Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies.
The three-dimensional structure of the anti-apoptotic protein Bcl-xL complexed to a 25-residue peptide from the death promoting region of Bad was determined using NMR spectroscopy. Although the overall structure is similar to Bcl-xL bound to a 16-residue peptide from the Bak protein (Sattler et al., 1997), the Bad peptide forms additional interactions with Bcl-xL. However, based upon site-directed mutagenesis experiments, these additional contacts do not account for the increased affinity of the Bad 25-mer for Bcl-xL compared to the Bad 16-mer. Rather, the increased helix propensity of the Bad 25-mer is primarily responsible for its greater affinity for Bcl-xL. Based on this observation, a pair of 16-residue peptides were designed and synthesized that were predicted to have a high helix propensity while maintaining the interactions important for complexation with Bcl-xL. Both peptides showed an increase in helix propensity compared to the wild-type and exhibited an enhanced affinity for Bcl-xL.


Relaxant effect and possible mechanism of 17-nor-subincanadine E in rabbit corpora cavernosa.
Compounds with dual action on cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) may be a treatment option for erectile dysfunction, as they not only promote penile erection but also prevent the upregulation of phosphodiesterase-5. In this study, we examined the possible relaxant effect and mechanism of 17-nor-subincanadine E (SEC, 0.2-200 µmol l⁻¹), a plant-derived alkaloid, in rabbit corpus cavernosum (RbCC) strips that had been precontracted by exposure to phenylephrine (10 µmol l⁻¹) or a high concentration of K(+) (60 mmol l⁻¹) in vitro. In addition to SEC's effect on cAMP and cGMP levels, electrical field stimulation (EFS) in phenylephrine-precontracted RbCC and calcium chloride (1-100 mmol l⁻¹) evoked responses in depolarized RbCC were analysed. SEC relaxed the phenylephrine-precontracted RbCCs in a concentration-dependent manner. Atropine, guanethidine and N-ω-nitro-l-arginine methyl ester (L-NAME) did not have any effect on the relaxation of RBCCs. When 1H-(1, 2, 4)oxadiazole[4,3-a] quinoxalin-1-one (ODQ) was added, it effectively blocked the relaxant response of SEC. Although SEC enhanced the maximal relaxation produced by sodium nitroprusside (SNP) and forskolin in phenylephrine-precontracted cavernosal smooth muscle, it caused a decrease in the maximal contractile response induced by calcium chloride in depolarized RbCCs. The relaxant effect of SEC was paralleled by an increase in the tissue levels of the cyclic nucleotides cAMP and cGMP. We conclude that SEC promotes the relaxation of RbCC, possibly favouring cAMP and cGMP accumulation and calcium blockade. This novel mechanism could be useful for patients who do not benefit from phosphodiesterase inhibitors and for those with endothelial and nitrergic dysfunction, such as patients with diabetes, hypertension and dyslipidaemias.


Disordered Eating: The Young Male Side.
Disordered eating (DE) is known to predominate among girls, and historically studies have focused primarily on them. This cross-sectional study aimed to investigate the characteristics of adolescent and young adult males at risk of DE. Participants (N = 2269; 15-24 years) in a study assessing their lifestyle were divided into two groups based on the SCOFF five-question screening tool: a SCOFF[+] group for participants at risk of disordered eating, and a SCOFF[-] group for everyone else. SCOFF[+] participants were more likely to be overweight and obese; have a lower socio-economic status and non-Swiss parents; experience weight issues; and report a chronic condition, poorer emotional well-being and a less positive attitude towards life. With 10% of males at risk of DE, clinicians should be aware of their specific characteristics, which should be considered red flags. DE is no longer a female-specific issue.


The enigma of dendritic cell-immunodeficiency virus interplay.
A dendritic cell (DC) encountering an immunodeficiency virus should pose a threat to the virus, by efficiently processing and presenting viral antigenic determinants to activate specific anti-viral T and B cell immunity. While this may occur in vivo, it is apparent that DC-entrapped viruses can freely spread between cells, move to distal tissues, and proliferate rapidly particularly upon meeting CD4+ T cells. In fact, the latter is further augmented when the T cells are activated. Thus, it seems that immunodeficiency viruses exploit the unique ability of DCs to survey the periphery and capture incoming pathogens, traffic around the body often targeting the lymphoid tissues, and efficiently communicate with naïve and memory T cells. Combined with the fact that DCs are likely the first leukocytes interacting with virions crossing the mucosae, these features provide the basis on which the virus maximizes its chance to establish infection even in the face of immune activation. How this is actually achieved by the virus is still an enigma. Herein, we intend to summarize what is known about how distinct DC subsets and immunodeficiency viruses interact, what cellular and viral factors influence these events, and how this drives virus replication versus stimulation of protective immunity. Clarifying these issues is necessary to define the exact role of DCs in the transmission and dissemination of HIV infection, to facilitate the development of methods to improve the immune-activating capacity of DCs as well as the design of strategies to prevent DC-driven infection.


Quantitative recommendations for amphibian terrestrial habitat conservation derived from habitat selection behavior.
Conservation scientists have noted that conservation managers rarely use scientific information when making decisions. One of the reasons why managers rarely use scientific information may be that conservation scientists rarely provide their knowledge in a way that can directly be used by conservation practitioners. Here we show how quantitative recommendations for conservation can be derived. Previous research on terrestrial habitat selection behavior of toads (Bufo bufo and Bufo viridis) showed that wood deposits are a key resource in the terrestrial habitat. We used habitat-dependence analysis to estimate the amount of this key resource, wood deposits, that individual toads require. Based on these estimates we then quantify the requirements for wood deposits for a population. Additionally, we quantified the area that a population requires. Although wood deposits vary strongly in size, we found little evidence for size preferences: only one species preferred smallest sizes of wood deposits. We report all the estimates in a way that can be directly used by conservation managers. Habitat-dependence analysis is a simple and useful tool to quantify habitat requirements. Provisioning of wood deposits may improve the quality of terrestrial habitat for amphibians. Thereby, managers may increase the carrying capacity of terrestrial habitats and support elevated population densities.


Theory of mind and psychoses.
A cardinal feature of schizophrenia is the sufferer's difficulty in interacting appropriately within the social milieu. This deficit has recently been associated with the concept of theory of mind, more commonly constructed as a working model to understand behavioural patterns in autistic children. In this paper the complex relationships between theory of mind, IQ and psychoses are addressed. Five experimental groups were used; non-psychiatric controls, affective disorder, schizophrenia with normal pre-morbid IQ, schizophrenia with pre-morbid IQ in the mildly learning disabled range, and mild learning disability with no history of psychiatric illness. All subjects were given a first order Theory of Mind Task and if successful, a second order Theory of Mind Task was then administered. All subjects were rated using the Positive and Negative Symptom Scale (PANSS). Subjects with schizophrenia and subjects with mild learning disability show impaired ability on a second order theory of mind task. However, when patients who are unable to answer reality questions are removed from the analysis specific impairment of theory of mind is only seen in subjects with schizophrenia. Furthermore, this impairment is relatively specific to particular psychopathological clusters in subjects with schizophrenia. Even though the same clusters of psychopathology are also seen in patients with affective disorder, their presence is not associated with poor second order theory of mind performance. Impaired theory of mind on second order tests is specific to schizophrenia when compared to mild learning disability and affective disorder control groups. Subjects with schizophrenia and pre-morbid mild learning disability show greater impairment than subjects with schizophrenia and a pre-morbid IQ within the normal range.


Caffeine and performance.
Caffeine ingestion (3-9 mg/kg body weight) prior to exercise increases performance during prolonged endurance exercise and short-term intense exercise lasting approximately 5 min in the laboratory. These results are generally reported in well-trained elite or recreational subjects. However, there is a lack of well-controlled field studies to determine the applicability of laboratory results to the athletic world. Caffeine does not appear to enhance performance during incremental exercise tests lasting 8-20 min and during sprinting lasting less than 90 s, although research examining sprinting is rare. In addition, the mechanisms responsible for any improvement in endurance and short-term exercise have not been clearly established. The ergogenic effects of caffeine are present with urinary caffeine levels that are below the limit of 12 micrograms/ml allowed by the International Olympic Committee, which raises serious ethical issues regarding the use of caffeine to improve athletic performance. One solution would be to add caffeine to the list of banned substances, thereby requiring athletes to abstain from caffeine ingestion 48-72 hr prior to competition.


Influence of temperature and performance level on pacing a 161 km trail ultramarathon.
Even pacing has been recommended for optimal performances in running distances up to 100 km. Trail ultramarathons traverse varied terrain, which does not allow for even pacing. This study examined differences in how runners of various abilities paced their efforts in the Western States Endurance Run (WSER), a 161 km trail ultramarathon in North America, under hot vs cooler temperatures. Temperatures in 2006 (hot) and 2007 (cooler) ranged from 7-38°C and 2-30°C, respectively. Arrival times at 13 checkpoints were recorded for 50 runners who finished the race in both years. After stratification into three groups based on finish time in 2007 (<22, 22-24, 24-30 h), paired t tests were used to compare the difference in pace across checkpoints between the years within each group. The χ2 test was used to compare differences between the groups on the number of segments run slower in the hot vs cooler years. For all groups, mean pace across the entire 161 km race was slower in 2006 than in 2007 (9:23 ± 1:13 min/km vs 8:42 ± 1:15 min/km, P < .001) and the pace was slower from the start of the race when temperatures were still relatively cool. Overall, the <22 h cohort ran slower in 2006 than 2007 over 12 of the 14 segments examined, the 22-24 h cohort was slower across 10 of the segments, and the >24 h cohort was slower across only 6 of the segments χ(2)2 = 6.00, P = .050). Comparable pacing between the 2 y corresponded with onset of nighttime and cooling temperatures. Extreme heat impairs all runners' ability to perform in 161 km ultramarathons, but faster runners are at a greater disadvantage compared with slower competitors because they complete a greater proportion of the race in the hotter conditions.


Reference values of the Strengths and Difficulties Questionnaire (SDQ) version for parents in the Spanish population, 2006.
The Strengths and Difficulties Questionnaire (SDQ) is one of the most frequently used screening test for children and adolescents mental health (MH). In 2006, the Spanish National Health Survey included the child's MH section through the SDQ version for parents. To obtain reference values of the SDQparents Spanish version for the 4-15 year-old population living in Spain during 2006-2007. From the Spanish National Health Survey-2006, measurements of central tendency, dispersion and percentiles scores were calculated for the "Total Difficulties Score" (TDS-SDQ) Index and for the five dimensions of the questionnaire. A sample made up of 6266 children, ages 4 to 15 years, having national representativeness was obtained. Regarding the TDS-SDQ Index, scores were higher (worse MH) in boys than in girls (9.66 vs 9.04) and were higher in the younger age group in the total sample (9.90, 9.49 and 8.73) and also in boys. Girls scored higher than boys on the emotional symptoms and prosocial dimensions, and the scores were higher in older age group for the total sample. Regarding behavior problems, the younger age group scored higher in the total sample (2.19, 1.87 and 1.76) and by sex. Boys scored higher than girls on hyperactivity (4.51 vs. 3.92) and scores were lower in older ages in total sample (4.71, 4.19 and 3.82) and by sex. Peer problems dimension has no statistically significant differences by sex or age. The population values shown are informative and extend the knowledge and interpretation of the SDQ results.


Responses of cloned rainbow trout Oncorhynchus mykiss to an attenuated strain of infectious hematopoietic necrosis virus.
The objective of this work was to examine the response of homozygous clones of rainbow trout to vaccination by an attenuated strain (Nan Scott Lake; NSL) of infectious hematopoietic necrosis virus (IHNV). Adult rainbow trout of the Hot Creek Strain (YY males maintained in a recirculating system at 12 degrees C) were injected 3 times with 10(5) to 10(7) plaque forming units (pfu) of NSL. Intraperitoneal injections were given at Day 0 and at 2 and 4 mo post-infection. All fish were nonlethally bled at monthly intervals for 18 mo. Serum from each fish was analyzed by the complement-dependent neutralization assay and by western blot against purified NSL virus. The highest virus neutralization titers were detected 4 mo after the first injection, and peaked at 1280. When sera were analyzed by western blot, the predominating responses of the serum from immunized fish on the reduced western blot were against M1, a matrix protein of the virus and to a 90 kDa stress protein. The 90 kDa protein was identified by a monoclonal antibody as a stress protein derived from the CHSE-214 cells in which the purified IHN virus was grown and which associates with the virus during purification.


Dense plexus of substance P immunoreactive nerve terminals in eminentia medialis of the primate hypothalamus.
The indirect immunofluorescence technique of Coons and collaborators was used to study the distribution of substance P-like and luliberin (luteinizing hormone-releasing hormone)-like immunoreactivity in the eminentia mediana (eminentia medialis or infundibulum) of rats, monkeys, and human beings. In rats, abundant luliberin-positive fibers were present in the external layer (mainly lateral parts) whereas almost no substance P-immunoreactive nerves were observed in this region. In contrast, in the external layer of the primate eminentia medialis a dense plexus of substance P-positive nerve terminals was observed close to the blood vessels supplying the anterior pituitary gland. Luliberin-immunoreactive fibers were also present, but with a more even distribution all over the eminentia medialis and in lower numbers. The present findings indicate that substance P may play a role in the control of hormone secretion from the anterior pituitary, either by being released into the portal vessels, i.e., acting as a releasing or inhibitory hormone, or by an action as local regulator (modulator or transmitter) at the level of the eminentia medialis. Thus, in agreement with many earlier studies, substances other than the "classical" releasing and inhibitory hormones may be important for the regulation of the pituitary gland. Furthermore, there may exist marked species differences with regard to the type of substances involved in the central control of the pituitary.


Liver function test alterations associated with parenteral nutrition in hospitalized adult patients: incidence and risk factors.
Parenteral nutrition-associated liver dysfunction can be progressive and irreversible, particularly in children and patients with long-term treatment. This study has assessed the incidence of abnormal liver function tests in hospitalized adults during short term parenteral nutrition (PN) and has investigated risk factors for developing alterations of each parameter. A prospective cohort study of parenteral nutrition treated patients with preserved liver function at baseline. Variables examined included nutritional and clinical data and laboratory parameters. Determinations were performed before starting PN and weekly until liver function test alteration was observed. Risk factors were investigated by four stepwise forward logistical regressions. Eighty patients were included, 57.5% had liver function test alterations. PN mean duration was 15.9 (8-54) days. Mean days with PN and additional enteral/ oral nutrition were 1.5 (0-20). The following associations were found: gamma-glutamyl-transferase increased with soybean lipid intake and absolute diet; alkaline phosphatase increased with septic shock; alanine transaminase increased with septic shock, hyperglycemia and elevated creatinine; total bilirubin increased with septic shock, absolute diet, low prealbumin and glucose, and high creatinine. The incidence of altered liver function tests is high in adult hospitalized patients treated with short-term PN. However, the effect of nutritional factors in this alteration is low. Oral/enteral nutrition and reduction of soybean lipid supply can reduce increases in some liver function tests such as gamma-glutamyl-transferase and total bilirubin. The high association between all liver function tests and clinical systemic-hypermetabolic variables suggest the importance of specific nutritional strategies for this condition.


Magnetron-sputtered Ag surfaces. New evidence for the nature of the ag ions intervening in bacterial inactivation.
DC-magnetron sputtering with an Ag target on textile surfaces produced Ag particles with sizes approximately 4.7 nm (+/-15%). Sputtering for 15 s led to Ag layers of 15-20 nm. The threshold sputtering time precluding airborne bacterial growth was about 60 s. In this case, the coating was approximately 40-50 nm thick and the cotton Ag loading was 0.0026 wt %. The Ag particle size did not vary significantly with sputtering time between 15 and 600 s. Only coatings above this thickness lead to bacterial inactivation. Ag/Pt targets with sputtering times<60 s did not increase the bactericide performance of the Ag cotton samples with respect to sputtering from an Ag target alone, as expected from the position of Pt respect to Ag in the electrochemical series (Galvanic effect). The Ag cotton deposition led to very thin metallic semitransparent gray color coatings. X-ray of the Ag cotton suggested the presence of amorphous and crystalline Ag species. By X-ray photoelectron spectroscopy (XPS), it was found that the amount of oxidized silver species on the cotton was similar for sputtering times of 60 and 600 s, but the total amount of Ag deposited was almost two times higher after 600 s sputtering. This suggests that the positive silver-ions were located mainly at the silver interface. The type of silver ions produced using the Ag/Pt sputtering was determined to be very similar at 15, 60, and 600 s with the silver ions produced with the Ag target. This explains the lack of an increased inhibitory effect of Pt during the inactivation of airborne bacteria when present in the Pt/Ag target with respect to the Ag target, because in both cases similar silver ionic species were found.


Transmission enhancement through square coaxial aperture arrays in metallic film: when leaky modes filter infrared light for multispectral imaging.
The diffractive behavior of arrays of square coaxial apertures in a gold layer is studied. These structures exhibit a resonant transmission enhancement that is used to design tunable bandpass filters for multispectral imaging in the 7-13 μm wavelength range. A modal analysis is used for this design and the study of their spectral features. Thus we show that the resonance peak is due to the excitation of leaky modes of the open photonic structure. Fourier transform infrared (FTIR) spectrophotometry transmission measurements of samples deposited on Si substrate show good agreement with numerical results and demonstrate angular tolerance of up to 30 degrees of the fabricated filters.


Structure and organization of the chicken H2B histone gene family.
The results of Southern blotting experiments confirm that the chicken H2B histone gene family contains eight highly homologous members. One or two more sequences which are considerably divergent from the others appear to exist in the chicken genome. Seven of the eight H2B genes have been cloned and sequenced. All seven genes fall in two histone gene clusters, but no common arrangement exists for the clusters themselves. Three different H2B protein variants are encoded by these seven genes. The nucleotide sequence homology among the genes within their coding sequences appears to exceed that required for the corresponding protein sequences, suggesting that histone H2B mRNA sequence and structure are both selected during evolution. An analysis of the 5' flanking sequence data reveals that these genes possess CCAAT and TATA boxes, elements commonly associated with genes transcribed by RNA polymerase II. In addition, these genes all share an H2B-specific element of the form: ATTTGCATA. The 3' sequences of these genes contain the hyphenated symmetrical dyad homology and downstream purine-rich sequence shared by histone genes in general.


FADS1 FADS2 gene variants modify the association between fish intake and the docosahexaenoic acid proportions in human milk.
The genes encoding Delta(5)- and Delta(6)-desaturases (FADS1 FADS2 gene cluster) were reported to be associated with n-3 (omega-3) and n-6 (omega-6) fatty acid proportions in human plasma, tissues, and milk. Docosahexaenoic acid (DHA) can be supplied especially by dietary fish or fish oil and synthesized from alpha-linolenic acid through a pathway involving these desaturases. We evaluated whether FADS gene variants modify the effect of maternal fish and fish-oil intake on plasma and milk DHA proportions. FADS1 rs174561, FADS2 rs174575, and intergenic rs3834458 single nucleotide polymorphisms were genotyped in 309 women from the KOALA Birth Cohort Study in The Netherlands. Plasma was collected at 36 wk of pregnancy, and milk was collected at 1 mo postpartum. Fish and fish-oil intake was assessed by using a food-frequency questionnaire at 34 wk of pregnancy and updated for the week of milk collection. Gene-diet interactions were tested by linear regression analysis. DHA proportions were lower in women homozygous for the minor allele than in women who were homozygous for the major allele (DHA proportions in plasma phospholipids: P < 0.01; DHA proportions in milk: P < 0.05). Fish intake ranged from 0 to 2.5 portions of fatty fish/wk, and 12 women took fish-oil supplements during pregnancy. DHA proportions in plasma phospholipids increased with increasing fish and fish-oil intake, irrespective of the genotype. DHA proportions in milk increased only with fish and fish-oil intake in the major-allele carriers. Lower proportions of DHA in milk from women who were homozygous for the minor allele could not be compensated for by increasing fish and fish-oil intake, possibly because of limited incorporation into milk.


Can't get it out of my mind: employee rumination after customer mistreatment and negative mood in the next morning.
Drawing on cognitive rumination theories and conceptualizing customer service interaction as a goal attainment situation for service employees, the current study examined employee rumination about negative service encounters as an intermediate cognitive process that explains the within-person fluctuations in negative emotional reactions resulting from customer mistreatment. Multilevel analyses of 149 call-center employees' 1,189 daily surveys revealed that on days that a service employee received more (vs. less) customer mistreatment, he or she ruminated more (vs. less) at night about negative encounters with customers, which in turn led to higher (vs. lower) levels of negative mood experienced in the next morning. In addition, service rule commitment and perceived organizational support moderated the within-person effect of customer mistreatment on rumination, such that this effect was stronger among those who had higher (vs. lower) levels of service rule commitment but weaker among those who had higher (vs. lower) levels of perceived organizational support. Theoretical and practical implications of these findings are discussed.


Midlife obesity and trajectories of brain volume changes in older adults.
Although obesity has been linked to structural brain changes, little is known about its associations with the rates of brain atrophy. We examined associations between global (BMI) and central (waist circumference) midlife obesity and subsequent trajectories of regional brain atrophy in 152 individuals [M (age) = 69 ± 7.8] prospectively followed through the Baltimore Longitudinal Study of Aging; 21 individuals became impaired during follow-up. We report no associations (P > 0.05) between either global or central midlife obesity and subsequent rates of regional brain volume changes against a background of age-related atrophy in older individuals who remained nondemented. When looking at the entire sample, greater decline was observed in the volume of gray matter, precuneus, cingulate and orbito-frontal gyri for globally obese (P < 0.03), even though only data up to the point of dementia diagnosis were included in the analyses (i.e., while still considered clinically normal). Moreover, when trajectories of regional volume changes were examined across the range of BMI and waist circumference values instead of employing a cut-off point to define obesity, a different pattern of results emerged. Overall, our results suggest that midlife obesity may be an important modifier of brain atrophy in individuals who are developing cognitive impairment and dementia, while it has little effect on structural brain integrity in nondemented older adults. Moreover, the discrepancies in findings between studies may be in part due to participant sampling and methodological differences.


Evaluation of Prevalence and Morphology of Dimple among Population of Sullia Taluk.
Dimple is one of the special indentations in skin of the face, which is considered as a sign of beauty. Dimpleplasty/surgical creation of dimple is a cosmetic procedure done by surgeons. Determining accurate position of dimple to create maximum beauty is always challenging to surgeons. This study aimed at evaluating the prevalence and morphology (position and size) of naturally occurring dimple among population of Sullia taluk. In total, 1462 people were screened for the occurrence of natural dimples in face. Among them, 121 were found to have natural dimples. Prevalence of dimple, position of the dimple, and the variation in distance from the Khoo Boo-Chai's (KBC) point to the naturally occurring dimple was assessed. Among 121 patients with dimples, unilateral cheek dimples (72.88%) were more common than bilateral (27.11%). Ninety-one dimples (60.66%) were at KBC point and 59 dimples (39.33%) occurred anterior to KBC point at a mean distance of 9.86 mm. The mean size of dimple superoinferiorly on the right side was 8.29 mm and on the left side it was 8.96 mm. The mean size anteroposteriorly on the right side was 6.48 and on the left side it was 6.51 mm. The mean measurements in size and position of the dimple might help the surgeon in creating dimples resembling naturally occurring dimples.


Ultrasound-guided fine-needle aspiration biopsy of thyroid masses.
The purpose of this study was to determine the impact of ultrasound-guided fine-needle aspiration biopsy (USFNA) in the cytological diagnosis of nodular thyroid disease. It remains unclear exactly what role USFNA should play in the cytological diagnosis of nodular thyroid disease. All patients who underwent fine-needle aspiration (FNA) for nodular thyroid disease at Stanford University Medical Center from 1991 to 1996 were included in the study. Histopathologic diagnoses were compared to cytological diagnoses for those patients who underwent surgery. FNA was performed on a total of 497 thyroid nodules. Palpation-guided FNA (pFNA) was performed on 370 nodules, and USFNA was done on 127. The USFNAs were performed for the following reasons: 95 (75%) for nonpalpable or difficult-to-palpate nodules; 14 (11%) for previously failed FNA; and 18 (14%) for incidentally detected nodules. FNA had an unsuccessful biopsy rate of 16% and a sensitivity and specificity of 89% and 69%, respectively. USFNA had an unsuccessful biopsy rate of 7% and a sensitivity and specificity of 100% and 100%, respectively. The cancer yield at surgery for pFNA was 40%, and the cancer yield at surgery for USFNA was 59%. The complementary use of USFNA with pFNA improves the diagnostic approach to nodular thyroid disease. The use of USFNA has increased the cancer yield at surgery and the sensitivity of thyroid biopsy at our institution.


Therapeutic potential of stem cell in liver regeneration.
Liver transplantation is the only life-saving procedure for patients with end-stage liver disease. However, its potential benefits are hampered by many disadvantages, such as the relative shortage of donors, operative risks, and high costs. These issues have prompted the search for new alternative therapies for irreversible liver disease. Stem cell therapy, with the ability for self-renewal and potential for multilineage differentiation, is a promising alternative approach. Several studies have demonstrated that transplantation of hepatic stem/progenitor cells or hepatocyte-like cells derived from multipotent stem cells leads to donor cell-mediated repopulation of the liver and improved survival rates in experimental models of liver disease. However, a registered clinical application based on stem cell technology will take at least an additional 5 to 10 years because of some limitations; e.g. the lack of suitable cell sources and risk of teratoma formation. This review summarizes the general understanding of the therapeutic potentials of stem cells in liver disease, including the sources, mechanisms, and delivery methods of hepatic stem cells in liver regeneration, and discusses some challenges for their therapeutic application.


Time Trends in Physical Activity Using Wearable Devices: A Systematic Review and Meta-analysis of Studies from 1995 to 2017.
Conflicting evidence exists on whether physical activity (PA) levels of humans have changed over the last quarter-century. The main objective of this study was to determine if there is evidence of time trends in PA, from cross-sectional studies that assessed PA at different time points using wearable devices (e.g., pedometers and accelerometers). A secondary objective was to quantify the rate of change in PA. A systematic literature review was conducted of English-language studies indexed in PubMed, SPORTDiscus, and Web of Science (1960-2020) using search terms (time OR temporal OR secular) AND trends AND (steps per day OR pedometer OR accelerometer OR MVPA). Subsequently, a meta-analytic approach was used to aggregate data from multiple studies and to examine specific factors (i.e., sex, age-group, sex and age-group, and PA metric). Based on 16 peer-reviewed scientific studies conducted between 1995 and 2017, levels of ambulatory PA are trending downward in developed countries. Significant declines were seen in both males and females (P < 0.001) as well as in children (P = 0.020), adolescents (P < 0.001), and adults (P = 0.004). The average study duration was 9.4 yr (accelerometer studies, 5.3 yr; pedometer studies, 10.8 yr). For studies that assessed steps, the average change in PA was -1118 steps per day over the course of the study (P < 0.001), and adolescents had the greatest change in PA at -2278 steps per day (P < 0.001). Adolescents also had the steepest rate of change over time, expressed in steps per day per decade. Evidence from studies conducted in eight developed nations over a 22-yr period indicates that PA levels have declined overall, especially in adolescents. This study emphasizes the need for continued research tracking time trends in PA using wearable devices.


Neurocognitive functioning in early-onset and late-onset older patients with euthymic bipolar disorder.
Most neurocognitive studies have not taken into account the fact that older patients with bipolar disorder (BD) are a heterogeneous population. The main goal of this study was to compare neurocognitive performance and extrapyramidal symptoms in older patients with early-onset BD (EO-BD) and late-onset BD (LO-BD). Euthymic older patients with EO-BD (n = 20), LO-BD (n = 20), and healthy controls (n = 20) were evaluated with traditional clinical instruments and measures of exposure to psychotropic drugs, as well as extrapyramidal symptoms. All subjects completed an extensive neuropsychological battery. Patients with EO-BD showed poorer performance than healthy controls in two measures of verbal memory and two measures of executive functions, whereas patients with LO-BD exhibited lower performance scores than healthy controls in almost all of the measures assessed. Impairments in the LO-BD group included even neurocognitive domains typically spared in mixed-age patients. Additionally, there was a trend toward displaying higher extrapyramidal symptoms in the LO-BD group compared with both EO-BD and healthy control groups. In both patient groups, psychosocial functioning was related with executive dysfunction and extrapyramidal symptoms. Patients with LO-BD may have more extensive and severe cognitive impairments, as well as higher vulnerability to extrapyramidal symptoms, compared with patients with EO-BD. Cognitive-motor disturbances may help to explain impairments in daily functioning among older patients with EO-BD and LO-BD during remission.


Understanding the psychological motives behind microblogging.
This research aims to understand the psychological motives behind microblogging. We conducted two studies to investigate if social exclusion and existential anxiety would lead to a high tendency to microblog. Our results show that participants did not use microblogging to satisfy their needs for social connection and affiliation, but highly extraverted participants did use it to relieve their existential anxiety.


Socio-Behavioral Risk Factors Associated with Cryptosporidiosis in HIV/AIDS Patients Visiting the HIV Referral Clinic at Cape Coast Teaching Hospital, Ghana.
To identify the socio-behavioral risk factors associated with cryptosporidiosis among HIV/AIDS patients with chronic diarrhea symptoms visiting the HIV referral clinic at Cape Coast Teaching Hospital, Ghana. A cross-sectional study was conducted among 50 HIV/AIDS patients with recurrent diarrhea. Questionnaires were administered to collect social and behavioral risk factors associated with Cryptosporidium and other opportunistic protozoan parasitic infections in HIV patients. Stool samples were collected for the diagnosis of enteric protozoan pathogens using modified Ziehl-Neelsen and acid-fast staining methods. CD4+ cells counts of study subjects were obtained from patients clinical records. The data obtained were analyzed using Pearson chi-square and multivariate-adjusted statistics tool on SPSS 16 for Windows. Twenty-seven (54%) of the subjects were infected with enteric protozoan pathogens. The prevalences of Cryptosporidium, Cyclospora and Microsporidium infections were 46%, 32% and 16%, respectively. Cryptosporidium infection was significantly associated with drinking water (×2=13.528, p<0.001), Cyclospora was associated with the type of drinking water (×2=14.931, p<0.001) and toilet facilities used by the study subjects (×2=12.463, p<0.01), whiles Microsporidium infection was associated with hand washing behavior (×2=12.463, p<0.01). Enteric protozoans were frequently encountered among subjects with CD4+ T-cell count <200 cells/mm3. However, coinfection of Cyclospora spp & Cryptosporidium spp was not observed in CD4+ cell count <200 and >500 cells/mm3. Multivariate analysis showed that the risk factor for Cryptosporidium infection among HIV/AIDS patients was the source of drinking water (pipe borne water 76.2% prevalence: sachet water 25%; OR=0.10, 95%CI: 0.03-0.39, p<0.001). We report the risk factor for exposure of Cryptosporidium infection among HIV/AIDS patients for the first time in Ghana. The contamination of drinking water by protozoan parasites should be a public health concern. These results provide the stepping block to understand the transmission dynamics of Cryptosporidium and other opportunistic pathogens in HIV/AIDS infected patients in Ghana.


Interleukin 28B polymorphism predicts pegylated interferon plus ribavirin treatment outcome in chronic hepatitis C genotype 4.
Single nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) region are the strongest baseline predictors of a sustained virologic response (SVR) to peg-interferon (PegIFN) and ribavirin (Rbv) in patients with hepatitis C virus (HCV) genotype 1 infection. Whether this holds true for HCV-4 patients too is unknown. The aim was to investigate the predictive power of the rs12979860 IL28B SNP for a response to Peg-IFN and Rbv in HCV-4 patients. All HCV-4 patients consecutively treated between September 2004 and June 2010 with PegIFN and Rbv at two liver centers at the Maggiore Hospital Milan (Italy) underwent TaqMan SNP Genotyping assays for testing rs12979860 genotype. Of 112 treated patients (98 males, 75 of Egyptian descent, 26 with cirrhosis) 103 were included in the final analysis; five discontinued treatment for nonvirologic reasons and four did not consent to genetic testing. Twenty-four (23%) were genotype CC, 65 (63%) CT, and 14 (14%) TT. Overall, 50 (49%) achieved an SVR: 21 (88%) CC patients versus 29 (37%) CT/TT (P < 0.0001). CC patients more often had a rapid virologic response (RVR) than CT/TT patients (12, 50% versus 23, 29%; P = 0.08), while also showing lower relapse rates (0% [0/21] versus 36% [16/45] P = 0.0013). In non-RVR patients, SVR rates were higher in CC than CT/TT patients (9 [75%] versus 13 [23%] P = 0.001). By logistic regression, the IL28B rs12979860 CC genotype was an independent predictor of SVR with an odds ratio of 8.0 (95% confidence interval 2.00-32.01; P = 0.003). The IL28B rs12979860 SNP may have an added value in the treatment algorithm of HCV-4 patients because it is the strongest predictor of an SVR to PegIFN/Rbv therapy.


Dispersal patterns and influence of air travel during the global expansion of SARS-CoV-2 variants of concern.
The Alpha, Beta, and Gamma SARS-CoV-2 variants of concern (VOCs) co-circulated globally during 2020 and 2021, fueling waves of infections. They were displaced by Delta during a third wave worldwide in 2021, which, in turn, was displaced by Omicron in late 2021. In this study, we use phylogenetic and phylogeographic methods to reconstruct the dispersal patterns of VOCs worldwide. We find that source-sink dynamics varied substantially by VOC and identify countries that acted as global and regional hubs of dissemination. We demonstrate the declining role of presumed origin countries of VOCs in their global dispersal, estimating that India contributed <15% of Delta exports and South Africa <1%-2% of Omicron dispersal. We estimate that >80 countries had received introductions of Omicron within 100 days of its emergence, associated with accelerated passenger air travel and higher transmissibility. Our study highlights the rapid dispersal of highly transmissible variants, with implications for genomic surveillance along the hierarchical airline network.


Auditing senior management communication practices in the NHS: a regional study.
Increasingly, organizations are being confronted with significant strategic change. This process can only be managed effectively if human resource implications, including how effectively managers and staff communicate with each other, are taken into account. This paper outlines how communication audits provide managers with insights into patterns of communication within their organizations. The nature of communication audits are briefly delineated and explained. An investigation from within the National Health Service (NHS) is offered, which illustrates how a communication audit focusing on relationships between regional, district and local levels of management illuminated patterns of communication between senior managers at these levels. This resulted in the development of an action plan for the improvement of communication practices. The generalizability of these findings to the NHS is discussed.


Practitioner insights on obesity prevention: the voice of South Australian OPAL workers.
Knowledge based on science has been central to implementing community-based childhood obesity prevention interventions. The art of practitioner wisdom is equally critical to ensure locally relevant responses. In South Australia (SA), the OPAL (Obesity Prevention and Lifestyle) program has been implemented to reduce childhood obesity across 20 communities reaching nearly one quarter of the state's population. Staff from across the State come together at regular intervals to share practice challenges and insights and refine the model of practice. Over a 3-year period 12 reflective practice workshops were held with OPAL staff (n = 46). OPAL staff were guided by an external facilitator using inquiring questions to reflect on their health promotion practice within local government. Three themes were identified as central within the reflections. The first theme is shared clarity through the OPAL obesity prevention model highlighting the importance of working to a clearly articulated, holistic obesity prevention model. The second theme is practitioner skill and sensitivity required to implement the model and deal with the 'politics' of obesity prevention. The final theme is the power of relationships as intrinsic to effective community based health promotion. Insights into the daily practices and reflections from obesity prevention practitioners are shared to shed light on the skills required to contribute to individual and social change. OPAL staff co-authored this paper.


Geographic source estimation using airborne plant environmental DNA in dust.
Information obtained from the analysis of dust, particularly biological particles such as pollen, plant parts, and fungal spores, has great utility in forensic geolocation. As an alternative to manual microscopic analysis of dust components, we developed a pipeline that utilizes the airborne plant environmental DNA (eDNA) in settled dust to estimate geographic origin. Metabarcoding of settled airborne eDNA was used to identify plant species whose geographic distributions were then derived from occurrence records in the USGS Biodiversity in Service of Our Nation (BISON) database. The distributions for all plant species identified in a sample were used to generate a probabilistic estimate of the sample source. With settled dust collected at four U.S. sites over a 15-month period, we demonstrated positive regional geolocation (within 600 km2 of the collection point) with 47.6% (20 of 42) of the samples analyzed. Attribution accuracy and resolution was dependent on the number of plant species identified in a dust sample, which was greatly affected by the season of collection. In dust samples that yielded a minimum of 20 identified plant species, positive regional attribution was achieved with 66.7% (16 of 24 samples). For broader demonstration, citizen-collected dust samples collected from 31 diverse U.S. sites were analyzed, and trace plant eDNA provided relevant regional attribution information on provenance in 32.2% of samples. This showed that analysis of airborne plant eDNA in settled dust can provide an accurate estimate regional provenance within the U.S., and relevant forensic information, for a substantial fraction of samples analyzed.


ALD1 accumulation in Arabidopsis epidermal plastids confers local and non-autonomous disease resistance.
The Arabidopsis plastid-localized ALD1 protein acts in the lysine catabolic pathway that produces infection-induced pipecolic acid (Pip), Pip derivatives, and basal non-Pip metabolite(s). ALD1 is indispensable for disease resistance associated with Pseudomonas syringae infections of naïve plants as well as those previously immunized by a local infection, a phenomenon called systemic acquired resistance (SAR). Pseudomonas syringae is known to associate with mesophyll as well as epidermal cells. To probe the importance of epidermal cells in conferring bacterial disease resistance, we studied plants in which ALD1 was only detectable in the epidermal cells of specific leaves. Local disease resistance and many features of SAR were restored when ALD1 preferentially accumulated in the epidermal plastids at immunization sites. Interestingly, SAR restoration occurred without appreciable accumulation of Pip or known Pip derivatives in secondary distal leaves. Our findings establish that ALD1 has a non-autonomous effect on pathogen growth and defense activation. We propose that ALD1 is sufficient in the epidermis of the immunized leaves to activate SAR, but basal ALD1 and possibly a non-Pip metabolite(s) are also needed at all infection sites to fully suppress bacterial growth. Thus, epidermal plastids that contain ALD1 play a key role in local and whole-plant immune signaling.


Analysis of cellular factors that mediate nuclear export of RNAs bearing the Mason-Pfizer monkey virus constitutive transport element.
There is now convincing evidence that the human Tap protein plays a critical role in mediating the nuclear export of mRNAs that contain the Mason-Pfizer monkey virus constitutive transport element (CTE) and significant evidence that Tap also participates in global poly(A)(+) RNA export. Previously, we had mapped carboxy-terminal sequences in Tap that serve as an essential nucleocytoplasmic shuttling domain, while others had defined an overlapping Tap sequence that can bind to the FG repeat domains of certain nucleoporins. Here, we demonstrate that these two biological activities are functionally correlated. Specifically, mutations in Tap that block nucleoporin binding also block both nucleocytoplasmic shuttling and the Tap-dependent nuclear export of CTE-containing RNAs. In contrast, mutations that do not inhibit nucleoporin binding also fail to affect Tap shuttling. Together, these data indicate that Tap belongs to a novel class of RNA export factors that can target bound RNA molecules directly to the nuclear pore without the assistance of an importin beta-like cofactor. In addition to nucleoporins, Tap has also been proposed to interact with a cellular cofactor termed p15. Although we were able to confirm that Tap can indeed bind p15 specifically both in vivo and in vitro, a mutation in Tap that blocked p15 binding only modestly inhibited CTE-dependent nuclear RNA export. However, p15 did significantly enhance the affinity of Tap for the CTE in vitro and readily formed a ternary complex with Tap on the CTE. This result suggests that p15 may play a significant role in the recruitment of the Tap nuclear export factor to target RNA molecules in vivo.


Prevalence and clinical manifestations of ankylosing spondylitis in young Greek males.
Increased awareness and sensitivity of general physicians have increased the early diagnoses of seronegative arthritis in young patients, while new agents such as anti-TNF blockers have significantly changed the treatment of the disease. To investigate the prevalence, the clinical manifestations, and the ability for military service of young Greek males (18-30 years old) with ankylosing spondylitis (AS) in the pre-anti-TNF era. We retrospectively studied the AS cases recorded from 1989 to 1995 of the rheumatology department of the largest General Military Hospital in Greece; the diagnosis was based on the modified New York criteria for AS. A total of 285 AS cases were diagnosed among 357,184 young men. The overall prevalence of AS on December 1995 was estimated at 8.2 cases per 10,000 young men (95 % C.I. 7.2-9.2). All the patients had chronic back pain. Two hundred forty (84 %, 95 % C.I. 79-88 %) patients presented sacroiliitis of whom 163 (68 %, 95 % C.I. 62-73 %) were bilateral. Two hundred five patients (72 %, 95 % C.I. 66-77 %) had peripheral joint involvement. Thirty-one patients presented with anterior uveitis (11 %, 95 % C.I. 8-15 %). One patient had IgA nephropathy. None had gut involvement. HLA-B27 antigen was found in 257 patients (90 %, 95 % C.I. 86-93 %). Ninety-one patients (32 %, 95 % C.I. 27-38 %) had permanent discharge from the military service, while 128 (45 %, 95 % C.I. 39-51 %) were able for auxiliaries attendances. The prevalence of AS for the age group 18-30 years old in this young Greek men cohort was significantly lower than in other Caucasian European populations, and the clinical manifestations were considered as mild.


Differential quantification of CYP2D6 gene copy number by four different quantitative real-time PCR assays.
Copy number variations (CNVs) in the CYP2D6 gene contribute to interindividual variation in drug metabolism. As the most common duplicated allele in Asian populations is the nonfunctional CYP2D6*36 allele, the goal of this study was to identify CNV assays that can differentiate between multiple copies of the CYP2D6*36 allele and multiple copies of other CYP2D6 alleles. We determined CYP2D6 gene copy numbers in 32 individuals with known CYP2D6 CNVs from the Coriell Japanese-Chinese panel using four quantitative real-time PCR assays. These assays target different regions of the CYP2D6 gene: 5'-flanking region, intron 2, intron 6, and exon 9 (Ex9). The specific target site of the Ex9 assay was verified by sequencing the PCR amplicon. Three of the CYP2D6 CNV assays (5'-flanking region, intron 2, and intron 6) estimated CYP2D6 copy numbers that were concordant for all 32 individuals. However, the Ex9 assay was concordant in only 10 of 32 samples. The 10 concordant samples did not contain any CYP2D6*36 alleles and the 22 discordant samples contained at least one CYP2D6*36 allele. In addition, the Ex9 assay accurately quantified all of the non-CYP2D6*36 alleles in all samples. Ex9 amplicon sequencing indicated that it targets a region of CYP2D6 exon 9 that undergoes partial gene-conversion in the CYP2D6*36 allele. In conclusion, CYP2D6 Ex9 CNV assay can be used to determine the copy number of non-CYP2D6*36 alleles. Selective amplification of non-CYP2D6*36 sequence by the Ex9 assay should be useful in determining the number of functional copies of CYP2D6 in Asian populations.


The Voluntary Euthanasia (Legalization) Bill (1936) revisited.
In view of the continuing debate on euthanasia, the restrictions and safeguards which were introduced into the Voluntary Euthanasia (Legislation) Bill 1936 are discussed. Proposals for a new Terminal Care and Euthanasia Bill are suggested, based on some of the principles of the Mental Health Act 1983.


Continuity With Patients, Preceptors, and Peers Improves Primary Care Training: A Randomized Medical Education Trial.
Infusing continuity of care into medical student clerkships may accelerate professional development, preserve patient-centered attitudes, and improve primary care training. However, prospective, randomized studies of longitudinal curricula are lacking. All entering Northwestern University Feinberg School of Medicine students in 2015 and 2016 were randomized to the Education Centered Medical Home (ECMH), a 4-year, team-based primary care clerkship; or a mentored individual preceptorship (IP) for 2 years followed by a traditional 4-week primary care clerkship. Students were surveyed 4 times (baseline, M1, M2, and M3 year [through 2018]); surveys included the Maslach Burnout Inventory (MBI); the Communication, Curriculum, and Culture (C3) survey assessing the hidden curriculum; and the Attitudes Toward Health Care Teams (ATHCT) scale. The authors analyzed results using an intent-to-treat approach. Three hundred twenty-nine students were randomized; 316 (96%) participated in surveys. Seventy percent of all respondents would recommend the ECMH to incoming first-year students. ECMH students reported a more positive learning environment (overall quality, 4.4 ECMH vs 4.0 IP, P < .001), greater team-centered attitudes (ATHCT scale, 3.2 vs 3.0, P = .007), less exposure to negative aspects of the hidden curriculum (C3 scale, 4.6 vs 4.3, P < .001), and comparable medical knowledge acquisition. ECMH students established more continuity relationships with patients (2.2 vs 0.3, P < .001) and reported significantly higher professional efficacy (MBI-PE, 4.1 vs 3.9, P = .02). In this randomized medical education trial, the ECMH provided superior primary care training across multiple outcomes compared with a traditional clerkship-based model, including improved professional efficacy.


Microfabricated tuneable and transferable porous PDMS membranes for Organs-on-Chips.
We present a novel and highly reproducible process to fabricate transferable porous PDMS membranes for PDMS-based Organs-on-Chips (OOCs) using microelectromechanical systems (MEMS) fabrication technologies. Porous PDMS membranes with pore sizes down to 2.0 μm in diameter and a wide porosity range (2-65%) can be fabricated. To overcome issues normally faced when using replica moulding and extend the applicability to most OOCs and improve their scalability and reproducibility, the process includes a sacrificial layer to easily transfer the membranes from a silicon carrier to any PDMS-based OOC. The highly reliable fabrication and transfer method does not need of manual handling to define the pore features (size, distribution), allowing very thin (<10 μm) functional membranes to be transferred at chip level with a high success rate (85%). The viability of cell culturing on the porous membranes was assessed by culturing two different cell types on transferred membranes in two different OOCs. Human umbilical endothelial cells (HUVEC) and MDA-MB-231 (MDA) cells were successfully cultured confirming the viability of cell culturing and the biocompatibility of the membranes. The results demonstrate the potential of controlling the porous membrane features to study cell mechanisms such as transmigrations, monolayer formation, and barrier function. The high control over the membrane characteristics might consequently allow to intentionally trigger or prevent certain cellular responses or mechanisms when studying human physiology and pathology using OOCs.


The efficacy of loop diuretics in acute renal failure: assessment using Bayesian evidence synthesis techniques.
To quantify the therapeutic efficacy of loop diuretics in acute renal failure using Bayesian evidence synthesis, because despite widespread use, the role of diuretics is controversial. Randomized controlled trials or nonrandomized studies, 1966 to January 2007, identified from MEDLINE and EMBASE databases and manual bibliographic search. Studies with assessable predefined end points, exclusive of those pertaining to acute renal failure prophylaxis or chronic renal failure. Data extraction was performed jointly by the first two authors; independent study assessment was via standard checklist, unblinded. The primary outcome was mortality; secondary outcomes were time to renal function normalization and total number of dialyses. Bayesian hierarchical random effects estimates of treatment effects were determined as risk ratio for mortality, incidence rate ratio for dialysis number, and mean difference for continuous measures. Bayesian outcome probabilities were calculated as probability (P) that risk ratio or incidence rate ratio of loop diuretics >1 and probability that mean difference >0. Five randomized controlled trials and eight nonrandomized studies were identified. Loop diuretics were not associated with decreased mortality in either randomized controlled trials or nonrandomized studies: overall risk ratio 1.10; 95% credible interval 0.85, 1.42; P(risk ratio >1) > 83.8%. The oliguric period was decreased by loop diuretics: overall mean difference -7.70 days; 95% credible interval -12.51, -2.08; P (mean difference >0) = 0.7%. Although the dialysis rate credible interval, loop diuretics vs. control, spanned unity (incidence rate ratio 0.71; 95% credible interval 0.47, 1.06), the probability that the incidence rate ratio exceeded unity indicated a substantial benefit: P (incidence rate ratio >1 = 4.1%. Uremic duration was not substantially different, loop diuretics vs. control: overall mean difference -1.54 days; 95% credible interval -5.62, 2.46; P [mean difference >0] = 17.8%). Loop diuretics were not associated with improved survival benefit in acute renal failure, despite reduction in oliguric period and high probability of a significant reduction in dialysis numbers. Further studies to clarify this dichotomy appear mandated.


The UCSC Genome Browser database: extensions and updates 2011.
The University of California Santa Cruz Genome Browser (http://genome.ucsc.edu) offers online public access to a growing database of genomic sequence and annotations for a wide variety of organisms. The Browser is an integrated tool set for visualizing, comparing, analyzing and sharing both publicly available and user-generated genomic data sets. In the past year, the local database has been updated with four new species assemblies, and we anticipate another four will be released by the end of 2011. Further, a large number of annotation tracks have been either added, updated by contributors, or remapped to the latest human reference genome. Among these are new phenotype and disease annotations, UCSC genes, and a major dbSNP update, which required new visualization methods. Growing beyond the local database, this year we have introduced 'track data hubs', which allow the Genome Browser to provide access to remotely located sets of annotations. This feature is designed to significantly extend the number and variety of annotation tracks that are publicly available for visualization and analysis from within our site. We have also introduced several usability features including track search and a context-sensitive menu of options available with a right-click anywhere on the Browser's image.


Transcranial direct current stimulation as a treatment for auditory hallucinations.
Auditory hallucinations (AH) are a symptom of several psychiatric disorders, such as schizophrenia. In a significant minority of patients, AH are resistant to antipsychotic medication. Alternative treatment options for this medication resistant group are scarce and most of them focus on coping with the hallucinations. Finding an alternative treatment that can diminish AH is of great importance. Transcranial direct current stimulation (tDCS) is a safe and non-invasive technique that is able to directly influence cortical excitability through the application of very low electric currents. A 1-2 mA direct current is applied between two surface electrodes, one serving as the anode and the other as the cathode. Cortical excitability is increased in the vicinity of the anode and reduced near the cathode. The technique, which has only a few transient side effects and is cheap and portable, is increasingly explored as a treatment for neurological and psychiatric symptoms. It has shown efficacy on symptoms of depression, bipolar disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, epilepsy, and stroke. However, the application of tDCS as a treatment for AH is relatively new. This article provides an overview of the current knowledge in this field and guidelines for future research.


Inter-beat intervals of cardiac-cell aggregates during exposure to 2.45 GHz CW, pulsed, and square-wave-modulated microwaves.
Inter-beat intervals of aggregated cardiac cells from chicken embryos were studied during 190 s exposures to 2.45 GHz microwaves in an open-ended coaxial device. Averaged specific-absorption rates (SARs) and modulation conditions were 1.2-86.9 W/kg continuous-wave (CW), 1.2-12.2 W/kg pulse modulation (PW, duty cycle approximately 11%), and 12.0-43.5 W/kg square-wave modulation (duty cycle = 50%). The inter-beat interval decreased during microwave exposures at 42.0 W/kg and higher when CW or square-wave modulation was used, which is consistent with established effects of elevated temperatures. However, increases in the inter-beat interval during CW exposures at 1.2-12.2 W/kg, and decreases in the inter-beat interval after PW exposures at 8.4-12.2 W/kg, are not consistent with simple thermal effects. Analysis of variance indicated that SAR, modulation, and the modulation-SAR interaction were all significant factors in altering the inter-beat interval. The latter two factors indicated that the cardiac cells were affected by athermal as well as thermal effects of microwave exposure.


Remote Monitoring of Cardiac Implantable Devices: Ontology Driven Classification of the Alerts.
The number of patients that benefit from remote monitoring of cardiac implantable electronic devices, such as pacemakers and defibrillators, is growing rapidly. Consequently, the huge number of alerts that are generated and transmitted to the physicians represents a challenge to handle. We have developed a system based on a formal ontology that integrates the alert information and the patient data extracted from the electronic health record in order to better classify the importance of alerts. A pilot study was conducted on atrial fibrillation alerts. We show some examples of alert processing. The results suggest that this approach has the potential to significantly reduce the alert burden in telecardiology. The methods may be extended to other types of connected devices.


The improvement of salt tolerance in transgenic tobacco by overexpression of wheat F-box gene TaFBA1.
F-box protein is a major subunit of the Skp1-Cullin-F-box (SCF) complex. We previously isolated an F-box gene from wheat, TaFBA1, and here we show that overexpression of TaFBA1 in transgenic plants under salt stress increases germination rate, root elongation, and biomass accumulation compared with WT plants. Improvements in the photosynthetic rate and its corresponding parameters were also found in the transgenic plants. These results suggest that overexpression of TaFBA1 improves salt stress tolerance in transgenic tobacco. Further, the transgenic plants displayed less membrane damage, higher antioxidant enzyme activity, and less accumulation of ROS under salt stress. The transgenic plants also had lower Na+ content and higher K+ content than WT plants in leaves and roots. The activity of H+-ATPase on the plasma membrane in the transgenic plants was higher than in WT plants, and was accompanied by a net Na+ efflux. In the tonoplast, the activity levels of V-ATPase and PPase were also higher in the transgenic plants, thus helping to maximize intracellular Na+ compartmentalization. The expression of some stress-related genes was upregulated by salt stress. This suggests that the enhancement of plant salt stress tolerance may be associated with an improvement in antioxidative competition and Na+/K+ ion regionalization.


Detection of t(2;5) in anaplastic large cell lymphoma: comparison of immunohistochemical studies, FISH, and RT-PCR in paraffin-embedded tissue.
Anaplastic large cell lymphoma (ALCL) is associated with the t(2;5)(p23;q35) translocation involving the anaplastic lymphoma kinase gene (ALK) and the nucleophosmin gene (NPM), which result in expression of a novel fusion protein, NPM-ALK (p80). Clinicopathologic studies have shown that ALK expression in ALCL is associated with improved 5-year survival rates when compared with ALCL lacking ALK expression. This study used paraffin-embedded tissue to compare interphase fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) for the detection of t(2;5) with immunohistochemical analysis for the detection of ALK protein expression in 27 patients with CD30-positive ALCLs. ALK protein expression was detected with ALK1 antibody in 14 of the 27 patients. The neoplastic cells in 13 of these 14 lymphomas reacted with the p80NPM/ALK antibody. FISH, using a two-color ALK DNA probe, correlated 100% with the immunohistochemical results: a translocation involving the ALK gene was detected in all 14 lymphomas that reacted with anti-ALK1. RT-PCR, performed on 21 lymphomas, detected NPM-ALK mRNA in five of the lymphomas, all of which reacted with anti-ALK1 and showed ALK gene rearrangement by FISH. Lymphomas showing ALK1 reactivity occurred in a younger patient population (median age, 19.5 years) and were associated with improved 5-year survival rates (84%), as compared with lymphomas lacking ALK1 reactivity (median age, 68.0 years; 5-year survival rate, 35%; p = 0.008). We conclude that immunohistochemical studies, using antibody ALK1. and FISH for ALK gene rearrangement are equally effective for identifying patients with ALCL who have a favorable clinical outcome.


Seasonal analyses of air pollution and mortality in 100 US cities.
Time series models relating short-term changes in air pollution levels to daily mortality counts typically assume that the effects of air pollution on the log relative rate of mortality do not vary with time. However, these short-term effects might plausibly vary by season. Changes in the sources of air pollution and meteorology can result in changes in characteristics of the air pollution mixture across seasons. The authors developed Bayesian semiparametric hierarchical models for estimating time-varying effects of pollution on mortality in multisite time series studies. The methods were applied to the database of the National Morbidity and Mortality Air Pollution Study, which includes data for 100 US cities, for the period 1987-2000. At the national level, a 10-microg/m(3) increase in particulate matter less than 10 microm in aerodynamic diameter at a 1-day lag was associated with 0.15% (95% posterior interval (PI): -0.08, 0.39), 0.14% (95% PI: -0.14, 0.42), 0.36% (95% PI: 0.11, 0.61), and 0.14% (95% PI: -0.06, 0.34) increases in mortality for winter, spring, summer, and fall, respectively. An analysis by geographic region found a strong seasonal pattern in the Northeast (with a peak in summer) and little seasonal variation in the southern regions of the country. These results provide useful information for understanding particle toxicity and guiding future analyses of particle constituent data.


Carcass traits and M. longissimus lumborum palatability attributes of calf- and yearling-finished steers.
A 2-yr experiment was conducted to compare carcass characteristics and meat palatability attributes of steers ((3/4) British, (1/4) Continental) finished postweaning as calves or yearlings. Calves and yearlings of the same contemporary group were designated to a finishing system at weaning. Calves (n = 73) were finished in the feedlot (191 d) on a high-concentrate diet. Yearlings (n = 84) grazed crop residues after weaning, followed by spring and summer pasture grazing, and concluded with a short finishing period (91 d) in the feedlot. All steers were fed to a constant, fat thickness endpoint of 1 cm. The M. longissimus lumborum steaks from each production system were aged for 7, 14, or 21 d for Warner-Bratzler shear force determination and for 7 or 14 d for in-house sensory panel evaluation. Insoluble, percent soluble, and total collagen were determined. Yearlings produced heavier (P < 0.001) carcasses with larger (P < 0.001) LM areas and lower (P < 0.001) marbling scores and quality grades. Calves possessed greater amounts of total collagen (P < 0.001), with a significantly greater percentage of soluble collagen compared with yearlings (39.72 vs. 24.38%). Calves produced steaks with lower (P < 0.001) shear force values and greater (P < 0.001) sensory ratings for flavor. The USDA Choice steaks from the calves were more (P < 0.001) tender and more (P < 0.050) palatable than Choice steaks from yearlings, and USDA Select steaks from calves were rated more tender (P < 0.001), juicy (P = 0.012), and desirable (P < 0.001) than Select steaks from yearlings. As expected, increasing aging time from 7- to 14- to 21-d produced steaks with lower (P < 0.001) shear force values, regardless of the production system. Risk probabilities showed 1.24% of the steaks from calf-finished steers and 21.22% of steaks from yearling-finished steers to be tough. Sensory rating probabilities showed the steaks from the calves were most likely to be desirable for tenderness, whereas steaks from the yearlings were most likely to be undesirable for tenderness, juiciness, flavor, and overall acceptability. Thus, calf-finished steers produce carcasses superior in quality and palatability compared with those from yearling-finished steers. However, yearling-finished steers can produce tender beef with extended aging.


Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia.
Clinicians frequently identify anemia in their older patients, but national data on the prevalence and causes of anemia in this population in the United States have been unavailable. Data presented here are from the noninstitutionalized US population assessed in the third National Health and Nutrition Examination Survey (1988-1994). Anemia was defined by World Health Organization criteria; causes of anemia included iron, folate, and B(12) deficiencies, renal insufficiency, anemia of chronic inflammation (ACI), formerly termed anemia of chronic disease, and unexplained anemia (UA). ACI by definition required normal iron stores with low circulating iron (less than 60 microg/dL). After age 50 years, anemia prevalence rates rose rapidly, to a rate greater than 20% at age 85 and older. Overall, 11.0% of men and 10.2% of women 65 years and older were anemic. Of older persons with anemia, evidence of nutrient deficiency was present in one third, ACI or chronic renal disease or both was present in one third, and UA was present in one third. Most occurrences of anemia were mild; 2.8% of women and 1.6% of men had hemoglobin levels lower than 110 g/L (11 g/dL). Therefore, anemia is common, albeit not severe, in the older population, and a substantial proportion of anemia is of indeterminate cause. The impact of anemia on quality of life, recovery from illness, and functional abilities must be further investigated in older persons.


A review of cost-effectiveness of palivizumab for respiratory syncytial virus.
Palivizumab prophylaxis has been demonstrated to reduce the number of hospitalizations attributable to respiratory syncytial virus in high-risk infants. However, as palivizumab acquisition costs are high, quantifying cost-effectiveness is important. The primary aim of this review was to examine the cost-effectiveness of palivizumab across numerous indications in high-risk infants and to report on factors that may impact outcomes. A systematic literature search was conducted to identify pharmacoeconomic analyzes of palivizumab compared to no prophylaxis for respiratory syncytial virus in infants and young children. A total of 28 articles met inclusion criteria and were subsequently assigned quality scores according to the Quality of Health Economic Studies criteria. Results varied according to perspective, input parameters, outcome measures, populations and base-case and sensitivity analyses. Overall, cost-effectiveness results were inconsistent. Some studies reported favorable outcomes, while others did not, or were inconclusive. Factors to consider in the interpretation of such economic evaluations are discussed.


Measurement of the copy number of the master quorum-sensing regulator of a bacterial cell.
Quorum-sensing is the mechanism by which bacteria communicate and synchronize group behaviors. Quantitative information on parameters such as the copy number of particular quorum-sensing proteins should contribute strongly to understanding how the quorum-sensing network functions. Here, we show that the copy number of the master regulator protein LuxR in Vibrio harveyi can be determined in vivo by exploiting small-number fluctuations of the protein distribution when cells undergo division. When a cell divides, both its volume and LuxR protein copy number, N, are partitioned with slight asymmetries. We measured the distribution functions describing the partitioning of the protein fluorescence and the cell volume. The fluorescence distribution is found to narrow systematically as the LuxR population increases, whereas the volume partitioning is unchanged. Analyzing these changes statistically, we determined that N = 80-135 dimers at low cell density and 575 dimers at high cell density. In addition, we measured the static distribution of LuxR over a large (3000) clonal population. Combining the static and time-lapse experiments, we determine the magnitude of the Fano factor of the distribution. This technique has broad applicability as a general in vivo technique for measuring protein copy number and burst size.


Influence of superovulatory protocols on in vitro production of Nellore (Bos indicus) embryos.
There are indications in the literature that delaying the period between ovarian superestimulation and ovum pick up (OPU) would induce follicles to a condition of initial atresia, which could be beneficial to oocyte development. In this work, we compared three protocols for OPU and in vitro production (IVP) of embryos, in Nellore cattle. Nellore cows (n = 18) were randomly allocated in three groups: Group 1 (OPU), Group 2 [Follicle stimulating hormone (FSH) and OPU] and Group 3 (FSH deprivation and OPU). Three OPUs were performed, and the animals were switched to a different group each time (crossover), in such a way that at the end of the experiment all cows received the 3 protocols. At random stage of the oestrous cycle (D-2), all follicles ≥ 6 mm were aspirated to induce a new follicular wave 2 days afterwards (D0). In Group 1, OPU was performed on D2 and oocytes were processed to IVP. In Group 2, starting on D0, cows were superstimulated (FSH, Folltropin(®), 30 mg administered daily, i.m., during three consecutive days, total dose = 180 mg), and 6 h after the last FSH dose, they received exogenous luteinizing hormone (LH) (12.5 mg, i.m., Lutropin(®), D3). The OPU was performed 6 h after LH administration, i.e. 12 h after the last dose of FSH. Animals in Group 3 received the same treatment as those in Group 2, except that LH was administered 42 h after the last dose of FSH, and OPU occurred 6 h later. Therefore, in this group, follicles were deprived of FSH at 48 h. Both cleavage and blastocyst rates were similar (p > 0.05, anova) among oocytes from Groups 1, 2 and 3, respectively: 77.4% (144/185) and 42.70% (79/185); 75.54% (105/139) and 31.65% (44/139); 63.52% (101/159) and 33.33% (53/159). However, hatched blastocyst rate was higher (p < 0.01) in Group 1 (30.27%, 56/185) when compared with Group 2 (11.51%, 16/139) or 3 (15.72%, 25/159). It is concluded that, contrary to previous work on European breeds (Bos taurus), ovarian superstimulation associated with deprivation of FSH and OPU (Group 3) did not increase IVP of Nellore embryos (Bos indicus). On the contrary, the highest hatched blastocyst rates were observed in oocytes from non-superstimulated cows.


Anaesthesia for ultrasound guided oocyte retrieval: midazolam/remifentanil versus propofol/fentanyl regimens.
To evaluate the quality of intra-operative anaesthesia and recovery characteristics of two different anaesthesia regimens, 60 healthy women undergoing ultrasound guided oocyte retrieval for in vitro fertilization procedures were randomly allocated to receive either a propofol/fentanyl or a midazolam/remifentanil based anaesthesia. The surgical procedure was successful in all patients and no severe side effects were reported by any patient. Four patients in the midazolam/remifentanil group (13%) would not accept the same anaesthetic procedure for further in vitro fertilization treatment due to intra-operative awareness, while all propofol/fentanyl patients were prepared to accept the same procedure again (P < 0.05). Patients in the propofol/fentanyl group required manual ventilation more frequently through a facemask than those patients treated with the midazolam/remifentanil combination (50% and 30%, respectively; P < 0.05). The time to achieve an Aldrete's score of 10 was shorter in the midazolam/remifentanil patients (2 +/- 2 min) than in those who received propofol/fentanyl (4 +/- 2 min) (P < 0.001), but no differences were observed in the time required to be 'fit to discharge' from the post-anaesthesia care unit. We conclude that the use of a midazolam/remifentanil regimen is as effective and safe as a fentanyl/propofol regimen in patients undergoing transvaginal oocyte retrieval for in vitro fertilization procedures.


The effects of natural altered peptide ligands on the whole blood cytotoxic T lymphocyte response to human immunodeficiency virus.
Cytotoxic T lymphocytes (CTL) directed against human immunodeficiency virus (HIV)-1 are detectable in the majority of infected individuals, and their early appearance as the initial viremia is suppressed is thought to represent a potent antiviral response. Variation which arises in CTL epitopes can affect recognition by CTL, and we have observed previously that variant epitopes in HIV-1 gag which arise in HIV-1-seropositive donors may act as T cell receptor (TCR) antagonists of their own CTL (Klenerman et al., Nature 1994, 369: 403). The most important question arising from these observations is the extent of these immune escape mechanisms in vivo. Here we show that fresh, uncultured lymphocytes taken directly from HIV-1-infected patients are susceptible to TCR antagonism by variants present within their own virus. In contrast to HLA Class II-restricted T cell responses, where anergy may be induced, we find that in vitro, natural variants may stimulate and sustain growth of CTL. These CTL lines retain lytic specificity exclusively for the original peptide. If this represents events in vivo, natural HIV altered peptide ligands (APL) have the capacity to inhibit the range of CTL directed against an epitope, not simply those clones selected in vitro. Partial activation of CTL by APL could also act to drive an ineffectual CTL response incapable of lysing infected cells bearing these natural antigenic variants. Distortion of lymphocyte populations and function by APL might represent a further mechanism of immune evasion by HIV.


Pathological changes in basement membranes and dermal connective tissue of skin from patients with hereditary cystatin C amyloid angiopathy.
Hereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disease caused by a mutation in the cystatin C gene. Cystatin C is abundant in cerebrospinal fluid and the most prominent pathology in HCCAA is cerebral amyloid angiopathy due to mutant cystatin C amyloid deposition with associated cerebral hemorrhages, typically in young adult carriers. Analyses of post-mortem brain samples shows that pathological changes are limited to arteries and regions adjacent to arteries. The severity of pathological changes at post-mortem has precluded the elucidation of the evolution of histological changes. Mutant cystatin C deposition in carriers is systemic and has, for example, been described in the skin, suggesting similar pathological mechanisms both in the brain and outside of the central nervous system. The aim of this study was to use skin biopsies from asymptomatic and symptomatic carriers to study intermediate events in HCCAA pathogenesis. We found that cystatin C deposition in minimally affected samples was limited to the basement membrane (BM) between the dermis and epidermis. When the deposits were more advanced, they extended to other BM regions in the skin. Our results showed that the immunoreactivity of the BM protein COLIV was increased to a similar extent in all carrier biopsies and cystatin C deposits were in close association with COLIV. The density of fibroblasts in the upper dermis of carrier skin was increased, whereas the distribution of other cell types examined did not differ compared with control biopsies. COLIV and cystatin C immunoreactivity in carrier biopsies was closely associated with the fibroblasts. The results of this study, in conjunction with our previous results regarding pathological BM changes in leptomeningeal arteries of patients, suggest that BM changes are early and important events in HCCAA pathogenesis that could facilitate cystatin C deposition and aggregation.


Informed consent in genomic research and biobanking: taking feedback of findings seriously.
Genomic research and biobanking present several ethical, social and cultural challenges, particularly when conducted in settings with limited scientific research capacity. One of these challenges is determining the model of consent that should support the sharing of human biological samples and data in the context of international collaborative research. In this paper, we report on the views of key research stakeholders in Ghana on what should count as good ethical practice when seeking consent for genomic research and biobanking in Africa. This study was part of a multi-country qualitative case study conducted in three African countries: Ghana, Uganda and Zambia under the auspices of the Human Heredity and Health in Africa initiative (H3Africa). Our study suggests that while participants are willing to give consent for their samples and associated data to be used for future research purposes, they expect to receive feedback about the progress of the research and about the kinds of research being undertaken on their samples and data. These expectations need to be anticipated and discussed during the consent process which should be seen as part of an ongoing communication process throughout the research process.


Mechanism of ionic-liquid-based acidic aqueous biphasic system formation.
Ionic-liquid-based acidic aqueous biphasic systems (IL-based AcABS) represent a promising alternative to the solvent extraction process for the recovery of critical metals, in which the substitution of the inorganic salt by an acid allows for a 'one-pot' approach to the leaching and separation of metals. However, a more fundamental understanding of AcABS formation remains wanting. In this work, the formation mechanisms of AcABS are elucidated through a comparison with traditional aqueous biphasic systems (ABS). A large screening of AcABS formation with a wide range of IL identifies the charge shielding of the cation as the primary structural driver for the applicability of an IL in AcABS. Through a systematic study of tributyltetradecylphosphonium chloride ([P44414]Cl) with various chloride salts and acids, we observed the first significant deviation to the cationic Hofmeister series reported for IL-based ABS. Furthermore, the weaker than expected salting-out ability of H3O+ compared to Na+ is attributed to the greater interaction of H3O+ with the [P44414]+ micelle surface. Finally, the remarkable thermomorphic properties of [P44414]Cl based systems are investigated with a significant increase in the biphasic region induced by the increase in the temperature from 298 K to 323 K. These finding allows for the extension of ABS to new acidic systems and highlights their versatility and tunability.


Dynamics of force generation by spreading platelets.
In order to gain more insight into the role of human platelets for blood clot formation, here we investigate the dynamics of force generation by platelet spreading onto elastic substrates of variable stiffness. Despite their small size, platelets generate high and rapidly varying traction forces on their extracellular environment, which we reconstruct with adapted implementations of Fourier transform traction cytometry. We find that while the final spread area is reached within a few minutes, the build-up of forces typically takes 10-30 minutes. In addition, we identify two distinct behaviors of individual cells, namely oscillating and non-oscillating platelets. An eigenvalue analysis of the platelet dipole tensor reveals a small anisotropy of the exerted force, which is compatible with a random distribution of a few force transmitting centers, in agreement with the observed shapes and traction patterns. We find a correlation between the maximum force level a platelet reaches and its spread area, which we explain by a thin film model for the actively contracting cell. The model reveals a large internal stress of hundreds of kPa. Experimentally we do not find any statistically relevant relation between the force level reached and the substrate stiffness within the stiffness range from 19 to 83 kPa, which might be related to the high platelet activation level used in our study. In addition, our model suggests that due to the uniquely small thickness of platelets, their mechanosensitivity might be limited to a lower stiffness range.


Rhenium-osmium isotope constraints on the age of iron meteorites.
Rhenium and osmium concentrations and the osmium isotopic compositions of iron meteorites were determined by negative thermal ionization mass spectrometry. Data for the IIA iron meteorites define an isochron with an uncertainty of approximately +/-31 million years for meteorites approximately 4500 million years old. Although an absolute rheniumosmium closure age for this iron group cannot be as precisely constrained because of uncertainty in the decay constant of (187)Re, an age of 4460 million years ago is the minimum permitted by combined uncertainties. These age constraints imply that the parent body of the IIAB magmatic irons melted and subsequently cooled within 100 million years after the formation of the oldest portions of chondrites. Other iron meteorites plot above the IIA isocbron, indicating that the planetary bodies represented by these iron groups may have cooled significantly later than the parent body of the IIA irons.


Identifying environmental drivers of insect phenology across space and time: Culicoides in Scotland as a case study.
Interpreting spatial patterns in the abundance of species over time is a fundamental cornerstone of ecological research. For many species, this type of analysis is hampered by datasets that contain a large proportion of zeros, and data that are overdispersed and spatially autocorrelated. This is particularly true for insects, for which abundance data can fluctuate from zero to many thousands in the space of weeks. Increasingly, an understanding of the ways in which environmental variation drives spatial and temporal patterns in the distribution, abundance and phenology of insects is required for management of pests and vector-borne diseases. In this study, we combine the use of smoothing techniques and generalised linear mixed models to relate environmental drivers to key phenological patterns of two species of biting midges, Culicoides pulicaris and C. impunctatus, of which C. pulicaris has been implicated in transmission of bluetongue in Europe. In so doing, we demonstrate analytical tools for linking the phenology of species with key environmental drivers, despite using a relatively small dataset containing overdispersed and zero-inflated data. We demonstrate the importance of landcover and climatic variables in determining the seasonal abundance of these two vector species, and highlight the need for more empirical data on the effects of temperature and precipitation on the life history traits of palearctic Culicoides spp. in Europe.


Japanese Right-Wing Discourse in International Context: Minoda Muneki's Interwar Writings on Class and Nation.
It is often taken for granted that ultranationalist ideologues of interwar Japan were anti-western, uncritical mouthpieces of state ideology. This article considers the case of Minoda Muneki (1894-1946) who led the purge of liberals and Marxists from imperial universities. In articulating his theory of nationalism and critique of Marxism, Minoda drew upon a global discourse of social theory. Furthermore, his rise to power was a product of a short-lived convergence of interests between his organization and government figures. I argue for a global historical approach to right-wing ideology that accounts for the relation between nationalist discourse and political power.


Possible thermoregulatory functions of the internal vertebral venous plexus in man and various other mammals: evidence from comparative anatomical studies.
Comparative anatomy was used to collect more evidence for a thermoregulatory function of the internal vertebral venous plexus (IVVP). The venous connections of the IVVP were studied and compared in various mammals in order to find evidence for the existence of climate related anatomical adaptations. Humans and vervet monkeys were chosen as representatives of mammals living in moderate climates, the IVVP of the dolphin was studied because this animal is always surrounded by cold water. The springbok was chosen as a representative of mammalian species living under very hot conditions. The present study was exclusively performed on post mortem material. After filling the venous system with latex the IVVP and its venous connections were dissected. It appeared that in the dolphin, veins from the trunk muscles were directly and exclusively connected to the IVVP in the absence of an azygos vein. In the vervet monkey and human specimens, veins originating in the muscles drained both into the caval veins and into the IVVP. In these mammals veins draining from brown fat areas were also connected to the IVVP. In the springbok, drainage of blood from the muscles was prevented to enter the IVVP by the presence of valves. In humans and vervet monkeys we found that the lumbar parts of the IVVP were connected to subcutaneous veins of the back. It was concluded that the anatomy of the IVVP and its connecting veins may serve to thermoregulate the spinal cord and that climate related anatomical adaptations were present in the species studied.


The role of prefrontal cortex in working-memory capacity, executive attention, and general fluid intelligence: an individual-differences perspective.
We provide an "executive-attention" framework for organizing the cognitive neuroscience research on the constructs of working-memory capacity (WMC), general fluid intelligence, and prefrontal cortex (PFC) function. Rather than provide a novel theory of PFC function, we synthesize a wealth of single-cell, brain-imaging, and neuropsychological research through the lens of our theory of normal individual differences in WMC and attention control (Engle, Kane, & Tuholski, 1999; Engle, Tuholski, Laughlin, & Conway, 1999). Our critical review confirms the prevalent view that dorsolateral PFC circuitry is critical to executive-attention functions. Moreover, although the dorsolateral PFC is but one critical structure in a network of anterior and posterior "attention control" areas, it does have a unique executive-attention role in actively maintaining access to stimulus representations and goals in interference-rich contexts. Our review suggests the utility of an executive-attention framework for guiding future research on both PFC function and cognitive control.


Ac induces homologous recombination at the maize P locus.
The maize P gene conditions red phlobaphene pigmentation to the pericarp and cob. Starting from two unstable P alleles which carry insertions of the transposable element Ac, we have derived 51 P null alleles; 47 of the 51 null alleles have a 17-kb deletion which removes the 4.5-kb Ac element and 12.5 kb of P sequences flanking both sides of Ac. The deletion endpoints lie within two 5.2-kb homologous direct repeats which flank the P gene. A P allele which contains the direct repeats, but does not have an Ac insertion between the direct repeats, shows very little sporophytic or gametophytic instability. The apparent frequency of sporophytic mutations was not increased when Ac was introduced in trans. Southern analysis of DNA prepared from the pericarp tissue demonstrates that the deletions can occur premeiotically, in the somatic cells during development of the pericarp. Evidence is presented that the deletions occurred by homologous recombination between the two direct repeats, and that the presence of an Ac element at the P locus is associated with the recombination/deletion. These results add another aspect to the spectrum of activities of Ac: the destabilization of flanking direct repeat sequences.


Smoking cessation in relation to total mortality rates in women. A prospective cohort study.
To examine the temporal relationship between stopping smoking and total mortality rates among middle-aged women. Prospective cohort study with 12 years of follow-up. Registered nurses residing in the United States. 117,001 female registered nurses, ages 30 to 55 years, who were free of manifest coronary heart disease, stroke, and cancer (except nonmelanoma skin cancer) in 1976. Total mortality, further categorized into deaths from cardiovascular diseases, cancers, and violent deaths. A total of 2847 deaths (933 among "never smokers," 799 among former smokers, and 1115 among current smokers) occurred during 1.37 million person-years of follow-up. The multivariate relative risks for total mortality compared with never smokers were 1.87 (95% CI, 1.65 to 2.13) for current smokers and 1.29 (CI, 1.14 to 1.46) for former smokers. Participants who started smoking before the age of 15 years had the highest risks for total mortality (multivariate relative risk, 3.15; CI, 2.16 to 4.59), cardiovascular disease mortality (relative risk, 9.94; CI, 5.15 to 19.19), and deaths from external causes of injury (relative risk, 5.39; CI, 1.84 to 15.78). Compared with continuing smokers, former smokers had a 24% reduction in risk for cardiovascular disease mortality within 2 years of quitting. The excess risks for total mortality and both cardiovascular disease and total cancer mortality among former smokers approached the level of that for never smokers after 10 to 14 years of abstinence. The health benefits of cessation were clearly present regardless of the age at starting and daily number of cigarettes smoked. The risk of cigarette smoking on total mortality among former smokers decreases nearly to that of never smokers 10 to 14 years after cessation.


A role for the adenovirus inducible E2F transcription factor in a proliferation dependent signal transduction pathway.
Adenovirus E1A dependent trans-activation of transcription involves the utilization of cellular promoter specific transcription factors. One such factor termed E2F is important for the transcription of the viral E2 gene and appears to be a rate limiting component targeted during the trans-activation event. Since E2F is of cellular origin and likely to be involved in cellular gene control, we have identified E2F binding sites in cellular genes. Examples include the c-myc, c-myb and N-myc protoncogenes, the DHFR gene and the EGF receptor gene. The transcription of these genes is regulated by cell proliferation signals and each falls into the so-called immediate early class: genes that are activated independent of new protein synthesis. Because of these common properties of regulation, we have addressed the possible role of E2F in growth factor dependent activation of transcription. Expression of a c-myc promoter driven CAT gene, transfected into quiescent 3T3 cells, is stimulated by serum addition whereas an identical gene containing mutations in the E2F binding sites is not responsive. The DNA binding activity of E2F is increased 4-fold upon serum stimulation and the kinetics of activation parallel activation of c-myc transcription. Furthermore, this increase in E2F activity is independent of new protein synthesis indicating that serum stimulation results in an activation of a pre-existing factor. These results thus provide strong evidence linking E2F and proliferation dependent control of transcription. We also believe that the E2F transcription factor is the first example of a regulator of the class of immediate early genes that is slowly activated by stimulation of cell proliferation.


Winter dormancy in sea turtles: independent discovery and exploitation in the gulf of california by two local cultures.
Documentation is reported for sea turtles overwintering on the sea bottom. Seri Indians have traditionally hunted nonmigrating dormant green turtles (Chelonia mydas) along the bottom of the Infiernillo Channel in the Gulf of California. Mexican fishermen independently discovered dormant turtles during winter 1972-1973, and with new hunting technologies are rapidly decimating these unusual stocks.


From artisan to architect: the specialist and systems of provision of diabetes care in 2001.
To discuss the future role of the diabetes specialist and the endocrinologist in the care of patients with diabetes. We reviewed the literature on health care systems, integrated approaches to provision of health care, health care in the primary-care setting for patients with chronic illness, and population-based health care for patients with diabetes. Specialists who care for patients with diabetes will assume a more significant role as caretakers of teams of health care professionals who are responsible for the primary care of patients with diabetes. The integration of specialist care at the primary-care level may lead to improved outcomes at the primary-care level, increased access to specialty care, and decreased costs for the health care system. Alternative systems, such as regulatory barriers to specialist care, are less likely to accomplish these outcomes. In the near future, specialists will be expected to care for those who provide primary care for patients with diabetes. Endocrinologists and endocrinology training programs should recognize this emerging role and prepare for it.