Cellular HIV-1 immune responses in natural infection and after genetic immunization.
By eliminating infected cells, virus-specific cytotoxic T-lymphocytes (CTL) play a central role in host protection. Many studies to date seem to support the concept that human immunodeficiency virus (HIV)-specific CTL responses contribute to the control of viral replication, and thus delay the onset of disease. The feasibility of improving the virus-specific T-cell immunity by immunizing during the asymptomatic phase of infection has been studied in man. DNA vaccination is a novel strategy, involving direct inoculation of genetic material that is capable of producing antigen intracellularly for presentation to CTL. Such DNA-based immunization has been shown in animal models to be effective for the induction of both cellular and humoral immune responses as well as for protection from infectious challenge. This article reviews the cell-mediated immune responses in natural HIV-1 infection and the induction by DNA vaccination in humans.


Multiple order coded aperture spectrometer.
We introduce a multiple order coded aperture (MOCA) spectrometer. The MOCA is a system that uses a multiplex hologram and a coded aperture to increase the spectral range and throughput of the system over conventional spectrometers while maintaining spectral resolution. This results in an order of magnitude reduction in system volume with no loss in resolution.


Abundant triatomines in Texas dog kennel environments: Triatomine collections, infection with Trypanosoma cruzi, and blood feeding hosts.
Triatomine insects are vectors of the protozoan parasite Trypanosoma cruzi- the causative agent of Chagas disease. Chagas disease is endemic to Latin America and the southern United States and can cause severe cardiac damage in infected mammals, ranging from chronic disease to sudden death. Identifying interactions among triatomines, T. cruzi discrete typing units (DTUs), and blood feeding hosts is necessary to understand parasite transmission dynamics and effectively protect animal and human health. Through manual insect trapping efforts, kennel staff collections, and with the help of a trained scent detection dog, we collected triatomines from 10 multi-dog kennels across central and south Texas over a one-year period (2018-2019) and tested a subset to determine their T. cruzi infection status and identify the primary bloodmeal hosts. We collected 550 triatomines, including Triatoma gerstaeckeri (n=515), Triatoma lecticularia (n=15), Triatoma sanguisuga (n=6), and Triatoma indictiva (n=2), with an additional 10 nymphs and 2 adults unable to be identified to species. The trained dog collected 42 triatomines, including nymphs, from areas not previously considered vector habitat by the kennel owners. Using qPCR, we found a T. cruzi infection prevalence of 47% (74/157), with T. lecticularia individuals more likely to be infected with T. cruzi than other species. Infected insects harbored two T. cruzi discrete typing units: TcI (64%), TcIV (23%), and mixed TcI/TcIV infections (13%). Bloodmeal host identification was successful in 50/149 triatomines, revealing the majority (74%) fed on a dog (Canis lupus), with other host species including humans (Homo sapiens), raccoons (Procyon lotor), chickens (Gallus gallus), wild pig (Sus scrofa), black vulture (Coragyps atratus), cat (Felis catus), and curve-billed thrasher (Toxostoma curviostre). Given the frequency of interactions between dogs and infected triatomines in these kennel environments, dogs may be an apt target for future vector control and T. cruzi intervention efforts.


Patients' experiences in magnetic resonance imaging (MRI) and their experiences of breath holding techniques.
To describe patients' experiences of magnetic resonance examination of the liver and their experiences of two breath-hold techniques. Traditionally, patients are instructed by the radiographer to hold their breath during the examination. Alternatively, the patient can initiate the breath hold and start the image acquisition. Studies have revealed that magnetic resonance examinations can be experienced as challenging. Descriptive qualitative. Semi-structured interviews were conducted with 28 patients and analysed using qualitative content analysis. The data collection was carried out from autumn 2010 to spring 2011. The patients' main experience was that they felt loss of control. This was described in terms of feeling trapped, being lost in time and lost as a result of uncertainty. They had many questions in their mind that they did not ask. Although their statements often revealed no clear preference regarding the techniques, almost half of the patients seemed to prefer self-initiated breath hold, as it was easier and less stressful. Those who preferred the radiographer-directed technique felt more confident leaving the responsibility to the radiographer. In general, the patients understood the importance of achieving the best quality images possible. Magnetic resonance examination can be experienced as being in loss of control. Nevertheless, not all patients wished to actively participate in magnetic resonance examination. Some preferred to hand over the responsibility to the radiographer. These results can form a base for radiographers' reflections of how to individualize and optimize the nursing care of patients undergoing magnetic resonance examinations.


Elevated International Normalized Ratio in a Patient Taking Warfarin and Mauby: A Case Report.
We describe a 70-year-old Haitian man who had been taking warfarin for 5 years for atrial fibrillation and pulmonary hypertension. This patient had his international normalized ratio (INR) checked in the pharmacist-run anticoagulation clinic and was followed monthly. Prior to the interaction, his INR was therapeutic for 5 months while taking warfarin 10.5 mg/d. The patient presented with an INR > 8.0. Patient held 4 days of warfarin and restarted on warfarin 8.5 mg/d. Two weeks later, his INR was 2.5. After continuing dose, patient presented 2 weeks later and INR was 4.8. Upon further questioning, the patient stated he recently began ingesting mauby. Mauby is a bitter dark liquid extracted from the bark of the mauby tree that is commonly used in the Caribbean population as a folk remedy with many health benefits. This case report illustrates that mauby may have a probable drug-herb interaction (Naranjo Algorithm Score of 6) when given with warfarin. There is a lack of published literature and unclear information on the Internet describing the interaction of mauby and warfarin. Health professionals should be cautious regarding interactions between warfarin and mauby until the interaction is fully elucidated.


Evaluation of the effect of the sublingually administered nifedipine and captopril via transcranial doppler ultrasonography during hypertensive crisis.
This study was designed to show the effects of sublingually administered nifedipine and captopril on middle cerebral arterial blood flow during hypertensive crisis in the emergency department. Transcranial Doppler ultrasonography (TCD) was performed on the patients fulfilling the criteria (15 patients given captopril, 13 patients given nifedipine, mean (+/-SD) age 56 +/- 11 and 54 +/- 10 years, respectively). Then, patients were randomized into sublingually administered captopril or nifedipine groups and after the drug administration, TCD was repeated. Initial systolic and diastolic blood pressures were 200 +/- 21/125 +/- 21 mmHg in the captopril group and 199 +/- 17/ 123 +/- 20 mmHg in the nifedipine group. There was no significant difference between antihypertensive effects of the drugs after initiation of treatment. Before the treatment with captopril, middle cerebral artery (MCA) flow velocities (Vm) and pulsatility index (PI) were 76.74 +/- 6.38 cm/s and 1.18 +/- 0.09, respectively. The values after the treatment with captopril were 78.21 +/- 5.24cm/s (p < 0.05) and 0.92 +/- 0.08 (p < 0.001), respectively. Before the treatment with nifedipine, Vm and PIs were 64.73 +/- 5.11 cm/s and 1.14 +/- 0.18, respectively. After the treatment with nifedipine, Vm was 60.04 +/- 5.36 cm/s (p < 0.01) and PI was 1.21 +/- 0.09 (p < 0.01). After treatment with captopril, PIs were decreased to normal limits but in the group treated with nifedipine, PIs increased to more pathological values. These results showed that we should reconsider the use of nifedipine in the emergency departments as an antihypertensive agent in hypertensive attack treatment.


Combined antiretroviral therapy and immune pressure lead to in vivo HIV-1 recombination with ancestral viral genomes.
Studies on drug interruption have provided new insights on the adaptive evolution of rebounding HIV-1 during antiretroviral pressure. We investigated the origin of new viral variants after discontinuation of protease (PR) inhibitors as a treatment remained exclusively based on reverse transcriptase inhibitors, and whether drug susceptibility, viral fitness, and neutralizing antibodies could be major driving forces for the evolution of virus populations. The study comprised 3 treatment-experienced subjects. Phylogenetic analysis of the PR, reverse transcriptase, and the viral envelope were carried out to ascertain the origin of the new viral variants with samples obtained over a 10-year period before and after a PR inhibitor withdrawal. In addition, drug susceptibility, replication capacity, and neutralization assays were performed. New viral variants from all 3 subjects were derived through recombination with ancestral quasispecies. Computerized recombination models confirmed these results. Recombination was demonstrated by increased replication capacity, decreased drug susceptibility, and neutralization of ancestral virus envelope by contemporaneous plasma samples. These findings demonstrate the relevance of HIV-1 reservoirs in adaptive evolution throughout recombination in response to selective pressure, such as antiretroviral therapy and immune responses. This result might assist in the design of new treatment strategies for patients experiencing treatment failure.


Rapid kinetic studies of electron transfer in the three isoforms of nitric oxide synthase.
The nitric oxide synthases (NOSs) consist of a flavin-containing reductase domain, linked to a heme-containing oxygenase domain, by a calmodulin (CaM) binding sequence. The flavin-containing reductase domains of the NOS isoforms possess close sequence homology to NADPH-cytochrome P450 reductase (CPR). Additionally, the oxygenase domains catalyze monooxygenation of L-arginine through a cytochrome P450-like cysteine thiolate-liganded heme bound in the active site. With these considerations in mind, we conducted studies in an attempt to gain insight into the intermediates involved in flavoprotein-to-heme electron transfer in the NOSs. Static, steady-state, and stopped-flow kinetic studies indicated that nNOS must be reduced to a more than one-electron-reduced intermediate before efficient electron transfer can occur. Therefore, the possibility exists that the oxygenase domains of the NOS isoforms may receive their electrons from the reductase domains by a mechanism resembling the CPR-P450 interaction. Furthermore, the rate-limiting step in electron transfer appears to be the transfer of electrons from the flavoprotein to the oxygenase domain facilitated by the binding of CaM at increased intracellular Ca(2+) concentrations. Thus, modulation of electron transfer rates appears to be regulated at the level of the flavoprotein domains of the NOS isoforms.


Periodontal status of patients with Sjögren's syndrome: a cross-sectional study.
Sjögren's Syndrome (SS) is a chronic inflammatory disease characterized by xerostomia. Although it is confirmed that a common observation in SS is increased susceptibility to caries, the degree of influence of SS on periodontal disease has not been well-described. The purpose of this study was to determine the periodontal status of 14 SS female subjects and 14 age-matched females, who did not exhibit SS (controls). The mean age of the SS and control subjects were 52.9 +/- 11.6 and 53.7 +/- 8.9, respectively. The plaque (PI), gingival (GI), bleeding (BI) and calculus (CI) indexes, as well as probing depth (PD) and attachment level (AL), were estimated on 7 index teeth. Data were analyzed by means of the Student t-test. The results indicated that there were no statistically significant differences between the SS and control groups: PI, PD and GI (p greater than 0.05); AL and CI (p greater than 0.1); and BI (p greater than 0.01). Thus, it may be concluded from this study that Sjögren's syndrome has no observable influence upon the indices measured in evaluating periodontal disease.


Unsupervised speaker recognition based on competition between self-organizing maps.
We present a method for clustering the speakers from unlabeled and unsegmented conversation (with known number of speakers), when no a priori knowledge about the identity of the participants is given. Each speaker was modeled by a self-organizing map (SOM). The SOMs were randomly initiated. An iterative algorithm allows the data move from one model to another and adjust the SOMs. The restriction that the data can move only in small groups but not by moving each and every feature vector separately force the SOMs to adjust to speakers (instead of phonemes or other vocal events). This method was applied to high-quality conversations with two to five participants and to two-speaker telephone-quality conversations. The results for two (both high- and telephone-quality) and three speakers were over 80% correct segmentation. The problem becomes even harder when the number of participants is also unknown. Based on the iterative clustering algorithm a validity criterion was also developed to estimate the number of speakers. In 16 out of 17 conversations of high-quality conversations between two and three participants, the estimation of the number of the participants was correct. In telephone-quality the results were poorer.


Electrocardiographic PR Interval Duration and Cardiovascular Risk: Results From the Copenhagen ECG Study.
Because of ambiguous reports in the literature, we aimed to investigate the association between PR interval and the risk of all-cause and cardiovascular death, heart failure, and pacemaker implantation, allowing for a nonlinear relationship. We included 293,111 individuals, corresponding to one-third of the population in the greater region of Copenhagen. These individuals had a digital electrocardiogram recorded in a general practitioner's core facility from 2001-2011. Data on drug use, comorbidities, and outcomes were collected from Danish registries. We divided the population into 7 groups based on the population PR interval distribution. Cox models were used, with reference to a PR interval between 152 and 161 ms (40th to < 60th percentile). During follow-up, we identified 34,783 deaths from all causes, 9867 cardiovascular deaths, 9526 cases of incident heart failure, and 1805 pacemaker implantations. A short PR interval (< 125 ms; hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.08-1.41; P = 0.001) as well as a long PR interval (> 200 ms; HR, 1.23; 95% CI, 1.14-1.32; P < 0.001) was associated with an increased risk of cardiovascular death after multivariable adjustment. A long PR interval conferred an increased risk of heart failure (> 200 ms; HR, 1.31; 95% CI, 1.22-1.42; P < 0.001). An increasing PR interval conferred an increased risk of pacemaker implantation, in a dose-response manner, with the highest risk associated with a PR interval > 200 ms (HR, 3.49; 95% CI, 2.96-4.11; P < 0.001). PR interval was significantly associated with the risk of the adverse outcomes investigated. The nonlinear relationships, in combination with relatively weak associations, could contribute to previously reported conflicting results on the subject.


Kimchi and an active component, beta-sitosterol, reduce oncogenic H-Ras(v12)-induced DNA synthesis.
The Korean fermented vegetable food, kimchi, has been demonstrated to have anticancer functional properties. This study examined the effect of kimchi samples, methanol extracts of commercially grown baechu cabbage kimchi (CK) and organically grown baechu cabbage kimchi (OK), as well as the dichloromethane fraction (DCM fr.) from CK, and the active compound (AC), which has been identified as largely beta-sitosterol, from DCM fr., on the Ras-dependent signaling pathway. CK, OK, and DCM fr. exhibited a greater inhibition against the proliferation of Rat2 fibroblasts transformed with Ras(v12) (HO6) than parental Rat2 fibroblasts. In addition, OK and DCM fr. showed a higher inhibitory effect than CK. Furthermore, we employed the single-cell microinjection technique, combined with 3-bromo-5'-deoxyuridine incorporation, to examine the effects of kimchi samples on DNA synthesis induced by microinjected oncogenic Ras(v12). When the DCM fr. and AC were used to treat Rat1 fibroblasts overexpressing human insulin receptors (HIRc-B) and microinjected with oncogenic H-Ras(v12), the DNA synthesis of injected cells was decreased, suggesting that kimchi might block the signaling pathway of oncogenic Ras(v12), thus preventing the proliferation of transformed cells. This study provides additional evidence that kimchi and its active components, including beta-sitosterol, have potential in both the prevention and treatment of cancer, and presents convincing evidence that the anticancer effects may be a result of an inhibition of Ras oncogene signaling.


Repetitive scratching and noxious heat do not inhibit histamine-induced itch in atopic dermatitis.
Repetitive scratching is the most common behavioural response to itch in atopic dermatitis (AD). Patients with chronic itch often report that very hot showers inhibit itch. We recently reported that scratching and noxious heat stimuli inhibit histamine-induced itch in healthy subjects. However, no psychophysical studies have been performed in AD to assess the effects of repetitive heat pain stimuli and scratching on histamine-induced itch. To examine the effects of repetitive noxious heat and scratching on itch intensity in patients with AD using quantitative sensory testing devices. Itch was induced with histamine iontophoresis in 16 patients with AD in both lesional and nonlesional skin as well as in 10 healthy subjects. Repetitive noxious heat and scratching were applied 3 cm distal to the area of histamine iontophoresis. Subjects rated their perceived intensity of histamine-induced itch with a computerized visual analogue scale. Our results demonstrate that repetitive noxious heat and scratching do not inhibit itch intensity in lesional and nonlesional AD skin but do so in healthy skin. Of note, both these stimuli increase itch intensity in lesional AD skin. Our results strongly suggest that scratching and noxious thermal stimuli have a different effect upon histamine-induced itch perception in patients with AD when compared with healthy controls. This difference may be associated with both peripheral and central sensitization of nerve fibres in AD.


Flavivirus enzyme-substrate interactions studied with chimeric proteinases: identification of an intragenic locus important for substrate recognition.
The proteins of flaviviruses are translated as a single long polyprotein which is co- and posttranslationally processed by both cellular and viral proteinases. We have studied the processing of flavivirus polyproteins in vitro by a viral proteinase located within protein NS3 that cleaves at least three sites within the nonstructural region of the polyprotein, acting primarily autocatalytically. Recombinant polyproteins in which part of the polyprotein is derived from yellow fever virus and part from dengue virus were used. We found that polyproteins containing the yellow fever virus cleavage sites were processed efficiently by the yellow fever virus enzyme, by the dengue virus enzyme, and by various chimeric enzymes. In contrast, dengue virus cleavage sites were cleaved inefficiently by the dengue virus enzyme and not at all by the yellow fever virus enzyme. Studies with chimeric proteinases and with site-directed mutants provided evidence for a direct interaction between the cleavage sites and the proposed substrate-binding pocket of the enzyme. We also found that the efficiency and order of processing could be altered by site-directed mutagenesis of the proposed substrate-binding pocket.


Myosin switching during amoebo-plasmodial differentiation of slime mold, Physarum polycephalum.
We reported previously that myosins from amoebal and plasmodial stages in the life cycle of Physarum polycephalum differ in the primary structure of heavy chains and phosphorylatable 18,000 Mr light chains, while Ca-binding 14,000 Mr light chains are common to both myosins (Kohama & Takano-Ohmuro, Proc Jpn acad 60B (1984) 431; Kohama et al., J biol chem 260 (1986) 8022). We have carried out immunofluorescence microscopical studies upon differentiating cultures of amoebic colonies, which show apogamic amoebo-plasmodial differentiation as follows: Typical amoebae differentiate into mono-nucleate intermediate cells with swollen nuclei and then into two or multi-nucleate young plasmodia (Anderson et al., Protoplasma 89 (1976) 29. Antibodies against plasmodial myosin heavy chain (PMHC) and 18,000 Mr plasmodial myosin light chain (PMLC18) stained intermediate cells and young plasmodia, but not typical amoebae. On the other hand, antibody against amoebal myosin heavy chain (AMHC) stained typical amoebae and intermediate cells--but not young plasmodia. Thus staining was detected using antibodies against both PMHC and AMHC in intermediate cells. Intermediate cells were also stained by antibody against another plasmodium-specific cytoskeletal protein, viz., high molecular weight actin-binding protein (HMWP). We propose that synthesis of myosin subunits switches immediately from amoebal to plasmodial type in mono-nucleate cells with swollen nuclei. This myosin switching is associated with the initiation of HMWP synthesis.


Risk Stratification for Early-Onset Colorectal Cancer Using a Combination of Genetic and Environmental Risk Scores: An International Multi-Center Study.
The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants. Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve. Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores. Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.


Using the acetyl bromide assay to determine lignin concentrations in herbaceous plants: some cautionary notes.
The acetyl bromide assay was developed to provide a rapid and sensitive method for quantifying lignin in woody plant species. The original procedure cautioned against prolonged reaction times and advised keeping the reaction temperature at 70 degrees C to prevent excessive carbohydrate degradation that would skew the absorption spectra. Characterization of the reaction conditions revealed that the acetyl bromide reagent readily degrades xylans, a prominent polysaccharide group within all lignified plants. This degradation results in increased absorbance in the 270-280 nm region that is used to quantify lignin. The degradation of xylans is temperature dependent and is exacerbated by the addition of perchloric acid. Lowering the reaction temperature to 50 degrees C and increasing the reaction time from 2 to 4 h allows complete lignin solubilization but minimizes degradation of the xylans.


Involvement of hydrogen peroxide in repression of catalase in TMV-infected resistant tobacco.
Catalases are ubiquitous, and play a role in plant defense against pathogens. We have reported that catalase mRNA and enzyme activity are repressed in the vicinity of hypersensitive tobacco lesions following TMV infection. We wished to identify the signals involved in this repression. Inoculation with TMV reduced catalase levels 26 to 28 h following infection, coincident with the known timing of endogenous salicylic acid (SA) accumulation. Application of SA caused a transient reduction in Ngcat1 mRNA level and catalase activity 4 to 6 h after treatment. However, repression was also observed in transgenic plants harboring the salicylate hydroxylase gene (NahG) and in TMV susceptible plants, which do not accumulate SA following TMV infection. In the same blots there was no induction of PR-1 or enhanced expression of H2O2-inducible glutathione-S-transferase and found that exposure to H2O2 also repressed Ngcat1 mRNA. Our findings suggest that repression of catalase transcription may be caused by the accumulation of H2O2 rather than of SA.


In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium falciparum isolates from the Kenyan coast: emergence of parasites with Ile-164-Leu mutation.
We have analyzed the activities of the antifolates pyrimethamine (PM), chlorcycloguanil (CCG), WR99210, trimethoprim (TMP), methotrexate (MTX), and trimetrexate (TMX) against Kenyan Plasmodium falciparum isolates adapted in vitro for long-term culture. We have also assessed the relationship between these drug activities and mutations in dihydrofolate reductase (dhfr), a domain of the gene associated with antifolate resistance. As expected, WR99210 was the most potent drug, with a median 50% inhibitory concentration (IC50) of <0.075 nM, followed by TMX, with a median IC50 of 30 nM. The median IC50 of CCG was 37.80 nM, and that of MTX was 83.60 nM. PM and TMP were the least active drugs, with median IC50s of 733.26 nM and 29,656.04 nM, respectively. We analyzed parasite dhfr genotypes by the PCR-enzyme restriction technique. No wild-type dhfr parasite was found. Twenty-four of 33 parasites were triple mutants (mutations at codons 108, 51, and 59), and only 8/33 were double mutants (mutations at codons 108 and 51 or at codons 108 and 59). IC50s were 2.1-fold (PM) and 3.6-fold (TMP) higher in triple than in double mutants, though these differences were not statistically significant. Interestingly, we have identified a parasite harboring a mutation at codon 164 (Ile-164-Leu) in addition to mutations at codons 108, 51, and 59. This quadruple mutant parasite had the highest TMP IC50 and was in the upper 10th percentile against PM and CCG. We confirmed the presence of this mutation by sequencing. Thus, TMX and MTX are potent against P. falciparum, and quadruple mutants are now emerging in Africa.


Elastic ankle exoskeletons reduce soleus muscle force but not work in human hopping.
Inspired by elastic energy storage and return in tendons of human leg muscle-tendon units (MTU), exoskeletons often place a spring in parallel with an MTU to assist the MTU. However, this might perturb the normally efficient MTU mechanics and actually increase active muscle mechanical work. This study tested the effects of elastic parallel assistance on MTU mechanics. Participants hopped with and without spring-loaded ankle exoskeletons that assisted plantar flexion. An inverse dynamics analysis, combined with in vivo ultrasound imaging of soleus fascicles and surface electromyography, was used to determine muscle-tendon mechanics and activations. Whole body net metabolic power was obtained from indirect calorimetry. When hopping with spring-loaded exoskeletons, soleus activation was reduced (30-70%) and so was the magnitude of soleus force (peak force reduced by 30%) and the average rate of soleus force generation (by 50%). Although forces were lower, average positive fascicle power remained unchanged, owing to increased fascicle excursion (+4-5 mm). Net metabolic power was reduced with exoskeleton assistance (19%). These findings highlighted that parallel assistance to a muscle with appreciable series elasticity may have some negative consequences, and that the metabolic cost associated with generating force may be more pronounced than the cost of doing work for these muscles.


Childhood asthma: exhaled markers of airway inflammation, asthma control score, and lung function tests.
Exhaled markers of airway inflammation become increasingly important in the management of childhood asthma. The aims of the present study are: 1) to compare exhaled markers of inflammation (nitric oxide, carbon monoxide, and acidity of breath condensate) with conventional asthma measures (lung function tests and asthma control score) in childhood asthma; and 2) to investigate the detectability of albumin, CRP, IL-6, IL-8, TNF-alpha, sICAM-1, and sTNF-R75 in the exhaled breath condensate (EBC) of asthmatic children. Thirty-two children with mild to moderate persistent asthma and healthy controls aged 6-12 years were studied. We measured exhaled NO and CO, and subsequently EBC was collected. Inflammatory mediators in EBC were measured using an enzyme-linked immunosorbent assay. Respiratory symptoms and asthma control were assessed using the asthma control questionnaire (ACQ) of Juniper et al. (Eur Respir J 1999;14:902-907). Exhaled NO showed a significant correlation with exhaled CO (r = 0.59, P < 0.05) and FEV1 (r = -0.59, P < 0.05), but not with ACQ score (r = 0.48, P = 0.06). Exhaled CO was correlated with prebronchodilator FEV1 (r = -0.45, P < 0.05), but not with asthma control (r = 0.18, P = 0.35). Acidity of EBC was significantly lower in asthmatic children than in healthy controls (P < 0.05), but did not correlate with any of the conventional asthma measures. We were not able to demonstrate the presence of CRP, IL-6, IL-8, TNF-alpha, sICAM-1, and sTNF-R75 in EBC. Albumin was found in two EBC samples of asthmatic children. We conclude that exhaled NO had a better correlation with lung function parameters and asthma control than exhaled CO and acidity of EBC, in mild to moderate persistent childhood asthma. However, exhaled NO, CO, and deaerated pH of EBC did not differ between asthmatic children and controls, possibly because of a too homogeneous and well-controlled study population. To further evaluate the clinical utility of exhaled markers in monitoring childhood asthma, more studies are required on a wider range of asthma severity, and preferably with repeated measurements of markers and of asthma control.


Surgical anatomy of the parotid duct with emphasis on the major tributaries forming the duct and the relationship of the facial nerve to the duct.
Although there is a great amount in the literature to describe the anatomy of the parotid gland as a whole, little attention is given to the parotid duct. The purpose of this study is to examine the surgical anatomy of the parotid duct with special emphasis placed on the major tributaries forming the parotid duct and the relationship of the facial nerve to the duct. Twenty-nine fresh cadaver halves were dissected and the branching pattern of the ducts, position within the parotid, and their relationship to the facial nerve were studied. Of the complete heads studied, the parotid duct had the same pattern in 78.6% on the right and left sides. The parotid ducts in 31.0% of the half heads presented as a single discernible duct from parotid papilla to within the gland. In 62.1% of the half heads, the ducts were formed by a branching pattern within the gland. In the ducts with a branching pattern, 48.3% displayed a bifurcated pattern, 6.9% were trifurcated, and 6.9% had multiple branches. In 6.9% of the half heads studied, the parotid ducts bifurcated distal to the parotid gland. In all cases, the deep lobe of the parotid enveloped the parotid duct; only small ductules connected the superficial lobe with the duct. The facial nerve and its branches were always observed lateral to the parotid duct. Because one dissects lateral to the facial nerve during a superficial parotidectomy, generally the parotid duct remains intact and potential complications such as facial paralysis, sialoceles, and fistulizations are thereby minimized.


Towards new TB vaccines: What are the challenges?
New and effective tuberculosis (TB) vaccines are urgently needed to control pulmonary TB, and in particular to prevent the spread of drug-resistant strains of Mycobacterium tuberculosis. These drug-resistant strains can range from those resistant to first-line drugs to those that are almost impossible to treat. To develop new and effective vaccines for HIV and malaria has been difficult and it is proving to be just as challenging for TB. TB is a complicated disease with a spectrum from apparently controlled latent infection to active clinical disease and so different types of preventive or post-exposure vaccine may be needed. Identifying the most promising vaccine candidates to move into clinical trials is difficult, as we lack biomarker signatures that can predict protective efficacy. There is a risk that the failure of the MVA-85A vaccine to show efficacy when given to previously BCG-vaccinated South African infants will impact on the resources available for the development and trials of other candidate TB vaccines. Continued support for the development of new TB vaccines should remain a priority as an effective vaccine would bring huge public health benefits.


Relating faults in diagnostic reasoning with diagnostic errors and patient harm.
The relationship between faults in diagnostic reasoning, diagnostic errors, and patient harm has hardly been studied. This study examined suboptimal cognitive acts (SCAs; i.e., faults in diagnostic reasoning), related them to the occurrence of diagnostic errors and patient harm, and studied the causes. Four expert internists reviewed patient records of 247 dyspnea patients, using a specially developed questionnaire to detect SCAs. The patients were treated by 72 physicians between May 2007 and February 2008 in five Dutch hospitals. The findings of the record review were discussed with the treating physicians, and the causes of SCAs were classified using Reason's taxonomy of unsafe acts. Statistical analyses were performed with descriptive statistics and independent t tests to compare groups. Furthermore, a reliability study was conducted to assess the interrater reliability. SCAs occurred in 163 of 247 cases reviewed (66%). In 34 (13.8%) of all cases, a diagnostic error occurred, and in 28 (11.3%) cases, the patient was harmed. Cases with diagnostic errors or patient harm had more SCAs. However, in 10 (4.0%) of the cases, diagnostic errors or patient harm occurred, though there were no SCAs. The causes of SCAs were mostly mistakes (i.e., the planned action was incorrect). In cases with more SCAs, diagnostic errors and patient harm occurred more often, suggesting that the number of SCAs per case was predictive of the occurrence of these events. The most common causes were mistakes, meaning that physicians did not realize their actions were incorrect.


The role of interferon in the adenovirus-induced augmentation of granulocyte-mediated cytotoxicity in chicken.
The effects of human adenoviruses on the granulocyte-mediated natural cytotoxicity of chicken leukocytes were investigated. A significant, but transient augmentation of granulocyte cytotoxicity was observed 24 h after virus injection, followed by a relatively long period of its suppression. A good correlation was found between the augmented cytotoxicity and interferon induction. The interferon-inducing capacity of adenovirus type 6 and type 12 in vitro similarly ran parallel with their ability to stimulate granulocyte-mediated cytotoxicity. An adenovirus-induced elevation of cytotoxicity was not observed when IFN production was inhibited by pretreatment of the leukocytes with monoclonal antibody specific for bursal cells and monocytes. In addition, anti-IFN antibody abrogated the stimulation of cytotoxicity as well. During the in vitro experiments in which granulocyte-specific monoclonal antibody was applied, evidence was found that the effector cell activity is associated with the granulocytes. These results suggest that both the in vitro and the in vivo adenovirus-induced augmentation of granulocyte-mediated cytotoxicity is due to the IFN-inducing capacity of the virus. In chickens, the rapid augmentation of the granulocyte cytotoxicity may be important in the acute stage of infection, increasing the resistance to the virus in question and also to bacterial infections.


Infectious complications of open type III tibial fractures among combat casualties.
Combat is associated with high-energy explosive injuries, often resulting in open tibial fractures complicated by nonunion and infection. We characterize the infections seen in conjunction with combat-associated type III tibial fractures. We performed a retrospective medical records review to identify US military service members wounded in Iraq or Afghanistan with open diaphyseal tibial fractures who were admitted to our facility (Brooke Army Medical Center, Fort Sam Houston, Texas) between March 2003 and September 2006. Of the 62 patients with open tibial fractures who were identified in our initial search, 40 had fractures that met our inclusion criteria as type III diaphyseal tibial fractures. Three patients were excluded because their fractures were managed with early limb amputation, and 2 were excluded because of incomplete follow-up records. Twenty-seven of these 35 patients had at least 1 organism present in initial deep-wound cultures that were performed at admission to the hospital. The pathogens that were identified most frequently were Acinetobacter, Enterobacter species, and Pseudomonas aeruginosa. Thirteen of the 35 patients had union times of >9 months that appeared to be associated with infection. None of the gram-negative bacteria identified in the initial wound cultures were recovered again at the time of a second operation; however, all patients had at least 1 staphylococcal organism. One patient had an organism present during initial culture and in the nonunion wound; this organism was a methicillin-resistant Staphylococcus aureus strain that was inadvertently not treated. Five of 35 patients ultimately required limb amputation, with infectious complications cited as the reason for amputation in 4 of these cases. Combat-associated type III tibial fractures are predominantly associated with infections due to gram-negative organisms, and these infections are generally successfully treated. Recurrent infections are predominantly due to staphylococci.


[Recurrence of Clostridium difficile-associated diarrhoea prevented by the administration of a whey concentrate from specifically immunised cows; prospective study].
To try to prevent recurrences of Clostridium difficile-associated diarrhoea (CDAD) by treatment with a specific neutralising secretory IgA-enriched whey-protein concentrate (40%) made from the milk of cows immunised with C. difficile and its toxins. Prospective, non-blinded, clinical cohort study. In 2005-2006, 100 consecutive patients with CDAD received the whey concentrate for 2 weeks after completion of standard antibiotic therapy. For a period of 60 days after the start of the administration, the safety and preliminary efficacy of the whey concentrate were evaluated by means of a diary, blood determinations, active surveillance for adverse events, and the recurrence of CDAD. The whey concentrate was well tolerated and no safety issues were raised. Eleven out of 109 episodes (10%) were followed by a recurrence. After completion of the whey concentrate therapy, a positive test for faecal toxins or culture of C. difficile was predictive for the recurrence of CDAD (relative risk: 8.2 (95% CI: 1.04-64), and 4.7 (95% CI: 0.5-47), respectively). A positive faeces toxin during administration of the whey concentrate was also associated with an early recurrence of CDAD. Compared to historical and contemporary findings in control groups, the whey concentrate appeared to reduce the recurrence of CDAD by about 50%. However, the standard dose of the whey concentrate was probably not sufficient to fully neutralise the C. difficile toxins in faeces in all episodes.


Possible influence of bacterial quorum sensing on the hydrolysis of sinking particulate organic carbon in marine environments.
A central component of the ocean's biological carbon pump is the export of sinking, photosynthetically derived, particulate organic carbon (POC). Bacteria colonize these particles and produce enzymes that hydrolyse sinking POC thereby acting as one of the major controls on the biological pump. Here we provide evidence that a bacterial cell-cell communication mechanism, quorum sensing (QS), may influence the activity of hydrolytic enzymes on sinking particles. We collected sinking POC from a site off Vancouver Island, Canada and found that it contained acylated homoserine lactones (AHLs), a suite of well-known bacterial communication molecules. Furthermore, we observed that the addition of exogenous AHLs to incubations containing sinking POC affected the activity of key hydrolytic enzymes involved in POC degradation in some cases. Our results suggest that AHL-based QS could play an important role in regulating the degradation of sinking POC and that variability in AHL-triggered POC hydrolysis is a heretofore unrecognized process that impacts the marine biological carbon pump.


Retardation of ossification of the lumbar vertebral column in ankylosing spondylitis by means of phenylbutazone.
Does phenylbutazone exert an inhibitory influence on the progression of ossification of the lumbar vertebral column? In a retrospective study of 40 definite cases of ankylosing spondylitis the case histories were divided into periods demarcated by the radiological examinations. An adequately exact method was used for quantitative assessment of ossification. The periods were divided into three groups: (A) continuous phenylbutazone medication; (B) phenylbutazone medication, but not throughout the period; (C) no phenylbutazone medication. Rapid progression of ossification had occurred in group C. In group A, ossification had either remained absent or, if already in progress, had been arrested or substantially delayed. In early or relatively early stages of ankylosing spondylitis, continuous phenylbutazone medication can completely or largely control ossification of the vertebral column. Possibilities of further improvement of this therapy are discussed.


Obesity and food insecurity at the same table: how head start programs respond.
Head Start is a federally funded early childhood education program that serves just over 900,000 US children, many of whom are at risk for obesity, are living in food insecure households, or both. The objective of this study was to describe Head Start practices related to assessing body mass index (BMI), addressing food insecurity, and determining portion sizes at meals. A survey was mailed in 2008 to all eligible Head Start programs (N = 1,810) as part of the Study of Healthy Activity and Eating Practices and Environments in Head Start. We describe program directors' responses to questions about BMI, food insecurity, and portion sizes. The response rate was 87% (N = 1,583). Nearly all programs (99.5%) reported obtaining height and weight data, 78% of programs calculated BMI for all children, and 50% of programs discussed height and weight measurements with all families. In 14% of programs, directors reported that staff often or very often saw children who did not seem to be getting enough to eat at home; 55% saw this sometimes, 26% rarely, and 5% never. Fifty-four percent of programs addressed perceived food insecurity by giving extra food to children and families. In 39% of programs, staff primarily decided what portion sizes children received at meals, and in 55% the children primarily decided on their own portions. Head Start programs should consider moving resources from assessing BMI to assessing household food security and providing training and technical assistance to help staff manage children's portion sizes.


Substance abuse and homelessness: social selection or social adaptation?
Although substance abuse has for many years been documented as a serious problem among homeless populations, there is as yet no clear understanding of the nature of the relationship between substance abuse and homelessness. We evaluate alternative social selection and social adaptation models of this process. Using data from a random probability sample, the substance abuse and homeless experiences of 303 homeless people and people at risk of homelessness in Cook County, Illinois, were investigated. Proportional hazards regression models were employed to assess both social selection and social adaptation models. Drug but not alcohol abuse was associated with first homeless episode. Prior homeless experiences were found to be predictive of first symptoms of both alcohol and drug abuse. Other variables, including the availability of social and economic resources, were also associated with each of these outcomes. Models of both selection and adaptation processes are necessary to account for the association between homelessness and substance abuse, indicating that a multi-directional model is more appropriate. In addition findings suggest that, in recent years, drugs may have displaced alcohol as an important precursor of homelessness for many individuals.


Hypotension Prediction Index Software to Prevent Intraoperative Hypotension during Major Non-Cardiac Surgery: Protocol for a European Multicenter Prospective Observational Registry (EU-HYPROTECT).
Background: Intraoperative hypotension is common in patients having non-cardiac surgery and associated with postoperative acute myocardial injury, acute kidney injury, and mortality. Avoiding intraoperative hypotension is a complex task for anesthesiologists. Using artificial intelligence to predict hypotension from clinical and hemodynamic data is an innovative and intriguing approach. The AcumenTM Hypotension Prediction Index (HPI) software (Edwards Lifesciences; Irvine, CA, USA) was developed using artificial intelligence—specifically machine learning—and predicts hypotension from blood pressure waveform features. We aimed to describe the incidence, duration, severity, and causes of intraoperative hypotension when using HPI monitoring in patients having elective major non-cardiac surgery. Methods: We built up a European, multicenter, prospective, observational registry including at least 700 evaluable patients from five European countries. The registry includes consenting adults (≥18 years) who were scheduled for elective major non-cardiac surgery under general anesthesia that was expected to last at least 120 min and in whom arterial catheter placement and HPI monitoring was planned. The major objectives are to quantify and characterize intraoperative hypotension (defined as a mean arterial pressure [MAP] < 65 mmHg) when using HPI monitoring. This includes the time-weighted average (TWA) MAP < 65 mmHg, area under a MAP of 65 mmHg, the number of episodes of a MAP < 65 mmHg, the proportion of patients with at least one episode (1 min or more) of a MAP < 65 mmHg, and the absolute maximum decrease below a MAP of 65 mmHg. In addition, we will assess causes of intraoperative hypotension and investigate associations between intraoperative hypotension and postoperative outcomes. Discussion: There are only sparse data on the effect of using HPI monitoring on intraoperative hypotension in patients having elective major non-cardiac surgery. Therefore, we built up a European, multicenter, prospective, observational registry to describe the incidence, duration, severity, and causes of intraoperative hypotension when using HPI monitoring in patients having elective major non-cardiac surgery.


Pharmacological activation of the p53 pathway in haematological malignancies.
p53 gene mutations are rarely detected at diagnosis in common haematological cancers such as multiple myeloma (MM), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and Hodgkin's disease (HD), although their prevalence may increase with progression to more aggressive or advanced stages. Therapeutic induction of p53 might therefore be particularly suitable for the treatment of haematological malignancies. Some of the anti-tumour activity of current chemotherapeutics has been derived from activation of p53. However, until recently it was unknown whether p53 signalling is functional in certain haematological cancers including MM and if p53 activity is sufficient to trigger an apoptotic response. With the recent discovery of nutlins, which represent the first highly selective small molecule inhibitors of the p53-MDM2 interaction, pharmacological tools are now available to induce p53 irrespective of upstream signalling defects, and to functionally analyse the downstream p53 pathway in primary leukaemia and lymphoma cells. Combination therapy is emerging as a key factor, and development of non-genotoxic combinations seems very promising for tackling the problems of toxicity and resistance. This review will highlight recent findings in the research into molecules capable of modulating p53 protein activities and mechanisms that activate the p53 pathway, restoring response to therapy in haematological malignancies.


Generation of vector vortex beams by axially symmetric sheared polymer network liquid crystals.
Liquid crystals have been widely used in optoelectronic devices because of their fast response and excellent electro-optic properties. Featuring a unique ability to manipulate light, they are also proposed as a good candidate in topological photonics for further applications. In this study, an axially symmetric sheared polymer network liquid crystal (ASPNLC) is fabricated to demonstrate vector vortex beams. Linearly and circularly polarized light is used to illuminate the sample, and the output vector vortex beams generated from the ASPNLC indicate that the polarization states of the output beams are dependent on the polarization of the incident light. The measured phenomena are modeled on the bases of phase retardation and Jones calculus to eventually calculate the polarization-resolved intensity profiles accordingly. Hence, our experimental study provides a holistic understanding of the method for generating vector vortex beams by an ASPNLC, which is expected to enhance the knowledge of optical mechanisms for liquid crystal applications.


Metalloproteinase digestion of cartilage proteoglycan. Pattern of cleavage by stromelysin and susceptibility to collagenase.
The action of purified rabbit bone stromelysin was investigated on proteoglycan aggregates from pig laryngeal cartilage. The enzyme caused a rapid fall in viscosity of proteoglycan aggregate solution (6 mg/ml), and the products of a partial digest (60% loss of relative viscosity) and a complete digest (95% loss of relative viscosity) were characterized. Analysis by gel chromatography on Sepharose 2B under associative conditions showed that 95% of the glycosaminoglycans in the complete digest were in small-sized fragments, whereas most of the hyaluronan-binding G1 domain and link protein remained intact and bound to hyaluronan. In contrast, there was extensive digestion of the G2 domain which resulted in 76% loss in its detection by immunoassay. Analysis of the partial digest also showed considerable loss (40%) of detection of the G2 domain, but the glycosaminoglycan-rich fragments were much larger than in the complete digest. There was also much less cleavage to create small fragments containing the G1 domain. This was evident on SDS/PAGE analysis where a 58 kDa G1 domain fragment was abundant in the complete digest, but was only present in small amounts in the partial digest. There was also only very limited conversion of link protein from a 44 kDa form to a 40 kDa form. The digestion of proteoglycan aggregate (6 mg/ml) by stromelysin was unaffected by the addition of a high concentration of extra chondroitin sulphate chains (14 mg/ml), and the digestion of proteoglycan monomer showed that the G1 domain was resistant to stromelysin digestion even when not bound to hyaluronan and link protein. The results show that stromelysin degrades the proteoglycan protein core with major cleavages close to, but not within, the G1 domain, and extensive cleavage in other regions. Experiments with purified collagenase, a metalloproteinase structurally related to stromelysin, showed that it too cleaved proteoglycan at several sites within the glycosaminoglycan-rich region of the core protein. Metalloproteinase attack on proteoglycan thus not only occurs with stromelysin but also with collagenase.


The infection of rat tongue mucosa in vitro with five species of Candida.
Orthokeratinised mucosa from the dorsal surface of neonatal rat tongue was maintained in culture and then infected with Candida albicans, C. tropicalis C. krusei, C. parapsilosis or C. guilliermondii for up to 45 h. The five species showed varying abilities to invade the tissues, which appeared to reflect their different pathogenicities. C. albicans was the only species able to invade all the tissues present, including the stratum corneum. C. tropicalis and C. krusei were able to invade connective tissue and the deeper nucleated cells of the epithelium but failed to penetrate the keratin layer, while C. parapsilosis and C. guilliermondii showed only slight invasion of the connective tissue. The keratin layer of rat tongue mucosa thus appeared to act as a barrier to invasion of the epithelium by anything but virulent species of candidal fungi. The results suggest that oral mucosa in vitro retains its structural integrity and that the tissues do not act solely as a passive growth medium through which any fungal strain might proliferate. It seems that this in-vitro system is representative of the in-vivo situation and forms a useful experimental model in which to investigate the host-fungal relationship in mucosal candidiasis.


Usefulness of ultra-sensitive prostate-specific antigen following radical prostatectomy.
This study aimed to evaluate the usefulness of ultra-sensitive prostate-specific antigen (PSA) following radical prostatectomy (RP). Between September, 2003 and March, 2009, a total of 311 prostate cancer patients underwent antegrade RP; following the exclusion of 111 patients due to prior hormonal therapy, 200 patients were finally included in this study. The results of the multivariate analysis identified RP Gleason score, extraprostatic extension, lymph node metastasis and PSA nadir as significant predictors of biochemical failure (P=0.0116, 0.0216, 0.0178 and <0.0001, respectively) and PSA nadir <0.008 ng/ml exhibited the highest hazard ratio (HR) [HR=26.34; 95% confidence interval (CI): 7.34-104.69]. After a median follow-up period of 52.2 months, the biochemical failure-free rate in the PSA nadir <0.008 and ≥0.008 ng/ml groups was 94.3 and 58.8%, respectively, with a statistically significant difference according to the log-rank test (P<0.001). In the multivariate analysis, statistically significant differences were observed only in pathological nodel stage within the PSA nadir <0.008 ng/ml group (P=0.0107). For this reason, postoperative follow-up using ultra-sensitive PSA is considered to be of value, since the use of high-sensitivity PSA to confirm a reduction to below postoperative measurement threshold value (PSA nadir <0.008 ng/ml) may avert administering unnecessary additional treatment, regardless of pathological reccurrence factors.


Infection control practices in Minnesota nursing homes.
Because infection is a major cause of hospitalization among nursing home residents, we assessed infection control activities and related employee health policies in Minnesota nursing homes, using a questionnaire. The majority of institutions (378/440, 85.9%) responded. We found traditional isolation techniques were widely used, but blood and urine precautions were employed in less than half of the homes. Infection surveillance tended to focus on chart review. Antibiotic utilization studies were done in 76% of homes. Procedures for urinary catheter care were often at variance with current recommendations. Employee health policies required a physical examination of a new employee in a minority of institutions. Policies required by Minnesota statute (eg, skin testing for tuberculosis and documentation of employee illness) were carried out by most institutions. Infection control policies and procedures in nursing homes should be redefined so that, where appropriate, they are more consistent with practices in acute-care hospitals.


Comparative study of anxiety, depression, somatization, functional disability, and illness attribution in adolescents with chronic fatigue or migraine.
To compare adolescents with migraine, unexplained profound chronic fatigue of >6 months duration, and normal school controls on measures of anxiety, depression, somatization, functional disability, and illness attribution. Adolescents referred to Children's Hospital and Regional Medical Center for behavioral treatment of migraine (n = 179) or evaluation of chronic fatigue (n = 97) were compared with a group of healthy controls of similar age and sex from a middle school (n = 32). Subjects completed the Spielberger State-Trait Anxiety Inventory-Trait Form, the Children's Depression Inventory, the Childhood Somatization Inventory, and estimated the number of school days missed in the past 6 months because of illness. Migraine and fatigued subjects completed an illness attribution questionnaire. Subjects in the 3 groups were 56% to 70% female and ranged from 11 years old to 18 years old with a mean age of 14.0 +/- 2.0. Forty-six of the 97 chronically fatigued adolescents met 1994 Centers for Disease Control and Prevention (CDC) criteria for chronic fatigue syndrome (CDC-CFS), while 51 had idiopathic chronic fatigue syndrome (I-CFS) that did not meet full CDC criteria. Adolescents with migraine had significantly higher anxiety scores than those with I-CFS or controls and higher somatization scores than controls. Adolescents with CDC-CFS had significantly higher anxiety scores than those with I-CFS or controls, and higher depression and somatization scores than all other groups. There were significant differences between all groups for school days missed with CDC-CFS more than I-CFS more than migraine more than controls. Parents of adolescents with unexplained I-CFS had significantly lower attribution scores relating illness to possible psychological or stress factors than parents of adolescents with CDC-CFS or migraine. Adolescents referred to an academic center for evaluation of unexplained chronic fatigue had greater rates of school absenteeism than adolescents with migraine or healthy controls. Those meeting CDC-CFS criteria had higher anxiety scores than controls and higher depression and somatization scores than migraineurs or controls. Parents of adolescents with I-CFS were less likely to endorse psychological factors as possibly contributing to their symptoms than parents of adolescents with CDC-CFS or migraine.


Assessment of Reported Trial Characteristics, Rate of Publication, and Inclusion of Mandatory Biopsies of Research Biopsies in Clinical Trials in Oncology.
Research biopsies are frequently incorporated within clinical trials in oncology and are often a mandatory requirement for trial enrollment. However, limited information is available regarding the extent and completeness of research biopsy reporting. To determine the rate of research biopsy reporting for clinical trials registered in ClinicalTrials.gov and determine the clinical trial factors that correlated with research biopsy reporting. ClinicalTrials.gov (CTG) was searched for all oncologic therapeutic clinical trials with completion dates between January 1, 2000, and January 1, 2015, with end point category terms including biopsy, biopsies, or tissue. The date of the final publication search was March 12, 2018. Trials conducting only diagnostic biopsies or trials using bone marrow biopsies or liquid biopsies were excluded. Credit for biopsy reporting was given for any mention of performing or results from tissue biopsies in publications. Clinical trials were compared with the highest level of corresponding publication or registry report. Fisher exact test was used for analysis. A total of 301 clinical trials were identified, with a median of 37 patients (range, 1-1310 patients) enrolled per trial. After a median follow-up time of 5.8 years from trial completion, 244 of 301 trials (81.1%) reported results: publications in 195 (64.8%) and CTG registry in 49 (16.3%). Reporting of trial results was associated with later-stage trials (phase 2/3) (137 of 153 [89.5%] for phase 2/3 vs 107 of 148 [72.3%] for phase 1 or 1/2 trials; P < .001). Results from research biopsies were reported in 153 of 301 (50.8%) trials or in 153 of 244 (62.7%) trials with published results. Rates varied by type of presentation: 142 of 195 publications (72.8%) vs 11 of 49 CTG reports (22.4%) (P < .001). Conducting mandatory biopsies (82.1% [101 of 123] vs 43.0% [52 of 121]; P < .001), early-phase clinical trials (70.1% [75 of 107] vs 56.9% [78 of 137]; P = .03), and listing the biopsy as a primary objective in CTG (76.3% [45 of 59] vs 58.4% [108 of 185]; P = .01) was associated with improved biopsy reporting. Trials that met their primary end point (71.9% [115 of 160] vs 45.2% [38 of 84]; P < .001) and those published in higher-impact journals (81.1% [77 of 95] vs 65.0% [65 of 100]; P = .01) had improved biopsy reporting. Mandatory biopsies and biopsy reporting increased over time with similar slopes (P = .58). Despite ethical obligations to report research biopsies, only 50.8% of all trials that included a research biopsy-related end point in CTG reported on these biopsy-related results. Improved efforts are needed to report results obtained from research biopsies.


The impact of coronary artery endarterectomy on outcomes during coronary artery bypass grafting.
The impact of coronary artery endarterectomy during coronary artery bypass grafting (CABG) has been debated. We examined the early and late outcomes of CABG with endarterectomy (CE) compared to CABG alone. Patients undergoing isolated CABG operations from 2003 to 2008 were retrospectively reviewed. We identified 99 patients who underwent CE and 3:1 propensity matched them to 297 CABG-alone patients based upon clinical factors: Society of Thoracic Surgeons (STS) predicted risk of mortality, age, gender, year of surgery, and ejection fraction. Patient risk factors as well as short- and long-term outcomes were compared by univariate and Kaplan-Meier analysis. Preoperative risk factors were similar between patients undergoing CE or CABG alone. Cross-clamp times (95.6 vs. 71.8 minutes, p = 0.0001) and perfusion times (121.8 vs. 92.7 minutes, p = 0.0001) were longer in patients undergoing CE. Operative mortality (4.0% vs. 1.3%, p = 0.112) and postoperative complications were not significantly different between groups. Patients undergoing coronary endarterectomy incurred longer ICU (75.06 vs. 48.64 hours, p = 0.001) and hospital stays (9.01 vs. 7.7 days, p = 0.034). Long-term mortality (mean follow-up = 27.7 ± 17.7 months) was equivalent despite revascularization technique (p = 0.13); however, patients undergoing CE encountered worse overall freedom from myocardial infarction (MI) (p = 0.03). Patients undergoing CABG with coronary CE required longer ventilatory support and ICU stay yet have comparable operative mortality, major complication rates, and long-term survival to isolated CABG. Coronary endarterectomy should be considered an acceptable adjunct to CABG for patients with extensive coronary artery disease to achieve complete revascularization.


Multi-Fusarium mycotoxin exposure activates Nrf2 and Ahr pathway in the liver of laying hens.
This study investigates gene expression changes in laying hens exposed to trichothecene mycotoxins, known to induce oxidative stress and affect xenobiotic transformation and antioxidants. A 3-day feeding trial tested low and high doses of T-2/HT-2 toxin, DON/3-AcDON/15-AcDON, and FB1 in hen feed. Results showed increased expression of AHR, AHRR, HSP90, and CYP1A2 genes on days 2 and 3, suggesting a response to mycotoxin exposure. High doses down-regulated CYP1A2, AHR, and AHRR on day 1. KEAP1 expression decreased on day 1 but increased dose-dependently on days 2 and 3. NRF2 was up-regulated by low and down-regulated by high doses on day 1, then increased on days 2 and 3. Antioxidant-related genes (GPX3, GPX4, GSS, GSR) showed dose-dependent responses. Low doses up-regulated GPX3 and GPX4 throughout, while high doses up-regulated GPX3 on days 2 and 3 and GPX4 on day 3. GSS was up-regulated on day 3. Results indicate that toxic metabolites formed by phase I biotransformation rapidly induce ROS formation at low doses through the AHR/Hsp70/CYP1A2 pathway at the gene expression level, but at high levels, ROS-induced oxidative stress manifests later. Study showed simultaneous activation of redox-sensitive pathways: aryl hydrocarbon receptor (Ahr) and nuclear factor erythroid-derived 2-like 2 (Nrf2) by multi-mycotoxin exposure.


Comparison of Oral Montelukast and Intranasal Fluticasone in Patients with Asthma and Allergic Rhinitis.
Even though the links between upper and lower airway had been of interest to clinicians since long back, it has not attracted the attention of the researchers till recent past. But the evidence is still far from conclusive, due to limited number of randomized controlled trials available on subjects with concomitant allergic rhinitis and asthma. This gap in the knowledge is even more conspicuous in Indian population. The current study is conducted with an objective of comparing the efficacy and tolerability of intranasal Fluticasone and oral Montelukast in treatment of allergic rhinitis and bronchial asthma. The study was a prospective randomized, single blinded, comparative, parallel group study, with two intervention groups conducted in a tertiary teaching hospital in Chennai, Southern India. One hundred and twenty patients diagnosed with concomitant diagnosis of allergic rhinitis and bronchial asthma was randomly allocated to either Fluticasone propionate aqueous nasal spray or oral Montelukast group. Out of total 120 subjects recruited, 108 subjects were included in the final analysis. The mean reduction in asthma and rhinitis symptom scores and improvement in PEFR was higher for Group A, compared to Group B during all the follow-up periods. No statistically significant difference was observed in proportion of subjects reporting exacerbations in the current study. Both the treatments were well tolerated. Addition of intranasal Fluticasone propionate to Salmeterol plus Fluticasone is beneficial in improving asthma control, allergic rhinitis control and lung functions as compared to oral Montelukast. Thereby the use of intranasal Fluticasone Propionate in comparison to oral Montelukast in control of Allergic Rhinitis is justified as per the significant improvement in outcome measures.


A novel transcript encoding an N-terminally truncated AML1/PEBP2 alphaB protein interferes with transactivation and blocks granulocytic differentiation of 32Dcl3 myeloid cells.
The gene AML1/PEBP2 alphaB encodes the alpha subunit of transcription factor PEBP2/CBF and is essential for the establishment of fetal liver hematopoiesis. Rearrangements of AML1 are frequently associated with several types of human leukemia. Three types of AML1 cDNA isoforms have been described to date; they have been designated AML1a, AML1b, and AML1c. All of these isoforms encode the conserved-Runt domain, which harbors the DNA binding and heterodimerization activities. We have identified a new isoform of the AML1 transcript, termed AML1 deltaN, in which exon 1 is directly connected to exon 4 by alternative splicing. The AML1 deltaN transcript was detected in various hematopoietic cell lines of lymphoid to myeloid cell origin, as revealed by RNase protection and reverse transcriptase PCR analyses. The protein product of AML1 deltaN lacks the N-terminal region of AML1, including half of the Runt domain, and neither binds to DNA nor heterodimerizes with the beta subunit. However, AML1 deltaN was found to interfere with the transactivation activity of PEBP2, and the molecular region responsible for this activity was identified. Stable expression of AML1 deltaN in 32Dcl3 myeloid cells blocked granulocytic differentiation in response to granulocyte colony-stimulating factor. These results suggest that AML1 deltaN acts as a modulator of AML1 function and serves as a useful tool to dissect the functional domains in the C-terminal region of AML1.


The influence of neural tube-derived factors on differentiation of neural crest cells in vitro. I. Histochemical study on the appearance of adrenergic cells.
The neural crest gives rise to numerous derivatives including adrenergic and cholinergic neurons, supportive cells of the nervous system, and melanocytes. In tissue culture, neural crest cells explanted from both cranial and trunk regions were found to differentiate into adrenergic neuroblasts or into pigmented cells when grown in medium containing 10% chick embryo extract. When the embryo extract concentration was lowered to 2%, no catecholamine-containing cells (as assayed by formaldehyde-induced fluorescence) were detected, although pigment cells were observed. These results suggest the presence of a factor(s) in embryo extract that promotes or supports adrenergic differentiation. To examine the possible tissue sources of this factor(s), neural tube, notochord, or somite cells were used to condition medium containing 2% embryo extract. When neural crest cells were grown in medium conditioned by neural tube cells, adrenergic neuroblasts were observed in all cultures. However, somite- and notochord conditioned medium did not support adrenergic differentiation. In addition, medium supplemented with extracts derived from central nervous system components did support adrenergic expression, whereas medium supplemented with embryo extract from which the neural tissue was removed did not. Direct contact with neural tube cell ghost membranes was unable to substitute for high embryo extract concentrations or for neural tube-conditioned medium. These results suggest that the neural tube makes a diffusible factor(s) that will support adrenergic differentiation of neural crest cells.


Precision Tailoring Quasi-BIC Resonance of a-Si:H Metasurfaces.
The capability of tailoring the resonance wavelength of metasurfaces is important as it can alleviate the manufacturing precision required to produce the exact structure according to the design of the nanoresonators. Tuning of Fano resonances by applying heat has been theoretically predicted in the case of silicon metasurfaces. Here, we experimentally demonstrate the permanent tailoring of quasi-bound states in the continuum (quasi-BIC) resonance wavelength in an a-Si:H metasurface and quantitatively analyze the modification in the Q-factor with gradual heating. A gradual increment in temperature leads to a spectral shift in the resonance wavelength. With the support of ellipsometry measurements, the spectral shift resulting from the short-duration (ten minutes) heating is identified to be due to refractive index variations in the material rather than a geometric effect or amorphous/polycrystalline phase transition. In the case of quasi-BIC modes in the near-infrared, resonance wavelength could be adjusted from T = 350 °C to T = 550 °C without affecting the Q-factor considerably. Apart from the temperature-induced resonance trimming, large Q-factors can be attained at the highest analyzed temperature (T = 700 °C) in the near-infrared quasi-BIC modes. Resonance tailoring is just one of the possible applications of our results. We expect that our study is also insightful in the design of a-Si:H metasurfaces where large Q-factors are required at high temperatures.


Can rate of recovery be predicted in patients with acute low back pain? Development of a clinical prediction rule.
Some patients with low back pain recover quickly while others continue to experience pain beyond 3 months. The primary aim of this study was to develop a simple prediction rule to help clinicians identify patients with acute low back pain likely to recover at different rates. The secondary aim was to compare a clinician's prognosis judgement to the prediction rule. The study sample included 239 patients with acute low back pain who participated in a randomised controlled trial. The primary outcome was days to recovery from pain. Potential prognostic factors were initially tested for univariate association with recovery using Cox regression (p<0.1). Continuous prognostic factors with a significant association were dichotomised using a median split. Significantly associated prognostic factors were then included in a multivariate forward stepwise Cox regression. We then separated participants into strata according to the number of predictors in the final model for which they were positive. Our results suggest that a clinical prediction rule using three simple prognostic factors was able to differentiate between patients who recover quickly and those who recover slowly. Patients with lower than average initial pain intensity, shorter duration of symptoms and fewer previous episodes recovered more quickly (HR=3.5, 95% CI, 1.8-7.0) than patients without these characteristics. Therapists were able to predict patients likely to recover at different rates, (HR=1.6, 95% CI, 1.2-2.1), however, they did not perform as well as the clinical prediction rule. The rule requires validation in a different sample of patients.


The Effect of Thyroid-Stimulating Hormone on Tumor Size in Differentiated Thyroid Carcinoma.
We evaluated the correlation between serum thyroid-stimulating hormone (TSH) levels and tumor size and other invasiveness parameters of tumor in patients with differentiated thyroid carcinoma (DTC). Several clinical studies have reported that TSH may also have a role as a regulator of the development and function of the thyroid gland. It is currently not clear whether TSH is involved in the existence of thyroid cancer or progression of thyroid cancer or both. Patients with DTC who underwent thyroid surgery between 2003 and 2008 were included this study. Preoperative serum T3, T4, and TSH levels were compared with the size and invasiveness of cancer, retrospectively. DTC was observed in 110 patients over the 5-year period. Seventy-seven (70 %) of them were euthyroid and classified as the "normal-TSH group" (NTG), and 33 (30 %) have an overt or subclinical hyperthyroidism, classified as the "low-TSH group" (LTG). The mean tumor diameter in the LTG was found to be 8.91 ± 8.03 mm; however, it was found to be 18.19 ± 16.24 mm in the NTG. There were significantly differences among the groups related to the diameter of tumor (p = 0.001). Microcarcinoma was determined in 36 patients (46.8 %) in the NTG and 23 patients (69.7 %) in the LTG (p = 0.027). Although there were no significant differences, tumor capsule invasion (33.8 vs. 18.2 %, p = 0.099) and lymphovascular invasion (16.9 vs. 6.1 %, p = 0.130) rates were higher in the NTG. These findings suggest that TSH has effects on growing and proliferation of not only normal thyroid cells but also cancer cells in DTC. This study revealed that serum TSH level can be explored as an important factor that affects the size and invasiveness of tumor in DTC.


Signal Detection in EUROmediCAT: Identification and Evaluation of Medication-Congenital Anomaly Associations and Use of VigiBase as a Complementary Source of Reference.
Knowledge on the safety of medication use during pregnancy is often sparse. Pregnant women are generally excluded from clinical trials, and there is a dependence on post-marketing surveillance to identify teratogenic medications. This study aimed to identify signals of potentially teratogenic medications using EUROmediCAT registry data on medication exposure in pregnancies with a congenital anomaly, and to investigate the use of VigiBase reports of adverse events of medications in the evaluation of these signals. Signals of medication-congenital anomaly associations were identified in EUROmediCAT (21,636 congenital anomaly cases with 32,619 medication exposures), then investigated in a subset of VigiBase (45,749 cases and 165,121 exposures), by reviewing statistical reporting patterns and VigiBase case reports. Evidence from the literature and quantitative and qualitative aspects of both datasets were considered before recommending signals as warranting further independent investigation. EUROmediCAT analysis identified 49 signals of medication-congenital anomaly associations. Incorporating investigation in VigiBase and the literature, these were categorised as follows: four non-specific medications; 11 likely due to maternal disease; 11 well-established teratogens; two reviewed in previous EUROmediCAT studies with limited additional evidence; and 13 with insufficient basis for recommending follow-up. Independent investigations are recommended for eight signals: pregnen (4) derivatives with limb reduction; nitrofuran derivatives with cleft palate and patent ductus arteriosus; salicylic acid and derivatives with atresia or stenosis of other parts of the small intestine and tetralogy of Fallot; carbamazepine with atrioventricular septal defect and severe congenital heart defect; and selective beta-2-adrenoreceptor agonists with posterior urethral valve and/or prune belly. EUROmediCAT data should continue to be used for signal detection, accompanied by information from VigiBase and review of the existing literature to prioritise signals for further independent evaluation.


Mobile consulting as an option for delivering healthcare services in low-resource settings in low- and middle-income countries: A mixed-methods study.
Remote or mobile consulting is being promoted to strengthen health systems, deliver universal health coverage and facilitate safe clinical communication during coronavirus disease 2019 and beyond. We explored whether mobile consulting is a viable option for communities with minimal resources in low- and middle-income countries. We reviewed evidence published since 2018 about mobile consulting in low- and middle-income countries and undertook a scoping study (pre-coronavirus disease) in two rural settings (Pakistan and Tanzania) and five urban slums (Kenya, Nigeria and Bangladesh), using policy/document review, secondary analysis of survey data (from the urban sites) and thematic analysis of interviews/workshops with community members, healthcare workers, digital/telecommunications experts, mobile consulting providers, and local and national decision-makers. Project advisory groups guided the study in each country. We reviewed four empirical studies and seven reviews, analysed data from 5322 urban slum households and engaged with 424 stakeholders in rural and urban sites. Regulatory frameworks are available in each country. Mobile consulting services are operating through provider platforms (n = 5-17) and, at the community level, some direct experience of mobile consulting with healthcare workers using their own phones was reported - for emergencies, advice and care follow-up. Stakeholder willingness was high, provided challenges are addressed in technology, infrastructure, data security, confidentiality, acceptability and health system integration. Mobile consulting can reduce affordability barriers and facilitate care-seeking practices. There are indications of readiness for mobile consulting in communities with minimal resources. However, wider system strengthening is needed to bolster referrals, specialist services, laboratories and supply chains to fully realise the continuity of care and responsiveness that mobile consulting services offer, particularly during/beyond coronavirus disease 2019.


Distinctive anthocyanin accumulation responses to temperature and natural UV radiation of two field-grown (Vitis vinifera L.) cultivars.
The responses of two red grape varieties, Bovale Grande (syn. Carignan) and Cannonau (syn. Grenache), to temperature and natural UV radiation were studied in a three-years field experiment conducted in Sardinia (Italy), under Mediterranean climate conditions. Vines were covered with plastic films with different transmittances to UV radiation and compared to uncovered controls. Light intensity and spectral composition at the fruit zone were monitored and berry skin temperature was recorded from veraison. Total skin anthocyanin content (TSA) and composition indicated positive but inconsistent effects of natural UV light. Elevated temperatures induced alterations to a greater extent, decreasing TSA and increasing the degree of derivatives acylation. In Cannonau total soluble solids increases were not followed by increasing TSA as in Bovale Grande, due to both lower phenolic potential and higher sensitivity to permanence of high temperatures. Multi linear regression analysis tested the effects of different ranges of temperature as source of variation on anthocyanin accumulation patterns. To estimate the thermal time for anthocyanin accumulation, the use of normal heat hours model had benefit from the addition of predictor variables that take into account the permanence of high (>35 °C) and low (<15 °C and <17 °C) temperatures during ripening.


Root cortical aerenchyma inhibits radial nutrient transport in maize (Zea mays).
Formation of root cortical aerenchyma (RCA) can be induced by nutrient deficiency. In species adapted to aerobic soil conditions, this response is adaptive by reducing root maintenance requirements, thereby permitting greater soil exploration. One trade-off of RCA formation may be reduced radial transport of nutrients due to reduction in living cortical tissue. To test this hypothesis, radial nutrient transport in intact roots of maize (Zea mays) was investigated in two radiolabelling experiments employing genotypes with contrasting RCA. In the first experiment, time-course dynamics of phosphate loading into the xylem were measured from excised nodal roots that varied in RCA formation. In the second experiment, uptake of phosphate, calcium and sulphate was measured in seminal roots of intact young plants in which variation in RCA was induced by treatments altering ethylene action or genetic differences. In each of three paired genotype comparisons, the rate of phosphate exudation of high-RCA genotypes was significantly less than that of low-RCA genotypes. In the second experiment, radial nutrient transport of phosphate and calcium was negatively correlated with the extent of RCA for some genotypes. The results support the hypothesis that RCA can reduce radial transport of some nutrients in some genotypes, which could be an important trade-off of this trait.


[Expression of CLIC1 and IGFBP7 in complete hydatidiform mole].
To investigate the expression level of chloride intracellular channel 1 (CLIC1) and insulin-like growth factor binding protein 7 (IGFBP7) in complete hydatidiform mole (CHM) and estimate the relationship between the expression level and clinical prognosis. Immunohistochemistry (IHC) method was used to detect the expression level of P57(KIP2) in order to differentiate CHM. CLIC1 and IGFBP7 expression level of CHM were measured by IHC method then. (1) According to the P57(KIP2) expression result 66 patients were diagnosed as CHM (85.71%). Fourteen of 66 patients progressed into gestational trophoblastic neoplasia (GTN), which accounted for 21.21%. (2) The results of IHC showed that CLIC1 significantly higher expressed in malignant group than spontaneous regressive group (P = 0.014). IGFBP7 significantly down-regulated in malignant group (P = 0.002). (3) Pearson correlation analysis results revealed that there were no relation between the expression of CLIC1 and IGFBP7 (P = 0.761). Logistic regression analysis indicated that down-regulation of IGFBP7 was the independent risk factors of CHM progression, P = 0.005, OR = 8.493 (95% confidence interval (CI): 1.878-38.401); Serum hCG > 5 x 10(5) mIU/mL was the independent risk factors of CHM progression too, P = 0.011, OR = 11.251 (95% CI: 1.731-73.151). (4) Receiver operator characteristic curve (ROC curve) results showed that the area under the curve (AUC) of CLIC1 was 0.707. The optimum cut off was 10.5, and correspondingly sensitivity was 42.90%, specificity 94.20%. AUC of IGFBP7 was 0.764. The optimum cut off was 7.0, and the correspondingly sensitivity and specificity were 64.30% and 78.80% respectively. Combining the two markers in series, the sensitivity of predicting the prognosis of CHM was 21.42%, while the specificity was 100%. When combining in parallel, the sensitivity and specificity were 85.71% and 71.15% respectively. Up-regulation of CLIC1 and down-regulation of IGFBP7 might pay an important role in progression of CHM, but there was no relationship between the expression levels of them. The predictive values of malignance transformation of CHM with the two biomarkers were with certain accuracy, and combining them in parallel test could improve accuracy. They are promising to be candidate prognostic markers of CHM.


Lactobacillus reuteri DSM 20016 produces cobalamin-dependent diol dehydratase in metabolosomes and metabolizes 1,2-propanediol by disproportionation.
A Lactobacillus reuteri strain isolated from sourdough is known to produce the vitamin cobalamin. The organism requires this for glycerol cofermentation by a cobalamin-dependent enzyme, usually termed glycerol dehydratase, in the synthesis of the antimicrobial substance reuterin. We show that the cobalamin-synthesizing capacity of another L. reuteri strain (20016, the type strain, isolated from the human gut and recently sequenced as F275) is genetically and phenotypically linked, as in the Enterobacteriaceae, to the production of a cobalamin-dependent enzyme which is associated with a bacterial microcompartment (metabolosome) and known as diol dehydratase. We show that this enzyme allows L. reuteri to carry out a disproportionation reaction converting 1,2-propanediol to propionate and propanol. The wide distribution of this operon suggests that it is adapted to horizontal transmission between bacteria. However, there are significant genetic and phenotypic differences between the Lactobacillus background and the Enterobacteriaceae. Electron microscopy reveals that the bacterial microcompartment in L. reuteri occupies a smaller percentage of the cytoplasm than in gram-negative bacteria. DNA sequence data show evidence of a regulatory control mechanism different from that in gram-negative bacteria, with the presence of a catabolite-responsive element (CRE) sequence immediately upstream of the pdu operon encoding diol dehydratase and metabolosome structural genes in L. reuteri. The metabolosome-associated diol dehydratase we describe is the only candidate glycerol dehydratase present on inspection of the L. reuteri F275 genome sequence.


Successful management of Graves' disease in a patient undergoing regular dialysis therapy.
Classic Graves' disease associated with thyroid-stimulating hormone receptor antibodies developed in a woman undergoing regular hemodialysis for uremia from chronic pyelonephritis. Her condition responded well to treatment initially with carbimazole and then an ablative dose of sodium iodide I 131 therapy. To our knowledge this is only the second documented case of hyperthyroidism in a patient with chronic renal failure, and it demonstrates that conventional forms of therapy are efficacious and safe.


Plakophilin 2 couples actomyosin remodeling to desmosomal plaque assembly via RhoA.
Plakophilin 2 (PKP2), an armadillo family member closely related to p120 catenin (p120ctn), is a constituent of the intercellular adhesive junction, the desmosome. We previously showed that PKP2 loss prevents the incorporation of desmosome precursors enriched in the plaque protein desmoplakin (DP) into newly forming desmosomes, in part by disrupting PKC-dependent regulation of DP assembly competence. On the basis of the observation that DP incorporation into junctions is cytochalasin D-sensitive, here we ask whether PKP2 may also contribute to actin-dependent regulation of desmosome assembly. We demonstrate that PKP2 knockdown impairs cortical actin remodeling after cadherin ligation, without affecting p120ctn expression or localization. Our data suggest that these defects result from the failure of activated RhoA to localize at intercellular interfaces after cell-cell contact and an elevation of cellular RhoA, stress fibers, and other indicators of contractile signaling in squamous cell lines and atrial cardiomyocytes. Consistent with these observations, RhoA activation accelerated DP redistribution to desmosomes during the first hour of junction assembly, whereas sustained RhoA activity compromised desmosome plaque maturation. Together with our previous findings, these data suggest that PKP2 may functionally link RhoA- and PKC-dependent pathways to drive actin reorganization and regulate DP-IF interactions required for normal desmosome assembly.


Higher incidence of patellar incongruence after under correction of pre-arthritic coronal alignment following medial unicompartmental knee arthroplasty.
This study aimed to compare patellofemoral joint alignment of knees with restored pre-arthritic coronal alignment versus knees with under- or overcorrection from their pre-arthritic coronal alignment following medial unicompartmental knee arthroplasty (UKA) and evaluate the effect of patellofemoral joint alignment on patient-reported outcomes. A retrospective analysis of 517 knees following robotic-arm assisted medial UKA was conducted. Postoperative mechanical hip-knee-ankle angle (mHKA) was compared to estimated pre-arthritic coronal alignment, using the arithmetic hip-knee-ankle angle (aHKA). Knees were considered restored to the pre-arthritic coronal alignment if mHKA was within 2.0° of aHKA (Group 1). Non-restored knees were subdivided into > 2.0° over correction (Group 2), or > 2.0° under correction (Group 3) from the pre-arthritic coronal alignment. Patellar congruence and patellar tilt angles were compared between groups. The Kujala score and Knee Injury and Osteoarthritic Outcome Score for Joint Replacement (KOOS, JR) were analyzed by group. Continuous data was compared using analysis of variance or Kruskal-Wallis tests. Chi-squared tests were used to compare discrete variables. Logistic regressions were conducted to estimate the probability of postoperative patellofemoral malalignment. Group 1 included 357 knees (69.1%), Group 2 included 57 knees (11.0%), and Group 3 included 57 knees (11.0%). The prevalence of postoperative abnormal patellar congruence (i.e. ≥ 17°) was higher in Group 3 at 40.4% (p = 0.009), with a higher odds ratio of having an abnormal patellar congruence angle (2.3, p = 0.01) compared to Group 1. The prevalence of postoperative abnormal patellar tilt (i.e. ≥ 14°) was comparable between groups (n.s.). At mean follow up of 4.4 ± 1.6 years, Kujala was worse in Group 3 (76.6 ± 17.4 compared to 84.0 ± 14.9 and 85.0 ± 14.4 in Groups 1 and 2, respectively; p = 0.006). Mean KOOS, JR outcomes were comparable among groups. No significantly inferior Kujala or KOOS, JR outcomes were observed in patients across all groups with abnormal patellar congruence or tilt angles. Knees with under correction from their pre-arthritic coronal alignment following medial UKA were associated with a two-fold higher probability of having postoperative patellofemoral incongruence, as well as inferior mid-term Kujala scores compared to knees with restored pre-arthritic coronal alignment and knees with overcorrection from their pre-arthritic coronal alignment. Patellofemoral incongruence alone did not negatively impact functional outcome scores. IV, case series.


Anomalous Auditory Cortex Activations in Colored Hearing Synaesthetes: An fMRI-Study.
Color percept induction in synaesthetes by hearing words was previously shown to involve activation of visual and specifically color processing cortex areas. While this provides a rationale for the origin of the anomalous color percept the question of mechanism of this crossmodal activation remains unclear. We pursued this question with fMRI in color hearing synaesthetes by exposing subjects to words and tones. Brain activations in word condition accompanied by highly reliable color percepts were compared with activations in tone condition with only occasional color percepts and both contrasted to activations in normal subjects under the same stimulus conditions. This revealed that already the tone condition similar to the word condition caused abnormally high activations in various cortical areas even though synaesthetic percepts were more rare. Such tone activations were significantly larger than in normal subjects in visual areas of the right occipital lobe, the fusiform gyrus, and the left middle temporal gyrus and in auditory areas of the left superior temporal gyrus. These auditory areas showed strong word and tone activation alike and not the typically lower tone than word activation in normal subjects. Taken together these results are interpreted in favour of the disinhibited feedback hypothesis as the neurophysiological basis of genuine synaesthesia.


The program cost and cost-effectiveness of screening men for Chlamydia to prevent pelvic inflammatory disease in women.
Because men transmit Chlamydia trachomatis to women, screening men to prevent pelvic inflammatory disease in women may be a viable strategy. However, the cost-effectiveness of this approach requires careful assessment. Data from a demonstration project and longitudinal study that examined screening men for chlamydia were applied to a compartment-based transmission model to estimate the cost-effectiveness of screening men for chlamydia compared with alternative interventions, including expanded screening of women and combining disease investigation specialist-provided partner notification with screening. Cases of pelvic inflammatory disease and quality-adjusted life years lost were the primary outcome measures. A male screening program that screened 1% of men in the population annually was modeled. A program targeting high-risk men for screening (those with a larger number of partners in the previous year than the general population and a higher chlamydia prevalence) was cost saving compared with using equivalent program dollars to expand screening of lower-risk women. Combining partner notification with male screening was more effective than screening men alone. In sensitivity analyses, the male program was not always cost saving but averaged $10,520 per quality-adjusted life year saved over expanded screening of women. Screening men can be a cost-effective alternative to screening women, but the men screened must have a relatively high prevalence compared with the women to whom screening would be expanded (under baseline assumptions, the prevalence in screened men was 86% higher than that of screened women). These modeling results suggest that programs targeting venues that have access to high-risk men can be effective tools in chlamydia prevention.


The Eyes Test as a Measure of Individual Differences: How much of the Variance Reflects Verbal IQ?
Developed by Baron-Cohen et al. (1997, 2001), the Reading the Mind in the Eyes Test requires individuals to determine mental states from photos of pairs of eyes. Used in over 250 studies, it has been conceptualized as an advanced theory of mind test that is relatively free of general cognitive abilities. Given the sensitivity of the instrument, many studies with healthy adult samples have used this instrument as a measure of individual differences in social-perceptual processes that contribute to theory of mind and overall phenotype. We administered the two-subtest Wechsler Abbreviated Scale of Intelligence, a face-processing task (Cambridge Face Memory Test), and the Eyes Test to 42 college students. Surprisingly, verbal IQ contributed significantly to the variance in Eyes Test performance while the face perception measure did not. These findings have both practical and theoretical ramifications for interpreting Eyes Test results in normative adult samples.


Protein microarrays: promising tools for proteomic research.
Miniaturized and parallelized ligand binding assays are of great interest in postgenomic research because microarray technology allows the simultaneous determination of a large number of parameters from a minute amount of sample within a single experiment. Assay systems based on this technology are used for the identification and quantification of proteins as well as for the study of protein interactions. Protein affinity assays have been implemented that allow the analysis of interactions between proteins with other proteins, peptides, low molecular weight compounds, oligosaccharides or DNA. Microarray technology is an emerging technology used in global analytical approaches and has a considerable impact on proteomic research.