Population Pharmacokinetics of Amikacin in Adult Patients with Cystic Fibrosis.
Practitioners commonly use amikacin in patients with cystic fibrosis. Establishment of the pharmacokinetics of amikacin in adults with cystic fibrosis may increase the efficacy and safety of therapy. This study was aimed to establish the population pharmacokinetics of amikacin in adults with cystic fibrosis. We used serum concentration data obtained during routine therapeutic drug monitoring and explored the influence of patient covariates on drug disposition. We performed a retrospective chart review to collect the amikacin dosing regimens, serum amikacin concentrations, blood sampling times, and patient characteristics for adults with cystic fibrosis admitted for treatment of acute pulmonary exacerbations. Amikacin concentrations were retrospectively collected for 49 adults with cystic fibrosis, and 192 serum concentrations were available for analysis. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling with the first-order conditional estimation method. A two-compartment model with first-order elimination best described amikacin pharmacokinetics. Creatinine clearance and weight were identified as significant covariates for clearance and the volume of distribution, respectively, in the final model. Residual variability was modeled using a proportional error model. Typical estimates for clearance, central and peripheral volumes of distribution, and intercompartmental clearance were 3.06 liters/h, 14.4 liters, 17.1 liters, and 0.925 liters/h, respectively. The pharmacokinetics of amikacin in individuals with cystic fibrosis seems to differ from those in individuals without cystic fibrosis. However, further investigations are needed to confirm these results and, thus, the need for variations in amikacin dosing. Future pharmacodynamic studies will potentially establish the optimal amikacin dosing regimens for the treatment of acute pulmonary exacerbations in adult patients with CF.


Naming game on networks: let everyone be both speaker and hearer.
To investigate how consensus is reached on a large self-organized peer-to-peer network, we extended the naming game model commonly used in language and communication to Naming Game in Groups (NGG). Differing from other existing naming game models, in NGG everyone in the population (network) can be both speaker and hearer simultaneously, which resembles in a closer manner to real-life scenarios. Moreover, NGG allows the transmission (communication) of multiple words (opinions) for multiple intra-group consensuses. The communications among indirectly-connected nodes are also enabled in NGG. We simulated and analyzed the consensus process in some typical network topologies, including random-graph networks, small-world networks and scale-free networks, to better understand how global convergence (consensus) could be reached on one common word. The results are interpreted on group negotiation of a peer-to-peer network, which shows that global consensus in the population can be reached more rapidly when more opinions are permitted within each group or when the negotiating groups in the population are larger in size. The novel features and properties introduced by our model have demonstrated its applicability in better investigating general consensus problems on peer-to-peer networks.


Prevalence of diarrhoeagenic Escherichia coli in children from León, Nicaragua.
Diarrhoeal disease is a public health problem worldwide, mostly affecting children in developing countries. In Nicaragua, diarrhoea is the second greatest cause of infant mortality. During the period March 2005 to September 2006, a total of 526 faecal samples from children aged 0-60 months (381 with and 145 without diarrhoea) from León, Nicaragua, were studied. In order to detect five different diarrhoeagenic Escherichia coli pathotypes simultaneously [enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC), enteropathogenic E. coli (EPEC), enterohaemorrhagic E. coli (EHEC) and enteroinvasive E. coli (EIEC)], a mixture of eight primer pairs was used in a single PCR. At least one diarrhoeagenic E. coli pathotype was detected in 205 samples (53.8%) of the diarrhoea group and in 77 samples (53.1%) in the non-diarrhoea group. ETEC was detected significantly more often in children with diarrhoea (20.5%) than in children without diarrhoea (8.3%) (P=0.001). Atypical EPEC, EIEC and EAEC were detected with slightly lower frequencies in children with (16.0, 0.8 and 27.8%, respectively) than in children without (20.7, 1.4 and 33.1%, respectively) diarrhoea. EHEC was only detected in children with diarrhoea (2.1%). In conclusion, ETEC continues to be an important agent associated with diarrhoea in children from León, Nicaragua. Although not very frequent, the only findings that were 100% associated with diarrhoea were ETEC estA (4.7%) and EHEC (2.1%). Nevertheless, EAEC and EPEC were also frequent pathotypes in the population under study. In children with severe diarrhoea, more than half had EAEC, ETEC or EPEC, and EAEC was the most prevalent pathotype.


Effect of magnetic stimulation in spinal cord on limb angiogenesis and implication: a pilot study.
To investigate the effect of repetitive magnetic stimulation (rMS) of the spinal cord on limb angiogenesis in healthy rats and explore its implication for the treatment of lymphedema. Twelve adult male Sprague-Dawley rats were divided into four groups as follows: sham rMS followed by tissue harvest 5 minutes later (group 1, n=2), 1 Hz rMS and tissue harvest 5 minutes later (group 2, n=3), 20 Hz rMS and tissue harvest 5 minutes later (group 3, n=3), 20 Hz rMS and tissue harvest 30 minutes later (group 4, n=4). Animals were treated with 20-minute rMS with 120% of the motor threshold on their left side of upper lumbar spinal cord. Expression of angiogenic factors, that is, Akt, phospho-Akt (pAkt), endothelial nitric oxide synthase (eNOS), phospho-eNOS (p-eNOS) were measured by western blot. Bilateral hindlimb muscles (quadriceps and gastrocnemius) were harvested. Expression of Akt in left quadriceps increased in group 4 compared with group 2 and 3 (3.4 and 5.3-fold each, p=0.026). Expression of eNOS in left plus right quadriceps markedly increased in group 3 and 4 compared with group 1 and 2 (p=0.007). Expressions of eNOS, Akt and p-eNOS, pAkt in gastrocnemius were not comparable between four groups (p>0.05). Repetitive magnetic stimulation of the spinal cord may exert an angiogenic effect closely linked to lymphangiogenesis. It has clinical implication for the possible therapy of lymphedema caused by breast, cervical or endometrial cancer operation. Future studies with the specific lymphatic endothelial cell markers are required to confirm the effect of rMS on lymphangiogenesis.


Identification of sex-specific molecular markers using restriction site-associated DNA sequencing.
A major barrier to evolutionary studies of sex determination and sex chromosomes has been a lack of information on the types of sex-determining mechanisms that occur among different species. This is particularly problematic in groups where most species lack visually heteromorphic sex chromosomes, such as fish, amphibians and reptiles, because cytogenetic analyses will fail to identify the sex chromosomes in these species. We describe the use of restriction site-associated DNA (RAD) sequencing, or RAD-seq, to identify sex-specific molecular markers and subsequently determine whether a species has male or female heterogamety. To test the accuracy of this technique, we examined the lizard Anolis carolinensis. We performed RAD-seq on seven male and ten female A. carolinensis and found one male-specific molecular marker. Anolis carolinensis has previously been shown to possess male heterogamety and the recently published A. carolinensis genome facilitated the characterization of the sex-specific RAD-seq marker. We validated the male specificity of the new marker using PCR on additional individuals and also found that it is conserved in some other Anolis species. We discuss the utility of using RAD-seq to identify sex-determining mechanisms in other species with cryptic or homomorphic sex chromosomes and the implications for the evolution of male heterogamety in Anolis.


Functionality of a Bacillus cereus biological agent in response to physiological variables encountered in aquaculture.
The potential of a Bacillus cereus isolate (NRRL 100132) as a biological agent for aquaculture has been demonstrated in vitro and in vivo. The functionality of this isolate across a range of physiological conditions, including salinity, pH and temperature, based on rearing of high-value ornamental Cyprinus carpio, was investigated. Temperature had a significant influence on germination, specific growth rate and increase in cell number of B. cereus in shake-flask cultures, whilst salinity and pH did not have a measurable effect on growth. Controlled studies in bioreactors and modelling of the data to the Arrhenius function indicated the existence of high and low growth temperature domains. The rates of pathogenic Aeromonas hydrophila suppression and decrease in waste ion concentrations (ammonium, nitrite, nitrate and phosphate) were translated into a linear predictive indicator of efficacy of the B. cereus isolate at different temperatures. The present study confirmed the robustness of the B. cereus isolate (NRRL 100132) as a putative biological agent for aquaculture and further demonstrated a novel method for the assessment of in vitro biological efficacy as a function of temperature.


Age-dependent biologic response to orthodontic forces.
Orthodontic tooth movement results from increased inflammation and osteoclast activation. Since patients of all ages now routinely seek orthodontics treatment, we investigated whether age-dependent biologic responses to orthodontic force correlate with the rate of tooth movement. We studied 18 healthy subjects, adolescents (11-14 years) and adults (21-45 years), with Class II Division 1 malocclusion requiring 4 first premolar extractions. Canines were retracted with a constant force of 50 cN. Gingival crevicular fluid was collected before orthodontic treatment and at days 1, 7, 14, and 28 after the canine retraction. Cytokine (IL-1β, CCL2, TNF-α) and osteoclast markers (RANKL and MMP-9) were measured using antibody-based protein assays. Pain and discomfort were monitored with a numeric rating scale. The canine retraction rate was measured from study models taken at days 28 and 56. Although the cytokine and osteoclast markers increased significantly in both age groups at days 1, 7, and 14, the increases were greater in adults than in adolescents. Interestingly, the rate of tooth movement in adults was significantly slower than in adolescents over the 56-day study period. Adults also reported significantly more discomfort and pain. Age is a significant variable contributing to the biologic response to orthodontic tooth movement. Adults exhibited a significantly higher level of cytokine and osteoclasts activity but, counterintuitively, had a significantly slower rate of tooth movement.


The placenta in pre-eclampsia and intrauterine growth restriction: studies on exchange surface areas, diffusion distances and villous membrane diffusive conductances.
We test the null hypothesis that the morphometric diffusive conductance of the placental villous membrane does not alter in pregnancies complicated by intrauterine growth restriction (IUGR) or pre-eclampsia (PE). Placentas were collected from cases of normotensive IUGR, pure PE, PE+IUGR and from control pregnancies. Microscopical fields on formalin-fixed, trichrome-stained histological sections were randomly sampled for location and orientation. Using stereological methods, the exchange surface areas of peripheral (terminal and intermediate) villi and their fetal capillaries and the arithmetic and harmonic mean thicknesses of the villous membrane (maternal aspect of trophoblast to luminal aspect of vascular endothelium) were estimated. An index of the variability in thickness of this membrane, and an estimate of its oxygen diffusive conductance, was derived secondarily. Group comparisons were drawn using two-way analysis of variance to identify main effects (of PE or IUGR) and interaction effects (between PE and IUGR). PE did not have significant effects on placental morphology and there were no significant effects of PE or IUGR on membrane thickness or its variability. In contrast, IUGR (with or without PE) was associated with reduced surface areas and this was the principal factor leading to a smaller membrane diffusive conductance in these placentas. When account was taken of fetal mass, specific conductance showed no effects of PE or IUGR despite the mass-specific conductance in pure IUGR placentas appearing to be smaller than that in controls. The decline in total conductances is indicative of perturbations operating at the levels of villous trophoblast and fetal vasculature and these may contribute to fetal hypoxic stress.


Deferred empathy: a construct with implications for the mental health of older adults.
Deferred empathy occurs when an experience provokes a memory that after reflection allows people to say, "Now I understand." Heretofore, the concept was explored only in quantitative research; therefore, the purpose of this phenomenological study was to elicit a more detailed description of the construct of deferred empathy. For most of the participants (n = 20) triggering events involved personal challenges such as loss, loss of control, or interpersonal conflict that reminded them of, and changed, their perception of earlier relationships. Development of empathy involved reflection on past and present events, making choices, changing expectations, and learning acceptance. The process resulted in appreciative understanding of others as well as personal benefits. Findings have implications for mental health promotion in older adults in which life review promotes gerotranscendence.


About miRNAs, miRNA seeds, target genes and target pathways.
miRNAs are typically repressing gene expression by binding to the 3' UTR, leading to degradation of the mRNA. This process is dominated by the eight-base seed region of the miRNA. Further, miRNAs are known not only to target genes but also to target significant parts of pathways. A logical line of thoughts is: miRNAs with similar (seed) sequence target similar sets of genes and thus similar sets of pathways. By calculating similarity scores for all 3.25 million pairs of 2,550 human miRNAs, we found that this pattern frequently holds, while we also observed exceptions. Respective results were obtained for both, predicted target genes as well as experimentally validated targets. We note that miRNAs target gene set similarity follows a bimodal distribution, pointing at a set of 282 miRNAs that seems to target genes with very high specificity. Further, we discuss miRNAs with different (seed) sequences that nonetheless regulate similar gene sets or pathways. Most intriguingly, we found miRNA pairs that regulate different gene sets but similar pathways such as miR-6886-5p and miR-3529-5p. These are jointly targeting different parts of the MAPK signaling cascade. The main goal of this study is to provide a general overview on the results, to highlight a selection of relevant results on miRNAs, miRNA seeds, target genes and target pathways and to raise awareness for artifacts in respective comparisons. The full set of information that allows to infer detailed results on each miRNA has been included in miRPathDB, the miRNA target pathway database (https://mpd.bioinf.uni-sb.de).


Risk of hypothermia in elderly patients with diabetes.
The incidence of admissions of patients with hypothermia was determined to examine whether hypothermia was more common in elderly patients with diabetes than in the general population after diabetic metabolic emergency cases had been excluded. A prospective survey of three accident and emergency departments identified 134 cases of hypothermia admitted from a catchment population of almost 157,000 aged 65 or over during the winters of 1981-2 to 1983-4. The predicted number of patients with diabetes in the population was nearly 5600 (3.5%). Twenty three admissions for hypothermia (17%) occurred in 20 patients with previously diagnosed diabetes. Women made up 87% of the diabetic admissions; the ratio of diabetic to non-diabetic admission rates in women was 7.9 (95% confidence interval 5.3 to 12.0). After excluding diabetic metabolic emergency admissions the ratio was 6.4. The ratio in men was 2.4, but the small number of admissions produced wide confidence intervals. Ten of the admissions with diabetes (43%) had pathological disorders that are associated with an increased risk of hypothermia. The frequency of these conditions is higher in patients with diabetes than in the general population and partly explains the increased risk of hypothermia in these patients.


Regional hippocampal involvement and cognitive impairment in pediatric multiple sclerosis.
We assessed global and regional hippocampal volume abnormalities in pediatric multiple sclerosis (MS) patients and their correlations with clinical, neuropsychological and magnetic resonance imaging metrics. From 53 pediatric MS patients and 18 healthy controls, global hippocampal volume was computed using a manual tracing procedure. Regional hippocampal volume modifications were assessed using a radial mapping analysis. MS patients with abnormal performance in three or more tests of a neuropsychological battery for children were classified as cognitively impaired. Global hippocampal volume was reduced in MS patients compared with controls, but did not correlate with clinical, neuropsychological and magnetic resonance imaging measures. Compared to controls, MS patients experienced bilateral radial atrophy of the cornu ammonis, subiculum and dentate gyrus subfields as well as radial hypertrophy of the dentate gyrus subfield. Regional hippocampal volume modifications correlated with brain T2 lesion volume as well as attention and language abilities. Global hippocampal volume did not differ between cognitively impaired (n=12) and cognitively preserved MS patients. Compared to cognitively preserved, cognitively impaired MS patients had atrophy of the subiculum and dentate gyrus subfields of the right hippocampus. Hippocampal subregions have different vulnerability to damage in pediatric MS. Regional rather than global hippocampal involvement contributes to global cognitive impairment as well as to deficits of selected cognitive tests.


Epidemiological, Clinical and Molecular Characterization of Human Brucellosis in Bosnia and Herzegovina - An Ongoing Brucellosis Outbreak.
The aim of this study was to evaluate an ongoing outbreak of brucellosis in southern region of Bosnia and Herzegovina (BIH) on the epidemiological, clinical and molecular level. This study included 19 patients affected by brucellosis between 2015 and 2017, in Trebiševo (BIH). Out of 19 patients, 16 were admitted to and treated at the Department of Infectious diseases of the University Clinical Hospital Mostar, while three patients were treated in ambulatory care setting. Epidemiological, clinical and microbiological parameters were investigated. The Rose Bengal test (RBT) positive sera were serologically confirmed by complement fixation test (CFT). We also analyzed blood cultures, and isolates were additionally serotyped. Molecular analyses were performed with Bruce-ladder multiplex polymerase chain reaction (PCR) and multiple locus variable number of tandem repeat analysis of 16 loci (MLVA-16) assay. Fifteen out of 19 patients had been professionally exposed to the bacterium, while four patients acquired brucellosis without prior contact with infected animals. In seven out of eight (87.5%) patients with localized form of brucellosis, we detected significantly higher values of C-reactive protein (CRP) or erythrocyte sedimentation rate (P<0.001). B. melitensis was isolated from 13/16 (81.3%) blood culture samples, and additionally serotyped as biovar 3. Using MLVA16 assay, 11 isolates were genotyped. We observed complete genotype matches among 8/11 B. melitensis isolates, while 3/11 isolates differed in Bruce04 locus. Overall, our study confirms the usefulness of MLVA-16 method in the epidemiological and molecular research of brucellosis during epidemic that, most likely, originated from the same source.


Leadership as part of the nurse consultant role: banging the drum for patient care.
This paper draws upon an evaluation of the first group of nurse consultants in Scotland. The evaluation aimed to identify the extent to which they fulfilled the remit of their posts which comprised four core functions. One of these functions was to provide professional leadership and this paper focuses on this element of the role and aims to explore it in relation to the attributes of transformational leadership. Nurse consultants were introduced in the UK in 2000. Their purpose was to achieve better outcomes for patients and strengthen leadership. Nursing research identifies leadership as a key element of the role, with postholders adopting transformational leadership approaches. Research from the fields of sociology and psychology identifies difficulties in formulating a coherent theory of leadership, arguing for better understanding of leadership processes. Qualitative. This paper draws on 31 semi-structured interviews with four nurse consultants who were interviewed twice over six to nine months and 23 other 'stakeholders' who worked with them. Varied leadership activity at ward, NHS Trust and strategic levels was identified. Postholders used approaches that resonated with the attributes of transformational leadership. Leadership processes included developing a vision for the service, acting as mediator and champion, and exerting control over complex change initiatives. Techniques of leadership included taking a 'softly softly' approach, pacing change initiatives and arguing assertively with those in senior positions. Interview findings also identified the level of preparation that was required to meet the remit of the posts, highlighting the importance of interpersonal skills and intellectual effort in achieving outcomes. Nurse consultants require considerable technical expertise, cognitive and interpersonal skills, and the ability to take risks. The data suggest that the leadership attributes required are transformational in nature but that they also exceed those identified in much of the literature. These posts require appropriate support if they are to be sustainable. Relevance to clinical practice. This paper adds to our understanding of the complexity of the nurse consultant role and highlights the challenge of providing appropriate professional development for postholders.


Entropically driven MHC class I recognition by human inhibitory receptor leukocyte Ig-like receptor B1 (LILRB1/ILT2/CD85j).
The human inhibitory receptor, leukocyte immunoglobulin (Ig)-like receptor B1 (also called Ig-like transcript (ILT) 2, CD85j), is broadly expressed on leukocytes. LILRB1 binds to a wide range of major histocompatibility complex class I molecules (MHCIs) and transduces negative signals that can, for example, prevent killing of MHCI-expressing cells. Here we report the kinetic, thermodynamic, NMR and crystallographic analyses of MHCI recognition by LILRB1. Kinetic studies demonstrated that LILRB1 binds to MHCIs with fast association and dissociation rates, typical of cell-cell recognition receptors. Thermodynamic analyses showed that LILRB1-MHCI interactions are entropically driven (-TdeltaS = -9.4 approximately -6.6 kcal mol(-1)) with low heat capacity changes (deltaC(p) = -0.22 approximately -0.10 kcal mol(-1) K(-1)). The crystal structures of LILRB1 in the different crystal forms exhibited variation in the elbow angle between the two N-terminal Ig-like domains, indicating interdomain flexibility. Consistently, NMR analysis provided the direct evidence of the conformational changes of LILRB1 upon the MHCI binding. These findings suggest that LILRB1-MHCI interactions, while involving some conformational adjustment, are not accompanied by a very large reduction in conformational flexibility at the binding interface. This mode of binding is distinct from "induced-fit" binding, which is associated with large reductions in conformational flexibility, and would be suitable for rapid engagement of MHCIs to enable fast monitoring of the expression level of MHCIs on target cells.


Screening urine with a leukocyte esterase strip and subsequent chlamydial testing of asymptomatic men attending primary care practitioners.
The detection of asymptomatic urethritis using a leukocyte esterase (LE) strip may have a role in primary care screening to select men who need diagnostic testing for Chlamydia trachomatis and Neisseria gonorrhoeae. Eight-hundred and eighty-two men, 16 to 35 years of age were studied when they attended their family physician or university health clinic for nongenitourinary complaints. First void urine (FVU) was tested by an LE strip (Chemstrip 2 LN, Boehringer Mannheim Corp., Indianapolis, IN), Chlamydiazyme (Abbott Laboratories, N. Chicago, IL) enzyme immunoassay with confirmatory blocking and polymerase chain reaction (PCR) with chlamydial plasmid primers. Forty-five men (5.1%) were positive (> trace) by LE strip. Of the LE-positive urines, 9 (20.0%) were positive by EIA or PCR, and none of the LE-negatives were positive by EIA or PCR. Twenty-three LE positives (5 EIA/PCR-positive; 1 PCR-positive; 17 EIA/PCR-negative) were able to be followed with a second urine and 2 urethral swabs. All of the 6 chlamydia-positives who had follow-up tests were positive by both immunoassay and PCR on urine. Based on the FVU results, the prevalence of asymptomatic chlamydial infection was 1.0% (9/88) (95% CL, 0.5 to 1.9) for which the LE urine strip was 100% (9/9) sensitive and 95.9% (837/873) specific. Analyses based on screening 1,000 men, 16 to 25 years of age, showed that the cost per case detected was $192.00 using the LE strip (> 1+) to select urine specimens for EIA testing, compared to $1,326.00 using the EIA to test all urine specimens. In this low prevalence, primary care setting, the LE urine strip was an accurate screening test, which if used to preselect urine specimens for subsequent chlamydial testing, would be less costly per case detected than assaying each specimen for chlamydia.


Opportunities for better use of collective action theory in research and governance for invasive species management.
Controlling invasive species presents a public-good dilemma. Although environmental, social, and economic benefits of control accrue to society, costs are borne by only a few individuals and organizations. For decades, policy makers have used incentives and sanctions to encourage or coerce individual actors to contribute to the public good, with limited success. Diverse, subnational efforts to collectively manage invasive plants, insects, and animals provide effective alternatives to traditional command-and-control approaches. Despite this work, there has been little systematic evaluation of collective efforts to determine whether there are consistent principles underpinning success. We reviewed 32 studies to identify the extent to which collective-action theories from related agricultural and environmental fields explain collaborative invasive species management approaches; describe and differentiate emergent invasive species collective-action efforts; and provide guidance on how to enable more collaborative approaches to invasive species management. We identified 4 types of collective action aimed at invasive species-externally led, community led, comanaged, and organizational coalitions-that provide blueprints for future invasive species management. Existing collective-action theories could explain the importance attributed to developing shared knowledge of the social-ecological system and the need for social capital. Yet, collection action on invasive species requires different types of monitoring, sanctions, and boundary definitions. We argue that future government policies can benefit from establishing flexible boundaries that encourage social learning and enable colocated individuals and organizations to identify common goals, pool resources, and coordinate efforts.


A histopathological study of esophageal cancer on the western side of the Caspian littoral from 1994 to 2003.
Esophageal cancer (EC) accounts for a considerable proportion of carcinomas of the upper gastrointestinal tract in the population of the Caspian littoral. The global histologic pattern of the disease has changed recently. The intent of this study was to determine the incidence of EC over the past decade in Eastern Azerbaijan--a north-western province of Iran--on the western side of the Caspian littoral and to assess the alteration of the histological pattern of the disease. In a retrospective study, all 1792 documented EC cases of all registered cancer, surgery, pathology, and radiotherapy centers of the province over a period of 9 years (from March 1994 to March 2003) were enrolled in the study. Data concerning demographic characteristics, EC risk factors, and histological findings were recorded. The incidence and the relative incidence of the pathological subtypes of EC in the population of the province were determined. The change in incidence rates and the interaction between main risk factors and tumor histology of the patients were assessed over the study years. The average incidence of EC in the over 30-year-old population of the province was 16.2 (12.7 for squamous cell carcinoma [SCC] and 1.9 for adenocarcinoma [AC]) cases per 100 000 person-years. Incidence of SCC, as well as AC, peaked at ages older than 65. Compared to women, men had higher incidences of AC and lower incidences of SCC; the average incidence rate of EC was equal in men and women. AC and SCC accounted for 12.8% and 86.9% of cases, respectively. Upper, middle and lower thirds of the esophagus were the location of tumors in 9.8%, 32.9% and 57.3% of cases, respectively. During the study period, incidence rates of EC and SCC tended to decrease. The incidence rate of EC from 1995 to 1998 was almost 30% higher than that of the period from 1999 to 2002. Incidence rate of EC on the western side of the Caspian littoral is moderately high, but much lower than that of the eastern Caspian littoral as it was three decades ago. The incidence of EC was lower in the second half than the first half of the study period. Unlike the global pattern of EC, the incidence of EC as well as SCC in women is as high as or higher than in men, which is identical to the pattern in the eastern Caspian littoral.


A cost-effectiveness study of the management of intractable urinary incontinence by urinary catheterisation or incontinence pads.
The aim was to compare the costs and effects of management of intractable urinary incontinence by urinary catheterisation or incontinence pads. This was a prospective, randomised study comparing catheterisation with pads, supplemented by additional data collected from patients with chronic indwelling catheters. Main outcome measures were costs of equipment, nursing time, patient preference, nursing preference, and clinical and bacteriological assessment of urinary infection. 78 intractably incontinent elderly female patients were randomly allocated to management by urinary catheter or pads and toileting. Supplementary data on equipment costs and nursing time were collected from 27 patients, of whom 22 were already catheterised at the time of the randomisation and five were catheterised by the nursing staff after the last date for entry into the randomisation. Of the 38 patients randomised to catheterisation, 14 refused consent so only 24 were catheterised on day 1 of the study. There was a rapid removal of catheters, especially in the first six weeks of the study and only four of the randomised catheter patients completed the full 26 weeks of the study. However, eight of the pads patients were catheterised between the 7th and 22nd week because of deteriorating general condition and all retained their catheters for the remainder of the study period. Of 35 patients who had experienced catheters and pads, 12 expressed a clear preference for catheters, 12 for pads, and 11 were undecided. Nurses were in favour of the use of pads, mainly because of concerns about urinary infection with catheters. Comparing costs for patients managed with catheters (532 patient weeks) or pads (903 patient weeks), catheter patients required less nursing time (15.4 v 29.0 h per patient per week) but equipment costs were higher (19.20-24.65 pounds v 8.79-11.35 pounds per patient per week), mainly because of the cost of catheter care (12.75 pounds per patient per week). Asymptomatic bacteriuria was prevalent in both groups but 73% of catheterised patients received treatment for clinical signs of infection compared with 40% of pads patients. Only 30% of patients who were treated had any generalised symptoms of infection. Use of catheters reduces nursing time but may increase weekly equipment costs depending on the cost of laundry. Despite the high dropout rate among patients randomised to catheters a minority of patients (12/35) expressed a clear preference for catheters and we believe that more patients with intractable incontinence should be given a trial of catheterisation to assess acceptability. Bacteriuria was prevalent in pads or catheter patients but no major episodes of invasive infection were noted in either group.


Humour production may enhance observational learning of a new tool-use action in 18-month-old infants.
Many studies have shown that making children laugh enhances certain cognitive capacities such as attention, motivation, perception and/or memory, which in turn enhance learning. However, no study thus far has investigated whether laughing has an effect on learning earlier in infancy. The goal of this study was to see whether using humour with young infants in a demonstration of a complex tool-use task can enhance their learning. Fifty-three 18-month-old infants participated in this study and were included either in a humorous or a control demonstration group. In both groups infants observed an adult using a tool to retrieve an out-of-reach toy. What differed between groups was that in the humorous demonstration group, instead of playing with the toy, the adult threw it on the floor immediately after retrieval. The results show that infants who laughed at the demonstration in the humorous demonstration group reproduced significantly more frequent target actions than infants who did not laugh and those in the control group. This effect is discussed with regard to individual differences in terms of temperament and social capacities as well as positive emotion and dopamine release.


Recurrent pulmonary embolism due to echinococcosis secondary to hepatic surgery for hydatid cysts.
We describe the case of a 53-year-old man with recurrent pulmonary embolism due to intra-arterial cysts from Echinococcus. Both the patient's medical history and the computed tomographic (CT) scan abnormalities led to the diagnosis. The CT scan, performed during hospitalization in our ward, showed cystic masses in the left main pulmonary artery and in the descending branch of the right pulmonary artery. Within cystic masses, thin septa were visible, giving a chambered appearance, which was suggestive of a group of daughter cysts. In the past, our patient underwent multiple operations for recurring echinococcal cysts of the liver. After the last intervention, 4 years earlier, his postoperative course was complicated by pulmonary embolism: a CT scan showed a filling defect in the descending branch of the right pulmonary artery, which was caused by the same cystic mass as 4 years later, although smaller. This mass, not properly treated, increased in diameter. Moreover, after 4 years, there has been a new episode of embolism, which involved the left main pulmonary artery. This is the first case in which there are repeated episodes of pulmonary embolism echinococcosis after hepatic surgery for removal of hydatid cysts.


Investigating the effect of ciliary body photodynamic therapy in a glaucoma mouse model.
To investigate the morphologic and functional effects of verteporfin ciliary body photodynamic therapy (PDT) in a murine glaucoma model and normal mouse eyes. A glaucomatous mouse strain, DBA/2J and a normal control mouse strain (C57BL/6) were used in the study. Verteporfin was injected intravenously at doses of 1.0 (DBA/2J) or 2.0 or 4.0 (C57BL/6) mg/kg. Transscleral irradiation of the ciliary body was performed with light at a wavelength of 689 nm delivered through an optical fiber, with irradiance of 1800 mW/cm2 and fluence of 100 J/cm2. Laser irradiation was applied for 360 degrees of the corneoscleral limbus in C57BL/6 normal mice and for 180 degrees in DBA/2J mice. Retreatment was performed in C57BL/6 normal mice that had been treated with 2.0 mg/kg of verteporfin at post-PDT day 7. One eye of each animal was treated, and the fellow eye served as the control. The morphologic effect of PDT on the ocular structures was assessed by light and electron microscopy. The IOP was measured using an applanation tonometer with a fiber-optic pressure sensor. Surviving retinal ganglion cells (RGCs) in DBA/2J mice eyes were retrogradely labeled with a neurotracer dye at 12 weeks after PDT. In all groups, almost all ciliary body blood vessels in the treated area were thrombosed 1 day after PDT. In DBA/2J mice, ciliary epithelium and stroma were severely damaged 1 day after PDT. The mean IOP in treated eyes was significantly reduced compared with that in the control eyes in all groups. The reduction of mean IOP in DBA/2J mouse eyes persisted for 7 weeks, although the mean IOP in normal mouse eyes treated with 2 or 4.0 mg/kg verteporfin returned to the level of the fellow control eyes by 7 and 17 days after treatment, respectively. The mean number of RGCs in the DBA/2J treated eyes was significantly higher than in control eyes. Ciliary body PDT resulted in morphologic changes in the ciliary body, significant reduction of IOP, and prevention of ganglion cell loss in a mouse glaucoma model. These results suggest that ciliary body PDT is a more selective cyclodestructive technique with potential clinical application in the treatment of glaucoma.


Benign nonfunctioning thyroid adenomas are characterized by a defective targeting to cell membrane or a reduced expression of the sodium iodide symporter protein.
Nodular thyroid disease is the most common endocrine disorder. Nonfunctioning thyroid nodules are identified by their low radioiodide uptake compared with the normal extranodular tissue, which, at thyroid scintiscan, produces the typical picture of a cold thyroid nodule. Previous in vitro studies demonstrated that the majority of nonfunctioning thyroid nodules have a specific defect in iodide transport that accounts for their failure to accumulate radioactive iodide in vivo. A defect in the expression or structure of the sodium iodide symporter (NIS) gene has been hypothesized as a possible cause of the impaired iodide trapping in nonfunctioning thyroid nodules. We studied 22 patients who were submitted to surgery for a solitary nonfunctioning thyroid nodule that originated in an otherwise normal gland. Thyroid scintigraphy was performed at 1, 2, 3, 4, 6, and 24 h after the oral administration of a tracer dose of 131I (iodine). All patients showed absence of 131I uptake in the nodule, with normal uptake in the extranodular tissue and in the contralateral thyroid lobe. Eight patients with toxic adenomas who underwent lobectomy were also included in the study. We first studied the expression of human NIS (hNIS) protein by immunohistochemistry in paraffin-embedded tissue sections using a specific anti-hNIS monoclonal antibody. Subsequently, we searched for somatic mutations of hNIS gene in nonfunctioning thyroid nodules. The level of hNIS expression was determined in both the nodules and the normal tissue from the same thyroid gland. In all functioning thyroid nodules (toxic adenomas), a high expression of hNIS protein was detected with respect to normal surrounding tissue. Similar to the normal thyroid tissue, follicular cells of toxic thyroid adenomas showed an exclusive expression of hNIS protein at the cell membrane. Fifty-four percent of benign nonfunctioning thyroid nodules overexpressed hNIS protein compared with the normal surrounding tissue, but in these nodules the hNIS protein failed to target the cell membrane, being mostly localized inside the cytoplasm. hNIS protein was not detected by immunohistochemistry in 46% of nonfunctioning nodules, whereas it was expressed in the surrounding unaffected thyroid tissue. Direct sequencing of the hNIS gene in all of the nonfunctioning nodules did not reveal major genetic alterations. A silent polymorphism (GCC/GCG codon 544, exon 13) was found in one nodule. In conclusion, the results obtained in this study show that two mechanisms contribute to the reduced radioiodide uptake typical of benign nonfunctioning thyroid nodules: 1) reduced expression of the hNIS protein, and 2) defective targeting of hNIS to the cell membrane.


Overdiagnosis in low-dose computed tomography screening for lung cancer.
Screening for lung cancer has the potential to reduce mortality, but in addition to detecting aggressive tumors, screening will also detect indolent tumors that otherwise may not cause clinical symptoms. These overdiagnosis cases represent an important potential harm of screening because they incur additional cost, anxiety, and morbidity associated with cancer treatment. To estimate overdiagnosis in the National Lung Screening Trial (NLST). We used data from the NLST, a randomized trial comparing screening using low-dose computed tomography (LDCT) vs chest radiography (CXR) among 53 452 persons at high risk for lung cancer observed for 6.4 years, to estimate the excess number of lung cancers in the LDCT arm of the NLST compared with the CXR arm. We calculated 2 measures of overdiagnosis: the probability that a lung cancer detected by screening with LDCT is an overdiagnosis (PS), defined as the excess lung cancers detected by LDCT divided by all lung cancers detected by screening in the LDCT arm; and the number of cases that were considered overdiagnosis relative to the number of persons needed to screen to prevent 1 death from lung cancer. During follow-up, 1089 lung cancers were reported in the LDCT arm and 969 in the CXR arm of the NLST. The probability is 18.5% (95% CI, 5.4%-30.6%) that any lung cancer detected by screening with LDCT was an overdiagnosis, 22.5% (95% CI, 9.7%-34.3%) that a non-small cell lung cancer detected by LDCT was an overdiagnosis, and 78.9% (95% CI, 62.2%-93.5%) that a bronchioalveolar lung cancer detected by LDCT was an overdiagnosis. The number of cases of overdiagnosis found among the 320 participants who would need to be screened in the NLST to prevent 1 death from lung cancer was 1.38. More than 18% of all lung cancers detected by LDCT in the NLST seem to be indolent, and overdiagnosis should be considered when describing the risks of LDCT screening for lung cancer.


Thandai and chilam: traditional Hindu beliefs about the proper uses of Cannabis.
Hindu beliefs about appropriate use of cannabis illustrate the capacity of cultural systems to order and direct the course of complex phenomenal events. Cannabis manifests diverse and contradictory effects. These depend not only on dose, frequency and route of administration, but also on subjective and cultural contexts (e.g., Pihl, Shea & Costa 1979). It may very well be that the contradictory results of modern research investigations on cannabis stem from the intricacy of these interactions. Given the current state of the art, paradigms of research methodology may very well be inadequate to develop an understanding of such a paradoxical drug. The Hindu cultural system, on the other hand, accommodates the ambiguities of cannabis through its own complex nature. It provides diverse niches through which antithetical effects of the drug are expressed. Cannabis is said to both interfere with motivation to work and facilitate it. A closer examination reveals that these actions are probably related to the way in which this motivation toward action is defined, and the level of use of the drug. While cannabis appears to interfere with execution of highly complex tasks and the long-range planning that accompanies them, it may facilitate concentrated focus on repetitive endeavors. In some commonsense way, it may be quite simply that it changes a user's sense of time and the span of the present as well as the sense of relative importance of present and future. So long as an individual is under the influence of this effect (and living in the context that s/he has structured as a result of it), the urgency of accomplishment in the Western sense is diminished. The Hindu belief system accommodates this by prescribing use in such a way that this effect becomes beneficial. A key factor is that low potency preparations (bhang, thandai) are available. It allows individuals with complex life tasks, goals and obligations to indulge in moderation. The drug is also taken in a ritualized context, facilitating concentration and relaxation. It is taken at times, such as in the evening or on holidays, in which focus on the immediate present is a welcome change. Use of the more potent preparations (ganja, charas) is not condoned for this group. Above all, moderation is enjoined and popular folk belief warns of the potential problems of excess. Ganja and charas are regarded more ambivalently as poisons or semipoisons.(ABSTRACT TRUNCATED AT 400 WORDS)


EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination.
The presence of hypoxic regions in solid tumors is an adverse prognostic factor for patient outcome. Here, we show that hypoxia induces the expression of Ephrin-A3 through a novel hypoxia-inducible factor (HIF)-mediated mechanism. In response to hypoxia, the coding EFNA3 mRNA levels remained relatively stable, but HIFs drove the expression of previously unknown long noncoding (lnc) RNAs from EFNA3 locus and these lncRNA caused Ephrin-A3 protein accumulation. Ephrins are cell surface proteins that regulate diverse biological processes by modulating cellular adhesion and repulsion. Mounting evidence implicates deregulated ephrin function in multiple aspects of tumor biology. We demonstrate that sustained expression of both Ephrin-A3 and novel EFNA3 lncRNAs increased the metastatic potential of human breast cancer cells, possibly by increasing the ability of tumor cells to extravasate from the blood vessels into surrounding tissue. In agreement, we found a strong correlation between high EFNA3 expression and shorter metastasis-free survival in breast cancer patients. Taken together, our results suggest that hypoxia could contribute to metastatic spread of breast cancer via HIF-mediated induction of EFNA3 lncRNAs and subsequent Ephrin-A3 protein accumulation.


Effects of plasmapheresis and of hypoproteinemia on lung liquid conductance in awake sheep.
The Starling equation, which describes net transvascular liquid flow, does not include the possibility that a reduction in plasma protein concentration may have a direct effect on lung liquid conductance or microvascular protein permeability. Nevertheless, both effects have been reported. Since these results were not predictable, we wondered whether the changes were due to the decrease in plasma protein concentration or to the process by which protein depletion was accomplished (batch plasmapheresis which involves considerable handling of blood). To separate these factors, we did control (sham) and protein removal plasmapheresis in awake sheep by two plasmapheresis methods (batch and continuous-flow). We monitored pulmonary hemodynamics, measured lung lymph flow, and determined protein concentrations in lymph and plasma. We calculated or measured the protein osmotic pressures of plasma and lymph. After control plasmapheresis, lymph flow increased and lymph:plasma protein concentration decreased but had returned to baseline levels by 4 hours. After protein removal plasmapheresis, the changes persisted for 24 hours. However, lung microvascular conductance (filtration coefficient) was not increased, except during the first 4-hour period. The changes in lymph flow and protein concentration ratio are explained using a simple two-pore model. We conclude that, over the range studied, hypoproteinemia does not increase lung microvascular liquid conductance or protein permeability.


The challenges of antimicrobial drug resistance in Greece.
Antimicrobial drug resistance rates in Greece are among the highest in Europe. The prevalence of carbapenem-resistant Gram-negative species has increased considerably, including endemic strains in intensive care units. Pandrug-resistant Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are sporadically reported. Methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus rates are also high in Greek hospitals. Multidrug resistance increases risk of mortality, hospitalization duration and costs, and undermines the medical system. Administrative responses initiated include action plans, monitoring systems, and guidelines. Common terminology among involved parties for defining and grading resistance is required. Multidrug-resistant microorganisms challenge clinical laboratories; uniform recommendations towards detection of resistance mechanisms need to be established. Prospective multicenter outcome studies comparing antibiotic regimens and containment methods are needed. Because new antimicrobials against Gram-negative pathogens are not foreseeable, judicious use of the existing and strict adherence to infection control best practice might restrain resistance spread. Awareness of resistance patterns and organisms prevailing locally by reporting laboratories and treating physicians is important.


Corticosteroids as standalone or add-on treatment for sore throat.
Sore throat is a common condition associated with a high rate of antibiotic prescriptions, despite limited evidence for the effectiveness of antibiotics. Corticosteroids may improve symptoms of sore throat by reducing inflammation of the upper respiratory tract. To assess the clinical benefit and safety of corticosteroids for symptoms of sore throat in adults and children. We searched The Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL 2012, Issue 5) which includes the Acute Respiratory Infections (ARI) Group's Specialised Register, the Database of Reviews of Effects and the NHS Health Economics Database, MEDLINE (1966 to November Week 4, 2012) and EMBASE (1974 to June 2012). We included randomised controlled trials that compared steroids to either placebo or standard care in adults and children (older than three years of age) with sore throat. We excluded studies of hospitalised participants, those with infectious mononucleosis, sore throat following tonsillectomy or intubation, or peritonsillar abscess. Two review authors independently reviewed and selected trials from searches, assessed and rated study quality, and extracted relevant data. We included eight trials involving 743 participants (369 children and 374 adults). All trials gave antibiotics to both placebo and corticosteroid groups; no trials assessed corticosteroids as standalone treatment for sore throat. In addition to any effect of antibiotics and analgesia, corticosteroids increased the likelihood of complete resolution of pain at 24 hours by more than three times (risk ratio (RR) 3.2, 95% confidence interval (CI) 2.0 to 5.1, P < 0.001, I(2) statistic 44%) and at 48 hours by 1.7 times. Fewer than four people need to be treated to prevent one person continuing to experience pain at 24 hours. Corticosteroids also reduced the mean time to onset of pain relief and the mean time to complete resolution of pain by 6 and 14 hours, respectively, although significant heterogeneity was present. At 24 hours, pain (assessed by visual analogue scores) was reduced by an additional 14% by corticosteroids. No difference in rates of recurrence, relapse or adverse events were reported for participants taking corticosteroids compared to placebo, although reporting of adverse events was poor. Oral or intramuscular corticosteroids, in addition to antibiotics, increase the likelihood of both resolution and improvement of pain in participants with sore throat. Further trials assessing corticosteroids in the absence of antibiotics and in children are warranted.


Angiotensin II receptor blockade corrects altered expression of gap junctions in vascular endothelial cells from hypertensive rats.
Blockade of the renin-angiotensin system improves the impaired endothelium-dependent relaxations associated with hypertension and aging, partly through amelioration of endothelium-derived hyperpolarizing factor (EDHF)-mediated responses. Although the nature of EDHF is still controversial, recent studies have suggested the involvement of gap junctions in EDHF-mediated responses. Gap junctions consist of connexins (Cx), and we therefore tested whether the expression of Cx in vascular endothelial cells would be altered by hypertension and antihypertensive treatment. Spontaneously hypertensive rats (SHR) were treated with either the angiotensin II type 1 receptor antagonist candesartan or the combination of hydralazine and hydrochlorothiazide for 3 mo from 5 to 8 mo of age. Confocal laser scanning microscopy after immunofluorescent labeling with antibodies against Cx37, Cx40, and Cx43 revealed that the expression of Cx37 and Cx40 in endothelial cells of the mesenteric artery was significantly lower in SHR than in WKY. Treatment with candesartan, but not the combination of hydralazine and hydrochlorothiazide, significantly increased the expression of Cx37 and Cx40, although blood pressure decreased similarly. On the other hand, the expression of Cx43, though scarce and heterogeneous, was increased in SHR compared with WKY, and candesartan treatment lowered the expression of Cx43. These findings suggest that renin-angiotensin system blockade corrects the decreased expression of Cx37 and Cx40 in arterial endothelial cells of hypertensive rats, partly independently of blood pressure, whereas the expression of Cx43 changed in the opposite direction. It remains to be clarified whether these changes in Cx37 and Cx40 are related to endothelial function, particularly that attributable to EDHF.


Quantitative comparison of optimized nanorods, nanoshells and hollow nanospheres for photothermal therapy.
The purpose of this study is to get more efficient gold nanoparticles, for necrosis of cancer cells, in photothermal therapy. Therefore a numerical maximization of the absorption efficiency of a set of nanoparticles (nanorod, nanoshell and hollow nanosphere) is proposed, assuming that all the absorbed light is converted to heat. Two therapeutic cases (shallow and deep cancer) are considered. The numerical tools used in this study are the full Mie theory, the discrete dipole approximation and the particle swarm optimization. The optimization leads to an improved efficiency of the nanoparticles compared with previous studies. For the shallow cancer therapy, the hollow nanosphere seems to be more efficient than the other nanoparticles, whereas the hollow nanosphere and nanorod, offer comparable absorption efficiencies, for deep cancer therapy. Finally, a study of tolerance for the size parameters to guarantee an absorption efficiency threshold is included.


Prevalence studies in schizophrenia.
Over 70 prevalence studies of schizophrenia published since 1948 are reviewed. Despite problems of method, the studies suggest that there may be significant differences in prevalence among different populations and that prevalence may change over time. Further research is needed on how much differences in diagnosis or the course of schizophrenia contribute to the variable prevalence rates. The paper suggests the following as areas for additional enquiry: a possible north-south gradient, special populations (e.g. American Hutterites, northern Swedes, western Irish, castes in India) and ongoing case registers in areas of suspected high and low prevalence.


Lipopolysaccharide O-chain core region required for cellular cohesion and compaction of in vitro and root biofilms developed by Rhizobium leguminosarum.
The formation of biofilms is an important survival strategy allowing rhizobia to live on soil particles and plant roots. Within the microcolonies of the biofilm developed by Rhizobium leguminosarum, rhizobial cells interact tightly through lateral and polar connections, forming organized and compact cell aggregates. These microcolonies are embedded in a biofilm matrix, whose main component is the acidic exopolysaccharide (EPS). Our work shows that the O-chain core region of the R. leguminosarum lipopolysaccharide (LPS) (which stretches out of the cell surface) strongly influences bacterial adhesive properties and cell-cell cohesion. Mutants defective in the O chain or O-chain core moiety developed premature microcolonies in which lateral bacterial contacts were greatly reduced. Furthermore, cell-cell interactions within the microcolonies of the LPS mutants were mediated mostly through their poles, resulting in a biofilm with an altered three-dimensional structure and increased thickness. In addition, on the root epidermis and on root hairs, O-antigen core-defective strains showed altered biofilm patterns with the typical microcolony compaction impaired. Taken together, these results indicate that the surface-exposed moiety of the LPS is crucial for proper cell-to-cell interactions and for the formation of robust biofilms on different surfaces.


Environmental contaminants in pathogenesis of breast cancer.
This review is an attempt to comprehend the diverse groups of environmental chemical contaminants with a potential for pathogenesis of breast cancer, their probable sources and the possible mechanisms by which these environmental contaminants act and interplay with other risk factors. Estrogens are closely related to the pathogenesis of breast cancer. Oxidative catabolism of estrogen, mediated by various cytochrome P450 enzymes, generates reactive free radicals that can cause oxidative damage. The same enzymes of estrogenic metabolic pathways catalyze biological activation of several environmental (xenobiotic) chemicals. Xenobiotic chemicals may exert their pathological effects through generation of reactive free radicals. Breast tissue can be a target of several xenobiotic agents. DNA-reactive metabolites of different xenobiotic compounds have been detected in breast tissue. Many phase I and II xenobiotic metabolizing enzymes are expressed in both normal and cancerous breast tissues. These enzymes play a significant role in the activation/detoxification of xenobiotic and endogenous compounds including estrogens. More than 30 carcinogenic chemicals are present in tobacco smoke; many of them are fat-soluble, resistant to metabolism and can be stored in breast adipose tissue. Similarly, pesticides are also known to cause oxidative stress; while some act as endocrine disruptor, some are shown to suppress apoptosis in estrogen sensitive cell lines. Reports have shown an association of smoking (both active and passive) and pesticides with breast cancer risk. However, the issues have remained controversial. Different mutagenic substances that are generated in the cooking process e.g., heterocyclic amines and polycyclic aromatic hydrocarbons (PAHs) can be a threat to breast tissue. PAHs and dioxins exert their adverse effects through the aryl hydrocarbon receptor (AhR), which activates several genes involved in the metabolisms of xenobiotic compounds and endogenous estrogens. These chemicals also induce AhR-dependent mitochondrial dysfunction. Many of the environmental pollutants suppress the immune system, which are implicated to risk. A better understanding about the biological effects of different environmental carcinogenic compounds and determination of their impact on rising incidence of breast cancer will be beneficial in improving preventive policy against breast cancer.


Conditional control of fluorescent protein degradation by an auxin-dependent nanobody.
The conditional and reversible depletion of proteins by auxin-mediated degradation is a powerful tool to investigate protein functions in cells and whole organisms. However, its wider applications require fusing the auxin-inducible degron (AID) to individual target proteins. Thus, establishing the auxin system for multiple proteins can be challenging. Another approach for directed protein degradation are anti-GFP nanobodies, which can be applied to GFP stock collections that are readily available in different experimental models. Here, we combine the advantages of auxin and nanobody-based degradation technologies creating an AID-nanobody to degrade GFP-tagged proteins at different cellular structures in a conditional and reversible manner in human cells. We demonstrate efficient and reversible inactivation of the anaphase promoting complex/cyclosome (APC/C) and thus provide new means to study the functions of this essential ubiquitin E3 ligase. Further, we establish auxin degradation in a vertebrate model organism by employing AID-nanobodies in zebrafish.


Mosquito larvae can detect water vibration patterns from a nearby predator.
Mosquito larvae have been shown to respond to water-borne kairomones from nearby predators by reducing their activity, and thus visibility. If they can identify the predator, they can then alter their response depending upon the associated predation risk. No studies have shown that mosquito larva may also detect water-borne vibrations from the predator. Final instar larvae of three mosquitoes: Culiseta longiareolata, Culex perexiguus and C. quinquefasciatus, were exposed to recorded vibrations from feeding dragonfly nymphs, to dragonfly kairomones and the combined effect of both. Predator vibrations caused C. longiareolata to significantly reduce bottom feeding and instead increased the more passive surface filter feeding. The larvae also significantly increased escape swimming activity. These behavioural changes were not significantly different from the effect of dragonfly kairomones, and there was no synergistic or additional effect of the two. C. perexiguus gave a smaller (but still significant) response to both dragonfly vibrations and to kairomones, probably due to a different feeding behaviour: when lying on the bottom, it was an inactive filter feeder. C. quinquefasciatus did not respond to either vibrations or kairomones and during these experiments was entirely an inactive surface filter feeder. Both C. longiareolata and C. perexiguus were thus able to detect and identify vibrations from feeding dragonfly nymphs as an anti-predator strategy. The lack of response in C. quinquefasciatus is probably a result of living in water that is highly polluted with organic material, where few predators can survive.


Mathematical modeling of tumor growth and metastatic spreading: validation in tumor-bearing mice.
Defining tumor stage at diagnosis is a pivotal point for clinical decisions about patient treatment strategies. In this respect, early detection of occult metastasis invisible to current imaging methods would have a major impact on best care and long-term survival. Mathematical models that describe metastatic spreading might estimate the risk of metastasis when no clinical evidence is available. In this study, we adapted a top-down model to make such estimates. The model was constituted by a transport equation describing metastatic growth and endowed with a boundary condition for metastatic emission. Model predictions were compared with experimental results from orthotopic breast tumor xenograft experiments conducted in Nod/Scidγ mice. Primary tumor growth, metastatic spread and growth were monitored by 3D bioluminescence tomography. A tailored computational approach allowed the use of Monolix software for mixed-effects modeling with a partial differential equation model. Primary tumor growth was described best by Bertalanffy, West, and Gompertz models, which involve an initial exponential growth phase. All other tested models were rejected. The best metastatic model involved two parameters describing metastatic spreading and growth, respectively. Visual predictive check, analysis of residuals, and a bootstrap study validated the model. Coefficients of determination were [Formula: see text] for primary tumor growth and [Formula: see text] for metastatic growth. The data-based model development revealed several biologically significant findings. First, information on both growth and spreading can be obtained from measures of total metastatic burden. Second, the postulated link between primary tumor size and emission rate is validated. Finally, fast growing peritoneal metastases can only be described by such a complex partial differential equation model and not by ordinary differential equation models. This work advances efforts to predict metastatic spreading during the earliest stages of cancer.


Antemortem volume loss mirrors TDP-43 staging in older adults with non-frontotemporal lobar degeneration.
Over the past decade, the transactive response DNA-binding protein of 43 kDa (TDP-43) has been recognized as a major protein in normal and pathological ageing, increasing the risk of cognitive impairment and dementia. In conditions distinct from the frontotemporal lobar degenerations, TDP-43 appears to progress in a stereotypical pattern. In the present study, we aimed at providing a better understanding of the effects of TDP-43 and other age-related neuropathologies on cross-sectional grey matter volume in a cohort of non-FTLD subjects. We included 407 individuals with an antemortem MRI and post-mortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. All individuals were assigned pathological stages for TDP-43, tau, amyloid-β, Lewy bodies, argyrophilic grain disease and vascular pathologies. Robust regressions were performed in regions of interest and voxel-wise to explore the relationships between TDP-43 stages and grey matter volume while controlling for other pathologies. Grey matter volumes adjusted for pathological and demographic variables were also computed for each TDP-43-positive case to further characterize the sequential involvement of brain structures associated with TDP-43, irrespective of the TDP-43 staging scheme. Robust regressions showed that the extent of TDP-43 pathology was associated with the extent of grey matter atrophy. Specifically, we found that the volume in medial temporal regions (i.e. amygdala, entorhinal cortex, hippocampus) decreased progressively with advancing TDP-43 stages. Importantly, these effects were of similar magnitude to those related to tau stages. Additional analyses using adjusted grey matter volume demonstrated a sequential pattern of volume loss associated with TDP-43, starting within the medial temporal lobe, followed by early involvement of the temporal pole, and eventually encompassing additional temporal and frontal regions. Altogether, this study demonstrates the major and independent contribution of TDP-43 pathology on neurodegeneration and provides further insight into the regional distribution of TDP-43 in non-FTLD subjects. Along with previous studies, these findings emphasized the importance of targeting TDP-43 in future clinical trials to prevent its detrimental effect on grey matter volume and, eventually, cognition.


[Optimal way of administration of high dose intravenous furosemide - continuous infusion or bolus?].
Furosemide is a loop diuretic used in states of volume overload. The need for high doses is due to its reduced efficacy caused by lower concentration of furosemide achieved at the site of action in the renal tubule lumen and adaptation mechanisms. High doses have been associated with the development of ionic dysbalance, direct toxicity and intravascular volume fluctuations. The way of furosemide administration (intermitent versus continuously) to influence efficacy and safety is contradictory evaluated in EBM. The aim of this study is to analyze the available data for evaluation of the efficacy and safety of intermittent versus continuous dose regimens. A systematic search on PubMed from 1990 to 2013 using the keywords - furosemide, loop diuretic, bolus, continuous infusion, efficacy, safety, heart failure, ICU, critical care. The pharmacokinetic and pharmacodynamic knowledge of furosemide create a theoretical assumption for the preference of continuous infusions before intermittent boluses. Assessement of available studies, however, yet in clinical practice did not proof the advantage of one over the other route of administration.


MALDI mass spectrometry imaging workflow for the aquatic model organisms Danio rerio and Daphnia magna.
Lipids play various essential roles in the physiology of animals. They are also highly dependent on cellular metabolism or status. It is therefore crucial to understand to which extent animals can stabilize their lipid composition in the presence of external stressors, such as chemicals that are released into the environment. We developed a MALDI MS imaging workflow for two important aquatic model organisms, the zebrafish (Danio rerio) and water flea (Daphnia magna). Owing to the heterogeneous structure of these organisms, developing a suitable sample preparation workflow is a highly non-trivial but crucial part of this work and needs to be established first. Relevant parameters and practical considerations in order to preserve tissue structure and composition in tissue sections are discussed for each application. All measurements were based on high mass accuracy enabling reliable identification of imaged compounds. In zebrafish we demonstrate that a detailed mapping between histology and simultaneously determined lipid composition is possible at various scales, from extended structures such as the brain or gills down to subcellular structures such as a single axon in the central nervous system. For D. magna we present for the first time a MALDI MSI workflow, that demonstrably maintains tissue integrity during cryosectioning of non-preserved samples, and allows the mapping of lipids in the entire body and the brood chamber inside the carapace. In conclusion, the lipid signatures that we were able to detect with our method provide an ideal basis to analyze changes caused by pollutants in two key aquatic model organisms.


Tissue compatibility of interfacial polyelectrolyte complexation fibrous scaffold: evaluation of blood compatibility and biocompatibility.
Interfacial polyelectrolyte complexation (PEC) fiber has been proposed as a biostructural unit and biological construct for tissue engineering applications, with its ability to incorporate proteins, drug molecules, DNA nanoparticles, and cells. In this study, we evaluated the biocompatibility and blood compatibility of PEC fiber in order to assess its potential for in vivo applications in tissue engineering. Although chitosan-alginate PEC fibrous scaffold was found to be thrombogenic, the blood compatibility of the scaffold could be significantly improved by incorporating a small amount of heparin in the polyelectrolyte solution during fiber formation. The platelet microparticle production and platelet adhesion on the chitosan-alginate-heparin fibrous scaffold were comparable to those on the resting control. In vitro cytotoxicity test showed that the scaffold was not toxic to human mesenchymal stem cells (hMSCs). In the in vivo biocompatibility test in rats, no acute inflammation was observed in the subcutaneously or intramuscularly implanted specimens. Good cell infiltration and vascularization were observed after 2 months of implantations. Enhanced extracellular matrix (ECM) deposition was observed when hMSCs were cultured in the transforming growth factor-beta3 (TGF-beta3)-encapsulated PEC fibrous scaffold in vitro, or when the TGF-beta3-encapsulated PEC was implanted intramuscularly in vivo. The results showed that this versatile PEC fibrous scaffold could be used in various tissue engineering applications for its good biocompatible and blood compatible properties.


Comparison of J5 vaccinates and controls for incidence, etiologic agent, clinical severity, and survival in the herd following naturally occurring cases of clinical mastitis.
Holstein dairy cattle in 3 commercial herds were randomly allocated to J5 vaccination (n = 251) or untreated control (n = 306) groups. There were 221 new cases of clinical mastitis (CM) affecting 120 cows. Coliform mastitis cases had a higher percentage of severe quarter swelling or signs of systemic illness among control cows but not among J5 vaccinates, in comparison to noncoliform cases. Culling or death from CM affected 13 controls (4.3%) and 4 vaccinates (1.6%), with losses occurring earlier in lactation among controls, a higher hazard (probability of a cow dying on each day of lactation) for controls than vaccinates. The J5 vaccination was significantly associated with protection from culling for mastitis among the 15 Klebsiella cases; 2 out of 10 (20%) Klebsiella-infected controls were culled and 0 out of 5 vaccinates were culled. Cows in second lactation were at reduced hazard of culling for mastitis compared with older animals, even when adjusting for effects of J5 vaccination. When all CM cases (including subsequent new cases during the same lactation and multiple quarters or pathogens within the same cow on the same day) were evaluated, for the 221 cases of CM, the rate was significantly higher among vaccinates than controls (0.10 and 0.07 cases/30 d in milk, respectively). This was because J5 vaccinates had more subsequent new cases of CM in the same cow than controls. Pathogens isolated, which included mainly environmental bacteria, were not different among J5 vaccinates and controls. Immunization with J5 was associated with protection against severe clinical coliform mastitis signs, culling, and death loss from CM but not with any reduction in overall CM.


Hierarchical bivariate time series models: a combined analysis of the effects of particulate matter on morbidity and mortality.
In this paper we develop a hierarchical bivariate time series model to characterize the relationship between particulate matter less than 10 microns in aerodynamic diameter (PM10) and both mortality and hospital admissions for cardiovascular diseases. The model is applied to time series data on mortality and morbidity for 10 metropolitan areas in the United States from 1986 to 1993. We postulate that these time series should be related through a shared relationship with PM10. At the first stage of the hierarchy, we fit two seemingly unrelated Poisson regression models to produce city-specific estimates of the log relative rates of mortality and morbidity associated with exposure to PM10 within each location. The sample covariance matrix of the estimated log relative rates is obtained using a novel generalized estimating equation approach that takes into account the correlation between the mortality and morbidity time series. At the second stage, we combine information across locations to estimate overall log relative rates of mortality and morbidity and variation of the rates across cities. Using the combined information across the 10 locations we find that a 10 microg/m3 increase in average PM10 at the current day and previous day is associated with a 0.26% increase in mortality (95% posterior interval -0.37, 0.65), and a 0.71% increase in hospital admissions (95% posterior interval 0.35, 0.99). The log relative rates of mortality and morbidity have a similar degree of heterogeneity across cities: the posterior means of the between-city standard deviations of the mortality and morbidity air pollution effects are 0.42 (95% interval 0.05, 1.18), and 0.31 (95% interval 0.10, 0.89), respectively. The city-specific log relative rates of mortality and morbidity are estimated to have very low correlation, but the uncertainty in the correlation is very substantial (posterior mean = 0.20, 95% interval -0.89, 0.98). With the parameter estimates from the model, we can predict the hospitalization log relative rate for a new city for which hospitalization data are unavailable, using that city's estimated mortality relative rate. We illustrate this prediction using New York as an example.


Postnatally acquired cytomegalovirus infection in extremely premature infants: how best to manage?
Postnatal cytomegalovirus (pCMV) infection is a common viral infection typically occurring within the first months of life. pCMV refers to postnatal acquisition of CMV rather than postnatal manifestations of antenatal or perinatal acquired CMV. pCMV is usually asymptomatic in term infants, but can cause symptomatic disease in preterm (gestational age <32 weeks) and very low birth weight (<1500 g) infants resulting in sepsis, pneumonia, thrombocytopaenia, neutropaenia, hepatitis, colitis and occasionally death. There are significant uncertainties regarding the management of premature infants with pCMV disease which is in part due to our limited understanding of the natural history of this disease. This review describes the current epidemiology and clinical manifestations of pCMV disease which should alert clinicians to test for CMV and also outlines a strategy to manage the condition.


Capture-recapture analysis to estimate the incidence of invasive meningococcal disease in Germany, 2003.
The incidence of invasive meningococcal disease (IMD) in Germany in 2003 was estimated by the two-source capture-recapture method. As a unique personal identifier was unavailable, cases with IMD tested at the National Reference Centre for Meningococci (NRZM) were matched with cases reported to the Robert Koch Institute (RKI) through the statutory surveillance system by using demographic and disease-specific variables common to both datasets. The estimated overall incidence was 1.1 IMD cases/100,000 inhabitants, with a sensitivity of ascertainment of 64.8% for NRZM and 89.4% for RKI. Case-fatality rate was estimated at 8.8%. Adjustment for heterogeneity of capture according to age, region and serogroup observed in the NRZM (but not RKI) source had minimal effect on the estimated incidence. The IMD incidence estimated by capture-recapture analysis is thus only slightly higher than through statutory surveillance data. As a degree of positive dependence between the systems cannot be ruled out, this estimate may still be an underestimate. However, under ascertainment appears insufficient to explain the low incidence of IMD in Germany compared to other European countries.


Selective detection of Al(3+) and citric acid with a fluorescent amphiphile.
An amphiphilic fluorescent dye with a disulfonated BODIPY head group and a heptadecyl side chain is described. In buffered aqueous solution, the amphiphile can form aggregates with a critical micelle concentration of ∼20 μM. The aggregation of the dye is associated with a strong quenching of its fluorescence. Al(3+) promotes aggregation, whereas other metal ions have a much smaller effect, in particular when histidine is added as masking agent. The Al(3+)-induced aggregation can be used to sense Al(3+) in the low micromolar concentration range with high selectivity. Furthermore, we demonstrate that a dye-Al(3+) mixture can be used as a sensing ensemble for the detection of citric acid. The assay allows quantifying the citric acid content of commercial beverages such as energy drinks.


The effects of pioglitazone in reducing atherosclerosis progression and neointima volume in type 2 diabetic patients: prospective randomized study with volumetric intravascular ultrasonography analysis.
Pioglitazone has been known for its anti-atherogenic effects. We compared the effects of pioglitazone in reducing atherosclerosis progression and neointima volume in type 2 diabetic patients. This was a prospective, randomized single-blinded, 8-month follow-up study. Patients with significant coronary artery stenosis were randomly assigned to either pioglitazone (n=19) or placebo (n=18) following zotarolimus-eluting stent (ZES) implantation. Intravascular ultrasonography of the culprit vessel was performed from 20 mm distal and proximal to the stent at baseline. and at 8-month, and volumetric analysis was performed. Changes in inflammation markers, insulin resistance and lipid profile were compared. Changes in atherosclerosis progression from baseline in the pioglitazone group was significantly lower than that of the placebo group (0.06±0.73 vs. 1.16±1.41 mm(3)/mm, p=0.024, respectively), and neointima volume was significantly lower in the pioglitazone group compared to the placebo group (1.74±0.93 vs. 2.42±1.98 mm(3)/mm, p=0.007, respectively). Homeostatic model assessment-index, interleukin-6, and tumor necrosis factor-α levels were significantly lower in the pioglitazone group at 8 months. Adiponectin levels increased significantly only in the pioglitazone group. No significant differences in retinol binding protein-4 levels between the 2 groups were seen during the 8-month follow-up period. Compared to placebo, pioglitazone was associated with significant reduction in atherosclerosis progression and neointima formation in type 2 diabetic patients with ZES implantation.


2010 Survey on cell phone use while performing cardiopulmonary bypass.
Cell phone use in the U.S. has increased dramatically over the past decade and text messaging among adults is now mainstream. In professions such as perfusion, where clinical vigilance is essential to patient care, the potential distraction of cell phones may be especially problematic. However, the extent of this as an issue is currently unknown. Therefore, the purpose of this study was to (1) determine the frequency of cell phone use in the perfusion community, and (2) to identify concerns and opinions among perfusionists regarding cell phone use. In October 2010, a link to a 19-question survey (surveymonkey.com) was posted on the AmSECT (PerfList) and Perfusion.com (PerfMail) forums. There were 439 respondents. Demographic distribution is as follows; Chief Perfusionist (30.5%), Staff Perfusionist (62.0%), and Other (7.5%), with age ranges of 20-30 years (14.2%), 30-40 years (26.5%), 40-50 years (26.7%), 50-60 years (26.7%), >60 years (5.9%). The use of a cell phone during the performance of cardiopulmonary bypass (CPB) was reported by 55.6% of perfusionists. Sending text messages while performing CPB was acknowledged by 49.2%, with clear generational differences detected when cross-referenced with age groups. For smart phone features, perfusionists report having accessed e-mail (21%), used the internet (15.1%), or have checked/posted on social networking sites (3.1%) while performing CPB. Safety concerns were expressed by 78.3% who believe that cell phones can introduce a potentially significant safety risk to patients. Speaking on a cell phone and text messaging during CPB are regarded as "always an unsafe practice" by 42.3% and 51.7% of respondents, respectively. Personal distraction by cell phone use that negatively affected performance was admitted by 7.3%, whereas witnessing another perfusionist distracted with phone/text while on CPB was acknowledged by 33.7% of respondents. This survey suggests that the majority of perfusionists believe cell phones raise significant safety issues while operating the heart-lung machine. However, the majority also have used a cell phone while performing this activity. There are clear generational differences in opinions on the role and/or appropriateness of cell phones during bypass. There is a need to further study this issue and, perhaps, to establish consensus on the use of various communication modes within the perfusion community.


VEGFA Promoter Polymorphisms rs699947 and rs35569394 Are Associated With the Risk of Anterior Cruciate Ligament Ruptures Among Indian Athletes: A Cross-sectional Study.
Associations of genetic variants within certain fibril-forming genes have previously been observed with anterior cruciate ligament (ACL) injuries. Evidence suggests a significant role of angiogenesis-associated cytokines in remodeling the ligament fibril matrix after mechanical loading and maintaining structural and functional integrity of the ligament. Functional polymorphisms within the vascular endothelial growth factor A (VEGFA) gene have emerged as plausible candidates owing to their role in the regulation of angiogenic responses. VEGFA promoter polymorphisms rs699947 and rs35569394 are associated with ACL injury risk among athletes. Cross-sectional study; Level of evidence, 3. A total of 90 Indian athletes with radiologically confirmed or surgically proven isolated ACL tears and 76 matched-control athletes were selected for the present cross-sectional genetic association study. Oral mouthwash samples were collected from all the case and control athletes and genotyped for VEGFA rs699947 and rs35569394 using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The A allele (rs699947) was significantly overrepresented in the ACL group (C vs A allele: odds ratio [OR], 1.68 [95% CI, 1.08-2.60]; P = .021) (CC vs CA + AA: OR, 2.69 [95% CI, 1.37-5.26]; P = .004). There was a greater frequency of the AA genotype in the ACL group in comparison with the control group (OR, 3.38 [95% CI, 1.23-9.28]; P = .016) when only male athletes were compared. Likewise, there was a greater frequency of the I allele (rs35569394) in the ACL group (D vs I allele: OR, 1.64 [95% CI, 1.06-2.55]; P = .025) (DD vs ID + II: OR, 2.61 [95% CI, 1.31-5.21]; P = .006). The A-I haplotype was overrepresented in the ACL group compared with the control group (OR, 1.68 [95% CI, 1.08-2.60]; χ2 = 5.320; P = .021), and both the polymorphisms were found to be in complete linkage disequilibrium (r 2 = 0.929; logarithm of the odds score = 63.74; D' = 1.0). Female athletes did not show any difference in genotype or allele frequency. This is the first study to investigate the association of VEGFA promoter polymorphisms in ACL tears among Indian athletes. Increased frequencies of the A allele (rs699947) and I allele (rs35569394) were observed in the ACL group. These results suggest that sequence variants in the VEGF gene are associated with ACL injury risk among athletes. Further research with long-term follow-ups measuring VEGF expression levels during recovery is warranted to establish its role in ACL injuries and healing.


MW151 Inhibited IL-1β Levels after Traumatic Brain Injury with No Effect on Microglia Physiological Responses.
A prevailing neuroinflammation hypothesis is that increased production of proinflammatory cytokines contributes to progressive neuropathology, secondary to the primary damage caused by a traumatic brain injury (TBI). In support of the hypothesis, post-injury interventions that inhibit the proinflammatory cytokine surge can attenuate the progressive pathology. However, other post-injury neuroinflammatory responses are key to endogenous recovery responses. Therefore, it is critical that pharmacological attenuation of detrimental or dysregulated neuroinflammatory processes avoid pan-suppression of inflammation. MW151 is a CNS-penetrant, small molecule experimental therapeutic that restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis without immunosuppression. Post-injury administration of MW151 in a closed head injury model of mild TBI suppressed acute cytokine up-regulation and downstream cognitive impairment. Here, we report results from a diffuse brain injury model in mice using midline fluid percussion. Low dose (0.5-5.0 mg/kg) administration of MW151 suppresses interleukin-1 beta (IL-1β) levels in the cortex while sparing reactive microglia and astrocyte responses. To probe molecular mechanisms, we used live cell imaging of the BV-2 microglia cell line to demonstrate that MW151 does not affect proliferation, migration, or phagocytosis of the cells. Our results provide insight into the roles of glial responses to brain injury and indicate the feasibility of using appropriate dosing for selective therapeutic modulation of injurious IL-1β increases while sparing other glial responses to injury.


Mother's Own Milk and Bronchopulmonary Dysplasia: A Systematic Review and Meta-Analysis.
Background: Bronchopulmonary dysplasia (BPD) is the most common complication of very preterm birth and can lead to lifelong health consequences. Optimal nutrition is a cornerstone in the prevention and treatment of BPD. In very preterm infants, mother's own milk (MOM) feeding is associated with lower risks of necrotizing enterocolitis, retinopathy of prematurity, and sepsis. Although several studies have shown that MOM may protect against BPD, a systematic analysis of the evidence has not been performed to date. Methods: A comprehensive literature search was conducted using PubMed/MEDLINE and EMBASE, from their inception to 1 December 2017. Longitudinal studies comparing the incidence of BPD in preterm infants fed with exclusive MOM, MOM supplemented with preterm formula (PF), and/or exclusively fed with PF were selected. A random-effects model was used to calculate the Mantel Haenszel risk ratio (RR) and 95% confidence interval (CI). Results: Fifteen studies met the inclusion criteria (4,984 infants, 1,416 BPD cases). Use of exclusive MOM feedings was associated with a significant reduction in the risk of BPD (RR 0.74, 95% CI 0.57-0.96, 5 studies). In contrast, meta-analysis could not demonstrate a significant effect on BPD risk when infants fed with more than 50% MOM were compared with infants fed with <50% MOM (RR 0.98, 95% CI 0.77-1.23, 10 studies) or when infants fed with MOM supplemented with PF were compared with infants fed with exclusive PF (RR 1.00, 95% CI 0.78-1.27, 6 studies). Meta-regression showed that differences in gestational age were a significant confounder of the effect of MOM. Conclusion: To our knowledge, this is the first systematic review and meta-analysis that specifically evaluates the role of MOM on BPD. Our data indicate that MOM may reduce the incidence of BPD when used as an exclusive diet, but this result needs to be interpreted with caution. We did not find the same difference in analyses with other dosages of MOM. Further studies adequately powered to detect changes in BPD rates and that adjust for confounders are needed to confirm the beneficial effects of MOM on BPD.


Eosinophilic granulomatous with polyangiitis complicated by swelling of the oral cavity floor and cervical soft tissue as initial manifestation mimicking IgG4-related disease: A case report.
Eosinophilic granulomatous polyangiitis is a systemic vasculitis associated with bronchial asthma and eosinophilic sinusitis. Here we describe an unusual presentation of eosinophilic granulomatous polyangiitis that initially manifested as swelling of the oral cavity floor and cervical soft tissue. A 58-year-old Japanese man was diagnosed with bronchial asthma during childhood but did not receive regular medication. Prior to this presentation, he had a persistent cough for over 1 month, and a local physician diagnosed him with bronchial asthma. However, 6 months later, his cough worsened, and a blood test revealed elevated eosinophil levels. Immediately afterward, swelling of the floor of the oral cavity and cervical soft tissue developed. Cellulitis was suspected and antimicrobial treatment was initiated; however, the symptoms persisted and abdominal pain developed. An endoscopic examination revealed duodenitis and a duodenal ulcer. The patient was diagnosed with eosinophilic granulomatous polyangiitis based on three items of the 2022 American College of Rheumatology/European College of Rheumatology classification criteria: obstructive airway disease, blood eosinophil count ≥1×109 cells/L, and extravascular eosinophilic infiltration with a score of 10. Oral prednisolone (70 mg/day), intravenous cyclophosphamide (500 mg/m2), and subcutaneous mepolizumab (300 mg every 4 weeks) were administered. The patient's symptoms improved after these treatments, and the eosinophil count and inflammatory marker levels declined. When swelling of the oral cavity floor and cervical soft tissue following an increase in eosinophilia and allergic symptoms occurs, it is crucial to consider the likelihood of eosinophilic granulomatous polyangiitis and collaborate with otolaryngologists and dentists to ensure its prompt identification.


Induced fit and the catalytic mechanism of isocitrate dehydrogenase.
NADP(+) dependent isocitrate dehydrogenase (IDH; EC 126.96.36.199) belongs to a large family of α-hydroxyacid oxidative β-decarboxylases that catalyze similar three-step reactions, with dehydrogenation to an oxaloacid intermediate preceding β-decarboxylation to an enol intermediate followed by tautomerization to the final α-ketone product. A comprehensive view of the induced fit needed for catalysis is revealed on comparing the first "fully closed" crystal structures of a pseudo-Michaelis complex of wild-type Escherichia coli IDH (EcoIDH) and the "fully closed" reaction product complex of the K100M mutant with previously obtained "quasi-closed" and "open" conformations. Conserved catalytic residues, binding the nicotinamide ring of NADP(+) and the metal-bound substrate, move as rigid bodies during domain closure by a hinge motion that spans the central β-sheet in each monomer. Interactions established between Thr105 and Ser113, which flank the "phosphorylation loop", and the nicotinamide mononucleotide moiety of NADP(+) establish productive coenzyme binding. Electrostatic interactions of a Lys100-Leu103-Asn115-Glu336 tetrad play a pivotal role in assembling a catalytically competent active site. As predicted, Lys230* is positioned to deprotonate/reprotonate the α-hydroxyl in both reaction steps and Tyr160 moves into position to protonate C3 following β-decarboxylation. A proton relay from the catalytic triad Tyr160-Asp307-Lys230* connects the α-hydroxyl of isocitrate to the bulk solvent to complete the picture of the catalytic mechanism.


The treatment gap in mental health care.
Mental disorders are highly prevalent and cause considerable suffering and disease burden. To compound this public health problem, many individuals with psychiatric disorders remain untreated although effective treatments exist. We examine the extent of this treatment gap. We reviewed community-based psychiatric epidemiology studies that used standardized diagnostic instruments and included data on the percentage of individuals receiving care for schizophrenia and other non-affective psychotic disorders, major depression, dysthymia, bipolar disorder, generalized anxiety disorder (GAD), panic disorder, obsessive-compulsive disorder (OCD), and alcohol abuse or dependence. The median rates of untreated cases of these disorders were calculated across the studies. Examples of the estimation of the treatment gap for WHO regions are also presented. Thirty-seven studies had information on service utilization. The median treatment gap for schizophrenia, including other non-affective psychosis, was 32.2%. For other disorders the gap was: depression, 56.3%; dysthymia, 56.0%; bipolar disorder, 50.2%; panic disorder, 55.9%; GAD, 57.5%; and OCD, 57.3%. Alcohol abuse and dependence had the widest treatment gap at 78.1%. The treatment gap for mental disorders is universally large, though it varies across regions. It is likely that the gap reported here is an underestimate due to the unavailability of community-based data from developing countries where services are scarcer. To address this major public health challenge, WHO has adopted in 2002 a global action programme that has been endorsed by the Member States.


Prevotella marshii sp. nov. and Prevotella baroniae sp. nov., isolated from the human oral cavity.
Eleven strains of anaerobic Gram-negative bacilli isolated from the human oral cavity were subjected to a comprehensive range of phenotypic and genotypic tests and were found to comprise two homogeneous groups, designated E2 and E4. 16S rRNA gene sequence analysis revealed that members of both groups belonged to the genus Prevotella but were distinct from any species with validly published names. This distinction was confirmed by DNA-DNA hybridization and phenotypic tests. Two novel species are therefore proposed: Prevotella marshii sp. nov. (group E2) and Prevotella baroniae (group E4). Both species are saccharolytic; the end-products of fermentation for P. marshii are acetic, propionic and succinic acids, while P. baroniae produces acetic and succinic acids with minor amounts of isovaleric and isobutyric acids. The G+C content of the DNA of the type strain of Prevotella marshii is 51 mol% and that of Prevotella baroniae is 52 mol%. The type strain for P. marshii is E9.34(T) (=DSM 16973(T)=CCUG 50419(T)) and that for P. baroniae is E9.33(T) (=DSM 16972(T)=CCUG 50418(T)).