, pain and dependence and for improving life quality was sought. Results: Collectively, despite almost no attention to this topic, available data reveal that while more research is indicated, Qigong exercises-practiced widely in China for many centuries as an exercise form, mind-body and relaxation technique-may be very useful as an intervention strategy for adults with different forms of painful disabling arthritis. Conclusion: Health professionals working with people who have chronic arthritis can safely recommend these exercises to most adults with this condition with the expectation they will heighten the life quality of the individual, while reducing pain and depression in adults with this condition.


[Impact of consumption of corn flour with low level enrichment in children of rural zones].
Corn has been from the prehispanic era, the most important feeding plant in the Mexican population, particularly in the most important sectors and in marginal areas. In this setting, enriching the product as flour implies an increase in its nutritional quality, especially because corn is the basic food. To assess the effect of the consumption of corn flour enriched with 3% soybean, vitamins, and minerals on the growth and development of infants and preschool children. experimental study lasting 10 months. The experimental group (n=195) received enriched corn flour whereas the control group (n=200) received non-enriched flour. The indicators were: nutritional status, mental and psychomotor development, and blood hemoglobin levels. in the total sample, there were no differences between the experimental group and the control group. However, there were improvements in the weight-to-height and weight-to-age indexes in the children consuming enriched flour and in children older than one year, who were the babies of indigenous women living in marginal areas. enriched corn flour appears to be an alternative benefitting the children population with higher nutritional deficiencies. However, a longer intervention is necessary to obtain better results.


Promotion of met-tRNAiMet binding to ribosomes by yIF2, a bacterial IF2 homolog in yeast.
Delivery of the initiator methionine transfer RNA (Met-tRNAiMet) to the ribosome is a key step in the initiation of protein synthesis. Previous results have indicated that this step is catalyzed by the structurally dissimilar translation factors in prokaryotes and eukaryotes-initiation factor 2 (IF2) and eukaryotic initiation factor 2 (eIF2), respectively. A bacterial IF2 homolog has been identified in both eukaryotes and archaea. By using a combination of molecular genetic and biochemical studies, the Saccharomyces cerevisiae IF2 homolog is shown to function in general translation initiation by promoting Met-tRNAiMet binding to ribosomes. Thus, the mechanism of protein synthesis in eukaryotes and prokaryotes is more similar than was previously realized.


Overexpression of the aldose reductase GRE3 suppresses lithium-induced galactose toxicity in Saccharomyces cerevisiae.
In Saccharomyces cerevisiae, lithium induces a 'galactosemia-like' phenotype as a consequence of inhibition of phosphoglucomutase, a key enzyme in galactose metabolism. Induced galactose toxicity is prevented by deletion of GAL4, which inhibits the transcriptional activation of genes involved in galactose metabolism and by deletion of the galactokinase (GAL1), indicating that galactose-1-phosphate, a phosphorylated intermediate of the Leloir pathway, is the toxic compound. As an alternative to inhibiting entry and metabolism of galactose, we investigated whether deviation of galactose metabolism from the Leloir pathway would also overcome the galactosemic effect of lithium. We show that cells overexpressing the aldose reductase GRE3, which converts galactose to galactitol, are more tolerant to lithium than wild-type cells when grown in galactose medium and they accumulate more galactitol and less galactose-1-phosphate. Overexpression of GRE3 also suppressed the galactose growth defect of the 'galactosemic'gal7- and gal10-deleted strains, which lack galactose-1-P-uridyltransferase or UDP-galactose-4-epimerase activities, respectively. Furthermore, the effect of GRE3 was independent of the inositol monophosphatases INM1 and INM2. We propose that lithium induces a galactosemic state in yeast and that inhibition of the Leloir pathway before the phosphorylation step or stimulation of galactitol production suppresses lithium-induced galactose toxicity.


The motivational properties of schedule-induced polydipsia.
Schedule-induced polydipsia occurred during initial magazine training to Noyes pellets (45 mg), disappeared when lever-pressing was acquired on a continuous reinforcement schedule (CRF), and reappeared when the food contingency was changed to a 1-min variable interval schedule (VI 1 min). Polydipsia also developed under a VI 1 min food schedule when water was concurrently available on various fixed ratios (FR), rather than being freely available. The level of the polydipsia and its motivating properties allow it to be classified as a form of adjunctive behavior.


Sciatic neuroendometriosis: Magnetic resonance imaging defined perineural spread of endometriosis.
Catamenial sciatic radiculopathy resulting from endometriosis is a rare presentation of a common disease in which the pathogenesis of pain is still under debate. A 32-year-old woman presented complaining of infertility, catamenial sciatica, and pelvic and gluteal pain. Magnetic resonance imaging showed endometriotic infiltration of the left proximal lumbosacral plexus, sacral nerve track, sciatic nerve at the sciatic notch and pudendal nerve along the iliococcygeus muscle, together with left endometrioma and deep infiltrating endometriosis lesions. Laparoscopic endometriosis surgery was performed after all of the complications and possible outcomes of the surgery were discussed with the patient. Our case report highlights the importance of magnetic resonance imaging evidence of perineural spread, outlining the pathophysiology of the pelvic pain associated with neuroendometriosis.


Total synthesis of (-)-laulimalide.
(-)-Laulimalide (1), a structurally novel macrolide isolated in trace amounts from marine sponges, promotes abnormal tubulin polymerization and apoptosis in vitro, with a similar mode of action to that of Taxol(R), but with potentially less susceptibility to multidrug resistance. Herein, a flexible and convergent asymmetric synthesis of (-)-laulimalide is described. This synthesis featured a highly diastereoselective Sakurai reaction of 2 with 3 and a regioselective macrolactonization of an unprotected vicinal diol. Laulimalide was synthesized in 25 steps (longest linear; 36 overall) in 3.5% overall yield, providing a uniquely short and efficient route to 1 and its analogues.


[Cardiovascular Risk Assessment: preliminary results].
The Italian National Prevention plan includes 10-year cardiovascular risk (CR) assessment of the Italian general population aged 35-69 years using the CUORE Project risk score. A national training program for general practitioners (GPs) was launched by the Ministry of Health in 2003. GPs were encouraged to collect data on risk factors and risk assessment and to contribute to the CUORE Project Cardiovascular Risk Observatory (CRO). The aim of this analysis is to demonstrate the feasibility and effectiveness of risk assessment in primary care. The cuore.exe software, free of charge for GPs and easily downloadable from the CUORE Project web site (www.cuore.iss.it), is the frame for the GP data collection. The CRO provides a platform to analyze data collected on risk assessment and risk factors, and compare results at regional and national level in order to support health policy makers in their decision process. From January 2007 to April 2009, 2858 GPs have downloaded the cuore.exe software; 102,113 risk assessments were sent to the CRO based on risk factors profile of 87,556 persons (3617 persons had more than 1 risk assessment). Mean level of CR was 3.1% in women and 8.4% in men; 30% of men and 65% of women were at low risk (CR < 3%), 9% of men and 0.4% of women were found at high risk (CR > or = 20%). Among those with at least 2 risk assessments, 8% shifted to a lower class of risk after 1 year. Mean level of systolic and diastolic blood pressure decreased by about 1% in 1 year; total cholesterol more than 2%, and prevalence of smokers decreased by about 3% in the second risk assessment. These data demonstrate that risk assessment can be included as a first step of prevention in primary care. The CUORE Project individual score is expected to become an important tool for GPs to assess their patients' CR, to promote primary prevention, and to focus attention to healthy lifestyle adoption.


Digital image analysis and identification of eggs from bovine parasitic nematodes.
Computer-assisted microscopy and multivariate statistics were used to establish and evaluate a procedure for identification of bovine strongylid eggs. Ostertagia ostertagi, Cooperia oncophora, Haemonchus placei, Trichostrongylus axei, and Oesophagostomum radiatum eggs were obtained from faeces voided by monospecifically infected calves. Images of single eggs (400 x magnification) were recorded by a CCD camera fitted onto a microscope and digitized on a PC. After separation of eggs from the image background, the pixel (picture element) positions of the egg outline were analysed by algorithms to describe size and shape. A stepwise discriminant analysis was subsequently used to select and rank descriptive features of 4207 eggs according to discriminatory power. Classification criteria were developed by linear discrimination analysis on the basis of selected features, and the criteria evaluated by cross-validation. A maximum average percentage of correct classification of 85.8% resulted when nineteen features were employed in a linear classification criterion. The percentages correct classification for each species were: O. ostertagi 76.3%, C. oncophora 90.8%, O. radiatum 87.8%, H. placei 90.1%, and T. axei 83.8%. Classification based on the five most important features gave an overall correct classification of 81.5%. Images of "unknown' eggs could be identified automatically by the classification criteria after procedural steps performed by PC were linked in a batch program.


Kluyveromyces nonfermentans sp. nov., a new yeast species isolated from the deep sea.
Eleven strains of a new species of the genus Kluyveromyces, characterized as having evanescent asci and Q-6 as the major ubiquinone, were isolated from sediments, a clam and a crab collected at depths of 1000-2000 m in Suruga Bay and Sagami Bay, Japan. A phylogenetic tree based on small-subunit (18S) rRNA gene sequences placed these isolates into a cluster of Kluyveromyces. DNA complementarity and phylogenetic trees of internal transcribed spacer (ITS) regions and 5.8S rRNA genes showed that the isolates are closely related to Kluyveromyces aestuarii, but that these two species are genetically distinct. The isolates are described as Kluyveromyces nonfermentans sp. nov. Because this species lacks the fermentative ability considered to be an important criterion for the genus Kluyveromyces, the definition of the genus has been emended. The type strain of K. nonfermentans is strain SY-33T (= JCM 10232T).


Monitoring of cytosolic free Ca2+ in C5a-stimulated neutrophils: loss of receptor-modulated Ca2+ stores and Ca2+ uptake in granule-free cytoplasts.
The cytosolic concentration of free Ca2+ in bovine neutrophils was monitored by using the intracellular Ca2+ indicator quin2, 2-[[2-bis(acetylamino)-5-methylphenoxy]methyl-6-methoxy-8- bis(acetylamino)]quinoline. Neutrophils at rest have a cytosolic Ca2+ concentration of 85 +/- 5 nM, which in 2-4 min increases to 300-400 nM upon interaction with the complement fragment C5a in a concentration range of 35 pM to 1.2 microM. In the same concentration range, C5a also sequentially activates neutrophil directional migration (ED50 less than 0.5 nM), O-2 production (ED50 = 9 nM), and secretion of the contents of specific granules (ED50 = 39 nM). The selective Ca2+ ionophore ionomycin also increases cytosolic Ca2+ concentration above 1 microM under conditions where it stimulates neutrophil functions. Conversely, phorbol 12-myristate 13-acetate markedly activates secretion and O-2 production without modifying the average cytosolic Ca2+ concentration. In the presence of EGTA (Ca2+out approximately equal to 20 nM), with both C5a and ionomycin, cytosolic Ca2+ increases to less than 200 nM, and functional responses are greatly decreased. Nucleus- and granule-free neutrophil cytoplasts accumulate Ca2+ and produce O-2 when exposed to ionomycin but not to C5a. These results and other considerations suggest that (i) activation of neutrophil functions may occur after cytosolic Ca2+ has exceeded the apparent threshold level of 200 nM; (ii) C5a receptor-mediated activation of Ca2+ influx may require cooperation between the neutrophil surface and some cytoplasmic organelle and/or redistribution of the C5a-receptor complexes on the cell surface; and (iii) the phorbol diester stimulates Ca2+-dependent pathways presumably by directly activating other mechanisms such as protein phosphorylation.


Teratogen update: methotrexate.
Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m(2) (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell-related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate-exposed children. Denominator-based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure.


Nutritional interventions in depression and perinatal depression.
Depression is the leading cause of mental disability worldwide. Women who are depressed during pregnancy are at a higher risk for preterm delivery, preeclampsia, birth difficulties, and postpartum depression. The treatment of depression in conventional medicine has focused on physiological factors that lead to impaired neurotransmitter function and treatments to improve neurotransmitter function. Pharmaceutical substances pose risks for pregnant and lactating women, and lower risk options are preferred. Micronutrients, including certain B vitamins, folate, and docosahexaenoic acid (DHA), play a role in the synthesis and absorption of neurotransmitters. Experimental studies suggest that supplementation with specific micronutrients may alleviate depressive symptoms and improve birth outcomes in patients with perinatal depression. Alternative treatments for depression, including nutritional supplements, are an important treatment option for depressive symptoms while limiting potential side effects and treatment costs. This article explores the biological basis of perinatal depression and reviews the potential benefits of non-pharmacological interventions.


Epidemiology of violence and war.
The magnitude of the threat that violence and war pose to the health, the quality of life, and the very survival of humanity is obvious. A number of scientific disciplines have provided, each through its own methodology, insights into the causation, genesis, and dynamics of violence and war. Although epidemiological and psychological methodologies received priority, the multidisciplinary approach to this problem seems to be the most appropriate. This essay attempts to approach holistically the study of epidemiology of violence and war and the ways of preventing these severe problems of the contemporary society. Conceptual models of the causative mechanisms and dynamics of violence and war, mapping the various psychic, social, and environmental factors, are presented. These models, besides advancing abstract ideas, also provide a concrete framework for determining and exploring the interactions and dynamics of the factors and processes which lead to violence and war. The types of interventions outlined for control and prevention are intended to make an impact upon "critical points" within the dynamics of the process which produces violence and war, and are conceived to be implemented on both the national and international level. The importance of family, community, and school influences is considered, but the role of international organizations, including the United Nations, and other governmental and non-governmental organizations is also stressed. Discussion is focused on the factors which favour peace and hamper aggression, on "internationalization" and global society versus xenophobia and nationalism. The conclusions state that there is sufficient knowhow to devise and implement a reasonable and effective international programme for the control and prevention of violence and war, provided there is adequate public and political willingness and support.


Donor-derived Kaposi's sarcoma in a liver-kidney transplant recipient.
Human herpes virus 8 (HHV-8), also known as Kaposi's sarcoma associated herpesvirus (KSHV), is an oncogenic virus that can cause Kaposi's sarcoma (KS). KS can develop following organ transplantation through reactivation of the recipient's latent HHV-8 infection, or less commonly through donor-derived infection which has higher risk for severe illness and mortality. We describe a case of probable donor-derived KS in the recipient of a liver-kidney transplant. The donor had multiple risk factors for HHV-8 infection. The KS was successfully treated by switching immunosuppression from tacrolimus to sirolimus. With an increasing number of human immunodeficiency virus (HIV)-positive persons seeking organ transplantation and serving as organ donors for HIV-positive recipients, HHV-8 prevalence among donors and recipients will likely increase and with that the risk for post-transplant KS. Predetermination of HHV-8 status can be useful when considering organ donors and recipients with risk factors, although there are currently no validated commercial tests for HHV-8 antibody screening.


Characterization and functional assessment of the NLRC3-like molecule of the goldfish (Carassius auratus L.).
The NLRC3-like (NLRC3L) molecule from the goldfish transcriptome database was identified and characterized. Quantitative gene expression analysis revealed the highest mRNA levels of NLRC3L were in the spleen and intestine, with lower mRNA levels observed in muscle and liver. Goldfish NLRC3L was differentially expressed in goldfish immune cell populations with highest mRNA levels measured in PBLs and macrophages. We generated a recombinant form of the molecule (rgfNLRC3L) and an anti-CT-NLRC3L IgG. Treatment of goldfish primary kidney macrophages in vitro with ATP, LPS and heat-killed Aeromonas salmonicida up-regulated the NLRC3L mRNA and protein. Confocal microscopy and co-immunoprecipitation assays indicated that goldfish rgfNLRC3L interacted with apoptosis-associated spec-like protein (ASC) in eukaryotic cells, indicating that NLRC3L may participate in the regulation of the inflammasome responses. The dual-luciferase reporter assay showed that NLRC3L over-expression did not cause the activation of NF-κB, but that it cooperated with RIP2 to down-regulate NF-κB activation. Our results indicate that the NLRC3L may function as a regulator of NLR pathways in teleosts.


An Annealed Sequential Monte Carlo Method for Bayesian Phylogenetics.
We describe an "embarrassingly parallel" method for Bayesian phylogenetic inference, annealed Sequential Monte Carlo (SMC), based on recent advances in the SMC literature such as adaptive determination of annealing parameters. The algorithm provides an approximate posterior distribution over trees and evolutionary parameters as well as an unbiased estimator for the marginal likelihood. This unbiasedness property can be used for the purpose of testing the correctness of posterior simulation software. We evaluate the performance of phylogenetic annealed SMC by reviewing and comparing with other computational Bayesian phylogenetic methods, in particular, different marginal likelihood estimation methods. Unlike previous SMC methods in phylogenetics, our annealed method can utilize standard Markov chain Monte Carlo (MCMC) tree moves and hence benefit from the large inventory of such moves available in the literature. Consequently, the annealed SMC method should be relatively easy to incorporate into existing phylogenetic software packages based on MCMC algorithms. We illustrate our method using simulation studies and real data analysis.


Trigeminal nerve stimulation does not acutely affect cortical excitability in healthy subjects.
Trigeminal nerve stimulation (TNS) has recently emerged as a new therapeutic option for patients with drug-resistant epilepsy but its potential mechanisms of action are not known. Since other antiepileptic treatments have been shown to alter cortical excitability, thereby reducing the liability to seizures, it has been suggested that cranial nerve stimulation such as TNS may act in the same way. To study whether TNS has the potential to alter cortical excitability in healthy subjects. An adaptive paired-pulse transcranial magnetic stimulation protocol stimulating the dominant hand motor area was used to measure resting motor threshold (rMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and long-interval intracortical inhibition (LICI) before, during, and after 40 min of 120 Hz bilateral external continuous trigeminal nerve stimulation. Neuronavigation was used for guidance. TNS was well tolerated by all subjects. No significant changes were seen in the parameters studied. Unlike for example anti-epileptic drugs and the ketogenic diet, trigeminal nerve stimulation does not seem to alter cortical excitability in healthy subjects. This is the first study on cortical excitability in relation to continuous trigeminal nerve stimulation. It still remains to be proven that TNS has the prerequisites to effectively counteract epileptic events in humans.


Collagen-stimulated unidirectional translocation of cholesterol in human platelet membranes.
When human platelets are stimulated with collagen or thrombin, the asymmetric distribution of membrane lipids is disrupted as phosphatidylserine and phosphatidylethanolamine translocate from the inner monolayer to the outer monolayer. Coincident with the stimulus-dependent rearrangement of membrane phospholipids is a rapid redistribution of cholesterol from the outer to the inner membrane monolayer. This redistribution of cholesterol was observed when the stimulus was collagen or ADP. The data presented here show that epinephrine stimulation does not promote cholesterol translocation but does potentiate collagen-promoted movement of cholesterol. To investigate the process of cholesterol translocation, experiments were performed to determine whether collagen stimulated reverse cholesterol movement; i.e. from the inner to the outer monolayer. For this study, the fluorescent sterol cholestatrienol (C-3) was incorporated into platelet membranes by exchange from cholesterol-containing phosphatidylcholine small unilamellar vesicles. C-3 was then removed selectively from the outer monolayer by treatment of the platelets with bovine serum albumin (BSA). During the subsequent incubation of BSA-treated platelets, C-3 moved spontaneously into the outer from the inner monolayer. This translocation had an apparent half-time of approximately 25 min and was unaltered by the presence of collagen. These results suggest that collagen treatment of platelets selectively facilitates the inward movement of the sterol. We have hypothesized that cholesterol translocation may be thermodynamically driven as a result of an unfavorable entropy, resulting in cholesterol translocation out of an environment becoming enriched in phosphatidylethanolamine. The unidirectional nature of collagen-promoted cholesterol movement from the phosphatidylethanolamine-rich outer monolayer is consistent with this interpretation.


Mathematical model for the mitigation of the economic effects of the Covid-19 in the Democratic Republic of the Congo.
Since the apparition of the SRAS-Cov-2 in Wuhan in China, several countries have set diverse measures to stop its spread. Measures envisaged include national or local lockdown and travels ban. In the DRC, these measures have seriously prejudiced the economy of the country which is mainly informal. In this paper, a mathematical model for the spread of Covid-19 in Democratic Republic of Congo (DRC) taking into account the vulnerability of congolese economy is proposed. To mitigate the spreading of the virus no national lockdown is proposed, only individuals affected by the virus or suspicious are quarantined. The reproduction number for the Covid-19 is calculated and numerical simulations are performed using Python software. A clear advice for policymakers is deduced from the forecasting of the model.


Interstitial lung disease is a risk factor for ischaemic heart disease and myocardial infarction.
Despite many shared risk factors and pathophysiological pathways, the risk of ischaemic heart disease (IHD) and myocardial infarction (MI) in interstitial lung disease (ILD) remains poorly understood. This lack of data could be preventing patients who may benefit from screening for these cardiovascular diseases from receiving it. A population-based cohort study used electronic patient records from the Clinical Practice Research Datalink and linked Hospital Episode Statistics to identify 68 572 patients (11 688 ILD exposed (mean follow-up: 3.8 years); 56 884 unexposed controls (mean follow-up: 4.0 years), with 349 067 person-years of follow-up. ILD-exposed patients (pulmonary sarcoidosis (PS) or idiopathic pulmonary fibrosis (PF)) were matched (by age, sex, registered general practice and available follow-up time) to patients without ILD or IHD/MI. Rates of incident MI and IHD were estimated. HRs were modelled using multivariable Cox proportional hazards regression accounting for potential confounders. ILD was independently associated with IHD (HR 1.85, 95% CI 1.56 to 2.18) and MI (HR 1.74, 95% CI 1.44 to 2.11). In all disease categories, risk of both IHD and MI peaked between ages 60 and 69 years, except for the risk of MI in PS which was greatest <50 years. Men with PF were at greatest risk of IHD, while women with PF were at greatest risk of MI. ILD, particularly PF, is independently associated with MI and IHD after adjustment for established cardiovascular risk factors. Our results suggest clinicians should prioritise targeted assessment of cardiovascular risk in patients with ILD, particularly those aged 60-69 years. Further research is needed to understand the impact of such an approach to risk management.


The development and psychometric properties of the selective mutism questionnaire.
Research on selective mutism (SM) has been limited by the absence of standardized, psychometrically sound assessment measures. The purpose of our investigation was to present two studies that examined the factor structure and initial reliability and validity of the Selective Mutism Questionnaire (SMQ), a 17-item parent report measure of failure to speak related to SM. Study 1 (N = 589) utilized an Internet sample of parents of children ages 3 to 11 to demonstrate that the SMQ has a theoretically and clinically meaningful factor structure accounting for a significant portion of variance in responses with good internal consistency. Study 2 (N = 66) supported the validity of the SMQ in that scores discriminated clinic-referred children with SM from children with other anxiety disorders. Scores on the SMQ were correlated with measures of several theoretically and clinically important dimensions.


Trigonal and peritrigonal lesions of the lateral ventricle-surgical considerations and outcome analysis of 20 patients.
The aim of this study is to review the results and clinical outcome of patients with surgically treated lesions within the trigone of the lateral ventricle. This is a retrospective case series of 20 (eight male, 12 female) patients with lesions of the trigone of the lateral ventricle operated between 1998 and 2008. All lesions were removed via the transcortical temporal and transcortical parietal route. Surgical complications and outcome were assessed using the modified Rankin Scale (mRS). There were four children and 16 adults with a mean age of 42 ± 22 years (min = 1, max = 74). Eight (40%) lesions grew within the trigone of the dominant hemisphere. In 17 cases, the lesion was purely intraventricular, and in three cases, a slight paraventricular extension was seen. The mean size was 4.5 cm of maximal diameter. Surgical removal was achieved via the transcortical parietal route in 13 cases (65%) and the transcortical temporal route in seven cases (35%). In all cases, complete resection was possible. According to the mRS, 13 patients improved, five remained the same, and two were lost to follow-up. One patient had an increased visual field deficit postoperatively and new hemiparesis and aphasia, but returned to the preoperative level within a few weeks. In one patient, an acute myocardial infarction occurred due to previous cardiac stent placement and in-stent stenosis. Even large trigonal lesions can be resected with low morbidity using a transcortical approach depending on the peritrigonal extension of the tumor.


Applications of a Capability approach to disability and the International Classification of Functioning, Disability and Health (ICF) in social work practice.
As disability rates increase more social workers will require greater preparation to practice effectively with individuals with disabilities. The Capability approach and the International Classification of Functioning, Disability and Health provide helpful tools for social worker training. The capability approach emphasizes the need to assess what individuals are able to do in their real-life environments (capabilities) rather than capacity or functional status. The ICF provides helpful disability-related terminology and an actual classification to assist social workers to develop appropriate interventions that facilitate capability development among individuals with disabilities. Using the capability framework with the ICF will contribute to improved understanding of disability among social work students and practitioners.


An Important Tool in Lymphedema Management: Validation of Turkish Version of the Patient Benefit Index-Lymphedema.
Background: The aim of this study was to investigate the Turkish adaptation, validity, and reliability of the Patient Benefit Index-Lymphedema (PBI-L) ensuring direct assessment of the benefit in patients with lymphedema (LE), lipedema, and lipolymphedema. Methods and Results: Eighty-one patients who were consulted for physiotherapy, whose diagnoses were LE, lipedema, and lipolymphedema, and who were treated or planned to be treated for these diagnoses, were included in this study. PBI-L was adapted to Turkish by considering the stages of the cultural adaptation process. Short Form-36 (SF-36) was applied for the validity of PBI-L. PBI-L was repeated after a 1-week interval for test-retest reliability. The mean age was 47.66 ± 14.23 years. The intraclass correlation coefficient (ICC) value was determined as 0.73 (p < 0.0001) for the total score. There was a moderate correlation between first (ICC = 0.63, p < 0.0001) and second subdimensions (ICC = 0.62, p < 0.0001). Cronbach's α values ranged between 0.83 and 0.89. Low correlations were found between total scores of PBI-L and mental health, physical function subdimensions of SF-36 (p < 0.05). The Kaiser Meyer Olkin value was 0.6, and it was found that the PBI-L was not consistent with factor analysis. Conclusion: The Turkish version of PBI-L is a valid and reliable tool in patients with LE, lipedema, and lipolymphedema. However, the reassessment validity of PBI-L would be suggested by using an LE-specific quality of life questionnaire.


Photoperiodic control of seasonal growth is mediated by ABA acting on cell-cell communication.
In temperate and boreal ecosystems, seasonal cycles of growth and dormancy allow perennial plants to adapt to winter conditions. We show, in hybrid aspen trees, that photoperiodic regulation of dormancy is mechanistically distinct from autumnal growth cessation. Dormancy sets in when symplastic intercellular communication through plasmodesmata is blocked by a process dependent on the phytohormone abscisic acid. The communication blockage prevents growth-promoting signals from accessing the meristem. Thus, precocious growth is disallowed during dormancy. The dormant period, which supports robust survival of the aspen tree in winter, is due to loss of access to growth-promoting signals.


Visible-light-induced oxidant and metal-free dehydrogenative cascade trifluoromethylation and oxidation of 1,6-enynes with water.
Generally, oxy-trifluoromethylation in olefins is achieved using oxidants and transition metal catalysts. However, labile olefins remain unexplored due to their incompatibility with harsh reaction conditions. Here, unprecedented light-induced oxidant and metal-free tandem radical cyclization-trifluoromethylation and dehydrogenative oxygenation of 1,6-enynes have been achieved using a photoredox catalyst, CF3SO2Na, and phenanthrene-9,10-dione (PQ), Langlois' reagent (CF3SO2Na) and water as the oxygen source. This benign protocol allows for access to various CF3-containing C3-aryloyl/acylated benzofurans, benzothiophenes, and indoles. Moreover, the oxidized undesired products, which are inherently formed by the cleavage of the vinylic carbon and heteroatom bond, have been circumvented under oxidant free conditions. The mechanistic investigations by UV-visible and ESR spectroscopy, electrochemical studies, isotope labelling and density functional theory (DFT) suggest that light induced PQ produced a CF3 radical from CF3SO2Na. The generated CF3 radical adds to the alkene, followed by cyclization, to provide a vinylic radical that transfers an electron to PQ and generates a vinylic cation. Alternatively, electron transfer may occur from the CF3-added alkene moiety, forming a carbocation, which would undergo cationic cyclization to generate a vinylic carbocation. The subsequent addition of water to the vinylic cation, followed by the elimination of hydrogen gas, led to the formation of trifluoromethylated C3-aryloyl/acylated heterocycles.


A persistent alcohol cue memory trace drives relapse to alcohol seeking after prolonged abstinence.
Alcohol use disorder is characterized by a high risk of relapse during periods of abstinence. Relapse is often triggered by retrieval of persistent alcohol memories upon exposure to alcohol-associated environmental cues, but little is known about the neuronal circuitry that supports the long-term storage of alcohol cue associations. We found that a small ensemble of neurons in the medial prefrontal cortex (mPFC) of mice was activated during cue-paired alcohol self-administration (SA) and that selective suppression of these neurons 1 month later attenuated cue-induced relapse to alcohol seeking. Inhibition of alcohol seeking was specific to these neurons as suppression of a non-alcohol-related or sucrose SA-activated mPFC ensemble did not affect relapse behavior. Hence, the mPFC neuronal ensemble activated during cue-paired alcohol consumption functions as a lasting memory trace that mediates cue-evoked relapse long after cessation of alcohol intake, thereby providing a potential target for treatment of alcohol relapse vulnerability.


Effect of growth temperature on the electron flow for photorespiration in leaves of tobacco grown in the field.
Photorespiration has been indicated as an important mechanism for maintaining CO2 assimilation and alleviating photodamage under conditions of high light and low CO2 . We tested the hypothesis that plants grown under a high temperature had greater electron flow for photorespiration compared with those grown under a relative low temperature. Responses of photosynthetic electron flow and CO2 assimilation to incident light intensity and intercellular CO2 concentration were examined in leaves of tobacco cultivar 'k326'. Plants were cultivated at three sites with different ambient temperatures (Zhengzhou, Zunyi and Jiangchuan). Under high light, plants grown in Zhengzhou (with the highest growth temperature in the three sites) showed higher effective quantum yield of photosystem II and total electron flow through photosystem II than that in Zunyi and Jiangchuan. However, regardless of light intensity and intercellular CO2 status, there were no significant differences among sites in the photosynthetic CO2 assimilation rate or electron flow devoted to the carboxylation of ribulose-1,5-bisphosphate (RuBP). As a result, plants grown at high temperature showed higher electron flow devoted to oxygenation of RuBP than plants grown at low temperature. These results suggested that enhancement of electron flow for photorespiration is an important strategy in tobacco for acclimating to high growth temperature.


Surface chemical modifications and surface reactivity of nanodiamonds hydrogenated by CVD plasma.
The present study focuses on the interaction of hydrogen microwave CVD plasma with nanodiamonds (NDs). Hydrogen treated NDs (H-NDs) were characterized using electron spectroscopies (XPS, AES) without air exposure. A surface temperature higher than 700 °C is needed to remove the oxygen present on raw NDs. The kinetics of oxygen removal were investigated. Moreover, UHV annealings of H-NDs after ageing in ambient air clearly underline that 75% of the oxygen is related to physisorbed species. Finally, H-NDs were efficiently grafted using photochemical reaction with alkenes and a spontaneous coupling of aryldiazonium salts. These results confirm similar electronic surface properties between bulk and nano diamond materials.


Modeling nosocomial transmission of rotavirus in pediatric wards.
Nosocomial transmission of viral and bacterial infections is a major problem worldwide, affecting millions of patients (and causing hundreds of thousands of deaths) per year. Rotavirus infections affect most children worldwide at least once before age five. We present here deterministic and stochastic models for the transmission of rotavirus in a pediatric hospital ward and draw on published data to compare the efficacy of several possible control measures in reducing the number of infections during a 90-day outbreak, including cohorting, changes in healthcare worker-patient ratio, improving compliance with preventive hygiene measures, and vaccination. Although recently approved vaccines have potential to curtail most nosocomial rotavirus transmission in the future, even short-term improvement in preventive hygiene compliance following contact with symptomatic patients may significantly limit transmission as well, and remains an important control measure, especially where resources are limited.


Quadratic spatial solitons in periodically poled KTiOPO4.
The evolution of fundamental beams into quadratic spatial solitons was investigated in a periodically poled bulk KTiOPO4 crystal near and at phase matching. Various soliton properties, such as trapping efficiency as a function of phase mismatch, poling-induced walk-off, and the effects of pulse width, beam width, and input beam quality, were measured. Effects attributed to the presence of cubic nonlinearities were also observed.


Immune responses of female BALB/c and C57BL/6 neonatal mice to vaccination or intestinal infection are unaltered by exposure to breast milk lycopene.
Lycopene, a carotenoid produced by some commonly consumed plants such as tomatoes, is not synthesized by animals. Thus, the levels of lycopene found in the breast milk of lactating females reflect the dietary lycopene supply. Lycopene has potent antioxidant activity but has also been implicated in modulating immune function. Therefore, lycopene in breast milk has the potential to affect the development and/or function of the immune system in the suckling pups. Here, we have investigated the impact of breast milk lycopene on systemic and mucosal immunity in mouse neonates. Diets containing 0.3 g/kg lycopene (Lyc) or control (Con) diets were fed to mouse dams beginning at late gestation and continuing throughout lactation. Seven-day-old female BALB/c pups were parenterally immunized with a model vaccine antigen dinitrophenyl-keyhole limpet hemocyanin (DNP-KLH) and then reimmunized as adults. The levels of DNP-KLH-specific IgG in the sera as well as keyhole limpet hemocyanin-specific IFNγ and IL-4 production by splenic CD4(+) cells were similar in the Lyc and Con pups. In addition, female neonatal (d7) C57BL/6 Lyc and Con pups were infected orally with the enteropathogen Yersinia enterocolitica. Breast milk lycopene had no effect on the recruitment of neutrophils to intestinal lymphoid tissues or on bacterial tissue colonization of the intestines, spleens, and livers. Thus, suckling pups exposed to lycopene in breast milk appear to develop normal innate and adaptive responses both systemically and at intestinal mucosal surfaces.


Visualisation of PCNA monoubiquitination in vivo by single pass spectral imaging FRET microscopy.
Monoubiquitination of the DNA sliding clamp, PCNA, plays a central role in the control of damage bypass during replication. By combining a widely-spaced FRET donor/acceptor pair (CFP and mRFP) with spectral imaging, we have developed a simple method for the visualisation of PCNA monoubiquitination in both fixed and live cells with a single imaging pass. We validate the method with genetic controls in the avian cell line DT40 and use it to examine the intracellular dynamics of PCNA ubiquitination following subnuclear UV irradiation. This general approach is likely to be of utility for live imaging of post-translational modifications of a wide range of substrates in vivo.


Inclusion biogenesis and reactivation of persistent Chlamydia trachomatis requires host cell sphingolipid biosynthesis.
Chlamydiae are obligate intracellular pathogens that must coordinate the acquisition of host cell-derived biosynthetic constituents essential for bacterial survival. Purified chlamydiae contain several lipids that are typically found in eukaryotes, implying the translocation of host cell lipids to the chlamydial vacuole. Acquisition and incorporation of sphingomyelin occurs subsequent to transport from Golgi-derived exocytic vesicles, with possible intermediate transport through endosomal multivesicular bodies. Eukaryotic host cell-derived sphingomyelin is essential for intracellular growth of Chlamydia trachomatis, but the precise role of this lipid in development has not been delineated. The present study identifies specific phenotypic effects on inclusion membrane biogenesis and stability consequent to conditions of sphingomyelin deficiency. Culturing infected cells in the presence of inhibitors of serine palmitoyltransferase, the first enzyme in the biosynthetic pathway of host cell sphingomyelin, resulted in loss of inclusion membrane integrity with subsequent disruption in normal chlamydial inclusion development. Surprisingly, this was accompanied by premature redifferentiation to and release of infectious elementary bodies. Homotypic fusion of inclusions was also disrupted under conditions of sphingolipid deficiency. In addition, host cell sphingomyelin synthesis was essential for inclusion membrane stability and expansion that is vital to reactivation of persistent chlamydial infection. The present study implicates both the Golgi apparatus and multivesicular bodies as key sources of host-derived lipids, with multivesicular bodies being essential for normal inclusion development and reactivation of persistent C. trachomatis infection.


Why did they "choose" to stay? Perspectives of Hurricane Katrina observers and survivors.
Models of agency--powerful implicit assumptions about what constitutes normatively "good" action--shaped how observers and survivors made meaning after Hurricane Katrina. In Study 1, we analyzed how 461 observers perceived survivors who evacuated (leavers) or stayed (stayers) in New Orleans. Observers described leavers positively (as agentic, independent, and in control) and stayers negatively (as passive and lacking agency). Observers' perceptions reflected the disjoint model of agency, which is prevalent in middle-class White contexts and defines "good" actions as those that emanate from within the individual and proactively influence the environment. In Study 2, we examined interviews with 79 survivors and found that leavers and stayers relied on divergent models of agency. Leavers emphasized independence, choice, and control, whereas stayers emphasized interdependence, strength, and faith. Although both leavers and stayers exercised agency, observers failed to recognize stayers' agency and derogated them because observers assumed that being independent and in control was the only way to be agentic.


Stopped-flow kinetic studies of electron transfer in the reductase domain of neuronal nitric oxide synthase: re-evaluation of the kinetic mechanism reveals new enzyme intermediates and variation with cytochrome P450 reductase.
The reduction by NADPH of the FAD and FMN redox centres in the isolated flavin reductase domain of calmodulin-bound rat neuronal nitric oxide synthase (nNOS) has been studied by anaerobic stopped-flow spectroscopy using absorption and fluorescence detection. We show by global analysis of time-dependent photodiode array spectra, single wavelength absorption and NADPH fluorescence studies, that at least four resolvable steps are observed in stopped-flow studies with NADPH and that flavin reduction is reversible. The first reductive step represents the rapid formation of an equilibrium between an NADPH-enzyme charge-transfer species and two-electron-reduced enzyme bound to NADP(+). The second and third steps represent further reduction of the enzyme flavins and NADP(+) release. The fourth step is attributed to the slow accumulation of an enzyme species that is inferred not to be relevant catalytically in steady-state reactions. Stopped-flow flavin fluorescence studies indicate the presence of slow kinetic phases, the timescales of which correspond to the slow phase observed in absorption and NADPH fluorescence transients. By analogy with stopped-flow studies of cytochrome P450 reductase, we attribute these slow fluorescence and absorption changes to enzyme disproportionation and/or conformational change. Unlike for the functionally related cytochrome P450 reductase, transfer of the first hydride equivalent from NADPH to nNOS reductase does not generate the flavin di-semiquinoid state. This indicates that internal electron transfer is relatively slow and is probably gated by NADP(+) release. Release of calmodulin from the nNOS reductase does not affect the kinetics of inter-flavin electron transfer under stopped-flow conditions, although the observed rate of formation of the equilibrium between the NADPH-oxidized enzyme charge-transfer species and two-electron-reduced enzyme bound to NADP(+) is modestly slower in calmodulin-depleted enzyme. Our studies indicate the need for significant re-interpretation of published kinetic data for electron transfer in the reductase domain of neuronal nitric oxide synthase.


How effective is drug testing as a workplace safety strategy? A systematic review of the evidence.
The growing prevalence of workplace drug testing and the narrow scope of previous reviews of the evidence base necessitate a comprehensive review of research concerning the efficacy of drug testing as a workplace strategy. A systematic qualitative review of relevant research published between January 1990 and January 2013 was undertaken. Inclusion criteria were studies that evaluated the effectiveness of drug testing in deterring employee drug use or reducing workplace accident or injury rates. Methodological adequacy was assessed using a published assessment tool specifically designed to assess the quality of intervention studies. A total of 23 studies were reviewed and assessed, six of which reported on the effectiveness of testing in reducing employee drug use and 17 which reported on occupational accident or injury rates. No studies involved randomised control trials. Only one study was assessed as demonstrating strong methodological rigour. That study found random alcohol testing reduced fatal accidents in the transport industry. The majority of studies reviewed contained methodological weaknesses including; inappropriate study design, limited sample representativeness, the use of ecological data to evaluate individual behaviour change and failure to adequately control for potentially confounding variables. This latter finding is consistent with previous reviews and indicates the evidence base for the effectiveness of testing in improving workplace safety is at best tenuous. Better dissemination of the current evidence in relation to workplace drug testing is required to support evidence-informed policy and practice. There is also a pressing need for more methodologically rigorous research to evaluate the efficacy and utility of drug testing.


Comparative studies on naturally occurring antikeratin antibodies in human sera.
Comparative studies on the specificity of the so-called antiepidermal antibodies (Abs) found in human sera were performed by immunoblotting, enzyme-linked immunosorbent assay (ELISA), and immunoelectron microscopy (IEM). After a screening test by indirect immunofluorescence (IF), sera obtained from patients with various diseases and controls could be classified in 5 different groups according to the IF patterns on the epidermis: sera reactive with: (1) the stratum corneum (SC); (2) the upper layer (U-Cyt); (3) the whole epidermis (G-Cyt); (4) basal cells (B-Cyt); and (5) negative ones. By immunoblotting, all the 23 IF-positive sera were found to bind to one or more keratin bands, and did not show any reactivity with epidermal Nonidet P-40 soluble proteins. SC-Abs were mainly directed against a 67 kD Keratin band, whereas U-Cyt- and G-Cyt-Abs bound to both 58-56 kD and 67-63 kD keratins. B-Cyt-Abs reacted strongly with 63 kD Keratins and slightly with a 50 kD band. Antikeratin Abs were detected by immunoblotting even in the IF-negative sera. The ELISA study showed that sera with high IF titers contained high levels of antikeratin Abs. In the IEM study using sera containing U-Cyt- or B-Cyt-Abs, 2 distinct reaction patterns were demonstrated: U-Cyt-Abs stained tonofilaments of suprabasal keratinocytes, while B-Cyt-Abs characteristically reacted with those of basal cells. Moreover, SC-, U-Cyt-, and G-Cyt-Abs were absorbed out by insoluble epidermal proteins, and B-Cyt-Abs were decreased in titer after the absorption test. The present study provides strong evidence that most, though not all, human antiepidermal Abs are directed against different keratin polypeptides, and that antikeratin Abs commonly occur in almost all human sera.


Protective autoimmunity and neuroprotection in inflammatory and noninflammatory neurodegenerative diseases.
Autoimmune diseases are traditionally viewed as an outcome of a malfunctioning of the immune system, in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis (MS), a disease of the white matter of the central nervous system (CNS), the attack is directed against myelin proteins. In this article we summarize a paradigm shift proposed by us in the perception of autoimmune disease. Observations by our group indicating that an autoimmune response is the body's mechanism for coping with CNS damage led us to suggest that all individuals are apparently endowed with a purposeful autoimmune response to CNS injuries, but have only limited inherent ability to control this response so that its effect will be beneficial. In animals susceptible to autoimmune diseases, the same autoimmune T cells are responsible both for neuroprotection and for disease development; the timing and strength of their activity will determine which of these effects is expressed. Individuals with non-inflammatory neurodegenerative diseases need a heightened autoimmunity. We discovered that autoimmunity could be boosted without risk of disease induction, even in susceptible strains, by the use of Copolymer-1 (Copaxone(R)), a weak agonist of a wide range of self-reactive T cells. Here we summarize the basic findings that led us to formulate the concept of protective autoimmunity, the mechanisms underlying its constitutive presence and its on/off regulation, and its therapeutic implications. We also offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals.


Perspectives on the behavior of entomopathogenic nematodes from dispersal to reproduction: traits contributing to nematode fitness and biocontrol efficacy.
The entomopathogenic nematodes (EPN) Heterorhabditis and Steinernema are widely used for the biological control of insect pests and are gaining importance as model organisms for studying parasitism and symbiosis. In this paper recent advances in the understanding of EPN behavior are reviewed. The "foraging strategy" paradigm (distinction between species with ambush and cruise strategies) as applied to EPN is being challenged and alternative paradigms proposed. Infection decisions are based on condition of the potential host, and it is becoming clear that already-infected and even long-dead hosts may be invaded, as well as healthy live hosts. The state of the infective juvenile (IJ) also influences infection, and evidence for a phased increase in infectivity of EPN species is mounting. The possibility of social behavior - adaptive interactions between IJs outside the host - is discussed. EPNs' symbiotic bacteria (Photorhabdus and Xenorhabdus) are important for killing the host and rendering it suitable for nematode reproduction, but may reduce survival of IJs, resulting in a trade-off between survival and reproduction. The symbiont also contributes to defence of the cadaver by affecting food-choice decisions of insect and avian scavengers. I review EPN reproductive behavior (including sperm competition, copulation and evidence for attractive and organizational effects of pheromones), and consider the role of endotokia matricida as parental behavior exploited by the symbiont for transmission.


A theory for the anisotropic and inhomogeneous dielectric properties of proteins.
Using results from the dielectric theory of polar solids and liquids, we calculate the mesoscopic, spatially-varying dielectric constant at points in and around a protein by combining a generalization Kirkwood-Fröhlich theory along with short all-atom molecular dynamics simulations of equilibrium protein fluctuations. The resulting dielectric permittivity tensor is found to exhibit significant heterogeneity and anisotropy in the protein interior. Around the surface of the protein it may exceed the dielectric constant of bulk water, especially near the mobile side chains of polar residues, such as K, N, Q, and E. The anisotropic character of the protein dielectric selectively modulates the attractions and repulsions between charged groups in close proximity.