Dynamic optical manipulation with a higher-order fractional bessel beam generated from a spatial light modulator.
Higher-order Bessel beams have been demonstrated to have the ability to trap and rotate low- and high-index particles simultaneously [Phys. Rev. A 66, 063402 (2002)]. The rotation and trapping is caused by the presence of orbital angular momentum arising from its azimuthal phase variation (that changes at integer multiples of 2pi) and the concentric rings of the Bessel mode. We demonstrate for the first time to our knowledge a branch from the family of higher-order Bessel beams that has fractional azimuthal variation at its beam axis. This new family of laser beams has the ability to perform dynamic optical manipulation with dynamic control of a spatial light modulator. Furthermore, we take the opportunity to explore the propagation characteristics of higher-order Bessel beams for which the azimuthal phase changes at noninteger multiples of 2pi.


Serotonin receptor 2c-expressing cells in the ventral CA1 control attention via innervation of the Edinger-Westphal nucleus.
The hippocampus is divided into dorsal and ventral zones along its principal axis. The dorsal hippocampus is critical for learning and memory, yet the basic function of the ventral hippocampus remains elusive. Here we genetically manipulate a subset of excitatory neurons expressing the serotonin receptor 2c (Htr2c) in the ventral hippocampus. Genetically modified virus tracing reveals that these Htr2c cells establish monosynaptic excitatory connections with newly identified neurons in the Edinger-Westphal nucleus (EW), which directly innervate the medial prefrontal cortex. Inactivation of Htr2c cells impairs behavioral performance in a visual-detection task that demands attention, without affecting novel-object recognition, learning, or memory. This attention deficit was recapitulated by inhibition of EW cells and rescued by activation of EW cells or synaptic projections from Htr2c cells onto EW cells. This study uncovers a synaptic pathway for control of attention.


Assessing the quality of care for paediatric depression and anxiety in Australia: A population-based sample survey.
We examine the prevalence of quality care (as measured by adherence to recommendations in clinical practice guidelines) for Australian paediatric patients (⩽15 years) with depression and/or anxiety, using data from the CareTrack Kids study; a population-based study of the quality of healthcare practice in inpatient and ambulatory healthcare settings. A multistage stratified sample identified records of 6689 children. Of these, 156 records were identified for depression and 356 for anxiety. These were assessed for adherence to 15 depression and 13 anxiety indicators, respectively, using a review of medical records. Adherence to assessment and management guidelines was low for both conditions: assessment bundle (depression = 33%, 95% confidence interval = [20, 48]; anxiety = 54%, 95% confidence interval = [43, 64] and depression management bundle = 35%, 95% confidence interval = [15, 60]). Across both conditions, the highest adherence was recorded for indicators that addressed prescription of medications (e.g. venlafaxine, 100%; benzodiazepines, 100%; selective serotonin reuptake inhibitor, 94% and antidepressants, 91%), while compliance was the lowest for ensuring children with depression had an emergency safety plan (44%), informing parents of the risks and benefits of prescribed anxiety medication (51%) and assessment for other causes (59% for depression; 68% for anxiety). These findings suggest that strategies are needed to improve guideline adherence for mental health disorders in children and adolescents, particularly among general practitioners. Learning from these indicators could inform clinical prompts in electronic medical records, as well as links to additional information, to assist in decision-making and streamline work practices.


Lens capsule as a model to study type IV collagen.
The study of collagen IV has benefited greatly from the seminal work conducted by Arthur Veis and colleagues over three decades ago. Through a series of electron microscopy studies focused on lens basement membrane, an appreciation was gained for the distinct network-forming properties of collagen IV. Veis correctly suggested that network assembly is a phenomenon of the non-collagenous termini of the molecule. This review seeks to document how the field advanced following these seminal conclusions, including recent discoveries regarding the molecular reinforcement of networks that support Veis' conclusions.


Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European Liver Transplant Registry.
This study was a retrospective analysis of the European Liver Transplant Registry (ELTR) performed to compare long-term outcomes with prolonged-release tacrolimus versus tacrolimus BD in liver transplantation (January 2008-December 2012). Clinical efficacy measures included univariate and multivariate analyses of risk factors influencing graft and patient survival at 3 years posttransplant. Efficacy measures were repeated using propensity score-matching for baseline demographics. Patients with <1 month of follow-up were excluded from the analyses. In total, 4367 patients (prolonged-release tacrolimus: n = 528; BD: n = 3839) from 21 European centers were included. Tacrolimus BD treatment was significantly associated with inferior graft (risk ratio: 1.81; p = 0.001) and patient survival (risk ratio: 1.72; p = 0.004) in multivariate analyses. Similar analyses performed on the propensity score-matched patients confirmed the significant survival advantages observed in the prolonged-release tacrolimus- versus tacrolimus BD-treated group. This large retrospective analysis from the ELTR identified significant improvements in long-term graft and patient survival in patients treated with prolonged-release tacrolimus versus tacrolimus BD in primary liver transplant recipients over 3 years of treatment. However, as with any retrospective registry evaluation, there are a number of limitations that should be considered when interpreting these data.


The Hippo pathway regulates homeostatic growth of stem cell niche precursors in the Drosophila ovary.
The Hippo pathway regulates organ size, stem cell proliferation and tumorigenesis in adult organs. Whether the Hippo pathway influences establishment of stem cell niche size to accommodate changes in organ size, however, has received little attention. Here, we ask whether Hippo signaling influences the number of stem cell niches that are established during development of the Drosophila larval ovary, and whether it interacts with the same or different effector signaling pathways in different cell types. We demonstrate that canonical Hippo signaling regulates autonomous proliferation of the soma, while a novel hippo-independent activity of Yorkie regulates autonomous proliferation of the germ line. Moreover, we demonstrate that Hippo signaling mediates non-autonomous proliferation signals between germ cells and somatic cells, and contributes to maintaining the correct proportion of these niche precursors. Finally, we show that the Hippo pathway interacts with different growth pathways in distinct somatic cell types, and interacts with EGFR and JAK/STAT pathways to regulate non-autonomous proliferation of germ cells. We thus provide evidence for novel roles of the Hippo pathway in establishing the precise balance of soma and germ line, the appropriate number of stem cell niches, and ultimately regulating adult female reproductive capacity.


Decarboxylative Alkynylation and Cyanation of Carboxylic Acids using Photoredox Catalysis and Hypervalent Iodine Reagents.
Alkynes and nitriles are important functional groups that serve as versatile building blocks in organic synthesis and find applications in material and medicinal sciences. A convenient and straightforward access to both classes of compounds under mild conditions is, therefore, highly desirable. Herein, we disclose the decarboxylative alkynylation and cyanation of broadly available carboxylic acids using photoredox catalysis and hypervalent iodine reagents. Choices of both catalysts and reagents were crucial. Computational and experimental studies revealed two different possible mechanisms that are dictated by the oxidation potential of the reagents: radical for alkynylation, ionic for cyanation.


Hepatic steatosis and disease activity in subjects with psoriatic arthritis receiving tumor necrosis factor-α blockers.
Little is known about tumor necrosis factor-α (TNF-α) blockers, disease activity, and liver steatosis (hepatic steatosis; HS) in subjects with psoriatic arthritis (PsA). We prospectively evaluated changes in HS during treatment with TNF-α blockers. In 48 patients with PsA who had evidence of HS before the beginning of TNF-α blocker treatment, an ultrasound followup examination was performed after a 12-month treatment period with TNF-α blockers. All subjects were stratified according to minimal disease activity (MDA) or not (n-MDA), during treatment with TNF-α blockers. Changes in grade of HS were evaluated in parallel in 42 controls with HS and without PsA. At baseline, no significant difference in HS score was found between PsA subjects and controls (HS scores 1.46 ± 0.65 vs 1.62 ± 0.66, respectively; p = 0.249). At 12-month followup, a worsening HS score was found in 20 (41.7%) patients with PsA and in 6 (14.3%) controls (p = 0.005). Overall, the grade of HS worsening was higher in patients with PsA (0.37 ± 0.70) than in controls (0.09 ± 0.43; p = 0.028). A significantly lower prevalence of worsening HS was found among patients with PsA with MDA, compared with n-MDA subjects (16.7% vs 66.7%, respectively; p = 0.001). Laboratory measures of liver function behaved similarly. The risk of worsening HS in patients with PsA who had MDA was similar to that in controls (HR 1.20, 95% CI 0.34-4.33, p = 0.77), and higher in patients who did not have MDA (HR 4.46, 95% CI 1.73-11.47, p = 0.001, regression analysis). Compared with patients with MDA, those with active disease after 12-month treatment with TNF-α blockers exhibited significantly higher incidence of worsening liver steatosis.


A quantitative analysis of the genetics of resting blood lactic acid levels in mice.
Resting blood lactate levels were measured in inbred mouse strains, their F(1), and several of their segregating generations to determine whether the level of lactic acid is influenced by genetic factors. The inbred strains in each of the two sets used differed significantly from one another for this character. Only one strain showed a significant sex difference. The data could not be fully analyzed because of the failure to fulfill Mather's first criterion for an adequate scale. Nonallelic interactions, in particular, additive x dominance and dominance x dominance, were found to influence the generation means. Genotype x environment interaction was detected and eliminated by log transformation. Negative heterosis was exhibited by all but one noninbred generation.-The data suggest that genes influencing the character are dispersed between the parental lines and that interactions are predominantly of the duplicate kind. A buffering system by which lactate levels are kept at a minimum is proposed.


Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: relation to common inflammatory diseases?
NALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1-mediated interleukin-1beta (IL-1beta) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic-resistant fever carried mutations in the genes encoding the NALP3 inflammasome. Genetic analysis of NLRP3 and the gene encoding TUCAN (CARD-8) was performed on genomic DNA from the patient and from a population-based collection of DNA (806 subjects). For in vitro studies of IL-1beta production and caspase 1 activity, blood was obtained from the patient at different time points after administration of anakinra, an IL-1 receptor antagonist, as well as from 5 healthy age- and sex-matched control subjects. Mutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD-8 (C10X) genes. The allele frequencies of these single-nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase 1 and the high levels of IL-1beta measured in samples from the patient returned to normal levels after treatment with anakinra. Our results indicate that the patient's symptoms were due to elevated levels of IL-1beta, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL-1beta levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.


Human exposure to potentially carcinogenic compounds.
Average exposures to suspected carcinogens were surveyed for the population in Finland. Alcohol, food and tobacco constitute the largest sources of exposure. Occupational populations may be more exposed than the population at large, by many orders of magnitude. For example, occupational exposure to airborne asbestos and trichloroethylene may be 10 000 times higher than exposure outside workplaces. Application of exposure data to health surveillance and epidemiological research is discussed.


Characterization of cyclin B1 expression in human cancer cell lines by a new three-parameter BrdUrd/cyclin B1/DNA analysis.
Flow cytometric cyclin expression/DNA content analysis, now commonly used, provides useful information on the mechanisms regulating cell cycle progression. However, this biparametric analysis does not make a clear-cut distinction between G1 and S-early or between S-late and G2M phase cells. This paper proposes a new three-parameter flow cytometric method with which to determine cyclin B1 levels in single cells in different cell cycle phases by coupling bromodeoxyuridine (BrdUrd) immunodetection and DNA content. DNA denaturation by HCl did not alter the level of cyclin B1. Differences in cyclin B1 expression were observed in seven human cancer cell lines of different origin. The percentage of cyclin B1-positive cells and the cyclin B1 content per cell indicated different patterns. In some cases cyclin B1 accumulation preceded the G2M checkpoint, at which its content usually started to rise. Using available easily reproducible techniques, this flow cytometric approach gives details of intracellular variability in cyclin expression.


Top-down modulations in the visual form pathway revealed with dynamic causal modeling.
Perception entails interactions between activated brain visual areas and the records of previous sensations, allowing for processes like figure-ground segregation and object recognition. The aim of this study was to characterize top-down effects that originate in the visual cortex and that are involved in the generation and perception of form. We performed a functional magnetic resonance imaging experiment, where subjects viewed 3 groups of stimuli comprising oriented lines with different levels of recognizable high-order structure (none, collinearity, and meaning). Our results showed that recognizable stimuli cause larger activations in anterior visual and frontal areas. In contrast, when stimuli are random or unrecognizable, activations are greater in posterior visual areas, following a hierarchical organization where areas V1/V2 were less active with "collinearity" and the middle occipital cortex was less active with "meaning." An effective connectivity analysis using dynamic causal modeling showed that high-order visual form engages higher visual areas that generate top-down signals, from multiple levels of the visual hierarchy. These results are consistent with a model in which if a stimulus has recognizable attributes, such as collinearity and meaning, the areas specialized for processing these attributes send top-down messages to the lower levels to facilitate more efficient encoding of visual form.


Inhibition of itch-related responses at spinal level in rats.
The goal was to develop a rat model for determination of the effects of intrathecally administered drugs on the peripherally induced pruritic behaviors. After chronic intrathecal catheterization, a serotonin derivative (5-methoxytryptamine: MeOT, 200 μg on both sides) was injected into the lower leg skin. After the first period (phase 0: 0-30 min) MeOT injection was repeated and opioid antagonist naltrexone (10 μg), NMDA receptor antagonists ketamine (10-100 μg), kynurenic acid (1-10 μg) or their combinations were injected intrathecally. The second observational period lasted for 60 min (phases I and II, 30-60 and 60-90 min, respectively). MeOT produced pruritic behavior with high degree of interindividual differences. The second MeOT injection caused an enhanced pruritic behavior in Phase I. Naltrexone decreased the pruritic activity, while neither doses of ketamine influenced the effects of MeOT. The higher doses of kynurenic acid resulted in notable decreases in the pruritic behavior. The combinations of naltrexone with ketamine or kynurenic acid produced a prolonged antipruritic effect. Our data suggest an important direction for the development of a new itch model in rats that focuses on the spinal mechanism of itching. Besides, the results revealed the role of the spinal opioid and NMDA receptors in this process.


Differential effect of arginine modification with 1,2-cyclohexanedione on the capacity of vimentin and desmin to assemble into intermediate filaments and to bind to nucleic acids.
When the intermediate filament proteins vimentin and desmin were reacted for a short period of time with the arginine-specific reagent 1,2-cyclohexanedione, the modification had a severe, inhibitory effect on the assembly of intermediate filaments and on the susceptibility of the basic, amino-terminal polypeptide of both proteins to degradation by the intermediate filament-specific, Ca2+-activated proteinase. However, it had only a slightly inhibitory effect on the binding of vimentin and desmin to ribosomal RNA from Ehrlich ascites tumour cells. Since the Ca2+-activated proteinase is very likely to be a trypsin-like enzyme, with a preference for arginyl and lysyl peptide bonds, the results indicate that the arginine residues of the amino-terminal polypeptide of vimentin and desmin are highly essential for filament assembly but largely dispensable for the binding of both proteins to nucleic acids. This was supported by the observation that two breakdown products of vimentin lacking a 5 X 10(3) Mr and an 8 X 10(3) Mr polypeptide from the amino terminus, respectively, did not assemble into intermediate filaments but were still capable of binding to rRNA. Both polypeptides also bound to single-stranded DNA-cellulose under non-denaturing conditions, but passed the affinity column in the presence of 6 M-urea. Thus, the binding of vimentin to nucleic acids appears to be based on two components: a non-specific electrostatic interaction mediated by the positively charged arginine residues of the amino-terminal polypeptide that is insensitive to denaturation by urea, and a specific interaction that is sensitive to denaturation by urea.


The Impact of Polypharmacy on Patient Outcomes in Older Adults With Cancer.
Polypharmacy is prevalent in older adults with cancer and may be advantageous for the management of certain chronic disease states, but uncertainty exists regarding potential hazards and consequences. Cancer-related therapy adds to the prevalence of polypharmacy, which can lead to compromised cancer management plans (i.e., postoperative complications, treatment delays, and/or premature treatment discontinuation). Polypharmacy has been identified as one of the domains commonly included in the Comprehensive Geriatric Assessment likely because of the potential influence on health outcomes. This review summarizes existing evidence regarding health outcomes associated with polypharmacy in older adults with cancer. Preliminary evidence demonstrated that relationships exist between polypharmacy and health outcomes including adverse drug events, falls, frailty, hospitalization, postoperative complications, and mortality. This research is limited by study confounders, inconsistent definitions for polypharmacy, heterogeneous cancer types and stages, and the complex relationship between medication regimens and outcomes. Additional studies are needed to enhance the accuracy and replicability of this research.


Repair of fingertip lacerations and amputations.
Even minor losses of fingertip skin or subcutaneous tissue can be disabling. The location, size and orientation of the defect must be meticulously assessed. Particular attention to technique is required in providing digital block anesthesia, in using Z-plasty to redirect wounds which cross flexion creases and in providing adequate coverage of fingertip amputations. A correct repair will allow rapid recovery and an early return to activities.


A longitudinal study of the relationship of physical activity to bone mineral accrual from adolescence to young adulthood.
Physical activity in adolescence is beneficial for increasing bone mineral accrual; however, it's unclear whether these benefits persist into adulthood. This prospective study investigated whether physically active adolescents maintained their higher bone mineral content (BMC) into the third decade of life when compared to their less active peers. Data were from 154 subjects (82 females and 72 males) who participated in the University of Saskatchewan's Pediatric Bone Mineral Accrual Study (1991-1997), entry age 8 to 15 years. Participants returned for follow-up as young adults (2002-2006), follow-up age 23 to 30 years. Dual energy X-ray absorptiometry was used to measure BMC of total body (TB), lumbar spine (LS), total hip (TH) and femoral neck (FN) annually from 1991 to 1997 and from 2002 to 2006. Peak height velocity (PHV) was determined for each child as a measure of maturity. Age and gender-specific activity Z-scores were calculated for each participant based on the mean physical activity scores obtained from bi-annual questionnaire data during childhood and adolescence. Subjects were ranked into three adolescent activity groups: active, average and inactive (top, middle two, and bottom quartiles, respectively). Analysis of covariance (ANCOVA) was used to compare adjusted TB, LS, TH and FN BMC across the three adolescent activity groups at 1 year post PHV and in young adulthood. When compared to the inactive group, active males had 8% greater adjusted BMC at the TB, 13% at the LS and 11% at the TH (p<0.05) in adolescence. Active females also had 8% and 15% more adjusted BMC (p<0.05) at the TB and LS, respectively, during adolescence. In young adulthood the male and female adolescent active groups were still significantly more active than their peers (p>0.05). It was found that active adolescent males had 8-10% more adjusted BMC at the TB, TH and FN (p<0.05) in young adulthood and that active adolescent females had 9% and 10% more adjusted BMC at the TH and FN. These results suggest that the skeletal benefits of physically activity in adolescents are maintained into young adulthood.


A Combined LD50 for Agrochemicals and Pathogens in Bumblebees (Bombus terrestris [Hymenoptera: Apidae]).
Neonicotinoid insecticides are the most commonly used insecticide in the world and can have significant sub-lethal impacts on beneficial insects, including bumblebees, which are important pollinators of agricultural crops and wild-flowers. This has led to bans on neonicotinoid use in the EU and has resulted in repeated calls for the agrochemical regulatory process to be modified. For example, there is increasing concern about 1) the underrepresentation of wild bees, such as bumblebees, in the regulatory process, and 2) the failure to determine how agrochemicals, such as neonicotinoids, interact with other commonly occurring environmental stressors, such as parasites. Here, we modify an OECD approved lethal dose (LD50) experimental design and coexpose bumblebees (Bombus terrestris) to the neonicotinoid thiamethoxam and the highly prevalent trypanosome parasite Crithidia bombi, in a fully crossed design. We found no difference in the LD50 of thiamethoxam on bumblebees that had or had not been inoculated with the parasite (Crithidia bombi). Furthermore, thiamethoxam dosage did not appear to influence the parasite intensity of surviving bumblebees, and there was no effect of either parasite or insecticide on sucrose consumption. The methodology used demonstrates how existing ring-tested experimental designs can be effectively modified to include other environmental stressors such as parasites. Moving forward, the regulatory process should implement methodologies that assess the interactions between agrochemicals and parasites on non-Apis bees and, in cases when this is not practical, should implement post-regulatory monitoring to better understand the real-world consequences of agrochemical use.


Functional and structural neural alterations in Internet gaming disorder: A systematic review and meta-analysis.
This meta-analytic study aimed to identify the common and specific neural alterations in Internet gaming disorder (IGD) across different domains and modalities. Two separate meta-analyses for functional neural activation and gray-matter volume were conducted. Sub-meta-analyses for the domains of reward, cold-executive, and hot-executive functions were also performed, respectively. IGD subjects, compared with healthy controls, showed: (1) hyperactivation in the anterior and posterior cingulate cortices, caudate, posterior inferior frontal gyrus (IFG), which were mainly associated with studies measuring reward and cold-executive functions; and, (2) hypoactivation in the anterior IFG in relation to hot-executive function, the posterior insula, somatomotor and somatosensory cortices in relation to reward function. Furthermore, IGD subjects showed reduced gray-matter volume in the anterior cingulate, orbitofrontal, dorsolateral prefrontal, and premotor cortices. These findings suggest that IGD is associated with both functional and structural neural alterations in fronto-striatal and fronto-cingulate regions. Moreover, multi-domain assessments capture different aspects of neural alterations in IGD, which may be helpful for developing effective interventions targeting specific functions.


Very low field magnetic resonance imaging with spintronic sensors.
A very low field magnetic resonance imaging (MRI) setup based on magnetoresistive-superconducting mixed sensors is presented. A flux transformer is used to achieve coupling between the sample to image and the mixed sensor. The novel detector was implemented in a spin echo MRI experiment, exposing the mixed sensor to RF pulses without use of any RF switch. The performance of the novel detector is given in terms of signal-to-noise ratio and is compared with classical tuned coils.


Postoperative course after simple ligation for superior mesenteric vein injury caused by blunt abdominal trauma: report of a case.
Traumatic injury of the superior mesenteric vein (SMV) by blunt trauma is a rare but frequently fatal injury. Although simple ligation should be considered for a patient in unstable condition, its complications have not been reported in detail. A 47-year-old man was struck on the abdomen during a fight. When he was transferred to a local hospital, he complained of severe abdominal pain. Computed tomography (CT) of the abdomen showed fluid accumulation in the peritoneal cavity and a hematoma around the root of the mesentery, with leakage of contrast material. When the patient was transferred to our emergency department, the hemodynamic status did not improve after rapid fluid resuscitation with 1,500 mL of crystalloid. Emergency laparotomy was performed 4 hours after the injury. Two lacerations of the proximal SMV were observed. The SMV was ligated owing to the unstable hemodynamic status. On postoperative day (POD) 5, abdominal radiography showed dilated loops of bowel, suggesting ileus of the small bowel. A CT scan with contrast enhancement showed that the wall of the small bowel was thickened. On POD 11, a CT scan showed that the collateral vessels that drain the mesenteric circulation had not developed. However, collateral vessels were revealed on a 3-dimensional CT scan, and, on POD 23, a CT scan showed that the collateral vessels had developed. The patient was discharged on POD 37. This case demonstrates that simple ligation of the proximal SMV leads to the development of collateral vessels and is useful for preventing side effects and improving outcomes.


[Normal values for relative Doppler indices. A/B ratio, resistance index and pulsatility index of the uterine artery and umbilical artery in normal pregnancy. A longitudinal study].
37 women (of a total of 50) with an uneventful obstetric history, normal course of a singleton pregnancy and spontaneous delivery at term (> 37 weeks, birthweight > 10th centile) were studied at two to four weeks intervals in a longitudinal design using cw-Doppler velocimetry (Doptek 9013,4MHz, SPTA 30 mWcm2, high pass filter 200 Hz, Chichester, U.K.) to establish normal reference values for Doppler flow velocity waveform indices (DI) A/B ratio, RI, PI obtained from uterine and umbilical arteries from 16 to 40 weeks of gestation. Readings from the placental (p) and non-placental (np) uterine and umbilical arteries formed the database from which percentiles (5th, 50th, 95th) were calculated for weeks 16, 20, 24, 28, 32, 36 and 40 of gestation. DI consistently decreased from week 16 to term. For the uterine arteries this decrease was significant from weeks 16 to 24 with a further but insignificant decrease from 24 weeks to term. Up to 24 weeks DI values obtained from the placental side were significantly lower than those from the non-placental side. DI values from the umbilical arteries decreased continuously from 16 weeks to term with a significantly negative correlation DI values to gestational age.


Cigarette experimentation and the population attributable fraction for associated genetic and non-genetic risk factors.
We, and others, have shown that experimenting with cigarettes is a function of both non-genetic and genetic factors. In this analysis we ask: how much of the total risk of experimenting with cigarettes, among those who had not experimented with cigarettes when they enrolled in a prospective cohort, is attributable to genetic factors and to non-genetic factors? Participants (N = 1,118 Mexican origin youth), recruited from a large population-based cohort study in Houston, Texas, provided prospective data on cigarette experimentation over three years. Non-genetic data were elicited twice - baseline and follow-up. Participants were genotyped for 672 functional and tagging variants in the dopamine, serotonin and opioid pathways. In the overall model, the adjusted combined non-genetic PAF was 71.2% and the adjusted combined genetic PAF was 58.5%. Among committed never smokers the adjusted combined non-genetic PAF was 67.0% and the adjusted combined genetic PAF was 53.5%. However, among cognitively susceptible youth, the adjusted combined non-genetic PAF was 52.0% and the adjusted combined genetic PAF was 68.4%. Our results suggest there may be differences in genotypes between youth who think they will try cigarettes in the future compared to their peers who think they will not and underscore the possibility that the relative influence of genetic vs. non-genetic factors on the uptake of smoking may vary between these two groups of youth. A clearer understanding of the relative role of genetic vs. non-genetic factors in the uptake of smoking may have implications for the design of prevention programs.


A prototype spatial-spectral CT system for material decomposition with energy-integrating detectors.
Spectral CT has great potential for a variety of clinical applications due to improved tissue and material discrimination over conventional single-energy CT. Many clinical and preclinical spectral CT systems have two spectral channels enabling dual-energy CT. Strategies include split filtration, dual-layer detectors, photon-counting detectors, and kVp switching. The motivation for this work is the development of an x-ray source spectral modulation device with three or more spectral channels to enable high-sensitivity multi-material decomposition with energy-integrating detectors. We present spatial-spectral filters which are a new x-ray source modulation technology with the potential for additional channel diversity. The filtering device consists of an array of K-edge materials which divide the x-ray beam into spectrally varied beamlets. This design allows for an arbitrary number of spectral channels-trading off spatial and spectral information. We use a one-step model-based material decomposition (MBMD) algorithm to iteratively estimate material density images directly from the spatial-spectral CT data. In this work, we present a prototype spatial-spectral filter integrated with an x-ray CT test bench. The filter is composed of an array of tin, erbium, tantalum, and lead filter tiles which spatially modulate the system spectral sensitivity pattern. In a simulation study, we investigate the particular problem of mis-calibration between the data acquisition and the reconstruction model. With an understanding of the required model accuracy, we present a spectral calibration method to estimate the critical model parameters. To demonstrate feasibility of the spatial-spectral filter with a calibrated beamlet model, we collected a spatial-spectral CT scan of a multicontrast-enhanced phantom containing water, iodine, and gadolinium solutions. With simulations, we show that material decomposition is possible with spatial-spectral-filtered CT data, and we demonstrate the importance of a well-calibrated physical model. We find a 50% increase in error for focal spot model mismatch of 0.27mm and gap width model mismatch of 16 mμ. With physical results, we demonstrate that the calibrated system model is in close agreement with the measured data, and that the reconstructed material density images match the ground truth concentrations for the multicontrast phantom. Empirical results indicate gadolinium density estimation had an error of 17-58% mostly due to a systematic constant bias of 0.30-0.60 mg/ml. Water density estimates are within 1% and iodine estimates are within 10% of ground truth. These preliminary results demonstrate the potential of spatial-spectral filters to enable multicontrast imaging. Moreover, this device is compatible with energy-integrating detectors and so provides a feasible modification to enable spectral CT imaging with existing single-energy systems.


[A case of hypernatremic dehydration due to breast-feeding].
The authors report an 11-day-old exclusively breast-fed female, with a birth weight of 3 300 g, who had suffered from dehydration stage I, with acute renal failure and metabolic acidosis, with 170 mmol/L of serum sodium. Renal ultrasounds were normal but the rate of sodium in mother's milk was three times higher than controls (87 versus 21 mmol/L). Intravenous rehydration allowed the correction of hydroelectrolytic disorders.


Immunopathogenesis of inflammatory bowel disease.
Inflammatory bowel disease (IBD) is a group of idiopathic, chronic and relapsing inflammatory conditions of the gastrointestinal tract. Familial and epidemiological studies have stressed the involvement of genetic factors and have also shown the critical role of environmental factors such as sanitation and hygiene in the development of IBD. However, the molecular mechanisms of intestinal inflammation in IBD have long remained unknown. In recent years, the study of susceptibility genes involved in the detection of bacterial components and in the regulation of the host immune response has shed light onto the potential role of intestinal pathogens and gut flora in IBD immunobiology. This review presents current knowledge on intestinal epithelial barrier alterations and on dysfunction of mucosal innate and acquired immune responses in IBD. The data support the etiological hypothesis which argues that pathogenic intestinal bacteria and/or infectious agents initiate and perpetuate the inflammation of the gut through disruption of tolerance towards the commensal microbiota in an individual with genetic vulnerability.


The medical student's choice of psychiatry as a career: a survey of one graduating class.
The authors distributed a questionnaire to all members of a medical school graduating class (N = 85) to identify those students who had "seriously considered psychiatry as a career choice at any time." Eight such students were identified, 5 of whom chose specialties other than psychiatry. The authors' objective was to identify the critical factors in these 8 students' final selection. Their results support the importance of the clinical clerkship in the students' decision making; the results also indicate considerable shifting in career choice during the students' medical school years and reveal a strong antipsychiatry bias on the part of nonpsychiatric faculty.


Ultrastructure of spontaneous neoplasms induced by diethylnitrosamine and dieldrin in the C3H mouse.
The spontaneous hepatocellular neoplasms of C3H (MTV-ve) male mice were compared with the hepatic tumors induced in these animals by diethylnitrosamine (DEN) and dieldrin. No morphologic differences could be detected by light or electron microscopy between the spontaneous and induced lesions. However, the animals given diethylnitrosamine or dieldrin developed the lesions earlier, in greater numbers and of larger size. The earliest change was the development of foci composed of clear cells. Later nodules appeared which were composed of clear or basophilic cells. These lesions were followed by and presumably progressed to nodules of trabecular hepatocellular carcinomas. It is postulated that in this series, the first morphological step in the neoplastic transformation is the appearance of unusually clear hepatocytes. Ultrastructurally, the clear cells had increased glycogen and lipid droplets and a decrease in smooth endoplasmic reticulum. The basophilic cells seen later resembled the clear cells except for having a greatly increased rough endoplasmic reticulum. Trabecular hepatocellular carcinomas differed from benign nodules in the greater secretory activity of the rough endoplasmic reticulum, in the development of basement membranes at the vascular pole and of microvilli along the lateral cell membranes. The stepwise progression of normal hepatocytes to hepatocellular carcinoma is discussed on the basis of these sequential light microscopic and ultrastructural observations.


Immunoglobulin containing cells in the tracheobronchial tree of cattle: relationship to age.
The cells of the pulmonary immune system of cattle were examined using an immunoperoxidase technique to identify cytoplasmic immunoglobulins. Cells reacting immunohistochemically with bovine IgG1, IgG2, IgA and IgM antisera were quantified in formalin-fixed paraffin embedded tissues from systematically selected sites within the tracheobronchial tree. Non-pneumonic lungs were selected for study from five groups of cattle which ranged in age from neonatal calves to aged adult cattle. Age associated differences were found. Neonatal calves lacked immunoglobulin containing cells (ICC). The numbers of ICC in 18-month-old cattle were significantly greater than in other age groups. The relative frequency of each immunoglobulin class among the cells of the airway mucosa was IgA greater than IgG1 greater than IgG2 greater than IgM for all cattle four months and older (n = 20) with an IgA to IgG1 ratio of 3.46. All airway categories from trachea to bronchiole had similar proportions of cells in each immunoglobulin class although the cell density declined in the distal airways.


Controlling the crystallization of porous organic cages: molecular analogs of isoreticular frameworks using shape-specific directing solvents.
Small structural changes in organic molecules can have a large influence on solid-state crystal packing, and this often thwarts attempts to produce isostructural series of crystalline solids. For metal-organic frameworks and covalent organic frameworks, this has been addressed by using strong, directional intermolecular bonding to create families of isoreticular solids. Here, we show that an organic directing solvent, 1,4-dioxane, has a dominant effect on the lattice energy for a series of organic cage molecules. Inclusion of dioxane directs the crystal packing for these cages away from their lowest-energy polymorphs to form isostructural, 3-dimensional diamondoid pore channels. This is a unique function of the size, chemical function, and geometry of 1,4-dioxane, and hence, a noncovalent auxiliary interaction assumes the role of directional coordination bonding or covalent bonding in extended crystalline frameworks. For a new cage, CC13, a dual, interpenetrating pore structure is formed that doubles the gas uptake and the surface area in the resulting dioxane-directed crystals.


[Treatment of peripheral aneurysms of the posterior circulation].
Peripherally located aneurysms of the posterior circulation are extremely rare. The outcome of patients with peripherally located aneurysms has been poor, and the treatment of such aneurysms has been surgically challenging. We report a consecutive series of peripherally located ruptured aneurysms in the posterior circulation, and discuss in this article the optimal treatment strategy for such lesions. Clinical presentation, neuroradiological findings, treatment method, and the outcome were reviewed retrospectively. Two cases with distal posterior cerebral artery aneurysm, two with distal posterior inferior cerebellar artery aneurysm, two with anterior inferior cerebellar aneurysm, and one with superior cerebellar artery aneurysm were included in this study (mean age, 59.3 +/- 16.0, M:F = 1:6). Three patients with good neurological status on admission who underwent clipping of the aneurysmal neck via craniotomy showed a favorable outcome. In contrast, four patients with poor neurological status on admission who underwent endovascular proximal occlusion of the parent artery showed an unfavorable outcome. Although the outcome of patients who underwent endovascular surgery was poor, endovascular proximal occlusion was effective in preventing re-rupture of the aneurysms. Proximal occlusion of the parent artery has several shortcomings such as cerebral infarction, but proximal occlusion at the very distal area of the parent arteries would not be critical because of good collateral circulation. Thus, endovascular proximal occlusion may provide us another option in the treatment of peripherally located aneurysms especially in patients with poor neurological status. Further data is needed to discover the optimal treatment for patients with peripherally located cerebral aneurysms.


Molecular identity and functional properties of the mitochondrial Na+/Ca2+ exchanger.
The mitochondrial membrane potential that powers the generation of ATP also facilitates mitochondrial Ca(2+) shuttling. This process is fundamental to a wide range of cellular activities, as it regulates ATP production, shapes cytosolic and endoplasmic recticulum Ca(2+) signaling, and determines cell fate. Mitochondrial Ca(2+) transport is mediated primarily by two major transporters: a Ca(2+) uniporter that mediates Ca(2+) uptake and a Na(+)/Ca(2+) exchanger that subsequently extrudes mitochondrial Ca(2+). In this minireview, we focus on the specific role of the mitochondrial Na(+)/Ca(2+) exchanger and describe its ion exchange mechanism, regulation by ions, and putative partner proteins. We discuss the recent molecular identification of the mitochondrial exchanger and how its activity is linked to physiological and pathophysiological processes.


Complex Training: The Effect of Exercise Selection and Training Status on Postactivation Potentiation in Rugby League Players.
This study compared the postactivation potentiation (PAP) response of the hex bar deadlift (HBD) and back squat (BS) exercises. The PAP response between different levels of athletes was also compared. Ten professional and 10 amateur rugby league players performed 2 experimental sessions. Participants performed a countermovement jump (CMJ) before and 2, 4, 6, 8, 10, 12, 14, and 16 minutes after a conditioning activity (CA) that contained 1 set of 3 repetitions at 93% 1 repetition maximum of either HBD or BS. A force platform determined peak power output (PPO), force at PPO, velocity at PPO, and jump height of each CMJ. Surface electromyography (EMG) of the vastus lasteralis, rectus femoris, tibialis anterior, and gastrocnemius medialis of each participant's dominant leg was recorded during each CMJ. A further 10 participants performed a control trial without a CA. The HBD expressed PAP between 2 and 6 minutes post-CA, whereas the BS did not. The HBD exhibited a significantly (p ≤ 0.05) greater PAP response than the BS for PPO. There were no significant (p > 0.05) differences between stronger and weaker players. There were no significant (p > 0.05) changes in the EMG variables. These results suggest that HBD is a suitable CA for eliciting PAP in stronger and weaker athletes. Strength and conditioning coaches should consider the CA and time frame between the CA and the plyometric exercise for optimal PAP responses.


Loss of sense transgene-induced post-transcriptional gene silencing by sequential introduction of the same transgene sequences in tobacco.
RNA silencing is an epigenetic inhibition of gene expression and is guided by small interfering RNAs. Sense transgene-induced post-transcriptional gene silencing (S-PTGS) occurs in a portion of a transgenic plant population. When a sense transgene encoding a tobacco endoplasmic reticulum omega-3 fatty acid desaturase (NtFAD3) was introduced into tobacco plants, an S-PTGS line, S44, was obtained. Introduction of another copy of the NtFAD3 transgene into S44 plants caused a phenotypic change from S-PTGS to overexpression. Because this change was associated with the methylation of the promoter sequences of the transgene, reduced transcriptional activity may abolish S-PTGS and residual transcription of the sense transgene may account for the overexpression. To clarify whether RNA-directed DNA methylation (RdDM) can repress the transcriptional activity of the S44 transgene locus, we introduced several RdDM constructs targeting the transgene promoter. An RdDM construct harboring a 200-bp-long fragment of promoter sequences efficiently abrogated the generation of NtFAD3 small interfering RNAs in S44 plants. Transcription of the transgene was partially repressed, but the resulting NtFAD3 mRNAs successfully accumulated and an overexpressed phenotype was established. Our results indicate an example in which overexpression of the transgene is established by complex epigenetic interactions among the transgenic loci.


Electrocatalytic reduction of dioxygen on a glassy carbon electrode modified with adsorbed cobaloxime complex.
The preparation and electrochemical properties of a glassy carbon (GC) electrode modified with cobaloxime complex were investigated. The complex of the type [CoIII(DO)(DOH)pn)Cl2] where (DO)(DOH)pn = N2,N2'-propanediylbis-2,3-butanedione-2-imine-3-oxime) was adsorbed irreversibly and strongly on the surface of preanodized glassy carbon electrode. Electrochemical behavior and stability of modified GC electrode were investigated by cyclic voltammetry. The electrocatalytic reduction of dioxygen has been studied using this modified glassy carbon electrode by cyclic voltammetry, chronoamperometry and rotating disk electrode voltammetry as diagnostic techniques. The modified electrode showed excellent eletrocatalytic ability for the reduction of dioxygen to hydrogen peroxide in acetate buffer (pH 4.0) with overpotential 1.0 V lower than the plain glassy carbon electrode. The formal potential for this modified electrode is not shifted to more negative potentials by repeated reduction-oxidation cycles in oxygen-saturated supporting electrolyte solution. The apparent electron transfer rate constant (kS), the transfer coefficent (alpha) and the catalytic rate constant of O2 reduction at a GC modified electrode were determined by cyclic voltammetry and rotating disk electrode voltammetry and were found to be around 2.6 s(-1), 0.33 and 2.25 x 10(4) M(-1) s(-1). Based on the results, a catalytic mechanism is proposed and discussed.


[New medical therapies for the treatment of systolic heart failure].
Heart failure is characterized by sodium and fluid retention, sympathetic overactivation, parasympathetic withdrawal, vasoconstrictor activation and cytokine elevation. New therapies for heart failure attempt to control neurohormonal activation and limit progressive left ventricular dysfunction. Nesiritide (human B-type natriuretic peptide) is a recently approved new vasodilator that has been given to almost 1000 patients in numerous clinical investigations, it belongs to a new class of heart failure drugs known as natriuretic peptides. Nesiritide decreases pulmonary capillary wedge pressure, systemic vascular resistance, mean right atrial pressure and pulmonary artery pressure, while improving cardiac index, stroke volume and heart failure symptoms. Many endothelin receptor antagonists are in various stages of development. Early clinical studies have demonstrated beneficial cardiovascular hemodynamic effects. Other new drugs for heart failure also include calcium sensitizers, neutral endopeptidase and vasopeptidase inhibitors, aldosteron receptor antagonists, vasopressin antagonists and cytokine inhibitors. All are being actively investigated and many show significant promise as beneficial therapies in the treatment of heart failure.


Cholesterol deficiency as a mechanism for autism: A valproic acid model.
Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.


Control of chemokine gradients by the retinal pigment epithelium.
Proinflammatory cytokines in degenerative diseases can lead to the loss of normal physiology and the destruction of surrounding tissues. In the present study, the physiological responses of human fetal retinal pigment epithelia (hfRPE) were examined in vitro after polarized activation of proinflammatory cytokine receptors. Primary cultures of hfRPE were stimulated with an inflammatory cytokine mixture (ICM): interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. Western blot analysis and immunofluorescence were used to determine the expression/localization of the cytokine receptors on hfRPE. Polarized secretion of cytokines was measured. A capacitance probe technique was used to measure transepithelial fluid flow (J(V)) and resistance (R(T)). IL-1R1 was mainly localized to the apical membrane and TNFR1 to the basal membrane, whereas IFN-gammaR1 was detected on both membranes. Activation by apical ICM induced a significant secretion of angiogenic and angiostatic chemokines, mainly across the hfRPE apical membrane. Addition of the ICM to the basal but not the apical bath significantly increased net fluid absorption (J(V)) across the hfRPE within 20 minutes. Similar increases in J(V) were produced by a 24-hour exposure to ICM, which significantly decreased total R(T). Chemokine gradients across the RPE can be altered (1) through an ICM-induced change in polarized chemokine secretion and (2) through an increase in ICM-induced net fluid absorption. In vivo, both of these factors could contribute to the development of chemokine gradients that help mediate the progression of inflammation/angiogenesis at the retina/RPE/choroid complex.


Primary brain tumors in the elderly population.
Elderly cancer patients are an important challenge in oncology, and clinical data from younger populations cannot be automatically considered applicable to unselected elderly patients with brain tumors, who tend to have more comorbidities and tolerate chemotherapy and radiotherapy less well than their younger counterparts. Most data available on elderly cancer patients are from retrospective studies that do not include age-specific enrollment criteria and are biased by intrinsic selection criteria governing enrollment. Most clinicians are unwilling to enroll elderly patients because of ageism and a fear of toxicity and poor outcome. Specifically designed trials based on genetic features and clinical factors are required to clearly establish the standard of care required for elderly patients with brain tumors, especially those with glioblastoma. Currently, surgery followed by radiotherapy is widely used for elderly glioblastoma patients, but temozolomide is the chemotherapeutic approach of choice for those with a relatively good clinical condition and prognosis. However, the schedule to follow and the best dosage have yet to be satisfactorily established.


Mollicutes-related endobacteria thrive inside liverwort-associated arbuscular mycorrhizal fungi.
Arbuscular mycorrhizal fungi (AMF) can host Gram-positive endobacteria (BLOs) in their cytoplasm. These have been identified as Mollicutes-related microbes based on an inventory of AMF spores from fungal collections. Bacteria-like organisms (BLOs) of unknown identity have also been reported in the cytoplasm of AMF associated with liverworts, the earliest-diverged extant lineage of land plants. A combination of morphological, molecular and phylogenetic analyses revealed that three samples of two liverwort species (Conocephalum conicum and Lunularia cruciata) growing spontaneously in a botanical garden harboured AMF belonging to Glomerales, and these, in turn, hosted coccoid BLOs. 16S rDNA sequences from these BLOs clustered with the Mollicutes sequences identified from the spore collections but revealed the presence of novel phylotypes. Electron microscopy and fluorescence in situ hybridization (FISH) confirmed the presence of BLOs inside the cytoplasm of AMF hyphae colonizing the liverwort thalli. The high genetic variability of BLOs in liverwort-AMF associations thriving in the same ecological niche raises questions about the mechanisms underlying such diversity.


Reducing deaths from severe pneumonia in children in Malawi by improving delivery of pneumonia case management.
To evaluate the pneumonia specific case fatality rate over time following the implementation of a Child Lung Health Programme (CLHP) within the existing government health services in Malawi to improve delivery of pneumonia case management. A prospective, nationwide public health intervention was studied to evaluate the impact on pneumonia specific case fatality rate (CFR) in infants and young children (0 to 59 months of age) following the implementation of the CLHP. The implementation was step-wise from October 1st 2000 until 31st December 2005 within paediatric inpatient wards in 24 of 25 district hospitals in Malawi. Data analysis compared recorded outcomes in the first three months of the intervention (the control period) to the period after that, looking at trend over time and variation by calendar month, age group, severity of disease and region of the country. The analysis was repeated standardizing the follow-up period by using only the first 15 months after implementation at each district hospital. Following implementation, 47,228 children were admitted to hospital for severe/very severe pneumonia with an overall CFR of 9.8%. In both analyses, the highest CFR was in the children 2 to 11 months, and those with very severe pneumonia. The majority (64%) of cases, 2-59 months, had severe pneumonia. In this group there was a significant effect of the intervention Odds Ratio (OR) 0.70 (95%CI: 0.50-0.98); p = 0.036), while in the same age group children treated for very severe pneumonia there was no interventional benefit (OR 0.97 (95%CI: 0.72-1.30); p = 0.8). No benefit was observed for neonates (OR 0.83 (95%CI: 0.56-1.22); p = 0.335). The nationwide implementation of the CLHP significantly reduced CFR in Malawian infants and children (2-59 months) treated for severe pneumonia. Reasons for the lack of benefit for neonates, infants and children with very severe pneumonia requires further research.


Severe spontaneous acute tumor lysis syndrome and hypoglycemia in patient with germ cell tumor.
Tumor lysis syndrome has been observed in patients with bulky, treatment-sensitive tumors, in particular hematological malignancies, especially after medical treatment (chemotherapy, corticosteroids, radiation, hormonal agents, and biological response modifiers). Tumor lysis syndrome has been observed also in solid malignancies and it very rarely occurs spontaneously. Tumor lysis syndrome-associated metabolic abnormalities include hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and uremia. Severe hypoglycemia is another rare metabolic disorder, uncommonly associated with solid malignancies. The case described here is peculiar for the abrupt onset of these two rare conditions in a patient with a metastatic germ cell tumor.


Effect of umbelliferone on adjuvant-induced arthritis in rats by MAPK/NF-κB pathway.
Umbelliferone (Umb), a member of coumarin family, is found in many plants and is a promising molecule with potential anti-inflammatory, anti-oxidative, and anti-tumor activities. However, the effect of Umb on arthritis remains unclear. A rat model with Freund's complete adjuvant (FCA)-induced arthritis was developed and used to test the efficacy of Umb on arthritis rats. Rats were given an intragastric injection of Umb (20 and 40 mg/kg) once daily from days 21 to 28 after the administration of FCA. Hind paw volume was assessed using a volume meter. The pro-inflammatory cytokine levels and prostaglandin E2 (PEG2) level in serum and synovial fluid were detected by ELISA. HE staining was used to determine representative histological changes in joint tissues, and Western blot analysis was employed to study the effects of Umb on MAPK/NF-κB signaling pathway. Our results showed that Umb suppressed the release of IL-6, IL-1β, tumor necrosis factor-alpha, and PEG2. In addition, Umb could also dramatically ameliorate the pathological changes observed in rat joints. Based on the results of Western blot, we also observed that Umb could strikingly suppress the expression of MAPK/NF-κB pathway molecules. These results proved that treatment with Umb is very effective for arthritis and inhibiting the MAPK/NF-κB signaling pathway may be a potential therapeutic target for treatment of arthritis.


Identification of binding sites for both dsRBMs of PKR on kinase-activating and kinase-inhibiting RNA ligands.
The RNA-dependent protein kinase (PKR) is an interferon-induced, RNA-activated enzyme that phosphorylates and inhibits the function of the translation initiation factor eIF-2. PKR has a double-stranded RNA-binding domain (dsRBD) composed of two copies of the dsRNA binding motif (dsRBM). PKR's dsRBD is involved in the regulation of the enzyme as dsRNAs of cellular and viral origins bind to the dsRBD, leading to either activation or inhibition of PKR's kinase activity. In this study, we site-specifically modified each of the dsRBMs of PKR's dsRBD with the hydroxyl radical generator EDTA small middle dotFe and performed cleavage studies on kinase-activating and kinase-inhibiting RNAs. These experiments led to the identification of binding sites for the individual dsRBMs on various RNA ligands including a viral activating RNA (TAR from HIV-1), a viral inhibiting RNA (VA(I) RNA from adenovirus), an aptamer RNA that activates PKR, and a small synthetic inhibiting RNA. These results indicate that some RNAs interact only with one dsRBM, while others can bind both dsRBMs of PKR. In addition, EDTA small middle dotFe modification coupled with site-directed mutagenesis was used to assess the extent of cooperativity in the binding of the two dsRBMs. These experiments support the hypothesis that simultaneous binding of both dsRBMs of PKR occurs on kinase activating RNA ligands.


Worldwide experience with the Oka-strain live varicella vaccine.
Sufficient safety and efficacy data have been obtained on a live varicella vaccine (Varilrix, Smith Kline-RIT) derived from the Oka-strain attenuated varicella-zoster virus to justify its recent licensure in several European countries for use in special indication groups. This review article summarizes the data obtained in Japan, Europe, and the United States. In addition, a survey of the published literature on clinical studies performed on as yet unlicensed Oka-strain varicella vaccines produced by the Biken Institute and Merck Sharp & Dohme is presented.


Benign prostatic hypertrophy: retrograde transurethral dilation of the prostatic urethra in humans. Work in progress.
Retrograde transurethral balloon dilation of the prostatic urethra was performed in five human volunteers with benign prostatic hypertrophy. Each patient underwent cystoscopy, uroflow studies, voiding cystourethrography, retrograde urethrography, and magnetic resonance imaging before dilation and at defined intervals afterward. The longest follow-up to date is 8 months. Patients were given topical anesthetics and mild sedatives, and dilation was performed with a 25-mm urethroplasty balloon catheter inflated at 3-6 atm for 10 minutes. All catheter manipulations were done with a guide wire and under fluoroscopic control. Significant resolution of symptoms of prostatism was seen in four patients. The unsatisfactory results in the last patient were believed to be caused by ineffectual dilation of predominantly middle lobe hypertrophy--a condition that is now regarded as a contraindication to dilation. This technique has promise to replace transurethral resection of the prostate as the treatment of choice for this common male ailment.


Validity and Reliability of Hindi version of Foot and Ankle Disability Index in patients with chronic recurrent lateral ankle sprain.
Lateral Ankle Sprain (LAS) is a recurrent musculoskeletal injury commonly noticed in primary care, podiatry, orthopaedics, and physical therapy centers. The Foot and Ankle Disability Index (FADI) is a self-reported and region-specific tool with no previous literature available on the translation of the FADI scale into Hindi language. The study aims to translate and evaluate each translated domain of FADI to see its cross-cultural adaptation, content validity and reliability for patients with chronic recurrent LAS. A Cross-Sectional Study. The scale was translated from the reference language to the target language, Hindi, using the instructions provided in the literature. Delphi survey was conducted for content validation followed by recruitment of 51 participants with a history of long lasting repetitive lateral sprain of ankle to evaluate test-retest reliability of Hindi version of FADI. The S-CVI/Ave and S-CVI/UA came out to be 0.988 and 0.884, respectively and I-CVI for all items of Hindi version of FADI were more than 0.90. The ICC (Intra-class Correlation Coefficient) and internal consistency was evaluated, which came out to 0.961 and 0.980, respectively for Hindi version of FADI. Hindi version of FADI is a valid and reliable scale that has been translated and adapted to be implemented among Indian population suffering from long lasting repetitive LAS.


A three-genome ultraconserved element phylogeny of cryptophytes.
Cryptophytes are single celled protists found in all aquatic environments. They are composed of a heterotrophic genus, Goniomonas, and a largely autotrophic group comprising many genera. Cryptophytes evolved through secondary endosymbiosis between a host eukaryotic heterotroph and a symbiont red alga. This merger resulted in a four-genome system that includes the nuclear and mitochondrial genomes from the host and a second nuclear genome (nucleomorph) and plastid genome inherited from the symbiont. Here, we make use of different genomes (with potentially distinct evolutionary histories) to perform a phylogenomic study of the early history of cryptophytes. Using ultraconserved elements from the host nuclear genome and symbiont nucleomorph and plastid genomes, we produce a three-genome phylogeny of 91 strains of cryptophytes. Our phylogenetic analyses find that that there are three major cryptophyte clades: Clade 1 comprises Chroomonas and Hemiselmis species, Clade 2, a taxonomically rich clade, comprises at least twelve genera, and Clade 3, comprises the heterotrophic Goniomonas species. Each of these major clades include both freshwater and marine species, but subclades within these clades differ in degrees of niche conservatism. Finally, we discuss priorities for taxonomic revision to Cryptophyceae based on previous studies and in light of these phylogenomic analyses.


Long-term mitral valve repair outcomes and hospital volume: 15 years' analysis of an administrative dataset.
Procedural volume has been documented as an important contributor to operative outcomes for most complex surgical procedures. Mitral valve repair (MVRep) has been associated with excellent results, and it is increasingly adopted in many cardiac surgical centers. We sought to investigate if procedural volume is associated with better clinical long-term outcomes after MVRep. We analyzed the 10-year outcomes after MVRep by procedural volume for each cardiac surgery center in an Italian Region, Lazio, during the last 15 years, using a regional administrative dataset. Between 2006 and 2020, 4961 patients were treated in seven cardiac surgery centers for an isolated mitral valve surgery (2677 underwent MVRep). At multivariate analysis, mitral valve replacement (MVR) (vs. MVRep) resulted one of the independent predictors of 30-day mortality [adjusted odds ratio (OR) 3.40; 95% confidence interval (CI) 1.96-5.90; P < 0.0001]. Notably, a clear association between hospital volume of mitral valve surgery (>40 per year) and high rate of MVRep (>50%) was found. At 10 years, the incidence of mortality and the rate of death and rehospitalization for heart failure after MVRep were significantly lower in high-volume vs. low-volume hospitals. Our data suggest that hospital volume is associated with a high rate of MVRep and long-term benefits in terms of mortality and recurrence of heart failure.


Long-term exercise adherence after public health training in at-risk adults.
Sustainment of healthy exercise behavior is essential in preventing cardiovascular disease and diabetes. Few studies have explored long-term exercise adherence after an exercise referral scheme. The objective of this study was to examine 12-month exercise adherence after an exercise intervention program. This was a pragmatic follow-up study in at-risk people performed between June 2012 and January 2014. The main outcome measure was self-reported single-item exercise adherence. Secondary outcomes were change in exercise level, quality of life rated on a visual analog scale and self-rated health. Predictors of long-term exercise adherence were assessed by logistic regression, estimating crude odds-ratios (OR) and 95% confidence intervals (95% CIs) and adjusting for age, gender, education, smoking, moderate and vigorous exercise. In total, 214 adults (mean age 58.8±11.97 years, 71% women) participated in the study and received a 12-week training intervention: 62% had hypertension, 64% dyslipidemia and 15% impaired glucose tolerance. Attrition rate was 84% (n=179). During the 12-month follow-up, 48% (n=85) reported long-term exercise adherence. The main predictors of long-term exercise adherence were participation in sport activities at baseline (adjusted odds-ratio [aOR] 4.22, 95% CI 1.72-10.40), self-rated health (aOR 2.60, 1.00-6.75) and quality of life (aOR 2.39, 1.03-5.54). Long-term non-adherence was associated with low education (<10 years; aOR 3.27, 1.14-9.43) and age<50 years (aOR 3.53, 1.32-9.43). In this pragmatic study, long-term exercise adherence was associated with participation in sport activities and self-rated health at baseline.


A change in temporal muscle thickness is correlated with past energy adequacy in bedridden older adults: a prospective cohort study.
Energy inadequacy has a great impact on health outcomes in older adult patients; however, it is difficult to evaluate energy adequacy in these patients, especially in home-care settings. We recently reported that temporal muscle thickness can be an indicator of nutritional status. The present study aims to examine whether a change in temporal muscle thickness is directly correlated with energy adequacy and, if so, to determine the cutoff value of a change in temporal muscle thickness to detect energy inadequacy. A prospective cohort study was conducted from September 2015 to June 2016 in two hospitals in Japan, and included bedridden older adult patients aged ≥65 years. Temporal muscle thickness was measured using ultrasonography. Energy intake was estimated by photographic diet records. Total energy expenditure (TEE) was estimated by multiplying basal energy expenditure calculated using the Harris- Benedict equation by activity and stress factors. Energy adequacy was then calculated by dividing TEE by energy intake. Pearson's correlation coefficient was used to examine the relationship between percentage change in temporal muscle thickness and energy adequacy. Multiple logistic regression analysis was conducted to determine the direct relationship between percentage change in temporal muscle thickness and moderate energy inadequacy (energy adequacy< 75%). Receiver operating characteristic (ROC) analysis was performed to determine the cutoff point for percentage change in temporal muscle thickness to detect moderate energy inadequacy. Forty-eight patients were analyzed (mean age 84.4 ± 7.8 years; 54.2% were women). The percentage change in muscle thickness was significantly correlated with energy adequacy (r = 0.733, p < 0.001). ROC analysis identified a percentage change in temporal muscle thickness of - 3.6% as the optimal cutoff point for detecting moderate energy inadequacy. Percentage change in muscle thickness was independently correlated with energy inadequacy after adjusting for age, sex, and masticatory status (AOR 0.281, 95% CI 0.125-0.635). Changes in temporal muscle thickness are directly correlated with energy adequacy and can indicate moderate energy inadequacy in bedridden older adults. These results suggest the assessment of changes in temporal muscle thickness could be useful for guiding nutritional care in older adult patients in home-care settings.


Patterns of Thyroid Cancers in Southeastern Nigeria: A 15 Year Histopathologic Review (2000-2014).
Thyroid Cancer (TC) continues to be the most common endocrine cancer with a worldwide increase in incidence over the last three decades. This trend has been reported in all continents except Africa, where detection is adjudged to be insufficient, making it imperative for us to re-evaluate the patterns in our environment. To determine the patterns of TCs in Southeastern Nigeria. This was a 15-year retrospective review of all thyroidectomy specimens received at the Depart-ment of Morbid Anatomy, University of Nigeria, Enugu Campus, Enugu, Nigeria. The age, sex and histologic subtypes of diagnosed TCs were analysed using Predictive Analytics Software (PASW) Statistics for Windows, Version 18 (Chicago: SPSS Inc.) and the results were expressed in descriptive statistics. Sixty one cases of TCs were identified in this study constituting 10.8% of thyroid biopsies received at our centre during the period under review. There were 51 (83.6%) females and 10 (16.4%) males giving a ratio of 5.1:1, and a mean age of 45.9 years. The commonest histologic type was Papillary Thyroid Carcinoma (PTC) (42.6%), followed by; follicular thyroid carcinoma (37.7%), medullary thyroid carcinoma (4.9%), anaplastic carcinomas (3.3%), Non-Hodgkin lymphoma (1.6%) and metastatic squamous cell carcinoma (3.3%). Mixed papillary/ follicular carcinoma (4.9%) and mixed papillary/ anaplastic carcinoma (1.6%) were also identified. TC continues to predominate amongst females, occurring mainly in early middle age group in Southeastern Nigeria. PTC is now the commonest histologic type.


Pregnane X receptor activation constrains mucosal NF-κB activity in active inflammatory bowel disease.
The Pregnane X Receptor (PXR) is a principal signal transducer in mucosal responses to xenobiotic stress. It is well-recognized that inflammatory bowel disease is accompanied by xenobiotic stress, but the importance of the PXR in limiting inflammatory responses in inflammatory bowel disease remains obscure at best. We stimulate a total of 106 colonic biopsies from 19 Crohn's disease patients with active disease, 36 colonic biopsies from 8 control patients, colonic organoids and various cell culture models (either proficient or genetically deficient with respect to PXR) in vitro with the PXR ligand rifampicin or vehicle. Effects on NF-κB activity are assessed by measuring interleukin-8 (IL-8) and interleukin-1ß (IL-1ß) mRNA levels by qPCR and in cell culture models by NF-κB reporter-driven luciferase activity and Western blot for signal transduction elements. We observe a strict inverse correlation between colonic epithelial PXR levels and NF-κB target gene expression in colonic biopsies from Crohn's disease patients. PXR, activated by rifampicin, is rate-limiting for mucosal NF-κB activation in IBD. The correlation between colonic epithelial PXR levels and NF-κB target gene expression was also observed in intestinal organoids system. Furthermore, in preclinical in vitro models of intestinal inflammation, including intestinal organoids, genetic inactivation of PXR unleashes NF-κB-dependent signal transduction whereas conversely NF-κB signaling reduces levels of PXR expression. Our data indicate that the PXR is a major and clinically relevant antagonist of NF-κB activity in the intestinal epithelial compartment during inflammatory bowel disease.


Rate of resistance development in wild Culex quinquefasciatus (Say) selected by malathion and permethrin.
Wild caught female Culex quinquefasciatus (Say) from Kuala Lumpur were blood fed and reared in the insectarium. The late third stage of the F1 larvae which survived the high selection pressure of malathion and permethrin were reared and colonies were established from adults that emerged. Larvae from these colonies were then subjected in the subsequent 9 generations to higher selection pressure. The rate of resistance development were measured by LC50 value of larval bioassay, LT50 value of adult bioassay and the frequency of the elevated esterase levels. In another set of experiments using the same batch of Culex mosquitos, the larvae were not exposed to any insecticides and the decrease in resistance rate was monitored in each subsequent 9 generations by using similar methods. The heterozygous standard laboratory strain was selected for susceptibility using the single raft sib-selection method. The result showed that the field collected F1 generation was 96.0 and 6.3 fold more resistant to malathion and permethrin, respectively. After selection for about 9 generations the resistance ratio to malathion and permethrin was 6.2 and 767.3 fold more compared to the LC50 values of F1 generations, respectively. Esterase in F1 larvae was 6.0 fold more than the standard laboratory strain.


A pseudohypoparathyroidism type Ia patient with normocalcemia.
Pseudohypoparathyroidism type Ia (PHP-Ia), one of 4 types of PHP, is a genetic disease characterized by clinical hypoparathyroidism caused by parathyroid hormone (PTH) resistance. In addition, patients with PHP-Ia show resistance to other hormones as well as Albright's hereditary osteodystrophy (AHO), a constellation of features including short stature, obesity, brachydactyly, ectopic ossifications, and/or mental retardation. Hypocalcemia is one of the hallmarks of PHP-Ia, but several PHP-Ia patients have been described to have normocalcemia. We encountered a 10-year-old girl with typical Albright's hereditary osteodystrophy with round face, short stature, brachydactyly, and obesity. Biochemical examination showed normocalcemia and increased PTH levels. Ellsworth-Howard test did not show any responses of urinary cAMP and phosphate. Based on these findings, she was diagnosed as having PHP-Ia with normocalcemia. Sequencing analysis of the GNAS gene identified a heterozygous missense mutation in exon 13 (R385H), which was previously reported in a PHP-Ia patient. The exact reason for her normocalcemia is not determined, but we must recognize heterogeneous biochemical findings even in PHP-Ia.


Two new pathogenic ascomycetes in Guignardia and Rosenscheldiella on New Zealand's pygmy mistletoes (Korthalsella: Viscaceae).
Two new pathogens, Guignardia korthalsellae and Rosenscheldiella korthalsellae, are described from New Zealand's pygmy mistletoes (Korthalsella, Viscaceae). Both form ascomata on living phylloclades with minimal disruption of the tissue. Fungal hyphae within the phylloclade are primarily intercellular. Guignardia korthalsellae disrupts a limited number of epidermal cells immediately around the erumpent ascoma, while the ascomata of Rosenscheldiellakorthalsellae develop externally on small patches of stromatic tissue that form above stomatal cavities. Rosenscheldiella is applied in a purely morphological sense. LSU sequences show that R. korthalsellae as well as another New Zealand species, Rosenscheldiella brachyglottidis, are members of the Mycosphaerellaceaesensu stricto. Genetically, Rosenscheldiella, in the sense we are using it, is polyphyletic; LSU and ITS sequences place the two New Zealand species in different clades within the Mycosphaerellaceae. Rosenscheldiella is retained for these fungi until generic relationships within the family are resolved. Whether or not the type species of Rosenscheldiella, R. styracis, is also a member of the Mycosphaerellaceae is not known, but it has a similar morphology and relationship to its host as the two New Zealand species.


Haplotypes of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 Gene Polymorphisms in Age-Related Macular Degeneration.
To determine the impact of HTRA1 rs1120638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 genotypes on the development of age-related macular degeneration (AMD) in the Lithuanian population. A total of 916 subjects were examined: 309 patients with early AMD, 301 patients with exudative AMD, and 306 healthy controls. The genotyping of HTRA1 rs11200638, TIMP3 rs9621532, VEGFA rs833068, CFI rs10033900, ERCC6 rs3793784, and KCTD10 rs56209061 was carried out using the RT-PCR method. Our study showed that single-nucleotide polymorphisms rs3793784 and rs11200638 were associated with increased odds of early and exudative AMD, and the variant in KCTD10 (rs56209061) was found to be associated with decreased odds of early and exudative AMD development after adjustments for age and gender in early AMD analysis and after adjustments only for age in exudative AMD. The haplotype containing two minor alleles C-A and the G-A haplotype in rs3793784-rs11200638 were statistically significantly associated with an increased risk of exudative AMD development after adjustment for age, while the G-G haplotype showed a protective role against early and exudative AMD and the haplotype C-G in rs3793784-rs11200638 was associated with a decreased risk only of exudative AMD development. Our study identified two markers, rs11200638 and rs3793784, as risk factors for early and exudative AMD, and one marker, rs56209061, as a protective factor for early and exudative AMD development. The haplotypes constructed of rs3793784-rs11200638 were found to be associated with AMD development, as well.


Molecular and epigenetic regulatory mechanisms of normal stem cell radiosensitivity.
Ionizing radiation (IR) therapy is a major cancer treatment modality and an indispensable auxiliary treatment for primary and metastatic cancers, but invariably results in debilitating organ dysfunctions. IR-induced depletion of neural stem/progenitor cells in the subgranular zone of the dentate gyrus in the hippocampus where neurogenesis occurs is considered largely responsible for deficiencies such as learning, memory, and spatial information processing in patients subjected to cranial irradiation. Similarly, IR therapy-induced intestinal injuries such as diarrhea and malabsorption are common side effects in patients with gastrointestinal tumors and are believed to be caused by intestinal stem cell drop out. Hematopoietic stem cell transplantation is currently used to reinstate blood production in leukemia patients and pre-clinical treatments show promising results in other organs such as the skin and kidney, but ethical issues and logistic problems make this route difficult to follow. An alternative way to restore the injured tissue is to preserve the stem cell pool located in that specific tissue/organ niche, but stem cell response to ionizing radiation is inadequately understood at the molecular mechanistic level. Although embryonic and fetal hypersensity to IR has been very well known for many decades, research on embryonic stem cell models in culture concerning molecular mechanisms have been largely inconclusive and often in contradiction of the in vivo observations. This review will summarize the latest discoveries on stem cell radiosensitivity, highlighting the possible molecular and epigenetic mechanism(s) involved in DNA damage response and programmed cell death after ionizing radiation therapy specific to normal stem cells. Finally, we will analyze the possible contribution of stem cell-specific chromatin's epigenetic constitution in promoting normal stem cell radiosensitivity.


Treatment of small cell lung cancer with VP-16, vincristine, doxorubicin (Adriamycin), cyclophosphamide (EVAC), and high-dose chest radiotherapy.
Seventy-one previously untreated patients with small cell lung cancer (SCLC) received a combination of VP-16, vincristine, doxorubicin (Adriamycin), and cyclophosphamide (EVAC) repeated every three weeks. Limited-disease (LD) patients and extensive-disease (ED) patients achieving a complete response (CR) or partial response (PR) after four to six cycles of EVAC received 4,000 rads over four weeks whole-brain radiotherapy (RT) and 5,000 rads over five weeks RT to the original pulmonary primary and mediastinum. ED patients with persisting disease outside the chest after six cycles of EVAC continued chemotherapy and did not receive RT. After RT was completed, EVAC was continued for a total treatment duration of 24 months. Of 65 patients evaluable for response 76% (25 of 33) of LD patients and 34% (11 of 32) of ED patients achieved a CR prior to RT; two additional ED patients achieved a CR after RT. Median survival for all 71 patients was 48 weeks (range, one to 207 weeks); median survival for 33 LD patients was 92 weeks and for 38 ED patients it was 36 weeks. Nine of 25 LD patients and 10 of 13 ED patients have relapsed from CR. The EVAC-RT protocol is promising in view of the high CR rate and long remission duration achieved, especially among patients with LD.


An in silico glioblastoma microenvironment model dissects the immunological mechanisms of resistance to PD-1 checkpoint blockade immunotherapy.
The PD-1 immune checkpoint-based therapy has emerged as a promising therapy strategy for treating the malignant brain tumor glioblastoma (GBM). However, patient response varies in clinical trials due in large to the tumor heterogeneity and immunological resistance in the tumor microenvironment. To further understand how mechanistically the niche interplay and competition drive anti-PD-1 resistance, we established an in-silico model to quantitatively describe the biological rationale of critical GBM-immune interactions, such as tumor growth and apoptosis, T cell activation and cytotoxicity, and tumor-associated macrophage (TAM) mediated immunosuppression. Such an in-silico experimentation and predictive model, based on the in vitro microfluidic chip-measured end-point data and patient-specific immunological characteristics, allowed for a comprehensive and dynamic analysis of multiple TAM-associated immunosuppression mechanisms against the anti-PD-1 immunotherapy. Our computational model demonstrated that the TAM-associated immunosuppression varied in severity across different GBM subtypes, which resulted in distinct tumor responses. Our prediction results indicated that a combination therapy co-targeting of PD-1 checkpoint and TAM-associated CSF-1R signaling could enhance the immune responses of GBM patients, especially those patients with mesenchymal GBM who are irresponsive to the single anti-PD-1 therapy. The development of a patient-specific in silico-in vitro GBM model would help navigate and personalize immunotherapies for GBM patients.


CALCIUM ION REQUIREMENT FOR PROLIFERATION OF BACTERIOPHAGE PHI MU-4.
Shafia, Fred (University of Nebraska, Lincoln), and T. L. Thompson. Calcium ion requirement for proliferation of bacteriophage phimu-4. J. Bacteriol. 88:293-296. 1964.-Divalent ions are essential for proliferation of phage phimu-4. Small amounts of citrate interfere with efficient adsorption of phage to the host cells. Penetration of phage material into the cell is strictly dependent on divalent ions and is inhibited by low levels of citrate. Inhibition of infection can be partially reversed, in early latent period, by calcium ions. Synthesis of new phage particles is also dependent on divalent ions. Addition of citrate to infected cell suspensions significantly reduced the number of phage progeny produced. Chelates such as phosphate and citrate rapidly inactivated the free phage particles at 65 C. Chelate inactivation of phage is not reversible; however, it can be prevented to some degree by calcium ions.


Variation of superoxide dismutase levels in extracts of Mycobacterium leprae from armadillo liver.
Recent improvements in the sensitivity of assay methods for superoxide dismutase (SOD) have enabled the detection of this enzyme in 18 cell-free extracts of purified Mycobacterium leprae. By converting back to units of SOD obtained in the cytochrome c-based method previously used in work on this enzyme in mycobacteria, it was shown that extracts of M. leprae had 0.15-3.84 U SOD/mg protein (this study). A mean value of 1.31 U/mg protein was calculated. It was not possible to find any factors which could explain the very high levels in some extracts, although correlation with the period of tissue storage at -80 degrees C suggested that M. leprae in freshly killed tissue would have 1.77 U SOD/mg protein. The possibility of contamination by SODs from host and other organisms was unlikely since on gel electrophoresis extracts of M. leprae with high levels of SOD showed only a single band of activity characteristic of manganese-dependent SOD previously demonstrated.


[Clinical course of mitral insufficiency after commissurotomy].
In 172 patients in whom transventricular mitral commissurotomy had been complicated by the development of post-operative regurgitation the immediate and remote results of the surgery were studied. Among patients with mitral incompetence a complicated post-operative period with regurgitation of the I degree was registered in 51 per cent of the cases, with the II degree-in 73 and with the III-in 100 per cent of the patients. The principal complications included cardiac insufficiency and various derangements of the cardiac rhythm. The nature of cardiac insufficiency depended upon the degree of emerging regurgitation. A study of such patients over periods from 1 to 10 years after surgery proved good and satisfactory results to be recorded more seldom than in the case of an adequate commissurotomy and that they are dependent upon the degree of regurgitation. In the event of mitral incompetence of the II degree an urgent surgical correction of the defect is indicated. In need for operative treatment are also patients with mitral incompetence of the II degree with a possible progressive decompensation of the circulation.


Achieving a balance between risk and return.
Because risk management is costly, many health plans and providers practice risk avoidance by transferring risk to other entities. Risk-bearing healthcare organizations can improve their return on assets, but to do so they need complete information about patients' health status and the availability of effective medical treatment. To improve their return on assets, providers can use risk-management strategies such as growth, designing incentives to encourage providers and health plans to reduce or eliminate unnecessary variations in resource use, and improving information about the reasons for variations in resource use and controlling those variations when possible. Providers need data to analyze why variations in resource use occur and to evaluate the efficiency of their resource use.


Human error and human factors engineering in health care.
Human error is inevitable. It happens in health care systems as it does in all other complex systems, and no measure of attention, training, dedication, or punishment is going to stop it. The discipline of human factors engineering (HFE) has been dealing with the causes and effects of human error since the 1940's. Originally applied to the design of increasingly complex military aircraft cockpits, HFE has since been effectively applied to the problem of human error in such diverse systems as nuclear power plants, NASA spacecraft, the process control industry, and computer software. Today the health care industry is becoming aware of the costs of human error and is turning to HFE for answers. Just as early experimental psychologists went beyond the label of "pilot error" to explain how the design of cockpits led to air crashes, today's HFE specialists are assisting the health care industry in identifying the causes of significant human errors in medicine and developing ways to eliminate or ameliorate them. This series of articles will explore the nature of human error and how HFE can be applied to reduce the likelihood of errors and mitigate their effects.


Dynamics of zonula occludens-2 expression during preimplantation embryonic development in the hamster.
The objective was to study the expression of zonula occludens-2, a tight junction protein, during preimplantation hamster embryonic development, to predict its possible localization, source, and roles in trophectoderm differentiation and blastocyst formation in this species. Comparison of zonula occludens-2 expression pattern between the hamster and mouse preimplantation embryos from the zygote up to the blastocyst stage was also an objective of this study. Zonula occludens-2 localization was noted in nuclei of blastomeres in all stages of hamster and mouse embryonic development. Compared to mice, where zonula occludens-2 was first localized in the interblastomere membrane at the morula stage, hamster embryos had membranous zonula occludens-2 localization from the 2-cell stage onwards. Based on combined results of immunolocalization study in parthenogenic embryos and ovarian and epididymal sections, and quantitative PCR done in oocytes and all developmental stages of preimplantation embryos, perhaps there was a carry-over of zonula occludens-2 proteins or mRNA from the dam to the embryo. Based on these findings, we inferred that maternally derived zonula occludens-2 was involved in nuclear functions, as well as differentiation of blastomeres and blastocoel formation during preimplantation embryonic development in the hamster.


Ethical review of health research: a perspective from developing country researchers.
Increasing collaboration between industrialised and developing countries in human research studies has led to concerns regarding the potential exploitation of resource deprived countries. This study, commissioned by the former National Bioethics Advisory Commission of the United States, surveyed developing country researchers about their concerns and opinions regarding ethical review processes and the performance of developing country and US international review boards (IRBs). Contact lists from four international organisations were used to identify and survey 670 health researchers in developing countries. A questionnaire with 169 questions explored issues of IRB review, informed consent, and recommendations. The majority of the developing country researchers were middle aged males who were physicians and were employed by educational institutions, carrying out research on part time basis. Forty four percent of the respondents reported that their studies were not reviewed by a developing country IRB or Ministry of Health and one third of these studies were funded by the US. During the review process issues such as the need for local language consent forms and letters for approval, and confidentiality protection of participants were raised by US IRBs in significantly higher proportions than by host country IRBs. This survey indicates the need for the ethical review of collaborative research in both US and host countries. It also reflects a desire for focused capacity development in supporting ethical review of research.


Diffuse myocardial calcification in a drug addict, complicating advanced life support.
Myocardial calcification is a rare echocardiographic finding, which is often found in patients who have suffered from a myocardial infarction. Rarely, myocardial calcification may be present in individuals without a significant medical history. Until today, there has not been a published case report emphasising the relation between myocardial calcification and cocaine usage. Herein, we report a case of a young male with diffuse calcification of the left ventricular myocardium, who had an addiction to cocaine. This case highlights an uncommon etiology for myocardial calcification and it may lead to further studies about cardiotoxic effects of cocaine.


Phagocytic cell function in response to immunosuppressive therapy.
The increased incidence of pulmonary infection in human renal allograft recipients is presumably related to antirejection immunosuppressive therapy. To assess immunosuppressive-related disturbances of the immune responses of the lung, we evaluated the functional abilities of the pulmonary alveolar macrophage (PAM) and polymorphonuclear leukocyte (PMN) of rats in chemotaxis, phagocytosis, and superoxide-release assays following 30 days of intraperitoneal administration of cyclosporine, azathioprine, and/or prednisolone sodium succinate. None of these drugs affected superoxide release by stimulated PAMs or PMNs. Except for a transient inhibition by azathioprine, the drugs had no effect on phagocytosis of Staphylococcus aureus by either cell type. On the other hand, cyclosporine inhibited formyl-methionyl-leucyl-phenylalanine (FMLP)-directed chemotaxis by PAMs, and both FMLP and C5a stimulated chemotaxis by PMNs. Azathioprine had more dramatic effects on PAMs than on PMNs and prednisolone at 2 mg/kg inhibited PAMs. The results indicated that, with the exception of chemotaxis, the immunosuppressive agents largely spare nonspecific elements of host defense.