Invasive aspergillosis localised to the colon presenting as toxic megacolon.
Primary gut involvement by Aspergillus is an exceedingly rare and often a fatal complication of intensive chemotherapy in patients with acute leukaemia. We report a 46-yr-old patient with granulocytic sarcoma of the testis. He received acute myeloid leukaemia type treatment with ADE chemotherapy (Cytosine Arabinoside, Daunorubicin and Etoposide). While neutropenic he presented with pyrexia, abdominal pain and massive abdominal distention. He was treated with intravenous antibiotics and antifungals according to our usual institutional protocol without any response. He was found to have toxic megacolon on plain X-ray and subsequently underwent total colectomy and ileostomy. The colon histology showed Aspergillus fungal hyphae infiltrating the bowel wall. There was no any evidence of pulmonary, hepatic, splenic or renal lesions on the computerised tomography scan. Following colectomy, he was treated with 2 wk of antifungal treatment. He recovered well and was discharged home. The increased awareness, high degree of clinical suspicion of unusual presentation and early surgical intervention with aggressive antifungal treatment, has a key role in the management of these rare and often fatal cases.


Neurogliaform neurons form a novel inhibitory network in the hippocampal CA1 area.
We studied neurogliaform neurons in the stratum lacunosum moleculare of the CA1 hippocampal area. These interneurons have short stellate dendrites and an extensive axonal arbor mainly located in the stratum lacunosum moleculare. Single-cell reverse transcription-PCR showed that these neurons were GABAergic and that the majority expressed mRNA for neuropeptide Y. Most neurogliaform neurons tested were immunoreactive for alpha-actinin-2, and many stratum lacunosum moleculare interneurons coexpressed alpha-actinin-2 and neuropeptide Y. Neurogliaform neurons received monosynaptic, DNQX-sensitive excitatory input from the perforant path, and 40 Hz stimulation of this input evoked EPSCs displaying either depression or initial facilitation, followed by depression. Paired recordings performed between neurogliaform neurons showed that 85% of pairs were electrically connected and 70% were also connected via GABAergic synapses. Injection of sine waveforms into neurons during paired recordings resulted in transmission of the waveforms through the electrical synapse. Unitary IPSCs recorded from neurogliaform pairs readily fatigued, had a slow decay, and had a strong depression of the synaptic response at a 5 Hz stimulation frequency that was antagonized by the GABA(B) antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid (CGP55845). The amplitude of the first IPSC during the 5 Hz stimulation was also increased by CGP55845, suggesting a tonic inhibition of synaptic transmission. A small unitary GABA(B)-mediated IPSC could also be detected, providing the first evidence for such a component between GABAergic interneurons. Electron microscopic localization of the GABA(B1) subunit at neurogliaform synapses revealed the protein in both presynaptic and postsynaptic membranes. Our data disclose a novel interneuronal network well suited for modulating the flow of information between the entorhinal cortex and CA1 hippocampus.


Paracrine signaling through plasma membrane hemichannels.
Plasma membrane hemichannels composed of connexin (Cx) proteins are essential components of gap junction channels but accumulating evidence suggests functions of hemichannels beyond the communication provided by junctional channels. Hemichannels not incorporated into gap junctions, called unapposed hemichannels, can open in response to a variety of signals, electrical and chemical, thereby forming a conduit between the cell's interior and the extracellular milieu. Open hemichannels allow the bidirectional passage of ions and small metabolic or signaling molecules of below 1-2kDa molecular weight. In addition to connexins, hemichannels can also be formed by pannexin (Panx) proteins and current evidence suggests that Cx26, Cx32, Cx36, Cx43 and Panx1, form hemichannels that allow the diffusive release of paracrine messengers. In particular, the case is strong for ATP but substantial evidence is also available for other messengers like glutamate and prostaglandins or metabolic substances like NAD(+) or glutathione. While this field is clearly in expansion, evidence is still lacking at essential points of the paracrine signaling cascade that includes not only messenger release, but also downstream receptor signaling and consequent functional effects. The data available at this moment largely derives from in vitro experiments and still suffers from the difficulty of separating the functions of connexin-based hemichannels from gap junctions and from pannexin hemichannels. However, messengers like ATP or glutamate have universal roles in the body and further defining the contribution of hemichannels as a possible release pathway is expected to open novel avenues for better understanding their contribution to a variety of physiological and pathological processes. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.


The toxicities of A30P and A53T α-synuclein fibrils can be uniquely altered by the length and saturation of fatty acids in phosphatidylserine.
Progressive degeneration of dopaminergic neurons in the midbrain, hypothalamus, and thalamus is a hallmark of Parkinson's disease (PD). Neuronal death is linked to the abrupt aggregation of α-synuclein (α-syn), a small protein that regulates vesicle trafficking in synaptic clefts. Studies of families with a history of PD revealed several mutations in α-syn including A30P and A53T that are linked to the early onset of this pathology. Numerous pieces of evidence indicate that lipids can alter the rate of protein aggregation, as well as modify the secondary structure and toxicity of amyloid oligomers and fibrils. However, the role of lipids in the stability of α-syn mutants remains unclear. In this study, we investigate the effect of phosphatidylserine (PS), an anionic lipid that plays an important role in the recognition of apoptotic cells by macrophages, in the stability of WT, A30P, and A53T α-syn. We found PS with different lengths and saturation of fatty acids accelerated the rate of WT and A30P aggregation. At the same time, the opposite effect was observed for most PS on A53T. We also found that PS with different lengths and saturation of fatty acids change the secondary structure and toxicities of WT, A30P, and A53T fibrils. These results indicate that lipids can play an important role in the onset and spread of familial PD.


Report of the 20th Nationwide follow-up survey of primary liver cancer in Japan.
In the 20th Nationwide Follow-up Survey of Primary Liver Cancer in Japan, data from 21 075 new patients and 40 769 previously followed patients were compiled from 544 institutions over a 2-year period from 1 January 2008 to 31 December 2009. Compared with the previous 19th survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, included more female patients, included more patients with non-B non-C HCC, had smaller tumor diameters and more frequently received radiofrequency ablation as local ablation therapy. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and by background characteristics for patients newly registered between 1998 and 2009 whose final outcome was survival or death. Cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter, and Child-Pugh grade) and by treatment types (hepatectomy, local ablation therapy, and transcatheter arterial chemoembolization). Cumulative survival rates and median overall survival in patients treated by resection, transcatheter arterial chemoembolization, and local ablation therapy were calculated. The same values were also calculated by the registration date by dividing patients newly registered between 1978 and 2009 into four time period groups . The results of the analysis show that the prognosis of HCC is improving dramatically. It is expected that the data obtained from this nationwide follow-up survey will contribute to advancing clinical research, including the design of clinical trials, as well as the treatment strategy of primary liver cancer in the clinical practice setting.


Fatty acids, not insulin, modulate alpha1-adrenergic reactivity in dorsal hand veins.
Resistance to the vasodilator action of insulin and its capacity to antagonize vascular alpha-adrenergic reactivity may contribute to the increased neurovascular tone and blood pressure in obese hypertensive subjects. We showed that nonesterified fatty acids (NEFAs) were elevated in obese hypertensive subjects and that raising NEFAs locally in dorsal hand veins of healthy normotensive subjects enhances alpha1adrenoceptor reactivity. Research by others suggests that insulin antagonizes alpha1-adrenoceptor tone in dorsal hand veins. Taken together with evidence that NEFAs antagonize several of the metabolic actions of insulin, these observations raise the possibility that NEFAs participate in resistance to the vascular effects of insulin and suggest that dorsal hand veins represent a good model for studying these interactions. Thus, we produced local hyperinsulinemia in the dorsal hand veins of six lean normal volunteers and quantified changes of venous distensibility in response to phenylephrine in the presence and absence of a local elevation of NEFAs. We confirmed that raising NEFAs locally decreased by twofold to threefold the phenylephrine ED50 (P<.01), but this alpha1-sensitizing action of NEFAs was not antagonized by insulin concentrations up to approximately 1000 microU/mL. Moreover, local hyperinsulinemia alone did not affect vascular alpha1-adrenergic sensitivity as measured by the phenylephrine ED50. To address the possibility that the absence of an insulin effect reflected a lack of nitric oxide-mediated, endothelium-dependent dilation in hand veins, responses to acetylcholine were obtained. Acetylcholine relaxed preconstricted hand veins by 60% to 80% (P<.01) in the presence and absence of indomethacin, which suggests substantial endothelium-dependent, cyclooxygenase-independent vasodilation. The results confirm that raising NEFAs locally enhances vascular alpha1-adrenoceptor sensitivity. Despite the presence of significant endothelium-dependent dilation in dorsal hand veins, insulin does not antagonize vascular alpha1-adrenoceptor sensitivity in the presence of either ambient or locally elevated fatty acids.


Evaluation outcomes of a Western Australian campaign designed to reduce alcohol use in pregnancy.
To assess (i) the effectiveness of a mass media campaign communicating the potential harms associated with consuming even small amounts of alcohol in pregnancy and (ii) changes in females' intentions to abstain during pregnancy after campaign exposure. Independent samples of ∼400 Western Australian adults (18-45 years) were recruited at two time points (before and after the 'One Drink' campaign) to complete online surveys. Attitudinal and behavioural intention outcomes were assessed at both time points. Descriptive analyses and generalised linear models were used to assess outcomes. Three-quarters (76%) of the post-campaign sample members reported awareness of the campaign. In the descriptive analyses there were significant improvements in three of the seven attitudinal items. The regression models yielded significant increases in agreement that pregnant women should not drink alcohol (assessed among females and males) and intentions to abstain during pregnancy (assessed among females only). The results indicate favourable understanding and behavioural intention effects from exposure to a campaign promoting alcohol abstinence during pregnancy. This study demonstrates that investment in campaigns warning about alcohol use in pregnancy is likely to be a worthwhile approach to reduce the burden of alcohol-related harms to individuals and society.


Mouse model of erectile dysfunction due to diet-induced diabetes mellitus.
To determine whether diet-induced diabetes mellitus (DM) in mice would reproduce the major features of human erectile dysfunction (ED) because DM is a significant risk factor in the development of ED. In total, 150 C57BL6 (bl6) mice were divided into six groups of 25 mice each. Of these 150 mice, 125 were fed a high-fat (45% of total calories) diet for the final 4 (group 2), 8 (group 3), 12 (group 4), 16 (group 5), or 22 (group 6) weeks. Group 1 was fed a normal diet. The mice were 22 to 25 weeks old at study termination. The corporal tissues were harvested and studied for endothelium-dependent and endothelium-independent vasoreactivity, endothelial and smooth muscle cell content by immunohistochemistry, nitric oxide synthase expression by nicotinamide adenine dinucleotide-diaphorase staining, and apoptosis by terminal deoxynucleotidyl transferase biotin-D-UTP nick-end labeling staining. The blood glucose levels were greater in groups 2 to 6 compared with those in group 1. The vasoreactivity, endothelial cell content, and smooth muscle/collagen ratio were lower and apoptosis were greater in the DM mice (P = 0.0001, P = 0.10, P = 0.0002, P <0.001, and P <0.001, respectively). Significantly decreased nitric oxide synthase expression and significantly increased apoptosis (P <0.0001 each) was found in the high-fat diet mice. Corporal tissue from mice with diet-induced DM demonstrated many of the major functional, structural, and biochemical changes found in humans with ED. This model should serve as a valuable tool for advancing our understanding of the role DM plays in the pathogenesis of ED.


BDNF protects against spatial memory deficits following neonatal hypoxia-ischemia.
Hypoxic-ischemic (H-I) brain injury in the human perinatal period often leads to significant long-term neurobehavioral dysfunction in the cognitive and sensory-motor domains. Using a neonatal H-I injury model (unilateral carotid ligation followed by hypoxia) in postnatal day seven rats, previous studies have shown that neurotrophins, such as brain-derived neurotrophic factor (BDNF), can be protective against neural tissue loss. The present study explored potential relationships between neural protective and behavioral protective strategies in this neonatal H-I model by determining if neonatal H-I was associated with behavioral spatial learning and memory deficits and whether the neurotrophin BDNF was protective against both brain injury and spatial learning/memory dysfunction. Postnatal day seven rats received vehicle or BDNF pretreatments (intracerebroventricular injections) followed by H-I or sham treatments and then tested for spatial learning and memory on the simple place task in the Morris water maze from postnatal days 20 to 30, and their brains were histologically analyzed at 4 weeks following treatments. H-I rats with vehicle pretreatment displayed significant tissue loss in the hippocampus (including CA1 neurons), cortex, and striatum, as well as severe spatial memory deficits (e.g., short probe times). BDNF pretreatment resulted in significant protection against both H-I-induced brain tissue losses and spatial memory impairments. These findings indicate that unilateral H-I brain injury in a neonatal rodent model is associated with cognitive deficits, and that BDNF pretreatment is protective against both brain injury and spatial memory impairment.


Exercise Thermoregulation with a Simulated Burn Injury: Impact of Air Temperature.
The U.S. Army's Standards of Medical Fitness (AR 40-501) states: "Prior burn injury (to include donor sites) involving a total body surface area of 40% or more does not meet the standard." However, the standard does not account for the interactive effect of burn injury size and air temperature on exercise thermoregulation. To evaluate whether the detrimental effect of a simulated burn injury on exercise thermoregulation is dependent on air temperature. On eight occasions, nine males cycled for 60 min at a fixed metabolic heat production (6 W·kg) in air temperatures of 40°C or 25°C with simulated burn injuries of 0% (Control), 20%, 40%, or 60% of total body surface area (TBSA). Burn injuries were simulated by covering the skin with an absorbent, vapor-impermeable material to impede evaporation from the covered areas. Core temperature was measured in the gastrointestinal tract via telemetric pill. In 40°C conditions, greater elevations in core temperature were observed with 40% and 60% TBSA simulated burn injuries versus Control (P < 0.01). However, at 25°C, core temperature responses were not different versus Control with 20%, 40%, and 60% TBSA simulated injuries (P = 0.97). The elevation in core temperature at the end of exercise was greater in the 40°C environment with 20%, 40%, and 60% TBSA simulated burn injuries (P ≤ 0.04). Simulated burn injuries ≥20% TBSA exacerbate core temperature responses in hot, but not temperate, air temperatures. These findings suggest that the U.S. Army's standard for inclusion of burned soldiers is appropriate for hot conditions, but could lead to the needless discharge of soldiers who could safely perform their duties in cooler training/operational settings.


Endothelial PTP4A1 mitigates vascular inflammation via USF1/A20 axis-mediated NF-κB inactivation.
The nuclear factor-κB (NF-κB) signalling pathway plays a critical role in the pathogenesis of multiple vascular diseases. However, in endothelial cells (ECs), the molecular mechanisms responsible for the negative regulation of the NF-κB pathway are poorly understood. In this study, we investigated a novel role for protein tyrosine phosphatase type IVA1 (PTP4A1) in NF-κB signalling in ECs. In human tissues, human umbilical artery ECs, and mouse models for loss of function and gain of function of PTP4A1, we conducted histological analysis, immunostaining, laser-captured microdissection assay, lentiviral infection, small interfering RNA transfection, quantitative real-time PCR and reverse transcription-PCR, as well as luciferase reporter gene and chromatin immunoprecipitation assays. Short hairpin RNA-mediated knockdown of PTP4A1 and overexpression of PTP4A1 in ECs indicated that PTP4A1 is critical for inhibiting the expression of cell adhesion molecules (CAMs). PTP4A1 increased the transcriptional activity of upstream stimulatory factor 1 (USF1) by dephosphorylating its S309 residue and subsequently inducing the transcription of tumour necrosis factor-alpha-induced protein 3 (TNFAIP3/A20) and the inhibition of NF-κB activity. Studies on Ptp4a1 knockout or transgenic mice demonstrated that PTP4A1 potently regulates the interleukin 1β-induced expression of CAMs in vivo. In addition, we verified that PTP4A1 deficiency in apolipoprotein E knockout mice exacerbated high-fat high-cholesterol diet-induced atherogenesis with upregulated expression of CAMs. Our data indicate that PTP4A1 is a novel negative regulator of vascular inflammation by inducing USF1/A20 axis-mediated NF-κB inactivation. Therefore, the expression and/or activation of PTP4A1 in ECs might be useful for the treatment of vascular inflammatory diseases.


Women with malignant pleural mesothelioma have a threefold better survival rate than men.
Many studies have reported that women with malignant pleural mesothelioma (MPM) experience longer survival compared with men, whereas others have not. To date, no large population-based studies have evaluated MPM outcome and its determinants in female patients. All pathologically confirmed cases of MPM in the Surveillance, Epidemiology and End Results database from 1973 to 2009 were evaluated. Age, year of diagnosis, race, stage, cancer-directed surgery, radiation, and vital status were analyzed according to gender. Cox proportional hazard models were derived to assess the association between prognostic factors and survival. There were 14,228 cases of MPM, of which 3,196 (22%) were women. Despite similar baseline characteristics for both genders, 5-year survival was 13.4% in women and 4.5% in men (p < 0.0001). The effect of female gender on survival persisted when stratified by age (dichotomized at 50 years), stage, or race, but differed depending on treatment. Even when adjusted for age, stage, race, and treatment, female MPM patients experienced longer survival than men (hazard ratio = 0.78; 95% confidence interval 0.75 to 0.82). This large data set confirms that although MPM is less common in women, they present with similar stage and are offered similar treatment options compared with men. Nevertheless, survival is far better in women compared with men, independent of confounders such as age, stage, and treatment. Differences in asbestos exposure, tumor biology, and the impact of circulating hormones on host response must be investigated to understand this survival advantage and improve prognosis for patients of both genders.


Correlations of flow velocity changes during mental activity and recovery from aphasia in ischemic stroke.
Mean flow velocity in the middle cerebral arteries (MCAs) during a rest period and during execution of a word-fluency task were measured by means of bilateral transcranial Doppler ultrasonography in 26 stroke patients with Broca's aphasia and in 25 healthy controls. Changes in flow velocity were calculated as percentage of increase from rest to mental activity. In patients, the evaluation was made within 21 days from onset of symptoms and after 2 months of speech therapy, when they were classified into two groups on the basis of extent of recovery from aphasia: absent or slight recovery (group 1, 10 patients) and good recovery (group 2, 16 patients). During the word-fluency task in the first evaluation, the increase in flow velocity in the left MCA was similar in controls and in group 2 patients. In both groups the increase was higher than in group 1 patients (p < 0.0001). Changes in mean flow velocity on the right side were slight and comparable in the three groups of study subjects. After speech therapy, group 1 patients showed a hemodynamic pattern on both sides similar to that observed in the first examination. In group 2 patients, comparison between values of the first and second evaluations showed that the increase of flow velocity in the left MCA was similar. On the right side, the increase was higher in the second than in the first examination (p < 0.01). These data further support the involvement of cerebral areas contralateral to the lesion in functional recovery after stroke. Moreover, the presence of an activation of areas in the lesioned hemisphere, soon after stroke onset, seems to be a predictor of recovery from aphasia.


Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease.
The global epidemic of obesity has been accompanied by a rising burden of non-alcoholic fatty liver disease (NAFLD), with manifestations ranging from simple steatosis to non-alcoholic steatohepatitis, potentially developing into hepatocellular carcinoma. Although much attention has focused on NAFLD, its pathogenesis remains largely obscure. The hallmark of NAFLD is the hepatic accumulation of lipids, which subsequently leads to cellular stress and hepatic injury, eventually resulting in chronic liver disease. Abnormal lipid accumulation often coincides with insulin resistance in steatotic livers and is associated with perturbed endoplasmic reticulum (ER) proteostasis in hepatocytes. In response to chronic ER stress, an adaptive signalling pathway known as the unfolded protein response is triggered to restore ER proteostasis. However, the unfolded protein response can cause inflammation, inflammasome activation and, in the case of non-resolvable ER stress, the death of hepatocytes. Experimental data suggest that the unfolded protein response influences hepatic tumour development, aggressiveness and response to treatment, offering novel therapeutic avenues. Herein, we provide an overview of the evidence linking ER stress to NAFLD and discuss possible points of intervention.


Metabolic and electrophysiological changes in the basal ganglia of transgenic Huntington's disease rats.
Huntington's disease (HD) is characterized by neuronal loss in the striatum, ultimately leading to an 'imbalance' in the electrical activity of the basal ganglia-thalamocortical circuits. To restore this 'imbalance' in HD patients, which is held responsible for (some) of the motor symptoms, different basal ganglia nuclei have been targeted for surgical therapies, such as ablative surgery and deep brain stimulation. However, evidence to target brain nuclei for surgical therapies in HD is lacking. We reasoned that a neuronal and metabolic mapping of the basal ganglia nuclei could identify a functional substrate for therapeutic interventions. Therefore, the aim of the present study was to investigate the metabolic and neuronal activity of basal ganglia nuclei in a transgenic rat model of HD (tgHD). Subjects were 10-12 month old tgHD rats and wildtype littermates. We examined the striatum, globus pallidus, entopeduncular nucleus, the subthalamic nucleus and substantia nigra at different levels. First, we determined the overall neuronal activity at a supracellular level, by cytochrome oxidase histochemistry. Secondly, we determined the subcellular metabolic activity, by immunohistochemistry for peroxisome proliferator-activated receptor-γ transcription co-activator (PGC-1α), a key player in the mitochondrial machinery. Finally, we performed extracellular single unit recordings in the nuclei to determine the cellular activity. In tgHD rats, optical density analysis showed a significantly increased cytochrome oxidase levels in the globus pallidus and subthalamic nucleus when compared to controls. PGC-1α expression was only enhanced in the subthalamic nucleus and electrophysiological recordings revealed decreased firing frequency of the majority of the neurons in the globus pallidus and increased firing frequency of the majority of the neurons in the subthalamic nucleus. Altogether, our results suggest that the globus pallidus and subthalamic nucleus play a role in the neurobiology of HD and can be potential targets for therapeutic interventions.


Evolution of shear zones in granular packings under pressure.
Stress transmission in realistic granular media often occurs under external load and in the presence of boundary slip. We investigate shear localization in a split-bottom Couette cell with smooth walls subject to a confining pressure experimentally and by means of numerical simulations. We demonstrate how the characteristics of the shear zone, such as its center position and width, evolve as the confining pressure and wall slip modify the local effective friction coefficient of the material. For increasing applied pressure, the shear zone evolves toward the center of the cylinder and grows wider and the angular velocity reduces compared to the driving rate of the bottom disk. Moreover, the presence of slip promotes the transition from open shear zones at the top surface to closed shear zones inside the bulk. We also systematically vary the ratio of the effective friction near the bottom plate and in the bulk in simulations and observe the resulting impact on the surface flow profile. Besides the boundary conditions and external load, material properties such as grain size are also known to influence the effective friction coefficient. However, our numerical results reveal that the center position and width of the shear zone are insignificantly affected by the choice of the grain size as far as it remains small compared to the radius of the rotating bottom disk.


Nutritional Deficiency-Related Oral and Cutaneous Lesions in an Obese Patient.
The cutaneous and oral lesions related to nutritional deficiencies are scarcely reported. Micronutrient deficiencies may significantly affect mouth mucosa and skin, causing great morbidity. We report an extraordinary case with detailed clinical and microscopic findings affecting the oral cavity and skin. Physicians must be familiar with these manifestations to suspect the diagnosis.


Sex-Specific Moderation Effect of Age on the Associations Between Insomnia Symptoms and Various Psychological Distresses.
Insomnia is closely related to psychological distress. This study aims to examine the role of age and sex in the association between various psychological distresses and insomnia symptoms. This population-based study used data provided by cumulative respondents of the annual survey of the Taiwan Suicide Prevention Center between 2006 and 2019. Potential respondents were aged ≥15 years and were selected by a stratified proportional randomization method according to the distribution of population size, sex, and age in different geographic areas of Taiwan. The Five-Item Brief Symptom Rating Scale was used to measure insomnia symptoms and four psychological distresses: depression, anxiety, hostility, and inferiority. The independent relationship between insomnia symptoms with depression, anxiety, hostility, and inferiority was further examined according to age and sex. A total of 28,649 participants were included (women, 50.2%). The four types of psychological distress correlated differentially with insomnia symptoms. Concerning interaction effects, sex moderated the interaction effects between age with depression, anxiety, and hostility. In men, and not in women, age moderated the relationship between insomnia symptoms and all four psychological distresses. Specifically, the effect sizes of the associations between insomnia symptoms and depression, anxiety, and hostility showed an age-dependent decreasing trend in men. The associations between psychological distresses and insomnia symptoms varied in strength and according to age in a sex-specific manner.


DNA damage inhibits proteolysis of the B-type cyclin Clb5 in S. cerevisiae.
Cell cycle progression is mediated by waves of specific cyclin dependent kinases (CDKs) in all eukaryotes. Cyclins are degraded by the ubiquitin pathway of proteolysis. The recent identification of several components of the cyclin proteolysis machinery has highlighted both the importance of proteolysis at multiple transition points in the cell cycle and the involvement of other substrates degraded by the same machinery. In this study, we have investigated the effects of DNA damage on the cyclin proteolytic machinery in Saccharomyces cerevisiae. We find that the half-life of the B-type cyclin Clb5 is markedly increased following DNA damage while that of G1 cyclins is not. This effect is independent of cell cycle phase. Clb5 turnover requires p34CDC28 activity. Stabilisation of Clb5 correlates with an increase in tyrosine phosphorylation of p34CDC28, but stabilisation does not require this tyrosine phosphorylation. The stabilisation is independent of the checkpoint genes Mec1 and Rad53. These observations establish a new link between the regulation of proteolysis and DNA damage.


Nasopharyngeal actinomycosis on 18F-fluorodeoxyglucose positron emission tomography/computed tomography: A case report.
Actinomycosis is a chronic disease characterized by slow progression, abscess formation, tissue fibrosis and draining sinuses. Occurrence originating from the nasopharynx is extremely low. The present study described the case of a 46-year-old otherwise healthy female, with no remarkable history of mucosal injury or teeth rottenness, who presented with an asymptomatic nasopharyngeal mass that was detected incidentally by 18F-fluorodeoxyglucose positron emission tomography/computed tomography. A nasopharyngoscopy revealed an unclear demarcated granular mass. The patient then underwent a biopsy. Based on the obtained clinical images, microbiological results and histological findings, a diagnosis of actinomycosis was established. The patient experienced an uneventful eradication of the disease after two months of oral antibiotic treatment with amoxicillin. In conclusion, these findings indicate that actinomycosis should be included in the differential diagnosis of nasopharyngeal neoplasms.


Gun storage practices and risk of youth suicide and unintentional firearm injuries.
Household firearms are associated with an elevated risk of firearm death to occupants in the home. Many organizations and health authorities advocate locking firearms and ammunition to prevent access to guns by children and adolescents. The association of these firearm storage practices with the reduction of firearm injury risk is unclear. To measure the association of specific household firearm storage practices (locking guns, locking ammunition, keeping guns unloaded) and the risk of unintentional and self-inflicted firearm injuries. Case-control study of firearms in events identified by medical examiner and coroner offices from 37 counties in Washington, Oregon, and Missouri, and 5 trauma centers in Seattle, Spokane, and Tacoma, Wash, and Kansas City, Mo. CASES AND CONTROLS: Case firearms were identified by involvement in an incident in which a child or adolescent younger than 20 years gained access to a firearm and shot himself/herself intentionally or unintentionally or shot another individual unintentionally. Firearm assaults and homicides were excluded. We used records from hospitals and medical examiners to ascertain these incidents. Using random-digit dial telephone sampling, control firearms were identified by identification of eligible households with at least 1 firearm and children living or visiting in the home. Controls were frequency matched by age group and county. The key exposures of interest in this study were: (1) whether the subject firearm was stored in a locked location or with an extrinsic lock; (2) whether the firearm was stored unloaded; (3) whether the firearm was stored both unloaded in a locked location; (4) whether the ammunition for the firearm was stored separately; and (5) whether the ammunition was stored in a locked location. Data regarding the storage status of case and control guns were collected by interview with respondents from the households of case and control firearms. We interviewed 106 respondents with case firearms and 480 with control firearms. Of the shootings associated with the case firearms, 81 were suicide attempts (95% fatal) and 25 were unintentional injuries (52% fatal). After adjustment for potentially confounding variables, guns from case households were less likely to be stored unloaded than control guns (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.16-0.56). Similarly, case guns were less likely to be stored locked (OR, 0.27; 95% CI, 0.17-0.45), stored separately from ammunition (OR, 0.45; 95% CI, 0.34-0.93), or to have ammunition that was locked (OR, 0.39; 95% CI, 0.23-0.66) than were control guns. These findings were consistent for both handguns and long guns and were also similar for both suicide attempts and unintentional injuries. The 4 practices of keeping a gun locked, unloaded, storing ammunition locked, and in a separate location are each associated with a protective effect and suggest a feasible strategy to reduce these types of injuries in homes with children and teenagers where guns are stored.


Determinants of breast-feeding patterns in an urban society of India.
Breast feeding is the focus of rapidly growing interest in many areas of demographic research. However, relatively few rigorous studies on breast-feeding patterns and correlates in contemporary India have been published. This study uses data from a retrospective survey conducted in 1991-1992 to investigate current breast-feeding patterns and to identify the key factors that influence the duration of exclusive breast feeding and infant's age at the time of weaning in an urban Hindu society of the northeast Indian state of Assam. Applying life table procedures and a hazards regression model, we found evidence that the median duration of exclusive breast feeding and infant's age at the time of weaning were negatively associated with mother's education, per capita income, and social status of the household. Those infants who were breast-fed longer at night than in the daytime were also at greater risk of earlier introduction of non-breast-milk foods and of earlier termination of breast feeding than infants who were breast-fed longer during the day. Gender bias toward males in rearing infants prevails in this urban society, and male infants were found to have a significantly lower risk of early weaning than female infants.


Paracetamol poisonings in the Czech and Slovak Republic and N-acetylcysteine treatment. Data analysis.
Paracetamol overdose belongs to frequent calls to Toxicological Information Centre (TIC) in the Czech Republic and to the National Toxicological Information Centre (NTIC) in Slovakia. The aim of the study was to evaluate outcomes and side effects of paracetamol overdose in both countries. Data concerning paracetamol poisoning extracted from TIC and NTIC databases 2000-2013 and discharge reports were analysed. Numbers and outcomes in patients presenting within 24 hours of a single paracetamol overdose were compared in relation to 3 paracetamol concentration bands (≤ 100 mg/l, 100-149 mg/l, and 150 mg/l). 5397 inquiries concerning paracetamol were recorded in TIS and NTIC. Data from 196 discharge reports with plasma level were studied. Median age of the patients was 18 (0.2-86) years. Eight/196 (4.1%) patients developed side effects after N-acetylcysteine (NAC) administration. 120 cases fulfilled time criteria of the study and were divided into 3 groups, where 55.7%, 73.1% and 96.9% patients have been treated with NAC. Among these 120 patients, favourable outcome was seen in 100%, 100%, and 92.8%, respectively. One death due to suicidal attempt with plasma level 407 mg/l presenting at 20 hours has been recorded among 120 patients. No patient without NAC treatment died due to acute overdose and plasma concentration ≤ 150 mg/I at 4 hours. These data support the opinion that NAC should not be used in patients with < 149 mg/l levels in absence of higher risk factors because of very low risk of hepatotoxicity on one side, and side effects on the other side.


[Concepts involved in the training and work processes of community healthcare agents: a bibliographical review].
This paper is the outcome of a bibliographical review that aims at systemizing references in the literature to concepts involved in the training and work processes of community health agents under the Community Health Agent Program (PACS) and the Family Health Program. Published in scientific journals, manuals and official documents through to October 2004, 504 articles were consulted, of which 49 were selected and examined in full. The findings were systematically arranged under four themes, reviewing controversial aspects raised by authors, outstanding among which are: the 'discourse of change' statements in official documents, defining the Family Health Program as a reorientation strategy for the Primary Healthcare Model; the scope and ambiguity of understandings of the role of mediator and definitions of the duties and responsibilities of Community Healthcare Agents, as well as the gaps in their training.


Questionnaires to Measure Process and Structure of Quality Indicators for Pediatric Nursing.
The quality of nursing care has a significant impact on the outcomes of care. The specific needs of children requiring hospital care make it essential to monitor and compare data not only on the medically oriented outcome measure but also on nursing care, structure, and process, requiring perspectives from registered nurses (RNs) and nurse managers (NMs). Thus, this project aimed to evaluate the structure and process of nursing quality indicators in pediatric hospital care with questionnaires distributed to RN and NM. We developed separate questionnaires for NMs and RNs to assess the process and structure of the quality indicators of breastfeeding, management of pain, venous access, medication management, and provision of a child-oriented environment. Nine NMs and 113 RNs from 9 pediatric wards answered the questionnaires. Local guidelines were available for 3 out of the 5 quality indicators: pain management, venous access, and medication management. RNs reported varying levels of adherence to pain management (62%), and venous access management (72%). Satisfaction with the conditions for safe medication management was 90%. Approximately, two-thirds (67%) of RN reported sufficient knowledge regarding the impact of the child-oriented environment and less than half (44%) regarding how to support breastfeeding. Structure and process is a prerequisite for quality of care outcomes. This study discloses areas for quality improvement and offers instruments to compare structure and process in pediatric nursing care to discuss with consumers, managers, staff, and other stakeholders.


Paternal care and the evolution of exaggerated sexual swellings in primates.
The exaggerated sexual swellings exhibited by females of some primate species have been of interest to evolutionary biologists since the time of Darwin. We summarize existing hypotheses for their function and evolution and categorize these hypotheses within the context of 3 types of variation in sexual swelling size: 1) variation within a single sexual cycle, 2) variation between the sexual cycles of a single female, and 3) differences between females. We then propose the Paternal Care Hypothesis for the function of sexual swellings, which posits that exaggerated sexual swellings function to elicit the right quantity and quality of male care for a female's infant. As others have noted, swellings may allow females to engender paternity confusion, or they may allow females to confer relative paternal certainty on one male. Key to our hypothesis is that both of these scenarios create an incentive for one or more males to provide care. This hypothesis builds on previous hypotheses but differs from them by highlighting the elicitation of paternal care as a key function of swellings. Our hypothesis predicts that true paternal care (in which males accurately differentiate and provide assistance to their own offspring) will be most common in species in which exaggerated swellings accurately signal the probability of conception, and males can monopolize females during the window of highest conception probability. Our hypothesis also predicts that females will experience selection to behave in ways that either augment paternity confusion or enhance paternal certainty depending on their social and demographic contexts.


Effect of a nutrition intervention during early childhood on economic productivity in Guatemalan adults.
Substantial, but indirect, evidence suggests that improving nutrition in early childhood in developing countries is a long-term economic investment. We investigated the direct effect of a nutrition intervention in early childhood on adult economic productivity. We obtained economic data from 1424 Guatemalan individuals (aged 25-42 years) between 2002 and 2004. They accounted for 60% of the 2392 children (aged 0-7 years) who had been enrolled in a nutrition intervention study during 1969-77. In this initial study, two villages were randomly assigned a nutritious supplement (atole) for all children and two villages a less nutritious one (fresco). We estimated annual income, hours worked, and average hourly wages from all economic activities. We used linear regression models, adjusting for potentially confounding factors, to assess the relation between economic variables and exposure to atole or fresco at specific ages between birth and 7 years. Exposure to atole before, but not after, age 3 years was associated with higher hourly wages, but only for men. For exposure to atole from 0 to 2 years, the increase was US$0.67 per hour (95% CI 0.16-1.17), which meant a 46% increase in average wages. There was a non-significant tendency for hours worked to be reduced and for annual incomes to be greater for those exposed to atole from 0 to 2 years. Improving nutrition in early childhood led to substantial increases in wage rates for men, which suggests that investments in early childhood nutrition can be long-term drivers of economic growth.


Improving the photostability of bright monomeric orange and red fluorescent proteins.
All organic fluorophores undergo irreversible photobleaching during prolonged illumination. Although fluorescent proteins typically bleach at a substantially slower rate than many small-molecule dyes, in many cases the lack of sufficient photostability remains an important limiting factor for experiments requiring large numbers of images of single cells. Screening methods focusing solely on brightness or wavelength are highly effective in optimizing both properties, but the absence of selective pressure for photostability in such screens leads to unpredictable photobleaching behavior in the resulting fluorescent proteins. Here we describe an assay for screening libraries of fluorescent proteins for enhanced photostability. With this assay, we developed highly photostable variants of mOrange (a wavelength-shifted monomeric derivative of DsRed from Discosoma sp.) and TagRFP (a monomeric derivative of eqFP578 from Entacmaea quadricolor) that maintain most of the beneficial qualities of the original proteins and perform as reliably as Aequorea victoria GFP derivatives in fusion constructs.


EspL is essential for virulence and stabilizes EspE, EspF and EspH levels in Mycobacterium tuberculosis.
The ESX-1, type VII, secretion system represents the major virulence determinant of Mycobacterium tuberculosis, one of the most successful intracellular pathogens. Here, by combining genetic and high-throughput approaches, we show that EspL, a protein of 115 amino acids, is essential for mediating ESX-1-dependent virulence and for stabilization of EspE, EspF and EspH protein levels. Indeed, an espL knock-out mutant was unable to replicate intracellularly, secrete ESX-1 substrates or stimulate innate cytokine production. Moreover, proteomic studies detected greatly reduced amounts of EspE, EspF and EspH in the espL mutant as compared to the wild type strain, suggesting a role for EspL as a chaperone. The latter conclusion was further supported by discovering that EspL interacts with EspD, which was previously demonstrated to stabilize the ESX-1 substrates and effector proteins, EspA and EspC. Loss of EspL also leads to downregulation in M. tuberculosis of WhiB6, a redox-sensitive transcriptional activator of ESX-1 genes. Overall, our data highlight the importance of a so-far overlooked, though conserved, component of the ESX-1 secretion system and begin to delineate the role played by EspE, EspF and EspH in virulence and host-pathogen interaction.


Infection by agnoprotein-negative mutants of polyomavirus JC and SV40 results in the release of virions that are mostly deficient in DNA content.
Human polyomavirus JC (JCV) is the etiologic agent of a brain disease, known as progressive multifocal leukoencephalopathy (PML). The JCV genome encodes a small multifunctional phospho-protein, agnoprotein, from the late coding region of the virus, whose regulatory functions in viral replication cycle remain elusive. In this work, the functional role of JCV and SV40 agnoproteins in virion release was investigated using a point mutant (Pt) of each virus, where the ATG codon of agnoprotein was mutated to abrogate its expression. Analysis of both viral protein expression and replication using Pt mutant of each virus revealed that both processes were substantially down-regulated in the absence of agnoprotein compared to wild-type (WT) virus. Complementation studies in cells, which are constitutively expressing JCV agnoprotein and transfected with the JCV Pt mutant genome, showed an elevation in the level of viral DNA replication near to that observed for WT. Constitutive expression of large T antigen was found to be not sufficient to compensate the loss of agnoprotein for efficient replication of neither JCV nor SV40 in vivo. Examination of the viral release process for both JCV and SV40 Pt mutants showed that viral particles are efficiently released from the infected cells in the absence of agnoprotein but were found to be mostly deficient in viral DNA content. The results of this study provide evidence that agnoprotein plays an important role in the polyomavirus JC and SV40 life cycle. Infection by agnoprotein-negative mutants of both viruses results in the release of virions that are mostly deficient in DNA content.


Magnetic bead-based hybridization assay for electrochemical detection of microRNA.
Aberrant expression of microRNAs (miRNAs), short non-coding RNA molecules regulating gene expression, is often found in tumor cells, making the miRNAs suitable candidates as cancer biomarkers. Electrochemistry is an interesting alternative to current standard methods of miRNA detection by offering cheaper instrumentation and faster assays times. In this paper, we labeled miRNA in a quick, simple, two-step procedure with electroactive complex of osmium(VI) and 2,2'-bipyridine, Os(VI)bipy, which specifically binds to the ribose at the 3'-end of the miRNA, and hybridized such labeled miRNA with biotinylated capture probe attached to the streptavidin magnetic beads. Labeled miRNA was then detected at hanging mercury drop electrode at femtomole level due to an electrocatalytic nature of the peak from the Os(VI)bipy label. We obtained good selectivity of the assay using elevated hybridization temperatures for better discrimination of perfect duplex from single and double mismatches. After optimization of the protocol, we demonstrated feasibility of our assay by detecting target miRNA in real total RNA samples isolated from human cancer cells.


The Japanese national health screening and intervention program aimed at preventing worsening of the metabolic syndrome.
Similar to the healthcare systems in other industrialized countries, the Japanese healthcare system is facing the problem of increasing medical expenditure. In Japan, this situation may be primarily attributed to advanced technological developments, an aging population, and increasing patient demand. Japan also faces the problem of a declining youth population due to a low birth rate. Taken together, these problems present the healthcare system with a very difficult financial situation. Several reforms have been undertaken to contain medical expenditure, such as increasing employee copayment for health insurance from 10% to 20% in 1997 and from 20% to 30% in 2003 in order to curb unnecessary visits to medical institutions. Since the aging of the Japanese population is inevitable, a suitable method to contain medical expenditure may be to screen individuals who are likely to develop lifestyle-related diseases and conduct early intervention programs for them to prevent the development of diseases such as myocardial infarction or stroke that are costly to treat. If this goal is attained, it may contribute to the containment of medical expenditure as well as to improving the quality of life of the elderly. Therefore, the Japanese Ministry of Health, Labor and Welfare has decided to introduce a nationwide health screening and intervention program specifically targeting the metabolic syndrome commencing April 2008. Here, we discuss (1) the background of the Japanese healthcare system and the problems facing it, (2) the underlying objective and details of the new screening program, and (3) the expected impact of the program.


Comparison of Intermediate-term Outcomes of Total Ankle Arthroplasty in Primary and Ligamentous Post-traumatic Osteoarthritis.
Ankle ligamentous injuries without fracture can result in end-stage ligamentous post-traumatic osteoarthritis, which may cause ligamentous imbalance after total ankle arthroplasty (TAA). However, outcomes of TAA in these patients are not well known. The purpose of this study was to evaluate intermediate-term clinical and radiographic outcomes of TAA in patients with ligamentous post-traumatic osteoarthritis and compare them with results of TAA for patients with primary osteoarthritis. We enrolled 114 patients (119 ankles) with consecutive primary TAA using HINTEGRA prosthesis at a mean follow-up duration of 6.0 years (range, 3-13). We divided all patients into 2 groups according to the etiology of osteoarthritis: (1) primary osteoarthritis group (69 ankles) and (2) ligamentous post-traumatic osteoarthritis group (50 ankles). There was no significant intergroup difference in mean Ankle Osteoarthritis Scale (AOS), American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score, Short Form-36 Physical Component Summary, visual analog scale pain score, ankle range of motion, or complications at the final follow-up. However, the final tibiotalar angle was less corrected to 4.2 degrees in the ligamentous post-traumatic osteoarthritis group compared to 2.7 degrees in the primary osteoarthritis group (P = .001). More concomitant procedures were required at the index surgery for the ligamentous post-traumatic osteoarthritis group (P = .001). The estimated 5-year survivorship was 93.4% (primary osteoarthritis group: 91.3%; ligamentous post-traumatic osteoarthritis group: 95.8%). Clinical outcomes, complication rate, and 5-year survivorship of TAA in ankles with primary and ligamentous post-traumatic osteoarthritis were comparable with intermediate-term follow-up. Our results suggest that TAA would be a reliable treatment in ankles with ligamentous post-traumatic osteoarthritis when neutrally aligned stable ankles are achieved postoperatively. Level III, retrospective cohort study.


Intravesical administration of small interfering RNA targeting PLK-1 successfully prevents the growth of bladder cancer.
The mainstay in the management of invasive bladder cancer continues to be radical cystectomy. With regard to improvement of quality of life, however, therapies that preserve the bladder are desirable. We investigated the use of intravesical PLK-1 small interfering RNA (siRNA) against bladder cancer. Patients with bladder cancers expressing high levels of PLK-1 have a poor prognosis compared with patients with low expression. Using siRNA/cationic liposomes, the expression of endogenous PLK-1 could be suppressed in bladder cancer cells in a time- and dose-dependent manner. As a consequence, PLK-1 functions were disrupted. Inhibition of bipolar spindle formation, accumulation of cyclin B1, reduced cell proliferation, and induction of apoptosis were observed. In order to determine the efficacy of the siRNA/liposomes in vivo, we established an orthotopic mouse model using a LUC-labeled bladder cancer cell line, UM-UC-3(LUC). PLK-1 siRNA was successfully transfected into the cells, reduced PLK-1 expression, and prevented the growth of bladder cancer in this mouse model. This is the first demonstration, to our knowledge, of inhibition of cancer growth in the murine bladder by intravesical siRNA/cationic liposomes. We believe intravesical siRNA instillation against bladder cancer will be useful as a therapeutic tool.


[European study of asthma. Prevalence of atopy in young adults of 5 areas in Spain. Spanish Group of European Asthma Study].
The aim of the current study is to show the prevalence of atopy in five Spanish areas, and its variability according to area, age and gender. From a populational based sample of 16,884 individuals aged 20 to 44 years-old, we obtained a randomized 20% subsample (n = 3,310). Participants performed specific IgE measurements, skin prick tests, forced spirometries and metacholine challenges to measure bronchial hyperresponsiveness. The response rate was 40%, and 1,313 individuals were finally included in the study. Specific atopy to the following aeroallargens was determined: cat dander, Cladosporium, Dermatophagoides, Phleum, Parietaria, birch, Alternaria, ambrosia, olive, rye grass and dog dander. The global prevalence of atopy (detectable specific antibodies IgE in serum and/or skin reactivity) widely varied by area, skin reactivity ranking in males from a minimum in Albacete (24.6%; 95% CI: 18-33) to a maximum in Huelva (39.6%; 95% CI: 30-53), and in females ranking from a minimun in Galdakao (10.3%; 95% CI: 6-17) to a maximum in Barcelona (28.8%; 95% CI: 19-43). Considering separately seropositivity and skin reactivity we observed a similar trend. Males showed a higher prevalence of global atopy (40.1%) than females (29.4%). Our data indicate that there is a decrease in the prevalence of atopy according to age in the general population, but only significant in men. Dermatophagoides pteronyssinus is the most common allergen in all ares but Albacete, where the most common allergen is the olive pollen. By means of a standard methodology, we report population data of the prevalence of atopy in five Spanish areas. The distribution of the prevalence of atopy varies widely in the five areas surveyed, according to the composition of the most common environmental allergens.


Prognostic value of uPAR expression and angiogenesis in primary and metastatic melanoma.
Angiogenesis is important for the progression of cutaneous melanoma. Here, we analyzed the prognostic impact of the angiogenic factor urokinase plasminogen activator resecptor (uPAR), vascular proliferation index (VPI) and tumor necrosis as a measure of hypoxia in a patient series of nodular melanomas (n = 255) and matched loco-regional metastases (n = 78). Expression of uPAR was determined by immunohistochemistry and VPI was assessed by dual immunohistochemistry using Factor-VIII/Ki67 staining. Necrosis was recorded based on HE-slides. As novel findings, high uPAR expression and high VPI were associated with each other, and with increased tumor thickness, presence of tumor necrosis, tumor ulceration, increased mitotic count and reduced cancer specific survival in primary melanoma. In matched cases, VPI was decreased in metastases, whereas the frequency of necrosis was increased. Our findings demonstrate for the first time the impact on melanoma specific survival of uPAR expression and VPI in primary tumors, and of increased necrosis as an indicator of tumor hypoxia in loco-regional metastases. These findings support the importance of tumor angiogenesis in melanoma aggressiveness, and suggest uPAR as an indicator of vascular proliferation and a potential biomarker in melanoma.


Enzyme function and evolution through the lens of bioinformatics.
Enzymes have been shaped by evolution over billions of years to catalyse the chemical reactions that support life on earth. Dispersed in the literature, or organised in online databases, knowledge about enzymes can be structured in distinct dimensions, either related to their quality as biological macromolecules, such as their sequence and structure, or related to their chemical functions, such as the catalytic site, kinetics, mechanism, and overall reaction. The evolution of enzymes can only be understood when each of these dimensions is considered. In addition, many of the properties of enzymes only make sense in the light of evolution. We start this review by outlining the main paradigms of enzyme evolution, including gene duplication and divergence, convergent evolution, and evolution by recombination of domains. In the second part, we overview the current collective knowledge about enzymes, as organised by different types of data and collected in several databases. We also highlight some increasingly powerful computational tools that can be used to close gaps in understanding, in particular for types of data that require laborious experimental protocols. We believe that recent advances in protein structure prediction will be a powerful catalyst for the prediction of binding, mechanism, and ultimately, chemical reactions. A comprehensive mapping of enzyme function and evolution may be attainable in the near future.


Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology.
Oncologists are aware that their patients use complementary/alternative medicine (CAM). As cancer incidence rates and survival time increase, use of CAM will likely increase. This study assessed the prevalence and predictors of CAM use in a comprehensive cancer center. Subjects were English-speaking cancer patients at least 18 years of age, attending one of eight outpatient clinics at The University of Texas M.D. Anderson Cancer Center, Houston, TX, between December 1997 and June 1998. After giving written informed consent, participants completed a self-administered questionnaire. Differences between CAM users and nonusers were assessed by chi(2) and univariate logistic regression analysis. A multivariate logistic regression model identified the simultaneous impact of demographic, clinical, and treatment variables on CAM use; P values were two-sided. Of the 453 participants (response rate, 51.4%), 99.3% had heard of CAM. Of those, 83.3% had used at least one CAM approach. Use was greatest for spiritual practices (80.5%), vitamins and herbs (62.6%), and movement and physical therapies (59.2%) and predicted (P <.001) by sex (female), younger age, indigent pay status, and surgery. After excluding spiritual practices and psychotherapy, 95.8% of participants were aware of CAM and 68.7% of those had used CAM. Use was predicted (P <.0001) by sex (female), education, and chemotherapy. In most categories, CAM use was common among outpatients. Given the number of patients combining vitamins and herbs with conventional treatments, the oncology community must improve patient-provider communication, offer reliable information to patients, and initiate research to determine possible drug-herb-vitamin interactions.


Cortical time-course of evidence accumulation during semantic processing.
Our understanding of the surrounding world and communication with other people are tied to mental representations of concepts. In order for the brain to recognize an object, it must determine which concept to access based on information available from sensory inputs. In this study, we combine magnetoencephalography and machine learning to investigate how concepts are represented and accessed in the brain over time. Using brain responses from a silent picture naming task, we track the dynamics of visual and semantic information processing, and show that the brain gradually accumulates information on different levels before eventually reaching a plateau. The timing of this plateau point varies across individuals and feature models, indicating notable temporal variation in visual object recognition and semantic processing.


Impact of baseline characteristics on outcomes of carotid artery stenting in acute ischemic stroke patients.
Carotid artery stenting is an effective treatment for ischemic stroke patients with moderate-to-severe carotid artery stenosis. However, the midterm outcome for patients undergoing this procedure varies considerably with baseline characteristics. To determine the impact of baseline characteristics on outcomes following carotid artery stenting, data from 107 eligible patients with a first episode of ischemic stroke were collected by retrospective chart review. A modified Rankin Scale (mRS) was used to divide patients into two baseline groups, mRS ≤2 and mRS >2. A three-step decision-tree statistical analysis was conducted. After weighting the decision-tree parameters, the following impact hierarchy was obtained: admission low-density lipoprotein, gouty arthritis, chronic kidney disease, ipsilateral common carotid artery resistance index, contralateral ophthalmic artery resistance index, sex, and dyslipidemia. The finite-state machine model demonstrated that, in patients with baseline mRS ≤2, 46% had an improved mRS score at follow-up, whereas 54% had a stable mRS score. In patients with baseline mRS >2, a stable mRS score was observed in 75%, improved score in 23%, and a poorer score in 2%. Admission low-density lipoprotein was the strongest predictive factor influencing poststenting outcome. In addition, our study provides further evidence that carotid artery stenting can be of benefit in first-time ischemic stroke patients with baseline mRS scores >2.


Membrane potentials and the energetics of intestinal Na+-dependent transport systems.
The transmembrane chemical gradient for Na+ that most living cells maintain represents an energy source which is not sufficient to account for observed cellular sugar or amino acid gradients. This short review summarizes the literature pointing to the above conclusion, and described experimental evidence from a variety of model systems which indicates that the membrane potential can provide an additional driving force. Ordinarily, solute leak pathways compromise the full gradient forming capability of the Na+-dependent concentration systems and obscure the extent to which membrane potentials are important. When these "leaks" are experimentally controlled, solute gradients are established that identify the membrane potential as a quantitatively very important energy input. Furthermore, if the electrochemical gradient for Na+ is the sole source of energy, an extremely high efficiency of energy transduction must occur during gradient-coupled transport. An experimental approach is described here which can provide clues to the mechanistic role for membrane potentials in intestinal Na+-dependent sugar transport.


Cytoplasmic mislocalization of p27 and CDK2 mediates the anti-migratory and anti-proliferative effects of Nodal in human trophoblast cells.
p27(Kip1), a cyclin-dependent kinase (CDK) inhibitor, is a multi-functional protein that regulates various cellular activities. Trophoblast proliferation, migration and invasion are some of the key processes of placental development. We have recently reported that Nodal, a member of the transforming growth factor-β (TGF-β) superfamily, inhibits human trophoblast cell proliferation, migration and invasion. In the present study, we investigated the mechanism by which Nodal regulates trophoblast activities. We found that Nodal increased p27 mRNA and protein levels by enhancing their stability. Interestingly, Nodal signaling also induced nuclear export of p27 and CDK2. Cytoplasmic translocation of p27 induced by Nodal requires p27 phosphorylation at S10. In addition, Nodal enhanced the association of p27 with CDK2, CDK5 and a microtubule-destabilizing protein, stathmin, and induced stathmin phosphorylation at S25 and S38. Furthermore, Nodal increased tubulin stability as revealed by immunofluorescent staining of acetylated tubulin. Finally, silencing of p27 reversed the inhibitory effect of Nodal on trophoblast cell proliferation, migration and invasion. Taken together, our findings revealed a novel function of simultaneous p27 and CDK2 cytoplasmic mislocalization in mediating growth-factor-regulated cell proliferation, migration and invasion.


Protein phosphorylation in electrically permeabilized islets of Langerhans. Effects of Ca2+, cyclic AMP, a phorbol ester and noradrenaline.
The incorporation of 32P from [gamma-32P]ATP into intracellular proteins was studied in electrically permeabilized rat islets of Langerhans. Ca2+ (10 microM), cyclic AMP (100 microM) and a protein kinase C-activating phorbol ester, phorbol 13-myristate 12-acetate (PMA; 100 nM) produced marked changes in the phosphorylation state of a number of proteins in permeabilized islets after incubation for 1 min at 37 degrees C. Ca2+ modified the effects of cyclic AMP and PMA on protein phosphorylation. Noradrenaline (10 microM) had no detectable effects on Ca2+-dependent protein phosphorylation, but significantly inhibited Ca2+-induced insulin secretion from electrically permeabilized islets. These results suggest that electrically permeabilized islets offer a useful model in which to study rapid events in protein phosphorylation as a mechanism of stimulus-secretion coupling. If the rapid Ca2+-induced effects on protein phosphorylation are involved in the control of insulin secretion, the results of this study also imply that part of the catecholamine inhibition of insulin secretion occurs at a stage in the secretory pathway beyond the activation of the regulated protein kinases.


[Physicians experience a decline in their professional right of voice].
The hospital reform of 2002 organized Norwegian hospitals into health enterprises (independent legal subjects) and transferred overall responsibility from the counties to the central government (also the owner of the hospitals). The reform aimed at clarification of responsibility levels, improved access for all and more effective use of available resources. The new organization requires that medical professionals to a larger extent than before relate to professional leaders without medical competence; there is therefore an inherent risk of making the budget balance more important than ethics and the profession itself. We wanted to study whether the reform influenced the physicians' perception of professional right of voice. In 2000 and 2004, a representative panel of 897 physicians responded to four statements about perceived (graded) professional right of voice related to putting forward criticism; two statements concerned the perceived risk of sanctions from their immediate professional and administrative superiors and two statements concerned the risk of heavy personal strain and having to find another job. A substantial proportion of physicians found it difficult to present criticism to superiors. 24 % perceived a risk of sanctions from professional superiors and 49 % from administrative superiors, 68 % felt they risked heavy personal strain and 29 % felt they would have to find another job. There was a statistically significant increase in four variables from 2000 to 2004. There is a clear tendency for hospital doctors to experience increased difficulties in reporting sub-standard conditions at their work. This represents a threat to patient safety, and is a signal to the administrative leaders to improve their dialogue with the physicians.


The Streptomyces coelicolor A3(2) bldB region contains at least two genes involved in morphological development.
Streptomyces coelicolor A3(2) bldB mutants are blocked in the formation of aerial hyphae. A phage library of wild-type S. coelicolor DNA was used to isolate recombinant phages which restore wild-type morphological development to several bldB mutants. Of several mutations, one, bld-28, previously mapped at bldB was not complemented by the cloned region, indicating that the bldB locus is composed of at least two distinct genes. Partial localization of bldB-complementing activity showed that a 1.5 kb fragment is sufficient for complementation of the bld-15 mutation whereas bld-17 requires the same region as well as additional sequences. Under stringent conditions, genomic DNA hybridizing to the cloned sequences was absent from other Streptomyces species, including the closely related Streptomyces lividans 66. DNA sequences causing marked plasmid structural instability in S. coelicolor, but not in S. lividans, are also located in this region.


The Perceived Added Value of Bimonthly Injectable Pre-Exposure Prophylaxis According to West African Men Who Have Sex with Men: A Focus Group Study.
Bimonthly long-acting injectable pre-exposure prophylaxis (LAI-PrEP) can become an important additional tool for HIV prevention among West African men who have sex with men (MSM). The objective was to explore the perceived added value of LAI-PrEP as an HIV prevention tool among MSM in Burkina Faso, Côte d'Ivoire, Mali, and Togo. We conducted eight focus group discussions among 62 HIV-negative MSM between April and May 2021. Participants were recruited via local community-based clinics. Data collection and analysis were guided by grounded theory and community-based participatory approaches. Participants were generally knowledgeable about HIV, and explained particular barriers for HIV prevention in their communities (e.g., denial of HIV). The added value of LAI-PrEP relative to condoms was similar to oral pre-exposure prophylaxis (PrEP) in terms of perceived advantages (e.g., improved sexual satisfaction) or disadvantages (e.g., no protection against other sexually transmitted infections). Compared with oral PrEP, LAI-PrEP was perceived to provide better protection against HIV and to be more convenient (e.g., no need to be mindful of intake and less risk for stigma). Concerns included fear of needles, doubts about efficacy, potential side effects, and difficulties for ensuring timely injections (e.g., when traveling abroad). The results demonstrate that injectable PrEP can be of particular interest to subgroups of West African MSM, although existing HIV prevention tools such as condoms and oral PrEP will remain valuable alongside of, or instead of, LAI-PrEP. Increasing awareness about HIV and tackling discrimination based on sexual orientation continue to be crucial factors to be addressed for HIV prevention.


Nucleoside and nucleotide inactivation of R17 coat protein: evidence for a transient covalent RNA-protein bond.
R17 coat protein forms a specific complex with a 21-nucleotide RNA hairpin containing the initiation site for the phage replicase gene. The RNA binding activity of the protein is inhibited by prior incubation with 5-bromouridine (BrU). The inactivation occurs with pseudo-first-order kinetics, and the inactive protein is stable to dilution. RNA binding activity of the BrU-inactivated protein is restored upon incubation with dithiothreitol. Inactivation of coat protein by N-ethylmaleimide or p-(chloromercuri)-benzenesulfonate indicates that a cysteine residue is located near the RNA binding site. Since 5-bromodeoxyuridine does not inactivate coat protein, a specific binding event appears to be required before inactivation can occur. Surprisingly, unmodified cytidine nucleotides also inactivate coat protein, with a specificity similar to the modified analogues. These results are discussed with regard to the formation of a transient covalent RNA-protein bond.


Serial Assessment of Shock Severity in Cardiac Intensive Care Unit Patients.
One-time assessment of the Society for Cardiovascular Angiography and Interventions (SCAI) shock classification robustly predicts mortality in the cardiac intensive care unit (CICU). We sought to determine whether serial SCAI shock classification could improve risk stratification. Unique admissions to a single academic level 1 CICU from 2015 to 2018 were included in this retrospective cohort study. Electronic health record data were used to assign the SCAI shock stage during 4-hour blocks of the first 24 hours of CICU admission. Shock was defined as hypoperfusion (SCAI shock stage C, D, or E). In-hospital death was evaluated using logistic regression. Among 2918 unique CICU patients, 1537 (52.7%) met criteria for shock during ≥1 block, and 266 (9.1%) died in the hospital. The SCAI shock stage on admission was: A, 37.6%; B, 31.5%; C, 25.9%; D, 1.8%; and E, 3.3%. Patients who met SCAI criteria for shock on admission (first 4 hours) and those with worsening SCAI shock stage after admission were at higher risk for in-hospital death. Each higher admission (adjusted odds ratio, 1.36 [95% CI, 1.18-1.56]; area under the receiver operating characteristic curve, 0.70), maximum (adjusted odds ratio, 1.59 [95% CI, 1.37-1.85]; area under the receiver operating characteristic curve, 0.73) and mean (adjusted odds ratio, 2.42 [95% CI, 1.99-2.95]; area under the receiver operating characteristic curve, 0.78) SCAI shock stage was incrementally associated with a higher in-hospital mortality rate. Discrimination was highest for the mean SCAI shock stage (P<0.05). Each additional 4-hour block meeting SCAI criteria for shock predicted a higher mortality rate (adjusted odds ratio, 1.15 [95% CI, 1.07-1.24]). Dynamic assessment of shock using serial SCAI shock classification assignment can improve mortality risk stratification in CICU patients by quantifying the magnitude and duration of shock.


Monosodium L-glutamate-induced convulsions--II. Changes in catecholamine concentrations in various brain areas of adult rats.
Norepinephrine (NE) and dopamine (DA) levels in various brain regions were measured in a model of experimentally produced convulsions by monosodium L-glutamate (MSG) administration to adult rats. Stress by injection of all solutions produced a 60% decrease in NE level in forebrain, recovering its basal value at 15 min after injection. A significant reduction of brain NE and DA levels of MSG-injected animals was found in the preconvulsive stage, particularly in the forebrain. No significant variations in catecholamine levels were seen in brain stem and cerebellum as a result of MSG injection. It is suggested that the changes found in endogenous catecholamine concentration in the forebrain may play a physiological role in the mechanisms of production of convulsions in the MSG model.


The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance.
Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide with a prominent role in feeding and energy homeostasis. The rodent MCH receptor (MCH1R) is highly expressed in the nucleus accumbens shell (AcSh), a region that is important in the regulation of appetitive behavior. Here we establish a role for MCH and MCH1R in mediating a hypothalamic-limbic circuit that regulates feeding and related behaviors. Direct delivery of an MCH1R receptor antagonist to the AcSh blocked feeding and produced an antidepressant-like effect in the forced swim test, whereas intra-AcSh injection of MCH had the opposite effect. Expression studies demonstrated that MCH1R is present in both the enkephalin- and dynorphin-positive medium spiny neurons of the AcSh. Biochemical analysis in AcSh explants showed that MCH signaling blocks dopamine-induced phosphorylation of the AMPA glutamate receptor subunit GluR1 at Ser845. Finally, food deprivation, but not other stressors, stimulated cAMP response element-binding protein-dependent pathways selectively in MCH neurons of the hypothalamus, suggesting that these neurons are responsive to a specific set of physiologically relevant conditions. This work identifies a novel hypothalamic-AcSh circuit that influences appetitive behavior and mediates the antidepressant activity of MCH1R antagonists.


Core Elements of Family Therapy for Adolescent Behavioral Health Problems: Validity Generalization in Community Settings.
The core elements of family therapy for adolescent mental health and substance use problems, originally distilled from high-fidelity sessions conducted by expert clinicians, were tested for validity generalization when delivered by community therapists in routine settings. The study sampled recorded sessions from 161 cases participating in one of three treatment pools: implementation trial of Functional Family Therapy (98 sessions/50 cases/22 therapists), adaptation trial of Multisystemic Therapy (115 sessions/59 cases/2 therapists), and naturalistic trial of non-manualized family therapy in usual care (107 sessions/52 cases/21 therapists). Adolescents were identified as 60% male and 40% female with an average age of 15.4 years; 49% were Latinx, 27% White Non-Latinx, 15% African American, 3% another race/ethnicity, 6% race/ethnicity unknown. Session recordings (n = 320) were randomly selected for each case and coded for 21 discrete family therapy techniques. Archived data of one-year clinical outcomes were gathered. Confirmatory factor analyses replicated the factor structure from the original distillation study, retaining all four clinically coherent treatment modules comprised of all 21 techniques: Interactional Change (ICC = .77, Cronbach's α = .81); Relational Reframe (ICC = .75, α = .81); Adolescent Engagement (ICC = .72, α = .78); Relational Emphasis (ICC = .76, α = .80). Exploratory analyses found that greater use of core techniques predicted symptom improvements in one treatment pool. Core techniques of family therapy distilled from manualized treatments for adolescent behavioral health problems showed strong evidence of validity generalization, and initial evidence of links to client outcomes, in community settings.


Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.
In vitro fertilization involving frozen embryo transfer and donor oocytes increases preeclampsia risk. These in vitro fertilization protocols typically yield pregnancies without a corpus luteum (CL), which secretes vasoactive hormones. We investigated whether in vitro fertilization pregnancies without a CL disrupt maternal circulatory adaptations and increase preeclampsia risk. Women with 0 (n=26), 1 (n=23), or >1 (n=22) CL were serially evaluated before, during, and after pregnancy. Because increasing arterial compliance is a major physiological adaptation in pregnancy, we assessed carotid-femoral pulse wave velocity and transit time. In a parallel prospective cohort study, obstetric outcomes for singleton livebirths achieved with autologous oocytes were compared between groups by CL number (n=683). The expected decline in carotid-femoral pulse wave velocity and rise in carotid-femoral transit time during the first trimester were attenuated in the 0-CL compared with combined single/multiple-CL cohorts, which were similar (group-time interaction: P=0.06 and 0.03, respectively). The blunted changes of carotid-femoral pulse wave velocity and carotid-femoral transit time from prepregnancy in the 0-CL cohort were most striking at 10 to 12 weeks of gestation ( P=0.01 and 0.006, respectively, versus 1 and >1 CL). Zero CL was predictive of preeclampsia (adjusted odds ratio, 2.73; 95% CI, 1.14-6.49) and preeclampsia with severe features (6.45; 95% CI, 1.94-25.09) compared with 1 CL. Programmed frozen embryo transfer cycles (0 CL) were associated with higher rates of preeclampsia (12.8% versus 3.9%; P=0.02) and preeclampsia with severe features (9.6% versus 0.8%; P=0.002) compared with modified natural frozen embryo transfer cycles (1 CL). In common in vitro fertilization protocols, absence of the CL perturbed the maternal circulation in early pregnancy and increased the incidence of preeclampsia.


[Vitamin A esters and their hydrolysis in different organs and tissues].
Hydrolysis of retinylpalmitate and retinylacetate was studied in rat blood, liver tissue, intestine, testes, placenta and embryonic liver. The retinylpalmitate hydrolase activity was observed only in walls of small intestine and, less distinctly, - in liver tissue of some animals. Retinylpalmitate was hydrolyzed in rat liver very slowly, that was determined apparently by the metabolic requirements of the organism. The retinylpalmitate hydrolase activity occurred in dog blood after absorption of vitamin A oil solutions. This phenomenon was probably related to an increased secretion of pancreatic enzymes into blood after the loading with oils.


Aldosterone modulates electrogenic Cl secretion in the colon of the hen (Gallus domesticus).
The regulation of Na and Cl transport in hen colon by mineralocorticoids was investigated with isolated epithelia in vitro by histological and electrophysiological techniques. The electrogenic transport of Na and Cl was measured in Ussing chambers by the short-circuit current technique and was identified by the specific inhibitors amiloride and bumetanide or by the secretagogue theophylline. Hens were maintained either on low (LS)- or on high-NaCl diets (HS), and the plasma aldosterone (PA) levels of these groups were measured with radioimmunoassay. A group of HS hens received injections of aldosterone at a 6-h schedule before experiments. A group of LS hens was resalinated, and experiments were carried out at a 24-h interval for up to 3 days after resalination. The LS diet stimulated PA levels ninefold, compared with HS hens. Na transport was modulated by the hormonal stimulus in a way that the apical Na entry switched from an electrogenic Na-amino acid-hexose cotransport system completely to an amiloride-sensitive Na channel. Electrogenic Cl secretion was induced by theophylline and was inhibited by bumetanide. NaCl deprivation, resalination or aldosterone injection modulated electrogenic Cl secretion in parallel between 7 (HS) and 14.4 mu eq.cm-2.h-1 (LS), with pronounced alteration in tissue conductance. These findings reveal a new action of aldosterone that, besides stimulating Na absorption, also directly or indirectly modulates Cl secretion.


Mechanistic Study of Selective Absorption of NO in Flue Gas Using EG-TBAB Deep Eutectic Solvents.
The selective absorption of NO in flue gas has been investigated using a series of deep eutectic solvents (DESs) as novel denitrifying agents. The EG-TBAB DESs used in this work are composed of a hydrogen donor ethylene glycol (EG) and a parent salt tetrabutylammonium bromide (TBAB). Effects of DES composition (EG:TBAB molar ratio), operation temperature, residence time, and O2 concentration in the flue gas on denitrification performances of EG-TBAB DESs have been investigated. The highest denitrification efficiency and capacity were achieved using EG to TBAB molar ratio of 50:1 at an operation temperature of 50 °C. The O2 partial pressure in the flue gas showed no noticeable effects on NO absorption in EG-TBAB DESs. EG-TBAB DESs maintain high denitrification stability after five absorption-desorption cycles. The calculated absorption equilibrium constant ( K0) and Henry's law constant ( H) showed that EG-TBAB DESs exhibited high absorption capacity for NO molecules, indicating that they are applicable in industrial denitrification processes. The kinetics analysis of NO absorption in EG-TBAB DESs indicated that EG-TBAB DESs could effectively absorb NO and the absorption of NO was strongly influenced by mass transfer.


Clinical and Immunological Factors That Distinguish COVID-19 From Pandemic Influenza A(H1N1).
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although COVID-19 has been extensively characterized clinically, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, and a histological pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients. Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1β, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against pandemic influenza A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical and immune factors to differentiate both diseases. These findings might be relevant for the ongoing and future influenza seasons in the Northern Hemisphere, which are historically unique due to their convergence with the COVID-19 pandemic.


Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model.
The APOE epsilon4 allele is the most significant genetic risk factor associated with Alzheimer's disease to date. Epidemiological studies have demonstrated that inheritance of one or more epsilon4 alleles affects both the age of onset and the severity of pathology development. Dosage of APOE epsilon2 and epsilon3 alleles, however, appear to be protective against the effects of epsilon4. Although much of the biology of APOE in peripheral cholesterol metabolism is understood, its role in brain cholesterol metabolism and its impact on AD development is less defined. Several APOE transgenic models have been generated to study the effects of APOE alleles on APP processing and Abeta pathology. However, these models have potential limitations that confound our understanding of the effects of apolipoprotein E (APOE) levels and cholesterol metabolism on disease development. To circumvent these limitations, we have taken a genomic-based approach to better understand the relationship between APOE alleles, cholesterol and Abeta metabolism. We have characterized APOE knock-in mice, which express each human allele under the endogenous regulatory elements, on a defined C57BL6/J background. These mice have significantly different serum cholesterol levels and steady-state brain APOE levels, and yet have equivalent brain cholesterol levels. However, the presence of human APOE significantly increases brain Abeta levels in a genomic-based model of AD, irrespective of genotype. These data indicate an independent role for APOE in cholesterol metabolism in the periphery relative to the CNS, and that the altered levels of cholesterol and APOE in these mice are insufficient to influence Abeta metabolism in a mouse model of Alzheimer's disease.


In vitro anti-leishmanial activities of germatranyl and Silicon incorporated diorganotin derivatives: synthesis and spectroscopic properties.
A series of germanium and silicon incorporated diorganotin derivatives of general formula [N(OCH2CH2)3GeCH(R(1)CH2CO2]2 SnR2(2) where R1 = H3C, C6H5, p-CH3C6H4, p-FC6H4; R2 = H2CSi(CH3)2C6H5, H2CC6H5, p-CH3C7H7 were synthesized by the reaction of appropriate diorganotin dichlorides and germatranyl (substituted) propionic acid in 1:2 mole ratio, respectively. The evidence regarding their structure is mainly based on spectroscopic data obtained by multinuclear (1H, 13C, 29Si, 119Sn) NMR and 119mSn Mössbauer, IR and mass spectral studies in combination with melting points and elemental analyses. The compounds have been screened for in vitro anti-leishmanial activity against promastigotes of Leishmania major and the results offer potent activities which are better than the standard drug, pentamidine, for one compound.


[Relationships of self-reported physical health, sociability, and spiritual life with mental health: an investigation according to gender and life stage].
To investigate the relationships of self-reported physical health, social and spiritual satisfactions with subjective mental health according to gender and life stage. Self-reported questionnaires with questions regarding subjective health status and lifestyles were sent to 1905 community residents aged 20 years or older selected by random sampling in Wakayama Prefecture, Japan. Subjective mental health, physical health, social and spiritual satisfactions as measures of subjective health status were assessed using a visual analogue scale. Multiple logistic regression analysis was used to evaluate the relationships between the subjective mental health and the other three components of the subjective health status with adjustment for life style factors related to the subjective mental health in the subjects without missing values of relevant factors (n=1,752). The subjects were divided into three life stages depending on their ages: young (20-39), middle (40-59), and old (60 or more). Overall, the poor statuses of the three components, namely, physical health, social and spiritual satisfactions, were significantly associated with poor mental health in both genders at any life stage. However, detailed analysis revealed some interesting characteristics. In young men, social dissatisfaction was strongly associated with poor mental health whereas spiritual dissatisfaction in addition to social dissatisfaction was strongly associated with poor mental health in young women. In the middle aged group, both social and spiritual dissatisfactions were strongly associated with poor mental health in both genders. On the other hand, poor physical health status was strongly associated with poor mental health in the old aged group. These results suggest the importance of the mental health interventions under consideration for each life stage and gender.


Radial Spin Texture in Elemental Tellurium with Chiral Crystal Structure.
The chiral crystal is characterized by a lack of mirror symmetry and inversion center, resulting in the inequivalent right- and left-handed structures. In the noncentrosymmetric crystal structure, the spin and momentum of electrons are expected to be locked in the reciprocal space with the help of the spin-orbit interaction. To reveal the spin textures of chiral crystals, we investigate the spin and electronic structure in a p-type semiconductor, elemental tellurium, with the simplest chiral structure by using spin- and angle-resolved photoemission spectroscopy. Our data demonstrate that the highest valence band crossing the Fermi level has a spin component parallel to the electron momentum around the Brillouin zone corners. Significantly, we have also confirmed that the spin polarization is reversed in the crystal with the opposite chirality. The results indicate that the spin textures of the right- and left-handed chiral crystals are hedgehoglike, leading to unconventional magnetoelectric effects and nonreciprocal phenomena.


Attributes of Society of Genitourinary Reconstructive Surgeons Fellows and Early Career Trajectory of the Recent Graduates.
We identified the attributes that the Society of Genitourinary Reconstructive Surgeons (GURS) fellowship directors prioritize in applicants. The secondary objective was to study the early career trajectory of recent GURS fellowship graduates. GURS fellowship directors and fellows from 2014 to 2018 were surveyed electronically using Qualtrics® software. We asked fellowship directors to rate 12 items for their importance in match selection on a Likert scale. Fellows were prompted for details of practice size, case mix and research time. We assessed research productivity based on published articles on PubMed® and Google Scholar™. Findings were summarized with descriptive statistics and continuous variables were reported as median with interquartile range. Fellowship directors (90% response rate) rated subjective personal qualities as more important compared to more objective measures and achievements. Personality (5, 5-5), overall interview performance (5, 4-5) and letters of recommendation (5, 4-5) were most important. About 4 papers were published during fellowship per fellow. However, research productivity did not persist during early career. Upon graduation the majority of graduates were the only reconstructionist at their practice, with approximately 40% of their operative time dedicated to such cases. While we identified a variety of practice settings, an academic career focusing on urethroplasty and male incontinence was the most common. Our data provide potential applicants with a better understanding of how to optimize their candidacy and what to expect in their early careers.


Longitudinal analysis of a secondary BRCA2 mutation using digital droplet PCR.
Development of resistance to platinum and poly(ADP-ribose) polymerase inhibitors via secondary BRCA gene mutations that restore functional homologous recombination has been observed in a number of cancer types. Here we report a case of somatic BRCA2 mutation in a patient with high grade serous ovarian carcinoma. A secondary mutation predicted to restore the BRCA2 open reading frame was detected at low frequency (2.3%) in whole exome sequencing of a peritoneal biopsy at disease progression after treatment that included carboplatin and olaparib. We used digital droplet PCR (ddPCR) to verify the presence and frequency of this mutation in the biopsy sample at progression and also used this approach to assess the presence of the secondary mutation in preceding biopsies at diagnosis and first relapse. We found no evidence for the secondary mutation being present prior to the final progression biopsy, suggesting that this mutation was acquired late in the course of treatment. ddPCR provides a sensitive and specific technique to investigate the presence of low frequency mutations in a time series of biopsies.


Frequency of HIV screening in the Veterans Health Administration: implications for early diagnosis of HIV infection.
We evaluated the frequency of HIV testing across the Department of Veterans Affairs (VA), the largest provider of HIV care in the United States. An electronic survey was used to determine the volume and location of HIV screening, confirmatory testing, rapid testing and laboratory consent policies in VA medical centers between October 1, 2005, and September 30, 2006. One hundred thirty-five VA laboratories reported that 112,033 HIV screening tests were performed (81% outpatients vs. 19% inpatients, p<.0001). Overall HIV prevalence was 1.49% (1.62% in inpatients vs. 1.46% in outpatients, p=N.S., range=0.2-3.8%). Rapid testing was available in 67% of facilities, 60% of which took place in the clinical laboratory. Sixty-four percent of labs required a copy of the informed consent in order to perform testing. We estimate that fewer than 10% of VA inpatients and fewer than 5% of VA outpatients were tested for HIV during the survey period. Substantial opportunities for increasing routine HIV testing exist in this population.


Novelty-seeking trait predicts the effect of methylphenidate on creativity.
In recent years the use of psychostimulants for cognitive enhancement in healthy individuals with no psychiatric disorders has been on the rise. However, it is still unclear whether psychostimulants improve certain cognitive functions at the cost of others, and how these psychostimulants interact with individual personality differences. In the current study, we investigated whether the effect of one common stimulant, methylphenidate (MPH), on creativity is associated with novelty seeking. Thirty-six healthy adults, without attention-deficit hyperactivity disorder (ADHD) symptomology, were assigned randomly in a double-blind fashion to receive MPH or placebo. We found that the effect of MPH on creativity was dependent on novelty-seeking (NS) personality characteristics of the participants. MPH increased creativity in individuals with lower NS, while it reduced creativity levels in individuals with high NS. These findings highlight the role of the dopaminergic system in creativity, and indicate that among healthy individuals NS can be seen as a predictor of the effect of MPH on creativity.