Does arsenic exposure increase the risk for circulatory disease?
Studies of residents in communities with high endemic concentrations of arsenic in drinking water suggest a deleterious effect on the circulatory system; however, studies among workers with high occupational exposures generally have shown either no or weak associations. This discrepancy could be a result of the healthy worker effect, including the healthy hire component and the healthy worker survivor effect (HWSE). Therefore, the authors conducted analyses of arsenic exposure in relation to circulatory disease mortality among 2,802 Tacoma, Washington, smelter workers by using 1) internal comparisons to control for the healthy hire effect and 2) the lagging method, adjustment for employment status, and the G-null test to control for the HWSE. Both lagging and adjustment for work status increased circulatory mortality rate ratios at all exposure levels, as compared with a baseline Poisson model. This excess mortality was limited to cardiovascular disease; no excess was observed for cerebrovascular disease. G-null analyses suggested no adverse effect, but power was very limited for this analysis. Overall, these results may indicate that the HWSE obscures an effect of arsenic on circulatory disease. Since cardiovascular deaths constitute about one-third of total mortality, small rate ratios translate into large numbers of excess deaths and, if causal, could be of wide public health significance. Further studies of arsenic exposure and cardiovascular disease are needed, and those conducted in occupational cohorts must control for the HWSE.


Application of near-infrared and Fourier transform infrared spectroscopy in the characterization of ligand-induced conformation changes in folate binding protein purified from bovine milk: influence of buffer type and pH.
Fourier transform infrared (FT-IR) and near-infrared (NIR) spectroscopy have been applied to detect structural alterations in folate binding protein (FBP) induced by ligation in different buffer types. The amide I region pointed to a beta-sheet to alpha-helix transition upon ligation in acetate and phosphate buffers, and the formation of intermolecular beta-sheet was indicated at pH 5.0, in agreement with a dimerization of FBP taking place at this pH. The ligand-induced changes in the 2100-2300 nm NIR region were significant for FBP in acetate and phosphate buffers of pH 5.0, and the variations were interpreted as secondary structure changes, based on previous assignments of secondary structures to the combination bands in the NIR region. In the case of acetate buffer, variations in the amide combination bands agreed with the amide I analysis, but for the other buffer types some discrepancies were found and explained by side-chain contributions to the NIR, which could reflect the tertiary and quaternary structure differences. NIR spectra of FBP at pH 7.4 and 5.0 revealed contradictory effects on the side chains, reflecting different polymerization events at the two pH values, whereas the amide I region indicated similar changes at the two pH values. Therefore, we suggest that FT-IR and NIR spectroscopy may complement each other, such that the two techniques in combination may give information on all three types of protein conformational changes. While the secondary structure changes are revealed by FT-IR, the tertiary and quaternary structure changes are reflected in the NIR spectra, although the general influence of the latter changes on the NIR spectra remains to be confirmed.


Randomised controlled trial of interferon alfa (lymphoblastoid interferon) in chronic non-A non-B hepatitis.
To determine the effect of low dose interferon alfa (human lymphoblastoid interferon) on aminotransferase activities in chronic non-A non-B hepatitis. Prospective randomised controlled parallel group study of active treatment versus no treatment carried out over 16 weeks and preceded by baseline measurements at weeks 8 and 4 and time zero. HEPATOLOGY outpatient clinics in secondary referral centres. Fourteen adults with histologically proved chronic hepatitis and persistently raised aminotransferase activities for six months or more. Seven patients randomised to receive interferon alfa 5 megaunits (MU) daily for one week, reducing to 5 MU thrice weekly for seven weeks, then 3 MU thrice weekly for eight weeks. Controls not treated. Control of hepatic enzyme activity in chronic non-A non-B hepatitis. Serum aspartate aminotransferase activity remained raised in controls (mean increase in study period 23.4 U/l) but fell rapidly to normal in the treated group (mean decrease 106.4 U/l). In four cases values were normal by eight weeks and in five cases by 16 weeks. Only minor side effects were recorded (fever, myalgia), which became less common as treatment progressed. Continuous low dose interferon alfa reduces aspartate aminotransferase activity to normal in most patients with chronic non-A non-B hepatitis and may prevent progression to cirrhosis.


The impact of highly active antiretroviral therapy on the burden of bacterial lower respiratory tract infections in children.
Respiratory diseases are common and associated with significant morbidity and mortality in children. To evaluate the prevalence and outcome of bacterial lower respiratory tract infections (LRTIs) in HIV-infected and uninfected children at a primary level hospital. A cross-sectional descriptive study of children aged 6 months-18 years was conducted. Recruitment included HIV-positive children who had been on highly active antiretroviral therapy (HAART) for at least 6 months. A comparator group of HIV-negative children admitted with bacterial pneumonia was included. Laboratory data collected included CD4+ T-cell counts, HIV viral load and C-reactive protein (CRP). Data collected in both groups included demographic data, immunisation status, zinc supplementation, previous LRTIs, environmental exposures and treatment. Fifty-nine HIV-infected and 20 uninfected children were enrolled. The HIV-positive children were older, with a mean age of 107.2 (standard deviation 50.0) months v. 12.0 (5.8) months (p<0.005). The HIV-infected group had a mean CD4 percentage of 31.5%, and had had an average of 3.9 visits for bacterial LRTIs. All were treated with amoxicillin with no complications. In the HIV-uninfected group, cough and rapid breathing were the most common presenting symptoms, and the mean CRP level was 463.0 mg/L. The mean hospital stay was 4 days. HAART is effective in reducing the burden of LRTIs in HIV-positive children, even when the diagnosis is delayed. Cough and fast breathing are still the most reliable presenting symptoms of pneumonia. The majority of children still respond to amoxicillin as first-line therapy, with low complication rates.


Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4).
The PDS gene encodes a transmembrane protein, known as pendrin, which functions as a transporter of iodide and chloride. Mutations in this gene are responsible for Pendred syndrome and autosomal recessive non-syndromic hearing loss at the DFNB4 locus on chromosome 7q31. A screen of 20 individuals from the midwestern USA with non-syndromic hearing loss and dilated vestibular aqueducts identified three people (15%) with PDS mutations. To determine whether PDS mutations in individuals with Pendred syndrome differ functionally from PDS mutations in individuals with non-syndromic hearing loss, we compared three common Pendred syndrome allele variants (L236P, T416P and E384G), with three PDS mutations reported only in individuals with non-syndromic hearing loss (V480D, V653A and I490L/G497S). The mutations associated with Pendred syndrome have complete loss of pendrin-induced chloride and iodide transport, while alleles unique to people with DFNB4 are able to transport both iodide and chloride, albeit at a much lower level than wild-type pendrin. We hypothesize that this residual level of anion transport is sufficient to eliminate or postpone the onset of goiter in individuals with DFNB4. We propose a model for pendrin function in the thyroid in which pendrin transports iodide across the apical membrane of the thyrocyte into the colloid space.


Oligomeric status of human cystathionine beta-synthase modulates AdoMet binding.
Cystathionine beta-synthase (CBS) plays a key role in the metabolism of sulfur-containing amino acids. CBS is a multidomain tetrameric enzyme allosterically activated by S-adenosylmethionine (AdoMet). Recent crystallographic analyses of engineered CBS lacking the loop made up of residues 516-525 revealed discrepancies in AdoMet binding compared to previous biophysical studies on a full-length CBS. Here, we show that removal of the loop 516-525 functionally eliminates the high affinity sites responsible for kinetic stabilization of the full-length enzyme and yields a dimeric AdoMet-inducible enzyme, in which kinetic stabilization is now exerted by AdoMet binding to the remaining low affinity sites.


The naturalness of the artificial and our concepts of health, disease and medicine.
This article isolates ten prepositions, which constitute the undercurrent paradigm of contemporary discourse of health disease and medicine. Discussion of the interrelationship between those prepositions leads to a systematic refutation of this paradigm. An alternative set is being forwarded. The key notions of the existing paradigm are that health is the natural condition of humankind and that disease is a deviance from that nature. Natural things are harmonious and healthy while human made artifacts are coercive interference with natural balance. It is suggested that the current paradigm is influenced by the world of finances and by instrumental reason. The alternative model suggests that human nature cannot be delineated. Humans fashion their own selves and nature by artificial means, medicine among them. The article discusses the implications of the paradigm adapted in various scholarly and popular debates such as the use of sex hormones for contraception, the care of the elderly, holistic medicine and distributive justice in health care. Medicine is not an isolated or a privileged realm. There is no unique entitlement to healthcare. It is always part of a broader agenda of social values and institutions. A open view of human societies, values and practices as they are situated within concrete material conditions is the platform required for an integrative and creative discourse of health care.


Cycling time to failure is better maintained by cold than contrast or thermoneutral lower-body water immersion in normothermia.
To examine the effects of four commonly used recovery treatments applied between two bouts of intense endurance cycling on the performance of the second bout in normothermia (~21 °C). Nine trained men completed two submaximal exhaustive cycling bouts (Ex1 and Ex2: 5 min at ~50 % [Formula: see text] peak, followed by 5 min at ~60 % [Formula: see text] peak and then ~80 % [Formula: see text] peak to failure) separated by 30 min of (a) cold water immersion at 15 °C (C15), (b) contrast water therapy alternating 2.5 min at 8 °C and 2.5 min at 40 °C (CT), (c) thermoneutral water immersion at 34 °C (T34) and (d) cycling at ~40 % [Formula: see text] peak (AR). Exercise performance, cardiovascular and metabolic responses during Ex1 were similar among all trials. However, time to failure (~80 % [Formula: see text] peak bout) during Ex2 was significantly (P < 0.05) longer in C15 (18.0 ± 1.6) than in CT (14.5 ± 1.5), T34 (12.4 ± 1.4) and AR (10.6 ± 1.0); and it was also longer (P < 0.05) in CT than AR. Core temperature and heart rate were significantly (P < 0.05) lower during the initial ~15 min of Ex2 during C15 compared with all other conditions but they reached similar levels at the end of Ex2. A 30 min period of C15 was more beneficial in maintaining intense submaximal cycling performance than CT, T34 and AR; and CT was also more beneficial than T34 and AR. These effects were not mediated by the effect of water immersion per se, but by the continuous (C15) or intermittent (CT) temperature stimulus (cold) applied throughout the recovery.


Onychophoran-like musculature in a phosphatized Cambrian lobopodian.
The restricted, exclusively terrestrial distribution of modern Onychophora contrasts strikingly with the rich diversity of onychophoran-like fossils preserved in marine Cambrian Lagerstätten The transition from these early forebears to the modern onychophoran body plan is poorly constrained, in part owing to the absence of fossils preserving details of the soft anatomy. Here, we report muscle tissue in a new early Cambrian (Stage 3) lobopodian, Tritonychus phanerosarkus gen. et sp. nov., preserved in the Orsten fashion by three-dimensional replication in phosphate. This first report of Palaeozoic onychophoran musculature establishes peripheral musculature as a characteristic of the ancestral panarthropod, but documents an unexpected muscular configuration. Phylogenetic analysis reconstructs T. phanerosarkus as one of a few members of the main onychophoran lineage-which was as rare and as cryptic in the Cambrian period as it is today.


Differential impairment of semantic and episodic memory in Alzheimer's and Huntington's diseases: a controlled prospective study.
A controlled prospective study compared the performance of 14 patients with dementia of Alzheimer type (DAT) and 14 patients with Huntington's Disease (HD), who were matched for overall level of dementia, on a battery of semantic and episodic memory tests. The DAT patients were significantly more impaired on measures of delayed verbal and figural episodic memory, and in addition showed a more rapid rate of decline on tests which depend upon the integrity of semantic knowledge (naming, number information, similarities and category fluency). In contrast, the HD patients were significantly worse, and showed a more rapid decline on the letter fluency test, a task especially sensitive to deficiencies in retrieval. The HD patients were also more impaired than DAT patients on a vocabulary test and on copying geometric figures. The observed double dissociations offer compelling evidence that aetiologically distinct forms of dementing illness result in different patterns of cognitive impairment.


Standard ultrastaging compared to one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node metastases in early stage cervical cancer.
We compared ultrastaging and one-step nucleic acid amplification (OSNA) examination of sentinel lymph nodes in two homogeneous patient populations diagnosed with early stage cervical cancer. The primary aim of our study was to evaluate the rate and type of sentinel lymph node metastases detected by ultrastaging and OSNA assay. Secondary aims were to define the sensitivity and the negative predictive value of sentinel lymph node biopsy assessed with OSNA and ultrastaging and to define the role of sentinel lymph node assessment in predicting non-sentinel lymph node status. Consecutive patients who underwent surgery (radical hysterectomy or trachelectomy or cervical conization) at our institution, between January 2018 and March 2020, were enrolled. All patients had a preoperative diagnosis of early-stage cervical carcinoma (International Federation of Gynecology and Obstetrics (FIGO) 2018 stages IA-IIB) and underwent sentinel lymph node assessment with ultrastaging or OSNA. Patients with advanced FIGO stages and special histology subtypes (other than squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma) or patients with sentinel lymph nodes analyzed only with hematoxylin and eosin were excluded. Clinical data were compared using the χ2 test and Fisher's exact test. A κ coefficient was determined with respect to lymph node assessment. A p value <0.05 was considered statistically significant. A total of 116 patients were included in this retrospective analysis (53 ultrastaging, 63 OSNA). Overall, 531 and 605 lymph nodes were removed in the ultrastaging and OSNA groups, respectively, and 140 and 129 sentinel lymph nodes were analyzed in the ultrastaging and OSNA groups, respectively. 22 patients had metastatic sentinel lymph nodes: 6 (11.3%) of 53 patients in the ultrastaging group and 16 (25.4%) of 63 patients in the OSNA group. The total amount of positive SLNs was 7 (5%) of 140 in the ultrastaging group and 21 (16.3%) of 129 in the OSNA group, respectively (p=0.0047). Pelvic lymphadenectomy was performed in 26 (49.1%) of 53 patients in the ultrastaging group and in 34 (54%) of 63 patients in the OSNA group due to comorbidities. Metastatic non-sentinel lymph nodes were found in 4 patients: 2 (7.7%) of 26 patients in the ultrastaging group and 2 (5.9%) of 34 patients in the OSNA group, respectively. The total amount of positive pelvic lymph nodes was 3 (0.6%) of 531 in the ultrastaging group and 4 (0.7%) of 605 in the OSNA group (p=0.61). In the OSNA group, only 2 patients with negative sentinel lymph nodes had metastatic disease in the pelvic lymph nodes. By contrast, no patients with OSNA-positive sentinel lymph nodes had metastases in the pelvic lymph nodes. In the ultrastaging group, all patients with negative sentinel lymph nodes did not have metastatic disease in other pelvic lymph nodes. OSNA assessment of sentinel lymph nodes was associated with a negative predictive value of 91% but poor reliability in detecting node metastases in non-sentinel pelvic lymph nodes. Of note, the ultrastaging protocol revealed higher sensitivity and more reliability in predicting pelvic non-sentinel lymph node status.


Reduced-dose warfarin or interrupted warfarin with heparin bridging for pacemaker or defibrillator implantation: a randomized trial.
Perioperative management with reduced-dose warfarin is of potential interest by eliminating the need for bridging while still maintaining a degree of anticoagulation. The outcomes of this regimen have not been well determined. In a randomized controlled trial we compared two regimens for management of anticoagulation with warfarin in patients with implantation of a pacemaker or defibrillator. Half dose of warfarin for 3-6 days, depending on the baseline international normalized ratio (INR), before surgery aiming at an INR of ≤ 1.7 was compared with interrupted warfarin for 5 days with preoperative bridging with low-molecular-weight heparin (LMWH) at therapeutic dose for 2.5 days. Main safety outcome was pocket hematoma. Secondary outcomes were major bleeding, thromboembolism - all within 1 month, days of hospitalization and number of patients requiring correction of INR with vitamin K. The study was planned for 450 patients but it was discontinued prematurely due to a change in practice. Pocket hematoma occurred in 4 of 85 patients (5%) randomized to the bridged regimen and in 3 of 86 patients (3%) randomized to reduced-dose warfarin. One pocket hematoma in each group was severe. There were no major hemorrhages or thromboembolism within the 1-month window. Duration of hospitalization was similar in the two groups. Correction of INR the day before surgery with vitamin K had to be used for significantly more patients in the reduced-dose warfarin group (41%) than in the bridged regimen group (6%). The reduced-dose warfarin regimen appeared to have similar safety after device implantation as interrupted warfarin with preoperative LMWH bridging. Due to premature discontinuation no firm conclusion can be drawn. The reduced-dose warfarin regimen often failed to achieve the intended preoperative INR. ClinicalTrials.gov Identifier: NCT 02094157.


[Genotypic diversity of Mycobacterium tuberculosis in the Guiana-Antilles region].
This investigation dealt with 226 strains (1 isolate/patient) of Mycobacterium tuberculosis isolated in the French West Indies and French Guiana over a three-year period (1994-1996). The genotypic diversity of the isolates was investigated using various molecular markers; essentially two PCR-based rapid methods, namely spoligotyping and double-repetitive-element (DRE)-PCR, as well as three restriction fragment length polymorphism (RFLP)-based methods, namely IS6110-RFLP, DR-RFLP and PGRS-RFLP. Out of 226 isolates investigated, a total of 166 isolates were distributed in 31 spoligotype-defined clusters containing 2-31 strains, which corresponded to a rate of 73% of primary clustering. After secondary typing with DRE-PCR, IS6110-RFLP, DR-RFLP and/or PGRS-RFLP, molecular clonality was established for 73 isolates organised in 25 clusters (32% of clustered isolates). Considering one reactivation case per cluster, the rate of recent transmission was estimated to a minimal rate of 21%, however the available epidemiologic information led to the positive conclusion for only 14% of cases. The data obtained demonstrated the presence of common genotypes of M. tuberculosis among the three overseas French territories, i.e. Guadeloupe, Martinique and French Guiana. The results obtained during this retrospective study clearly indicate the importance of future prospective epidemiological investigations around the clustered cases of tuberculosis, so as to detect the persisting foci of endemic disease and characterize the chain of transmission as well as the subpopulations which are at an increased risk of contracting and/or propagating the disease. Last but not least, the present study also deals with a first phylogenetic approach of M. tuberculosis based on a comparison of the spoligotyping results obtained locally with those reported elsewhere in the world.


A Whole-Genome RNA Interference Screen Reveals a Role for Spry2 in Insulin Transcription and the Unfolded Protein Response.
Insulin production by the pancreatic β-cell is required for normal glucose homeostasis. While key transcription factors that bind to the insulin promoter are known, relatively little is known about the upstream regulators of insulin transcription. Using a whole-genome RNA interference screen, we uncovered 26 novel regulators of insulin transcription that regulate diverse processes including oxidative phosphorylation, vesicle traffic, and the unfolded protein response (UPR). We focused on Spry2-a gene implicated in human type 2 diabetes by genome-wide association studies but without a clear connection to glucose homeostasis. We showed that Spry2 is a novel UPR target and its upregulation is dependent on PERK. Knockdown of Spry2 resulted in reduced expression of Serca2, reduced endoplasmic reticulum calcium levels, and induction of the UPR. Spry2 deletion in the adult mouse β-cell caused hyperglycemia and hypoinsulinemia. Our study greatly expands the compendium of insulin promoter regulators and demonstrates a novel β-cell link between Spry2 and human diabetes.


Numerical simulation of fluid field and in vitro three-dimensional fabrication of tissue-engineered bones in a rotating bioreactor and in vivo implantation for repairing segmental bone defects.
In this paper, two-dimensional flow field simulation was conducted to determine shear stresses and velocity profiles for bone tissue engineering in a rotating wall vessel bioreactor (RWVB). In addition, in vitro three-dimensional fabrication of tissue-engineered bones was carried out in optimized bioreactor conditions, and in vivo implantation using fabricated bones was performed for segmental bone defects of Zelanian rabbits. The distribution of dynamic pressure, total pressure, shear stress, and velocity within the culture chamber was calculated for different scaffold locations. According to the simulation results, the dynamic pressure, velocity, and shear stress around the surface of cell-scaffold construction periodically changed at different locations of the RWVB, which could result in periodical stress stimulation for fabricated tissue constructs. However, overall shear stresses were relatively low, and the fluid velocities were uniform in the bioreactor. Our in vitro experiments showed that the number of cells cultured in the RWVB was five times higher than those cultured in a T-flask. The tissue-engineered bones grew very well in the RWVB. This study demonstrates that stress stimulation in an RWVB can be beneficial for cell/bio-derived bone constructs fabricated in an RWVB, with an application for repairing segmental bone defects.


Oral intake of hydrogen-rich water inhibits intimal hyperplasia in arterialized vein grafts in rats.
Arterialized vein grafts often fail due to intimal hyperplasia. Hydrogen potently protects organs and cells from many insults via its anti-inflammatory and antioxidant properties. We investigated the efficacy of oral administration of hydrogen-rich water (HW) for prevention of intimal hyperplasia. The inferior vena cava was excised, stored in cold Ringer solution for 2 h, and placed as an interposition graft in the abdominal aorta of syngeneic Lewis rats. HW was generated by immersing a magnesium stick in tap water (Mg + 2H(2)O → Mg (OH)(2) + H(2)). Beginning on the day of graft implantation, recipients were given tap water [regular water (RW)], HW or HW that had been subsequently degassed water (DW). Six weeks after grafting, the grafts in the rats given RW or DW had developed intimal hyperplasia, accompanied by increased oxidative injury. HW significantly suppressed intimal hyperplasia. One week after grafting, the grafts in HW-treated rats exhibited improved endothelial integrity with less platelet and white blood cell aggregation. Up-regulation of the mRNAs for intracellular adhesion molecules was attenuated in the vein grafts of the rats receiving HW. Activation of p38 mitogen-activated protein kinase, matrix metalloproteinase (MMP)-2, and MMP-9 was also significantly inhibited in grafts receiving HW. In rat smooth muscle cell (A7r5) cultures, hydrogen treatment for 24 h reduced smooth muscle cell migration. Drinking HW significantly reduced neointima formation after vein grafting in rats. Drinking HW may have therapeutic value as a novel therapy for intimal hyperplasia and could easily be incorporated into daily life.


Oxygen-tolerant [NiFe]-hydrogenases: the individual and collective importance of supernumerary cysteines at the proximal Fe-S cluster.
An important clue to the mechanism for O(2) tolerance of certain [NiFe]-hydrogenases is the conserved presence of a modified environment around the iron-sulfur cluster that is proximal to the active site. The O(2)-tolerant enzymes contain two cysteines, located at opposite ends of this cluster, which are glycines in their O(2)-sensitive counterparts. The strong correlation highlights special importance for electron-transfer activity in the protection mechanism used to combat O(2). Site-directed mutagenesis has been carried out on Escherichia coli hydrogenase-1 to substitute these cysteines (C19 and C120) individually and collectively for glycines, and the effects of each replacement have been determined using protein film electrochemistry and electron paramagnetic resonance (EPR) spectroscopy. The "split" iron-sulfur cluster EPR signal thus far observed when oxygen-tolerant [NiFe]-hydrogenases are subjected to oxidizing potentials is found not to provide any simple, reliable correlation with oxygen tolerance. Oxygen tolerance is largely conferred by a single cysteine (C19), replacement of which by glycine removes the ability to function even in 1% O(2).


What pops out in positional priming of pop-out: insights from event-related EEG lateralizations.
It is well established that, in visual pop-out search, reaction time (RT) performance is influenced by cross-trial repetitions versus changes of target-defining attributes. One instance of this is referred to as "positional priming of pop-out" (pPoP; Maljkovic and Nakayama, 1996). In positional PoP paradigms, the processing of the current target is examined depending on whether it occurs at the previous target or a previous distractor location, relative to a previously empty location ("neutral" baseline), permitting target facilitation and distractor inhibition to be dissociated. The present study combined RT measures with specific sensory- and motor-driven event-related lateralizations to track the time course of four distinct processing levels as a function of the target's position across consecutive trials. The results showed that, relative to targets at previous target and "neutral" locations, the appearance of a target at a previous distractor location was associated with a delayed build-up of the posterior contralateral negativity wave, indicating that distractor positions are suppressed at early stages of visual processing. By contrast, presentation of a target at a previous target, relative to "neutral" and distractor locations, modulated the elicitation of the subsequent stimulus-locked lateralized readiness potential wave, indicating that post-selective response selection is facilitated if the target occurred at the same position as on the previous trial. Overall, the results of present study provide electrophysiological evidence for the idea that target location priming (RT benefits) does not originate from an enhanced coding of target saliency at repeated (target) locations; instead, they arise (near-) exclusively from processing levels subsequent to focal-attentional target selection.


Nurse educators' experiences of case-based education in a South African nursing programme.
A school of nursing at a university in the Western Cape experienced an increase in student enrolments from an intake of 150 students to 300 students in the space of one year. This required a review of the teaching and learning approach to ensure that it was appropriate for effective facilitation of large classes. The case-based education (CBE) approach was adopted for the delivery of the Bachelor of Nursing programme in 2005. The aim of the study was to explore nurse educators' experiences, current practices and possible improvements to inform best practice of CBE at the nursing school in the Western Cape. A participatory action research method was applied in a two day workshop conducted with nurse educators in the undergraduate nursing programme. The nominal group technique was used to collect the data. Three themes emerged from the final synthesis of the findings, namely: teaching and learning related issues, student issues and teacher issues. Amongst other aspects, theory and practice integration, as well as the need for peer support in facilitation of CBE, were identified as requiring strengthening. It was concluded that case-based education should continue to be used in the school, however, more workshops should be arranged to keep educators updated and new staff orientated in respect of this teaching and learning approach.


Diagnosis and treatment of venous lymphedema.
Chronic venous disease (CVD) is a common cause of secondary lymphedema. Venous lymphedema is sometimes misdiagnosed as primary lymphedema and does not receive optimal treatment. We have routinely used intravascular ultrasound (IVUS) imaging in all cases of limb swelling. The aim of this study is to show that (1) routine use of IVUS can detect venous obstruction missed by traditional venous testing, and (2) iliac-caval venous stenting can yield satisfactory clinical relief and can sometimes reverse abnormal lymphangiographic findings. The study comprised CVD patients who underwent iliac vein stenting. Lymphangiography was abnormal in 72 of 443 CEAP C(3) limbs, with leg swelling as the primary complaint (abnormal lymphangiography group). Clinical features and stent outcome were compared with a control group of 205 of 443 with normal lymphangiography (normal lymphangiographic group). Clinical features were a poor guide to the diagnosis of lymphedema. Isotope lymphangiography was not helpful in differentiating primary from secondary lymphedema. Venography had 61% sensitivity to the diagnosis of venous obstruction. IVUS had a sensitivity of 88% for significant (≥50% area stenosis) venous obstruction. At 40 months, cumulative secondary stent patency was similar for the abnormal (100%) and normal lymphangiographic (95%) groups. Swelling improved significantly after stent placement in the abnormal lymphangiographic group (mean [standard deviation] swelling grade improvement 0.8 ± 1.1) but was less (P < .004) than in the control group (1.4 ± 1.3). Complete swelling relief was 16% and 44% (P < .001) and partial improvement (≥1 grade of swelling) was 45% and 66% (P < .01) in the abnormal and normal lymphangiographic groups, respectively. Associated pain was present in 50% and 36% of the swollen limbs in the abnormal and normal lymphangiographic groups. Pain relief (≥3 visual analog scale) at 40 months was 87% and 83%, respectively (P = .3), with 65% and 71%, experiencing complete pain relief. Quality of life criteria improved after stent placement in both groups but to a better extent in the normal lymphangiographic group. Abnormal lymphangiography improved or normalized in 9 of 36 (25%) of those tested after stent correction. Prevailing practice patterns and diagnostic deficiencies probably result in the misdiagnosis of many cases of venous lymphedema as "primary" lymphedema. IVUS is recommended to rule out venous obstruction as the associated or initiating cause of lymphedema. Iliac venous stenting to correct the obstruction has excellent long-term patency and good clinical outcome, although results are not as good as in those with normal lymphatic function.


The oldest fossil cichlids (Teleostei: Perciformes): indication of a 45 million-year-old species flock.
Five closely related species of fossil cichlids collected from an Eocene site in Tanzania, East Africa, represent the oldest known cichlids. The specimens are whole-body, articulated fishes that are extremely well preserved and, therefore, have the potential to add to our knowledge of the history of this family. Modern cichlids are particularly well known for the numerous species flocks of the East African Great Lakes. A great deal of research is ongoing regarding all aspects of the fishes in these flocks, including their evolutionary history The new collection of fossils reported here is interpreted as representing a species flock that arose in a small crater lake. These fossils indicate that cichlids' ability to form species flocks evolved early in the history of this family.


Novel fiber Bragg grating fabrication system for long gratings with independent apodization and with local phase and wavelength control.
We proposed and demonstrated a novel practical fiber Bragg grating (FBG) fabrication setup constructed with high performance linear stages, piezoelectric translation (PZT) stages, and a highly stable continuous wave laser. The FBG fabrication system enables writing of long FBGs by a continuous translate-and-write process and allows implementation of arbitrary chirp and apodization. A key innovation is that the local Bragg wavelength is controlled by a simple movement of the phase mask by a PZT in the direction perpendicular to its surface. The focus position of the two writing beams is not changed during the Bragg wavelength change, an intrinsic feature of the design, ensuring simplicity, robustness and stability. Apodization can be achieved by vibrating the phase mask in the direction parallel to its surface by a PZT. Phase steps can also be inserted in FBGs at any desired locations by stepping the same PZT. A long uniform FBG and a linearly chirped FBG are written to demonstrate the performance of the setup.


Perioperative Temperature Measurement Considerations Relevant to Reporting Requirements for National Quality Programs Using Data From Anesthesia Information Management Systems.
Perioperative hypothermia may increase the incidences of wound infection, blood loss, transfusion, and cardiac morbidity. US national quality programs for perioperative normothermia specify the presence of at least 1 "body temperature" ≥35.5°C during the interval from 30 minutes before to 15 minutes after the anesthesia end time. Using data from 4 academic hospitals, we evaluated timing and measurement considerations relevant to the current requirements to guide hospitals wishing to report perioperative temperature measures using electronic data sources. Anesthesia information management system databases from 4 hospitals were queried to obtain intraoperative temperatures and intervals to the anesthesia end time from discontinuation of temperature monitoring, end of surgery, and extubation. Inclusion criteria included age >16 years, use of a tracheal tube or supraglottic airway, and case duration ≥60 minutes. The end-of-case temperature was determined as the maximum intraoperative temperature recorded within 30 minutes before the anesthesia end time (ie, the temperature that would be used for reporting purposes). The fractions of cases with intervals >30 minutes between the last intraoperative temperature and the anesthesia end time were determined. Among the hospitals, averages (binned by quarters) of 34.5% to 59.5% of cases had intraoperative temperature monitoring discontinued >30 minutes before the anesthesia end time. Even if temperature measurement had been continued until extubation, averages of 5.9% to 20.8% of cases would have exceeded the allowed 30-minute window. Averages of 8.9% to 21.3% of cases had end-of-case intraoperative temperatures <35.5°C (ie, a quality measure failure). Because of timing considerations, a substantial fraction of cases would have been ineligible to use the end-of-case intraoperative temperature for national quality program reporting. Thus, retrieval of postanesthesia care unit temperatures would have been necessary. A substantive percentage of cases had end-of-case intraoperative temperatures below the 35.5°C threshold, also requiring postoperative measurement to determine whether the quality measure was satisfied. Institutions considering reporting national quality measures for perioperative normothermia should consider the technical and logistical issues identified to achieve a high level of compliance based on the specified regulatory language.


Management of chronic staphylococcal osteomyelitis of the temporal bone: the use of hyperbaric oxygen.
Hyperbaric oxygen (HBO) is an effective adjunct in the management of selected otolaryngologic problems including radiation-induced necrosis of the temporal bone, malignant external otitis, mandibular osteoradionecrosis and refractory osteomyelitis, soft tissue head and necrotizing fasciitis, compromised skin flaps and grafts, acute air or gas embolism, and otologic barotrauma. We describe the management of a patient with insidious Staphylococcus aureus osteomyelitis of the temporal bone by the use of HBO preoperatively and postoperatively in conjunction with surgical debridement. The possible application of angiogenic agents and tetracycline bone-labeling in combination with HBO therapy in the management of refractory neurotologic disease is discussed.


Sexual responsiveness in women with spinal cord injuries: differential effects of anxiety-eliciting stimulation.
Sexual dysfunction is a common problem in women after spinal cord injuries (SCIs). Recently, the use of anxiety-provoking stimulation has been explored as a means of improving sexual responses in able-bodied sexually functional and dysfunctional women. In this laboratory-based study, we assessed the sexual and autonomic responses of women with SCIs with varying degrees of preservation of sympathetic innervation to their genitals to respond to anxiety-provoking audiovisual (AV) stimulation. Subjects were 45 women with SCIs and 11 able-bodied women. For purposes of analysis, SCI subjects were grouped on the basis of the degree of preservation of sensation in the T11-L2 dermatomes. Results revealed that women with low sensory scores in these dermatomes achieved higher vaginal pulse amplitude (VPA) responses to audiovisual erotic stimulation after anxiety preexposure than after neutral preexposure; however, women with SCIs and the greatest degree of preservation of sensory function in the T11-L2 dermatomes, as well as able-bodied controls, did not. Moreover, these same 2 groups of subjects had a decrease in VPA responses during baseline periods in which an anxiety-provoking video sequence was shown, but not during the neutral sequence. It is concluded that these findings are due to the proximity of sensory and autonomic neurologic elements in the spinal cord. Moreover, they demonstrate the differential effects of sympathetic stimulation on genital sexual arousal.


Experimental and computational analyses reveal that environmental restrictions shape HIV-1 spread in 3D cultures.
Pathogens face varying microenvironments in vivo, but suitable experimental systems and analysis tools to dissect how three-dimensional (3D) tissue environments impact pathogen spread are lacking. Here we develop an Integrative method to Study Pathogen spread by Experiment and Computation within Tissue-like 3D cultures (INSPECT-3D), combining quantification of pathogen replication with imaging to study single-cell and cell population dynamics. We apply INSPECT-3D to analyze HIV-1 spread between primary human CD4 T-lymphocytes using collagen as tissue-like 3D-scaffold. Measurements of virus replication, infectivity, diffusion, cellular motility and interactions are combined by mathematical analyses into an integrated spatial infection model to estimate parameters governing HIV-1 spread. This reveals that environmental restrictions limit infection by cell-free virions but promote cell-associated HIV-1 transmission. Experimental validation identifies cell motility and density as essential determinants of efficacy and mode of HIV-1 spread in 3D. INSPECT-3D represents an adaptable method for quantitative time-resolved analyses of 3D pathogen spread.


Phthalate metabolites in 24-h urine samples of the German Environmental Specimen Bank (ESB) from 1988 to 2015 and a comparison with US NHANES data from 1999 to 2012.
The German Environmental Specimen Bank (ESB) continuously collects 24-h urine samples since the early 1980s in Germany. In this study we analyzed 300 urine samples from the years 2007 to 2015 for 21 phthalate metabolites (representing exposure to 11 parent phthalates) and combined the data with two previous retrospective measurement campaigns (1988 to 2003 and 2002 to 2008). The combined dataset comprised 1162 24-h urine samples spanning the years 1988 to 2015. With this detailed set of human biomonitoring data we describe the time course of phthalate exposure in Germany over a time frame of 27 years. For the metabolites of the endocrine disrupting phthalates di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DnBP) and butylbenzyl phthalate (BBzP) we observed a roughly ten-fold decline in median metabolite levels from their peak levels in the late 1980s/early 1990s compared to most recent levels from 2015. Probably, bans (first enacted in 1999) and classifications/labelings (enacted in 2001 and 2004) in the European Union lead to this drop. A decline in di-isobutyl phthalate (DiBP) metabolite levels set in only quite recently, possibly due to its later classification as a reproductive toxicant in the EU in 2009. In a considerable number of samples collected before 2002 health based guidance values (BE, HBM I) have been exceeded for DnBP (27.2%) and DEHP (2.3%) but also in recent samples some individual exceedances can still be observed (DEHP 1.0%). A decrease in concentration for all low molecular weight phthalates, labelled or not, was seen in the most recent years of sampling. For the high molecular weight phthalates, DEHP seems to have been substituted in part by di-isononyl phthalate (DiNP), but DiNP metabolite levels have also been declining in the last years. Probably, non-phthalate alternatives increasingly take over for the phthalates in Germany. A comparison with NHANES (National Health and Nutrition Examination Survey) data from the United States covering the years 1999 to 2012 revealed both similarities and differences in phthalate exposure between Germany and the US. Exposure to critical phthalates has decreased in both countries with metabolite levels more and more aligning with each other, but high molecular weight phthalates substituting DEHP (such as DiNP) seem to become more important in the US than in Germany.


Discrepancies between self-reported years of education and estimated reading level among elderly community-dwelling African-Americans: Analysis of the MOAANS data.
The influence of education on cognition has received a great deal of attention in the literature. Although there is general consensus regarding the importance of education on cognitive functioning, the extent to which self-reported level of education corresponds to true educational attainment remains unclear, especially in ethnic minority populations where equal access to education has not always been available. Several investigators have suggested that reading skill may serve as a quantitative estimate of true education experience. Among African-Americans, however, research has shown that self-reported educational level consistently over predicts estimated reading level. The current study analyzed the discrepancy between self-reported years of education completed and estimated reading level in a sample of community-dwelling, elderly African-Americans participating in Mayo's Older African Americans Normative Studies (MOAANS) (Lucas, J.A., Ivnik, R.J., Willis, F.B., Ferman, T.J., Smith, G.E., Parfitt, F.C., Petersen, R.C., & Graff-Radford, N.R. (2005). Mayo's Older African Americans Normative Studies: Normative data for commonly used clinical neuropsychological measures. The Clinical Neuropsychologist, 19, 162-183). In this sample, 29% of the participants read at a level that was 3 or more years below what would be expected based on self-report of education attained. This study also sought to evaluate the extent to which this discrepancy fluctuated as a function of demographic variables such as location of schooling (urban, suburban, rural; North vs. South), parental education and literacy, and percentage of segregation in schooling. Implications of these results are discussed, as are areas for further inquiry.


Adherence Connection for Counseling, Education, and Support: Research Protocol for a Proof-of-Concept Study.
The highest rates of new HIV infections are observed in African Americans and Hispanics/Latinos (ethnic minority) adolescents and young adults (youth). HIV-infected ethnic minority youth are less likely to initiate and maintain adherence to antiretroviral treatment (ART) and medical care, as compared with their adult counterparts. The objective of this research protocol was to describe our proposed methods for testing a peer-led mobile health cognitive behavioral intervention, delivered via remote videoconferencing and smartphones with HIV-infected ethnic minority youth, Adherence Connection for Counseling, Education, and Support (ACCESS). Our secondary aim was to obtain initial estimates of the biobehavioral impact of ACCESS on HIV virologic outcomes and self-reported ART adherence, beliefs and knowledge about ART treatment, adherence self-efficacy, and health care utilization (retention in care). An exploratory, sequential mixed-methods study design will be used with conceptual determinants of adherence behavior informed by the information-motivation-behavioral skills model. HIV-infected ethnic minority youth aged 16 to 29 years with a detectable HIV serum viral load of more than 200 copies/ml (N=25) will be recruited. Qualitative pretesting will be conducted, including semistructured, in-depth, individual interviews with a convenience sample meeting the study inclusion criteria. Preliminary analysis of qualitative data will be used to inform and tailor the ACCESS intervention. Testing and implementation will include a one-group pre-posttest pilot, delivered by a trained successful peer health coach who lives with HIV and is well-engaged in HIV care and taking ART. A total of 5 peer-led remote videoconferencing sessions will be delivered using study-funded smartphones and targeting adherence information (HIV knowledge), motivation (beliefs and perceptions), and behavioral skills (self-efficacy). Participant satisfaction will be assessed with poststudy focus groups and quantitative survey methodology. Bivariate analyses will be computed to compare pre- and postintervention changes in HIV biomarkers, self-reported ART adherence, beliefs and knowledge about ART, adherence self-efficacy, and retention in care. As of December 2018, we are in the data analysis phase of this pilot and anticipate completion with dissemination of final study findings by spring/summer 2019. The major outcomes will include intervention feasibility, acceptability, and preliminary evidence of impact on serum HIV RNA quantitative viral load (primary adherence outcome variable). Self-reported ART adherence and retention in care will be assessed as secondary outcomes. Findings from the qualitative pretesting will contribute to an improved understanding of adherence behavior. Should the ACCESS intervention prove feasible and acceptable, this research protocol will contribute to a shift in existent HIV research paradigms by offering a blueprint for technology-enabled peer-led interventions and models. DERR1-10.2196/12543.


Variation of carbon contents in eelgrass ( Zostera marina) sediments implied from depth profiles.
Seagrass meadows are able to store significant amounts of organic carbon in their underlying sediment, but global estimates are uncertain partly owing to spatio-temporal heterogeneity between and within areas and species. In order to provide robust estimates, there is a need to better understand the fate of, and mechanisms behind, organic carbon storage. In this observational study, we analyse a suite of biotic and abiotic parameters in sediment cores from 47 different eelgrass ( Zostera marina) beds spanning the distributional range of the Northern Hemisphere. Depth profiles of particulate organic carbon (POC) revealed three patterns of vertical distribution where POC either increased, decreased or showed no pattern with sediment depth. These categories exhibited distinct profiles of δ13C and C:N ratios, where high POC profiles had a proportionally larger storage of eelgrass-derived material whereas low POC profiles were dominated by phytoplanktonic and macroalgal material. However, high POC did not always translate into high carbon density. Nevertheless, this large-scale dataset provides evidence that the variability in organic matter source in response to natural and anthropogenic environmental changes affects the potential role of eelgrass beds as POC sinks, particularly where eelgrass decline is observed.


'Athlete's heart' in prepubertal children.
Bradycardia, cardiomegaly, heart murmurs, and ECG changes are typically observed in adult endurance athletes, but frequency of such changes among children involved in sports training is unclear. Pediatricians need to be aware of whether these features of the "athlete's heart" occur in their patients, because such features may mimic those of cardiac disease. Fourteen prepubertal competitive male swimmers were evaluated by physical examination, ECG and echocardiogram, and findings were compared to those of a group of active but nontrained control boys. Lower resting heart rates and echocardiographic manifestations of chronic left ventricular volume overload were observed among the swimmers. These changes were not manifest on physical examination, however, and no significant ECG alterations were identified among the athletes. These findings indicate that, although features of the athlete's heart are present in children involved in endurance training, seldom will these findings simulate heart disease or be apparent on routine clinical examination.


Influenza vaccination and all-cause mortality in community-dwelling elderly in Ontario, Canada, a cohort study.
The objective of this study was to evaluate the effectiveness of influenza vaccines in reducing all-cause mortality among community-dwelling elderly. We included 25,922 Ontario residents over age 65 who responded to population health surveys. After full adjustment, influenza vaccination was associated with a statistically significant reduction in all-cause mortality during influenza seasons (hazard ratio (HR)=0.61; 95% CI 0.47-0.79). Contrary to expectations, statistically significant associations between influenza vaccination and mortality were also observed during periods preceding (HR=0.55; 95% CI 0.40-0.75) and following (HR=0.74; 95% CI 0.59-0.94) influenza seasons, indicating the presence of residual confounding. Adjustment for functional status indicators, excluding individuals with high one-year predicted mortality at baseline, and moving the start date of follow-up failed to eliminate the refractory confounding. Since observational studies are prone to bias, future efforts to estimate vaccine effectiveness in the elderly should strive to minimize bias through improved data quality, novel data sources, and/or new analytical techniques.


Characterization of a novel plasmid-mediated cephalosporinase (CMY-9) and its genetic environment in an Escherichia coli clinical isolate.
An Escherichia coli strain, HKYM68, which showed resistance to broad-spectrum cephalosporins was isolated from a sputum specimen in Japan. The high-level resistance of the strain to ceftazidime, cefpirome, and moxalactam was carried by a self-transferable plasmid. The beta-lactamase gene responsible for the resistance was cloned and sequenced. The deduced amino acid sequence of this gene product, CMY-9, had a single amino acid substitution (E85D), the residue reported to be part of the recognition site for the R1 side chain of beta-lactams, compared with the amino acid sequence of CMY-8 and also had 78% identity with the amino acid sequence of CepH, a chromosomal cephalosporinase of Aeromonas hydrophila. A sul1-type class 1 integron containing an aacA1-orfG gene cassette was identified upstream of bla(CMY-9) and ended with a truncated 3' conserved segment. The following 2.1 kb was almost identical to the common region of integrons In6 and In7 and the integron of pSAL-1, except that orf513 encoding a putative transposase was identified instead of orf341 due to addition of a single nucleotide. bla(CMY-9) was closely located downstream of the end of the common region. These observations are indicative of the exogenous derivation of bla(CMY-9) from some environmental microorganisms such as aeromonads.


Hippocampus, aging, and segregating memories.
Rats use time-of-day cues to modulate learned taste aversion memories. If adult rats are accustomed to drinking saline in the evening and they receive a lithium chloride injection after drinking saline in the morning, they form a stronger aversion to saline than rats that were conditioned after drinking saline at the familiar time. The difference indicated that the rats formed segregated representations of saline taste and the time of day the saline was consumed. This was inferred because the modulation of learning by time of day was observed when the aversions were tested at the familiar evening drinking time. If the rats had formed a compound representation of saline taste and the time of day it was consumed, the opposite pattern of differences would be expected. We used this modulation of learning by time of day to assay whether aged rats have an impaired ability to form segregated representations of experience. We find that aged rats had similar saline aversions if they were conditioned at either the familiar or the unfamiliar time of day. Furthermore, dorsal hippocampal lesions affecting also the overlying parietal cortex in the aged rats caused greater saline aversions if the rats were conditioned after drinking saline at the familiar time of day. This indicated that aged rats are aware of the time of day but after the lesion, they act as if they do not segregate saline taste from the time of day it was consumed. The results suggest that the ability to form segregated representations of a complex experience is impaired in aging and abolished by hippocampal lesions.


Trial watch: Dendritic cell-based interventions for cancer therapy.
Dendritic cells (DCs) occupy a privileged position at the interface between innate and adaptive immunity, orchestrating a large panel of responses to both physiological and pathological cues. In particular, whereas the presentation of antigens by immature DCs generally results in the development of immunological tolerance, mature DCs are capable of priming robust, and hence therapeutically relevant, adaptive immune responses. In line with this notion, functional defects in the DC compartment have been shown to etiologically contribute to pathological conditions including (but perhaps not limited to) infectious diseases, allergic and autoimmune disorders, graft rejection and cancer. Thus, the possibility of harnessing the elevated immunological potential of DCs for anticancer therapy has attracted considerable interest from both researchers and clinicians over the last decade. Alongside, several methods have been developed not only to isolate DCs from cancer patients, expand them, load them with tumor-associated antigens and hence generate highly immunogenic clinical grade infusion products, but also to directly target DCs in vivo. This intense experimental effort has culminated in 2010 with the approval by the US FDA of a DC-based preparation (sipuleucel-T, Provenge®) for the treatment of asymptomatic or minimally symptomatic metastatic castration-refractory prostate cancer. As an update to the latest Trial Watch dealing with this exciting field of research (October 2012), here we summarize recent advances in DC-based anticancer regimens, covering both high-impact studies that have been published during the last 13 mo and clinical trials that have been launched in the same period to assess the antineoplastic potential of this variant of cellular immunotherapy.


Contrast gain control in auditory cortex.
The auditory system must represent sounds with a wide range of statistical properties. One important property is the spectrotemporal contrast in the acoustic environment: the variation in sound pressure in each frequency band, relative to the mean pressure. We show that neurons in ferret auditory cortex rescale their gain to partially compensate for the spectrotemporal contrast of recent stimulation. When contrast is low, neurons increase their gain, becoming more sensitive to small changes in the stimulus, although the effectiveness of contrast gain control is reduced at low mean levels. Gain is primarily determined by contrast near each neuron's preferred frequency, but there is also a contribution from contrast in more distant frequency bands. Neural responses are modulated by contrast over timescales of ∼100 ms. By using contrast gain control to expand or compress the representation of its inputs, the auditory system may be seeking an efficient coding of natural sounds.


Physiological Status Drives Metabolic Rate in Mediterranean Geckos Infected with Pentastomes.
Negative effects of parasites on their hosts are well documented, but the proximate mechanisms by which parasites reduce their host's fitness are poorly understood. For example, it has been suggested that parasites might be energetically demanding. However, a recent meta-analysis suggests that they have statistically insignificant effects on host resting metabolic rate (RMR). It is possible, though, that energetic costs associated with parasites are only manifested during and/or following periods of activity. Here, we measured CO2 production (a surrogate for metabolism) in Mediterranean geckos (Hemidactylus turcicus) infected with a lung parasite, the pentastome Raillietiella indica, under two physiological conditions: rested and recently active. In rested geckos, there was a negative, but non-significant association between the number of pentastomes (i.e., infection intensity) and CO2 production. In recently active geckos (chased for 3 minutes), we recorded CO2 production from its maximum value until it declined to a stationary phase. We analyzed this decline as a 3 phase function (initial decline, secondary decline, stationary). Geckos that were recently active showed, in the secondary phase, a significant decrease in CO2 production as pentastome intensity increased. Moreover, duration of the secondary phase showed a significant positive association with the number of pentastomes. These results suggest that the intensity of pentastome load exerts a weak effect on the metabolism of resting geckos, but a strong physiological effect on geckos that have recently been active; we speculate this occurs via mechanical constraints on breathing. Our results provide a potential mechanism by which pentastomes can reduce gecko fitness.


The Transcription Factor ZafA Regulates the Homeostatic and Adaptive Response to Zinc Starvation in Aspergillus fumigatus.
One of the most important features that enables Aspergillus fumigatus to grow within a susceptible individual and to cause disease is its ability to obtain Zn2+ ions from the extremely zinc-limited environment provided by host tissues. Zinc uptake from this source in A. fumigatus relies on ZIP transporters encoded by the zrfA, zrfB and zrfC genes. The expression of these genes is tightly regulated by the ZafA transcription factor that regulates zinc homeostasis and is essential for A. fumigatus virulence. We combined the use of microarrays, Electrophoretic Mobility Shift Assays (EMSA) analyses, DNase I footprinting assays and in silico tools to better understand the regulation of the homeostatic and adaptive response of A. fumigatus to zinc starvation. We found that under zinc-limiting conditions, ZafA functions mainly as a transcriptional activator through binding to a zinc response sequence located in the regulatory regions of its target genes, although it could also function as a repressor of a limited number of genes. In addition to genes involved in the homeostatic response to zinc deficiency, ZafA also influenced, either directly or indirectly, the expression of many other genes. It is remarkable that the expression of many genes involved in iron uptake and ergosterol biosynthesis is strongly reduced under zinc starvation, even though only the expression of some of these genes appeared to be influenced directly or indirectly by ZafA. In addition, it appears to exist in A. fumigatus a zinc/iron cross-homeostatic network to allow the adaptation of the fungus to grow in media containing unbalanced Zn:Fe ratios. The adaptive response to oxidative stress typically linked to zinc starvation was also mediated by ZafA, as was the strong induction of genes involved in gliotoxin biosynthesis and self-protection against endogenous gliotoxin. This study has expanded our knowledge about the regulatory and metabolic changes displayed by A. fumigatus in response to zinc starvation and has helped us to pinpoint new ZafA target genes that could be important for fungal pathogens to survive and grow within host tissues and, hence, for virulence.


Transcriptome Analysis Suggests That Chromosome Introgression Fragments from Sea Island Cotton (Gossypium barbadense) Increase Fiber Strength in Upland Cotton (Gossypium hirsutum).
As high-strength cotton fibers are critical components of high quality cotton, developing cotton cultivars with high-strength fibers as well as high yield is a top priority for cotton development. Recently, chromosome segment substitution lines (CSSLs) have been developed from high-yield Upland cotton (Gossypium hirsutum) crossed with high-quality Sea Island cotton (G. barbadense). Here, we constructed a CSSL population by crossing CCRI45, a high-yield Upland cotton cultivar, with Hai1, a Sea Island cotton cultivar with superior fiber quality. We then selected two CSSLs with significantly higher fiber strength than CCRI45 (MBI7747 and MBI7561), and one CSSL with lower fiber strength than CCRI45 (MBI7285), for further analysis. We sequenced all four transcriptomes at four different time points postanthesis, and clustered the 44,678 identified genes by function. We identified 2200 common differentially-expressed genes (DEGs): those that were found in both high quality CSSLs (MBI7747 and MBI7561), but not in the low quality CSSL (MBI7285). Many of these genes were associated with various metabolic pathways that affect fiber strength. Upregulated DEGs were associated with polysaccharide metabolic regulation, single-organism localization, cell wall organization, and biogenesis, while the downregulated DEGs were associated with microtubule regulation, the cellular response to stress, and the cell cycle. Further analyses indicated that three genes, XLOC_036333 [mannosyl-oligosaccharide-α-mannosidase (MNS1)], XLOC_029945 (FLA8), and XLOC_075372 (snakin-1), were potentially important for the regulation of cotton fiber strength. Our results suggest that these genes may be good candidates for future investigation of the molecular mechanisms of fiber strength formation and for the improvement of cotton fiber quality through molecular breeding.


Heat waves, incidence of infectious gastroenteritis, and relapse rates of inflammatory bowel disease: a retrospective controlled observational study.
The objective of this study was to evaluate the effect of heat waves on flares of inflammatory bowel disease (IBD) and infectious gastroenteritis (IG). In this retrospective controlled observational study, data from 738 IBD and 786 IG patients admitted to the University Hospital of Zurich in the years 2001-2005, as well as from 506 other noninfectious chronic intestinal inflammations, which were used as control, were collected. Climate data were obtained from the Swiss Federal Office for Meteorology and Climatology. The presence of a heat wave increased the risk of IBD flares by 4.6% (95% confidence interval (CI): 1.6-7.4%, P=0.0035) and of IG flares by 4.7% (95% CI: 1.8-7.4%, P=0.0020) for every additional day within a heat wave period. In the control group there was no significant effect (95% CI: -6.2-2.9%, P=0.53). Screening of alternative forms for the effect of heat waves suggested that for IG the effect is strongest when lagged by 7 days (risk increase per day: 7.2%, 95% CI: 4.6-9.7%, P<0.0001), whereas for IBD no such transformation was required. Other formulations with additive effects, interactions between heat waves and time of the year, and additional adjustments for daily average temperature did not show any improvement in model fit. In this retrospective controlled observational study, we found a substantial increase in hospital admissions because of flares of IBD and IG during heat wave periods. Whereas the effect on IG is strongest with a delay of 7 days, the effect on IBD flares is immediate, suggesting different mechanisms.


Infrared spectroscopy of physisorbed and chemisorbed N2 in the Pt(111)(3x3)N2 structure.
Using infrared spectroscopy and low electron energy diffraction, we have investigated the adsorption of N(2), at 30 K, on the Pt(111) and the Pt(111)(1x1)H surfaces. At monolayer coverage, N(2) orders in commensurate (3x3) structures on both surfaces, and we propose that the unit cells contain four molecules in each case. The infrared spectra reveal that N(2) exclusively physisorbs on the Pt(111)(1x1)H surface, while both physisorbed and chemisorbed N(2) is detected on the Pt(111) surface. Physisorbed N(2) is the majority species in the latter case, and the two adsorption states show an almost identical uptake behavior, which indicates that they are intrinsic constituents of the growing (3x3) N(2) islands. An analysis of the infrared absorbance data, based on a simple scaling concept suggested by density functional theory calculations, supports a model in which the (3x3) unit cell contains one chemisorbed molecule in end-on atop configuration and three physisorbed molecules. We note that a classic "pinwheel" structure on a hexagonal lattice, with the end-on chemisorbed N(2) molecules acting as "pins," is compatible with this composition.


Characteristics of Postural Sway during Quiet Standing Before and After the Occurrence of Neurogenic Intermittent Claudication in Female Patients with Degenerative Lumbar Spinal Canal Stenosis.
[Purpose] This study investigated the effect of neurological symptoms and/or signs after the occurrence of neurogenic intermittent claudication (NC) on postural sway during quiet standing of patients with lumbar spinal canal stenosis (LSS). [Subjects and Methods] Thirty-two female patients with LSS at the L4/5 level were studied. We measured the path of center of foot pressure (COP) during quiet standing with eyes open for 30 s using a stabilometer before and after the occurrence of NC. [Results] The total path length of COP (LC) and area surrounded by the outline of the path of COP (AC) significantly increased after NC. Body mass index (BMI) correlated with both the NC rate (after NC/before NC) of LC and that of AC. The average lateral COP displacement from the center of the base of support (COPRL) before NC was located on the asymptomatic side from the center of the base of support in 29 of 32 patients. After NC, COPRL moved to the symptomatic side in 31 patients. [Conclusion] These results suggest that patients with LSS are at risk of falling after NC, especially those with high BMI.


Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue.
Taxotere (RP 56976; NSC 628503; N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol) is a new microtubule stabilizing agent. It is obtained by semisynthesis from a noncytotoxic precursor extracted from the needles of the tree, Taxus baccata L. Taxotere was evaluated for antitumor activity against a variety of transplantable tumors of mice. Taxotere had no marked schedule dependency and was found active by the i.v. and the i.p. routes. Upon i.v. administration, 9 of 11 tumor models tested responded to Taxotere. B16 melanoma was found highly sensitive to Taxotere, with a tumor growth inhibition of 0% and a 3.0 log10 tumor cell kill at the maximum tolerated dose. In the same trial, taxol produced only a 1.1 log10 tumor cell kill at the maximum tolerated dose. Taxotere cured early stage pancreatic ductal adenocarcinoma 03 (6 of 6 cures) and colon adenocarcinoma 38 (7 of 7 cures). It also effected greater than 80% complete regressions of advanced stage disease with both tumors. Taxotere was active against early and advanced stage colon adenocarcinoma 51, with 2.3 and 1.7 log10 cell kill, respectively. Four other tumors responded to a lesser extent: Lewis lung (5.5% tumor growth inhibition), Glasgow osteogenic sarcoma (27.2% tumor growth inhibition), L1210 and P388 leukemias (70 and 54% increase in life span, respectively). Because of its good preclinical activity and its unique mechanism of action, Taxotere has entered Phase I clinical trials.


L-type calcium channel activation up-regulates the mRNAs for two different sodium channel alpha subunits (Nav1.2 and Nav1.3) in rat pituitary GH3 cells.
Calcium entry through L-type Ca2+ channels has been shown to increase the number of Na+ channels in GH3 cells, a clonal line of rat pituitary cells. To test whether this Ca2+ influx affects the levels of Na+ channel mRNAs, we first examined which Na+ channel subunits are expressed in GH3 cells. By using RT-PCR with specific primers, we detected transcripts for four alpha subunits (Nav1.1, Nav1.2, Nav1.3 and Nav1.6) and two auxiliary subunits (beta1 and beta3) of Na+ channels in total RNA from control GH3 cells. Next, we optimized the RT-PCR conditions to allow detection of cDNAs in the linear range of the assay. These conditions were then used to assess the transcript levels of Na+ channels after chronic exposure (72 h) of GH3 cells to the L-type Ca2+ channel blocker nimodipine (1 microM) or the L-type channel agonist Bay K 8644 (0.5 microM). Nimodipine treatment caused a moderate reduction (approximately 30%) of the mRNA for Nav1.2 and a marked reduction (approximately 70%) of the mRNA for Nav1.3, whereas treatment with Bay K 8644 produced 90-130% increases in these same mRNAs. There were no concomitant changes in the mRNAs for Nav1.1 and Nav1.6. Moreover, beta1 and beta3 mRNA levels were also unchanged. Thus, GH3 cells express multiple Na+ channel subunits and L-type Ca2+ channel activity up-regulates in a specific way the mRNAs for Nav1.2 and Nav1.3. These findings improve our knowledge on the molecular diversity of Na+ channels in pituitary cells and extend the actual view about the regulation of Na+ channel gene expression by Ca2+ influx.


Diagnostic Experiences of Children With Attention-Deficit/Hyperactivity Disorder.
This report describes the diagnostic experiences of a sample of children in the United States diagnosed with attention-deficit/hyperactivity disorder (ADHD) as of 2011–2012. Data were drawn from the 2014 National Survey of the Diagnosis and Treatment of Attention-Deficit/Hyperactivity Disorder and Tourette Syndrome, a follow-up to the 2011–2012 National Survey of Children's Health. The median age at which children with ADHD were first diagnosed with the disorder was 7 years; one-third were diagnosed before age 6. Children with ADHD were diagnosed by a wide variety of health care providers, including primary care physicians and specialists. Regardless of age at diagnosis, the majority of children (53.1%) were first diagnosed by primary care physicians. Notable differences were found by age at diagnosis for two types of specialists. Children diagnosed before age 6 were more likely to have been diagnosed by a psychiatrist, and those diagnosed at ages 6 and over were more likely to have been diagnosed by a psychologist. Among children diagnosed with ADHD, the initial concern about a child's behavior was most commonly expressed by a family member (64.7%), but someone from school or daycare first expressed concern for about one-third of children later diagnosed with ADHD (30.1%). For approximately one out of five children (18.1%), only family members provided information to the child's doctor during the ADHD assessment.


Cytoprotective effects of olive mill wastewater extract and its main constituent hydroxytyrosol in PC12 cells.
Evidence from epidemiological studies indicates that adherence to diets rich in secondary plant metabolites, such as polyphenols and phenolic acids, possibly reduces the risk of age-dependent neurodegeneration and subsequent cognitive decline. Olive mill wastewater is particularly rich in the ortho-diphenol hydroxytyrosol (HT) that can be recovered with ad hoc techniques. In a previous study, we showed that hydroxytyrosol-rich olive mill wastewater extract protects dissociated brain cells not only in vitro but also ex vivo after subchronic oral administration of the extract to mice. As plant extracts often contain constituents with potentially confounding activities, our present study aimed to test in vitro whether HT at concentrations present in olive mill wastewater extract is able to protect PC12 cells with similar efficiency. Following a short-term exposure (30min) to the compounds of interest, cells were subjected to oxidative or nitrosative stress by adding either ferrous iron or sodium nitroprusside to the cell culture medium for 18h, respectively. Cytotoxicity was assessed by measuring MTT reduction, cellular ATP levels and mitochondrial membrane potential in the absence and presence of HT or HT-rich olive mill wastewater extract. The results we obtained mainly confirm our previous observation of promising cytoprotection of brain cells by HT-rich olive mill wastewater extract in different stressor paradigms. Furthermore, correlation analyses revealed that the observed cytoprotective effects in PC12 cells are likely due to HT present in the extract.


Central 5-HT receptors and their function; present and future.
Since our review of central 5-HT receptors and their function twenty years ago, no new 5-HT receptor has been discovered and there is little evidence that this situation will change in the near future. Nevertheless, over this time significant progress has been made in our understanding of the properties of these receptors and in the clinical translation of this information, and some of these developments are highlighted herein. Such highlights include extensive mapping of 5-HT receptors in both animal and human brain, culminating in readily-accessible brain atlases of 5-HT receptor distribution, as well as emerging data on how 5-HT receptors are distributed within complex neural circuits. Also, a range of important pharmacological and genetic tools have been developed that allow selective 5-HT receptor manipulation, in cells through to whole organism models. Moreover, unexpected complexity in 5-HT receptor function has been identified including agonist-dependent signalling that goes beyond the pharmacology of canonical 5-HT receptor signalling pathways set down in the 1980s and 1990s. This new knowledge of 5-HT signalling has been extended by the discovery of combined signalling of 5-HT and co-released neurotransmitters, especially glutamate. Another important advance has been the progression of a large number of 5-HT ligands through to experimental medicine studies and clinical trials, and some such agents have already become prescribed therapeutic drugs. Much more needs to be discovered and understood by 5-HT neuropharmacologists, not least how the diverse signalling effects of so many 5-HT receptor types interact with complex neural circuits to generate neurophysiological changes which ultimately lead to altered cognitions and behaviour. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.


Explore Transplant Ontario: Adapting the Explore Transplant Education Program to Facilitate Informed Decision Making About Kidney Transplantation.
In this article, we describe a province-wide collaborative project in which we adapted the Explore Transplant (ET) education program for use in Ontario, Canada, to develop Explore Transplant Ontario (ETO). Kidney transplantation (KT), especially living donor kidney transplantation (LDKT), is the best treatment for many patients with end-stage kidney disease (ESKD), with the best patient survival and quality of life and also reduced health care costs. Yet KT and LDKT are underutilized both internationally and in Canada. Research has demonstrated that patients with ESKD who receive personalized transplant education are more likely to complete the transplant evaluation process and to receive LDKT compared with patients who do not receive this education. Research expertise of the lead authors and Medline search of studies assessing the impact of education interventions on access to KT and LDKT. The ET program, developed by Dr Amy Waterman, has been used in thousands of patients with ESKD in the United States to enhance KT and LDKT knowledge. To adapt this program for use in Ontario, we convened a working group, including patient representatives, nephrologists, transplant coordinators, dialysis nurses, and patient educators from all Ontario KT centers and selected dialysis units. In an iterative process concluding in a consensus workshop, the working group reviewed and edited the text of the original ET program and suggested changes to the videos. The adapted program reflects the Ontario health care environment and responds to the specific needs of patients with chronic kidney disease (CKD) in the province. The videos feature Ontario transplant nephrologists, transplant coordinators, and patients, representative of the ethnic diversity in Ontario, sharing their transplant experience and expertise. Despite the changes, ETO is consistent with the quality and style of the original ET program. At the end of this article, we summarize subsequent steps to test and utilize ETO. Those projects, specifically the ETO pilot study and a multicomponent quality improvement initiative to increase utilization of KT and LDKT across Ontario, will be described in full in future papers. This article describes a provincial initiative; therefore, our findings may not be fully generalizable without further considerations. The adapted education program has not yet been tested in large trial for effectiveness. As a program grounded in the theoretical model of behavior change, ETO places patients with ESKD at the center of a complex process of navigating renal replacement therapy modalities and acknowledges a broad range of patient values, priorities, and states of readiness to pursue KT.


Occupational adaptation: the experiences of older persons with physical disabilities.
The purpose of this phenomenological study was to explore the experiences of occupational adaptation among a small number of older Dutch persons with physical disabilities. Occupational adaptation was tentatively defined as overcoming disabling influences on occupational functioning. Eight occupational therapy clients, who were living in the community, were interviewed using an open in-depth interview format. A phenomenological analysis resulted in descriptions of occupational adaptation as a process that required these clients' active engagement. The clients recruited already familiar problem-solving strategies and personal resources as well as resources in their social and physical environments to identify prospects of potential solutions and to create solutions to overcome constraints on occupational functioning. Furthermore, participants strived for finding satisfaction through occupations, a meaning theme which emerged as the object of occupational adaptation. Satisfaction through occupations was found in maintaining daily routines and engaging in fulfilling occupations.


FANCD2 monoubiquitination and activation by hexavalent chromium [Cr(VI)] exposure: activation is not required for repair of Cr(VI)-induced DSBs.
Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital abnormalities, progressive bone marrow failure, and cancer susceptibility. FA cells are hypersensitive to DNA crosslinking agents. FA is a genetically heterogeneous disease with at least 11 complementation groups. The eight cloned FA proteins interact in a common pathway with established DNA-damage-response proteins, including BRCA1 and ATM. Six FA proteins (A, C, E, F, G, and L) regulate the monoubiquitination of FANCD2 after DNA damage by crosslinking agents, which targets FANCD2 to BRCA1 nuclear foci containing BRCA2 (FANCD1) and RAD51. Some forms of hexavalent chromium [Cr(VI)] are implicated as respiratory carcinogens and induce several types of DNA lesions, including DNA interstrand crosslinks. We have shown that FA-A fibroblasts are hypersensitive to both Cr(VI)-induced apoptosis and clonogenic lethality. Here we show that Cr(VI) treatment induced monoubiquitination of FANCD2 in normal human fibroblasts, providing the first molecular evidence of Cr(VI)-induced activation of the FA pathway. FA-A fibroblasts demonstrated no FANCD2 monoubiquitination, in keeping with the requirement of FA-A for this modification. We also found that Cr(VI) treatment induced significantly more S-phase-dependent DNA double strand breaks (DSBs), as measured by gamma-H2AX expression, in FA-A fibroblasts compared to normal cells. However, and notably, DSBs were repaired equally in both normal and FA-A fibroblasts during recovery from Cr(VI) treatment. While previous research on FA has defined the genetic causes of this disease, it is critical in terms of individual risk assessment to address how cells from FA patients respond to genotoxic insult.


Genetics-based interactions of foundation species affect community diversity, stability and network structure.
We examined the hypothesis that genetics-based interactions between strongly interacting foundation species, the tree Populus angustifolia and the aphid Pemphigus betae, affect arthropod community diversity, stability and species interaction networks of which little is known. In a 2-year experimental manipulation of the tree and its aphid herbivore four major findings emerged: (i) the interactions of these two species determined the composition of an arthropod community of 139 species; (ii) both tree genotype and aphid presence significantly predicted community diversity; (iii) the presence of aphids on genetically susceptible trees increased the stability of arthropod communities across years; and (iv) the experimental removal of aphids affected community network structure (network degree, modularity and tree genotype contribution to modularity). These findings demonstrate that the interactions of foundation species are genetically based, which in turn significantly contributes to community diversity, stability and species interaction networks. These experiments provide an important step in understanding the evolution of Darwin's 'entangled bank', a metaphor that characterizes the complexity and interconnectedness of communities in the wild.


Involvement of intracellular calcium mobilization in IL-8 activation in human retinal pigment epithelial cells.
Calcium signaling is an important intracellular pathway. Increased intracellular calcium is associated with cytokine regulation and inflammatory signals secretion. The purpose of this study is to understand the molecular mechanisms by which calcium signaling controls IL-8 activation in human RPE cells. Fluorescence-based calcium imaging and different mutants of IL-8 plasmids were used in this study. The IL-8 promoter activation, gene expression, and secretion were detected by using luciferase reporter assay, quantitative real-time PCR (Q-PCR), and ELISA, respectively. In addition, pharmacological inhibitors and small interfering RNA (siRNA) were applied to clarify the mechanisms of IL-8 activation. Our study reported that intracellular calcium mobilization activated IL-8 gene expression and secretion. Application of pharmacological inhibitor BAY 11-7082, siRNA, and plasmids of the nuclear factor κ light chain enhancer of activated B cells (NF-κB) binding site, we identified that NF-κB is the main transcription factor involved in intracellular calcium mobilization-mediated IL-8 activation in human RPE cells. Collectively, our findings highlight the important role of intracellular calcium mobilization in the activation of IL-8. These findings may be helpful for the clinical applications in the age-related macular degeneration (AMD) prevention and treatment.


HIV risk and prevention among men who have sex with men in rural South Africa.
Rural South African men who have sex with men (MSM) are likely to be underserved in terms of access to relevant healthcare and HIV prevention services. While research in urban and peri-urban MSM populations has identified a range of factors affecting HIV risk in South African MSM, very little research is available that examines HIV risk and prevention in rural MSM populations. This exploratory study begins to address this lack by assessing perceptions of HIV risk among MSM in rural Limpopo province. Using thematic analysis of interview and discussion data, two overarching global themes that encapsulated participants' understandings of HIV risk and the HIV risk environment in their communities were developed. In the first theme, "community experience and the rural social environment", factors affecting HIV risk within the broad risk environment were discussed. These included perceptions of traditional value systems and communities as homophobic; jealousy and competition between MSM; and the role of social media as a means of meeting other MSM. The second global theme, "HIV/AIDS knowledge, risk and experience", focused on factors more immediately affecting HIV transmission risk. These included: high levels of knowledge of heterosexual HIV risk, but limited knowledge of MSM-specific risk; inconsistent condom and lubricant use; difficulties in negotiating condom and lubricant use due to uneven power dynamics in relationships; competition for sexual partners; multiple concurrent sexual partnerships; and transactional sex. These exploratory results suggest that rural South African MSM, like their urban and peri-urban counterparts, are at high risk of contracting HIV, and that there is a need for more in-depth research into the interactions between the rural context and the specific HIV risk knowledge and behaviours that affect HIV risk in this population.


Hyperprolactinemia in Acromegaly is Related to Prolactin Secretion by Somatolactotroph Tumours.
The aim of this study is to assess differences in patient characteristics, tumour characteristics and hormone levels between acromegalic patients with and without hyperprolactinemia. 44 patients of the University Hospital of Brussels, Belgium with acromegaly who were diagnosed between January 2007 and July 2018 were included in this study. Nineteen patients were classified in the hyperprolactinemia group and 25 patients were classified in the normoprolactinemia group. No significant differences between acromegalic patients with and without hyperprolactinemia were found in age at diagnosis, gender, presence of hyperprolactinemia symptoms, insulin-like growth factor 1, growth hormone and testosterone levels, tumour volume, tumour invasiveness, immunohistochemistry of growth hormone and prolactin, Ki-67 index and mitotic index. However, for a cut-off of 10% of prolactin-positive cells, there was a trend towards a higher percentage of prolactin-positive tumours in hyperprolactinemia patients (p=0.054) and higher mean prolactin level in case of positive prolactin immunostaining (p=0.007)). In our study there were no differences in characteristics between acromegaly patients with hyper- and normoprolactinemia. An association between the serum prolactin level and the positivity of prolactin immunohistochemistry of the adenoma tissue was found. The absence of a difference in tumour volume between patients with hyper- and normoprolactinemia suggests that the hyperprolactinemia is likely to be caused by the co-secretion of growth hormone and prolactin by the tumour. Finally, for the first time, the cut-off of 10% of prolactin cells was validated for the diagnosis of somatolactotroph tumours in acromegaly.


Discrete stochastic charging of aggregate grains.
Dust particles immersed in a plasma environment become charged through the collection of electrons and ions at random times, causing the dust charge to fluctuate about an equilibrium value. Small grains (with radii less than 1 μm) or grains in a tenuous plasma environment are sensitive to single additions of electrons or ions. Here we present a numerical model that allows examination of discrete stochastic charge fluctuations on the surface of aggregate grains and determines the effect of these fluctuations on the dynamics of grain aggregation. We show that the mean and standard deviation of charge on aggregate grains follow the same trends as those predicted for spheres having an equivalent radius, though aggregates exhibit larger variations from the predicted values. In some plasma environments, these charge fluctuations occur on timescales which are relevant for dynamics of aggregate growth. Coupled dynamics and charging models show that charge fluctuations tend to produce aggregates which are much more linear or filamentary than aggregates formed in an environment where the charge is stationary.


How readers process syntactic input depends on their goals.
During reading, the recognition of words is influenced by the syntactic compatibility of surrounding words: a sentence-superiority effect. However, when the goal is to make syntactic categorization decisions about single target words, these decisions are influenced by the syntactic congruency rather than compatibility of surrounding words. Although both these premises imply that readers can extract syntactic information from multiple words in parallel, they also suggest that how the brain organizes syntactic input-and consequently how surrounding stimuli affect word recognition-depends on the reader's top-down goals. The present study provides a direct test of this conception. Participants were offered nouns and verbs amidst a grammatical context ('this horse fell') and ungrammatical context ('fell horse this'). Using a conditional task setup, we manipulated the amount of emphasis put on respectively sentences and single words. In two blocks readers were instructed to make sentence grammaticality judgments only if the middle word was respectively noun or verb; in two other blocks readers were instructed to syntactically categorize the middle word only if the sentence was respectively correct or incorrect. We established an interaction effect whereby the impact of grammatical correctness on syntactic categorization decisions was greater than the effect of grammatical correctness per se. This first sentence-superiority effect in the categorization of single words, combined with the absence of this effect in prior flanker studies, leads us to surmise that word-to-word syntactic constraints only operate if the reader is engaged in sentence processing.


Reprogramming neutral lipid metabolism in mouse dendritic leucocytes hosting live Leishmania amazonensis amastigotes.
After loading with live Leishmania (L) amazonensis amastigotes, mouse myeloid dendritic leucocytes/DLs are known to undergo reprogramming of their immune functions. In the study reported here, we investigated whether the presence of live L. amazonensis amastigotes in mouse bone marrow-derived DLs is able to trigger re-programming of DL lipid, and particularly neutral lipid metabolism. Affymetrix-based transcriptional profiles were determined in C57BL/6 and DBA/2 mouse bone marrow-derived DLs that had been sorted from cultures exposed or not to live L. amazonensis amastigotes. This showed that live amastigote-hosting DLs exhibited a coordinated increase in: (i) long-chain fatty acids (LCFA) and cholesterol uptake/transport, (ii) LCFA and cholesterol (re)-esterification to triacyl-sn-glycerol (TAG) and cholesteryl esters (CE), respectively. As these neutral lipids are known to make up the lipid body (LB) core, oleic acid was added to DL cultures and LB accumulation was compared in live amastigote-hosting versus amastigote-free DLs by epi-fluorescence and transmission electron microscopy. This showed that LBs were both significantly larger and more numerous in live amastigote-hosting mouse dendritic leucocytes. Moreover, many of the larger LB showed intimate contact with the membrane of the parasitophorous vacuoles hosting the live L. amazonensis amastigotes. As leucocyte LBs are known to be more than simple neutral lipid repositories, we set about addressing two related questions. Could LBs provide lipids to live amastigotes hosted within the DL parasitophorous vacuole and also deliver? Could LBs impact either directly or indirectly on the persistence of L. amazonensis amastigotes in rodent skin?


The Comorbidity of Major Depression and Anxiety Disorders: Recognition and Management in Primary Care.
BACKGROUND: Depressive and anxiety disorders commonly occur together in patients presenting in the primary care setting. Although recognition of individual depressive and anxiety disorders has increased substantially in the past decade, recognition of comorbidity still lags. The current report reviews the epidemiology, clinical implications, and management of comorbidity in the primary care setting. METHOD: Literature was reviewed by 2 methods: (1) a MEDLINE search (1980-2001) using the key words depression, depressivedisorders, and anxietydisorders; comorbidity was also searched with individual anxiety diagnoses; and (2) direct search of psychiatry, primary care, and internal medicine journals over the past 5 years. RESULTS: Between 10% and 20% of adults in any given 12-month period will visit their primary care physician during an anxiety or depressive disorder episode (although typically for a nonpsychiatric complaint); more than 50% of these patients suffer from a comorbid second depressive or anxiety disorder. The presence of depressive/anxiety comorbidity substantially increases medical utilization and is associated with greater chronicity, slower recovery, increased rates of recurrence, and greater psychosocial disability. Typically, long-term treatment is indicated, although far less research is available to guide treatment decisions. Selective serotonin reuptake inhibitor antidepressants are the preferred treatment based on efficacy, safety, and tolerability criteria. Knowledge of their differential clinical and pharmacokinetic profiles can assist in optimizing treatment. CONCLUSION: Increased recognition of the high prevalence and negative psychosocial impact of depression and anxiety disorder comorbidity will lead to more effective treatment. While it is hoped that early and effective intervention will yield long-term benefits, research is needed to confirm this.


Regional sharing for adult status 1 candidates: reduction in waitlist mortality.
The intent of regional sharing for status 1 candidates is to promote timely access to donor livers. Presumably this decreases waitlist mortality. Little published data exists that supports this policy. Organ Procurement and Transplantation Network data was used to calculate region 4 and national adult waitlist death and transplant rates 4 yr prior to (period A) and after (period B) implementation of the sharing agreement in July 1999. Death and transplant rates were calculated using a competing risk analysis. Regional sharing resulted in a reduction in adult status 1 waitlist death rate and an increase in transplant rate for region 4 candidates at 7 and 14 days (P > 0.05) without a change in the death rate at 90 days for the non-status 1 candidates. National data showed a significant increase in transplant rate at 7 days and reduction in waitlist death rate at 14 days after listing (P < 0.05). Status 1 waiting time was decreased from 10 to 3 days (P < 0.05). Adult patient survival was not significantly different between the periods. In conclusion, regional sharing for status 1 candidates results in an increased transplant rate and a reduction in waitlist mortality. Sharing did not impact waitlist mortality for non-status 1 candidates.