Symmetry-breaking charge transfer in a zinc chlorodipyrrin acceptor for high open circuit voltage organic photovoltaics.
Low open-circuit voltages significantly limit the power conversion efficiency of organic photovoltaic devices. Typical strategies to enhance the open-circuit voltage involve tuning the HOMO and LUMO positions of the donor (D) and acceptor (A), respectively, to increase the interfacial energy gap or to tailor the donor or acceptor structure at the D/A interface. Here, we present an alternative approach to improve the open-circuit voltage through the use of a zinc chlorodipyrrin, ZCl [bis(dodecachloro-5-mesityldipyrrinato)zinc], as an acceptor, which undergoes symmetry-breaking charge transfer (CT) at the donor/acceptor interface. DBP/ZCl cells exhibit open-circuit voltages of 1.33 V compared to 0.88 V for analogous tetraphenyldibenzoperyflanthrene (DBP)/C60-based devices. Charge transfer state energies measured by Fourier-transform photocurrent spectroscopy and electroluminescence show that C60 forms a CT state of 1.45 ± 0.05 eV in a DBP/C60-based organic photovoltaic device, while ZCl as acceptor gives a CT state energy of 1.70 ± 0.05 eV in the corresponding device structure. In the ZCl device this results in an energetic loss between E(CT) and qV(OC) of 0.37 eV, substantially less than the 0.6 eV typically observed for organic systems and equal to the recombination losses seen in high-efficiency Si and GaAs devices. The substantial increase in open-circuit voltage and reduction in recombination losses for devices utilizing ZCl demonstrate the great promise of symmetry-breaking charge transfer in organic photovoltaic devices.


User-Centered Design and Printed Educational Materials: A Focus Group Study of Primary Care Physician Preferences.
It is challenging for primary care physicians (PCPs) to review and apply the growing amount of clinical evidence available. Printed educational materials (PEMs), which synthesize evidence, are often ineffective at improving knowledge, possibly due to poor design and limited uptake. In this study, we collected PCP preferences for the design and content of physician-oriented PEMs and determined key attributes that may increase their usability and uptake. We held 90-minute focus groups with PCPs in Toronto, ON, Canada. Focus groups included discussion about whether and how participants use PEMs, feedback on three examples of PEMs, and a discussion on general format and design preferences in PEMs. We analyzed focus group transcripts using a thematic analysis and summarized results in a list of user preferences. Four focus groups were held with 13 PCPs. We found that participants only read PEMs relevant to their patients and prefer short, concise documents, with links to sources that can provide more detailed information. Simplicity of materials was important, with many participants preferring PEMs without lengthy backgrounds or scientific explanations. Most participants wanted to see key messages highlighted to easily assess the relevance of the materials to their practice. Some participants shared physician-oriented PEMs with patients. This study shows that PCPs may prefer shorter, simpler, and more concise documents that have less scientific detail but provide references to further information sources. It is important to understand end user preferences for the design and content of these materials to enhance their uptake.


Typhoid Intestinal Perforations: Has the Clinical Importance Decreased in Eastern Anatolia for 36 Years?
Typhoid fever (TF) is an important health problem in developing countries, and typhoid intestinal perforation (TIP) is a serious complication of TF. The present report aims to determine the clinical importance of TIPs for the last 36 years in our region, eastern Anatolia. The clinical records of 84 surgically treated cases with TIPs were reviewed retrospectively. When the last 36-year period was sectioned by 6-year periods, the distribution of TIPs was found as 39 (46.4% of total), 31 (36.9%), 7 (8.3%), 4 (4.8%), 2 (2.4%) and 1 (1.2%), respectively. The mean age of the patients was 37.1 years (range: 7-68 years), and 66 patients (78.6%) were male. As a surgical procedure, 34 patients (40.5%) had primary repair, 9 (10.7%) had wedge resection with primary repair, 9 (10.7%) had resection with primary anastomosis, 28 (33.3%) had resection with ileostomy, and 4 (4.8%) had exteriorization. Complications were seen in 71 patients (84.5%), while the mortality rate was 10.7% (9 patients). Although eastern Anatolia is an endemic region for TF, a certain decrease in the incidence of TIPs was found for the last 36 years. Keeping in mind the TIP, patients with TF may improve the prognosis of this serious disease.


Travellers' malaria--'one shoe does not fit all'.
Travellers' malaria is an exciting topic. It is a field in flux with evolving options for chemoprophylaxis, self-diagnosis, self-treatment, risk/strategy analyses and surveillance. Ideologies vary and experts differ but debate is needed and can bring change. The launch of a new thematic series in the Malaria Journal--"Travellers' malaria"--creates an ideal forum to bring together research papers, reviews, opinion papers and commentaries, and will hopefully stimulate debate.


Chromatogram libraries improve peptide detection and quantification by data independent acquisition mass spectrometry.
Data independent acquisition (DIA) mass spectrometry is a powerful technique that is improving the reproducibility and throughput of proteomics studies. Here, we introduce an experimental workflow that uses this technique to construct chromatogram libraries that capture fragment ion chromatographic peak shape and retention time for every detectable peptide in a proteomics experiment. These coordinates calibrate protein databases or spectrum libraries to a specific mass spectrometer and chromatography setup, facilitating DIA-only pipelines and the reuse of global resource libraries. We also present EncyclopeDIA, a software tool for generating and searching chromatogram libraries, and demonstrate the performance of our workflow by quantifying proteins in human and yeast cells. We find that by exploiting calibrated retention time and fragmentation specificity in chromatogram libraries, EncyclopeDIA can detect 20-25% more peptides from DIA experiments than with data dependent acquisition-based spectrum libraries alone.


The mutation in the mitochondrial aldehyde dehydrogenase (ALDH2) gene responsible for alcohol-induced flushing increases turnover of the enzyme tetramers in a dominant fashion.
Deficiency in mitochondrial aldehyde dehydrogenase (ALDH2), a tetrameric enzyme, results from inheriting one or two ALDH2*2 alleles. This allele encodes a protein subunit with a lysine for glutamate substitution at position 487 and is dominant over the wild-type allele, ALDH2*1. The ALDH2*2-encoded subunit (ALDH2K) reduces the activity of ALDH2 enzyme in cell lines expressing the wild-type subunit (ALDH2E). In addition to this effect on the enzyme activity, we now report that ALDH2*2 heterozygotes had lower levels of ALDH2 immunoreactive protein in autopsy liver samples. The half-lives of ALDH2 protein in HeLa cell lines expressing ALDH2*1, ALDH2*2, or both were determined by the rate of loss of immunoreactive protein after inhibition of protein synthesis with puromycin and by pulse-chase experiments. By either measure, ALDH2E enzyme was very stable, with a half-life of at least 22 h. ALDH2K enzyme had an enzyme half-life of only 14 h. In cells expressing both subunits, most of the subunits assemble as heterotetramers, and these enzymes had a half-life of 13 h. Thus, the effect of ALDH2K on enzyme turnover is dominant. These studies indicate that the ALDH2*2 allele exerts its dominant effect both by interfering with the catalytic activity of the enzyme and by increasing its turnover. This represents the first example of a dominantly acting allele with this effect on a mitochondrial enzyme's turnover.


Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.
During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTC) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer. We showed that the majority (> 80%) of these CTCs in patients with metastatic CRPC coexpress epithelial proteins such as epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and E-cadherin, with mesenchymal proteins including vimentin, N-cadherin and O-cadherin, and the stem cell marker CD133. Equally, we found that more than 75% of CTCs from women with metastatic breast cancer coexpress CK, vimentin, and N-cadherin. The existence and high frequency of these CTCs coexpressing epithelial, mesenchymal, and stem cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs.


Influence of GnRH infusion on endocrine parameters and duration of postpartum anestrus in beef cows.
The effect of an intravenous infusion of gonadotrophin releasing hormone (GnRH) on the duration of postpartum anestrus in suckled beef cows was studied. Twenty-eight, mature, suckled beef cows were assigned in equal numbers to one of four treatment groups which were based on infusion with saline or GnRH (15ug/hour for 12 hours) and stage postpartum (pp) (20 or 35 days). Serum LH and progesterone were determined by radioimmunoassay for the period which began 5 days pre-infusion and ended at 55 days postpartum (ie: 35 or 20 days post-infusion). Serum LH remained below 5ng/ml during infusion in all control cows. Peak serum LH values, times of LH peaks, and duration of LH responses (means +/- SE) during infusion were 49 +/- 12 ng/ml, 162 +/- 42 minutes and 7.8 +/- 1.3 hours for the 20 day group and 44 +/- ng/ml, 144 +/- 6 minutes, and 8.2 +/- 1.1 hours for the 35 day group respectively. Serum progesterone levels indicated that the proportion of cows showing the onset of estrous cycles within 10 days of infusion was greater in the 20 day pp GnRH group (4/7) than the 20 day pp saline group (0/7) (p < .05) but was not significantly different between the 35 day pp GnRH (4/7) and 35 day pp saline (2/6) groups. The incidence of estrus was not affected by GnRH treatment and was 37% in all cows prior to 55 days pp. It was concluded that infusions of GnRH for 12 hours at a rate of 15 ug/hour could induce estrous cycles in suckled beef cows treated at 20 days postpartum.


Dating the late prehistoric dispersal of Polynesians to New Zealand using the commensal Pacific rat.
The pristine island ecosystems of East Polynesia were among the last places on Earth settled by prehistoric people, and their colonization triggered a devastating transformation. Overhunting contributed to widespread faunal extinctions and the decline of marine megafauna, fires destroyed lowland forests, and the introduction of the omnivorous Pacific rat (Rattus exulans) led to a new wave of predation on the biota. East Polynesian islands preserve exceptionally detailed records of the initial prehistoric impacts on highly vulnerable ecosystems, but nearly all such studies are clouded by persistent controversies over the timing of initial human colonization, which has resulted in proposed settlement chronologies varying from approximately 200 B.C. to 1000 A.D. or younger. Such differences underpin radically divergent interpretations of human dispersal from West Polynesia and of ecological and social transformation in East Polynesia and ultimately obfuscate the timing and patterns of this process. Using New Zealand as an example, we provide a reliable approach for accurately dating initial human colonization on Pacific islands by radiocarbon dating the arrival of the Pacific rat. Radiocarbon dates on distinctive rat-gnawed seeds and rat bones show that the Pacific rat was introduced to both main islands of New Zealand approximately 1280 A.D., a millennium later than previously assumed. This matches with the earliest-dated archaeological sites, human-induced faunal extinctions, and deforestation, implying there was no long period of invisibility in either the archaeological or palaeoecological records.


Does Silybum marianum play a role in the treatment of chronic hepatitis C?
The recent boom in patient education on chronic hepatitis C has resulted in a worldwide increase in the diagnosis of this condition. Available treatment is expensive and associated with significant side effects; therefore, many patients seek for alternative medicine. Silybum marianum is a natural herb known to mankind for over 2,000 years that has been used as a liver-protecting agent due to its antioxidant properties. The objective of this study is to evaluate the safety profile and the effects of this herb, using a commercially available extract; in the liver chemistry and viral load of hepatitis C in chronically infected patients. Patients aged 21-65 years old with a diagnosis of chronic hepatitis C who were not using antiviral therapy were asked to participate. Patients were randomized to treatment with S. marianum 160 mg orally three times a week for four weeks or to no-treatment (control). Blood tests for viral load and liver enzymes (ALT and AST) were done at randomization and at the end of treatment. Paired-t test was used to measure differences between baseline and week 4 values for ALT, AST and viral load. The percent change for ALT, AST and viral load of both groups was analyzed using the Mann Whitney statistical test. 34 patients were enrolled. Men and women were equally distributed. Mean age was 50 years old. Mean baseline measurements of AST, ALT and viral load in the treatment group were 85 +/- 12.41 IU/ml, 120 +/- 20.57 IU/ml and 8.77 +/- 4.12 copies x 10(6)/ml while for the no-treatment group were 71 +/- 9.46 IU/ml, 97 +/- 15.35 IU/ ml and 1.8 +/- 0.62 copies x 10(6)/ml respectively. For treated subjects the mean values of AST, ALT and viral load demonstrated a decrease from baseline values, but this difference was not statistically significant. For control patients the values of ALT (p= .049), AST (p = .005) and viral load (p = .005) showed a statistically significant increase at week 4. Week 4 measurement changes from baseline values were calculated for each participant. The percent change for ALT (p = .014), AST (p = .002) and viral load (p = .326) were compared between the treated and control group demonstrating a statistically significance difference for ALT and AST, but not for viral load. No side effects were reported using the herb extract. Sylibum marianum is a well-tolerated plant extract associated with a decrease in liver chemistries but with no apparent effect on viral load when given for 4 weeks. These results suggest that S. marianum may have a protective effect in the inflammatory response to HCV, but no role as an antiviral agent. Further investigations may consider using this plant extract for a longer period of time or as adjuvant to the standard therapy of chronic hepatitis C.


Sequences downstream of the translation initiation codon are important determinants of translation efficiency in chloroplasts.
The objective of this study was to determine if mRNA sequences downstream of the translation initiation codon are important for translation of plastid mRNAs. We have employed a transgenic approach, measuring accumulation of the neomycin phosphotransferase (NPTII) reporter enzyme translationally fused with 14 N-terminal amino acids encoded in the rbcL or atpB plastid genes. NPTII accumulation from wild-type and mutant rbcL and atpB segments was compared. We report that silent mutations in the rbcL segment reduced NPTII accumulation 35-fold. In contrast, mutations in the atpB mRNA reduced NPTII accumulation only moderately from approximately 7% (w/w) to approximately 4% (w/w) of the total soluble cellular protein, indicating that the importance of sequences downstream of the translation initiation codon are dependent on the individual mRNA. Information provided here will facilitate transgene design for high-level expression of recombinant proteins in chloroplasts by translational fusion with the N-terminal segment of highly expressed plastid genes or by introduction of silent mutations in the N-terminal part of the coding region.


Comprehensive structural model of the mechanochemical cycle of a mitotic motor highlights molecular adaptations in the kinesin family.
Kinesins are responsible for a wide variety of microtubule-based, ATP-dependent functions. Their motor domain drives these activities, but the molecular adaptations that specify these diverse and essential cellular activities are poorly understood. It has been assumed that the first identified kinesin--the transport motor kinesin-1--is the mechanistic paradigm for the entire superfamily, but accumulating evidence suggests otherwise. To address the deficits in our understanding of the molecular basis of functional divergence within the kinesin superfamily, we studied kinesin-5s, which are essential mitotic motors whose inhibition blocks cell division. Using cryo-electron microscopy and determination of structure at subnanometer resolution, we have visualized conformations of microtubule-bound human kinesin-5 motor domain at successive steps in its ATPase cycle. After ATP hydrolysis, nucleotide-dependent conformational changes in the active site are allosterically propagated into rotations of the motor domain and uncurling of the drug-binding loop L5. In addition, the mechanical neck-linker element that is crucial for motor stepping undergoes discrete, ordered displacements. We also observed large reorientations of the motor N terminus that indicate its importance for kinesin-5 function through control of neck-linker conformation. A kinesin-5 mutant lacking this N terminus is enzymatically active, and ATP-dependent neck-linker movement and motility are defective, although not ablated. All these aspects of kinesin-5 mechanochemistry are distinct from kinesin-1. Our findings directly demonstrate the regulatory role of the kinesin-5 N terminus in collaboration with the motor's structured neck-linker and highlight the multiple adaptations within kinesin motor domains that tune their mechanochemistries according to distinct functional requirements.


Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels.
Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.


Effects of computer-based intervention through acoustically modified speech (Fast ForWord) in severe mixed receptive-expressive language impairment: outcomes from a randomized controlled trial.
Seventy-seven children between the ages of 6 and 10 years, with severe mixed receptive-expressive specific language impairment (SLI), participated in a randomized controlled trial (RCT) of Fast ForWord (FFW; Scientific Learning Corporation, 1997, 2001). FFW is a computer-based intervention for treating SLI using acoustically enhanced speech stimuli. These stimuli are modified to exaggerate their time and intensity properties as part of an adaptive training process. All children who participated in the RCT maintained their regular speech and language therapy and school regime throughout the trial. Standardized measures of receptive and expressive language were used to assess performance at baseline and to measure outcome from treatment at 9 weeks and 6 months. Children were allocated to 1 of 3 groups. Group A (n = 23) received the FFW intervention as a home-based therapy for 6 weeks. Group B (n = 27) received commercially available computer-based activities designed to promote language as a control for computer games exposure. Group C (n = 27) received no additional study intervention. Each group made significant gains in language scores, but there was no additional effect for either computer intervention. Thus, the findings from this RCT do not support the efficacy of FFW as an intervention for children with severe mixed receptive-expressive SLI.


Middle cranial fossa sphenoidal region dural arteriovenous fistulas: anatomic and treatment considerations.
DAVFs rarely involve the sphenoid wings and middle cranial fossa. We characterize the angiographic findings, treatment, and outcome of DAVFs within the sphenoid wings. We reviewed the clinical and radiologic data of 11 patients with DAVFs within the sphenoid wing that were treated with an endovascular or with a combined endovascular and surgical approach. Nine patients presented with ocular symptoms and 1 patient had a temporal parenchymal hematoma. Angiograms showed that 5 DAVFs were located on the lesser wing of sphenoid bone, whereas the other 6 were on the greater wing of the sphenoid bone. Multiple branches of the ICA and ECA supplied the lesions in 7 patients. Four patients had cortical venous reflux and 7 patients had varices. Eight patients were treated with transarterial embolization using liquid embolic agents, while 3 patients were treated with transvenous embolization with coils or in combination with Onyx. Surgical disconnection of the cortical veins was performed in 2 patients with incompletely occluded DAVFs. Anatomic cure was achieved in all patients. Eight patients had angiographic and clinical follow-up and none had recurrence of their lesions. DAVFs may occur within the dura of the sphenoid wings and may often have a presentation similar to cavernous sinus DAVFs, but because of potential associations with the cerebral venous system, may pose a risk for intracranial hemorrhage. Curative embolization through a transarterial or transvenous approach is the primary therapeutic strategy for these lesions. In incompletely embolized patients, exclusion of any refluxing cortical veins is necessary.


Rhythmic Temporal Structure at Encoding Enhances Recognition Memory.
Presenting events in a rhythm has been shown to enhance perception and facilitate responses for stimuli that appear in synchrony with the rhythm, but little is known about how rhythm during encoding influences later recognition. In this study, participants were presented with images of everyday objects in an encoding phase before a recognition task in which they judged whether or not objects were previously presented. Blockwise, object presentation during encoding followed either a rhythmic (constant, predictable) or arrhythmic (random, unpredictable) temporal structure, of which participants were unaware. Recognition was greater for items presented in a rhythmic relative to an arrhythmic manner. During encoding, there was a differential neural activity based on memory effect with larger positivity for rhythmic over arrhythmic stimuli. At recognition, memory-specific ERP components were differentially affected by temporal structure: The FN400 old/new effect was unaffected by rhythmic structure, whereas the late positive component old/new effect was observed only for rhythmically encoded items. Taken together, this study provides new evidence that memory-specific processing at recognition is affected by temporal structure at encoding.


Origin and evolution of highly pathogenic H5N1 avian influenza in Asia.
Outbreaks of highly pathogenic avian influenza caused by H5N1 viruses were reported almost simultaneously in eight neighbouring Asian countries between December 2003 and January 2004, with a ninth reporting in August 2004, suggesting that the viruses had spread recently and rapidly. However, they had been detected widely in the region in domestic waterfowl and terrestrial poultry for several years before this, and the absence of widespread disease in the region before 2003, apart from localised outbreaks in the Hong Kong Special Autonomous Region (SAR), is perplexing. Possible explanations include limited virus excretion by domestic waterfowl infected with H5N1, the confusion of avian influenza with other serious endemic diseases, the unsanctioned use of vaccines, and the under-reporting of disease as a result of limited surveillance. There is some evidence that the excretion of the viruses by domestic ducks had increased by early 2004, and there is circumstantial evidence that they can be transmitted by wild birds. The migratory birds from which viruses have been isolated were usually sick or dead, suggesting that they would have had limited potential for carrying the viruses over long distances unless subclinical infections were prevalent. However, there is strong circumstantial evidence that wild birds can become infected from domestic poultry and potentially can exchange viruses when they share the same environment. Nevertheless, there is little reason to believe that wild birds have played a more significant role in spreading disease than trade through live bird markets and movement of domestic waterfowl. Asian H5N1 viruses were first detected in domestic geese in southern China in 1996. By 2000, their host range had extended to domestic ducks, which played a key role in the genesis of the 2003/04 outbreaks. The epidemic was not due to the introduction and spread of a single virus but was caused by multiple viruses which were genotypically linked to the Goose/GD/96 lineage via the haemagglutinin gene. The H5N1 viruses isolated from China, including the Hong Kong SAR, between 1999 and 2004 had a range of genotypes and considerable variability within genotypes. The rising incidence and widespread reporting of disease in 2003/04 can probably be attributed to the increasing spread of the viruses from existing reservoirs of infection in domestic waterfowl and live bird markets leading to greater environmental contamination. When countries in the region started to report disease in December 2003, others were alerted to the risk and disease surveillance and reporting improved. The H5N1 viruses have reportedly been eliminated from three of the nine countries that reported disease in 2003/04, but they could be extremely difficult to eradicate from the remaining countries, owing to the existence of populations and, possibly, production and marketing sectors, in which apparently normal birds harbour the viruses.


Carbon balance of a tropical savanna of northern Australia.
Through estimations of above- and below-ground standing biomass, annual biomass increment, fine root production and turnover, litterfall, canopy respiration and total soil CO(2) efflux, a carbon balance on seasonal and yearly time-scales is developed for a Eucalypt open-forest savanna in northern Australia. This carbon balance is compared to estimates of carbon fluxes derived from eddy covariance measurements conducted at the same site. The total carbon (C) stock of the savanna was 204+/-53 ton C ha(-1), with approximately 84% below-ground and 16% above-ground. Soil organic carbon content (0-1 m) was 151+/-33 ton C ha(-1), accounting for about 74% of the total carbon content in the ecosystem. Vegetation biomass was 53+/-20 ton C ha(-1), 39% of which was found in the root component and 61% in above-ground components (trees, shrubs, grasses). Annual gross primary production was 20.8 ton C ha(-1), of which 27% occurred in above-ground components and 73% below-ground components. Net primary production was 11 ton C ha(-1) year(-1), of which 8.0 ton C ha(-1) (73%) was contributed by below-ground net primary production and 3.0 ton C ha(-1) (27%) by above-ground net primary production. Annual soil carbon efflux was 14.3 ton C ha(-1) year(-1). Approximately three-quarters of the carbon flux (above-ground, below-ground and total ecosystem) occur during the 5-6 months of the wet season. This savanna site is a carbon sink during the wet season, but becomes a weak source during the dry season. Annual net ecosystem production was 3.8 ton C ha(-1) year(-1).


The usefulness of touch preparation cytological evaluation and prostatic capsule involvement in prediction of prostate cancer recurrence.
Touch preparation cytology has been used in oncology as a technique to assist in predicting local tumor recurrence. We prospectively investigated the relationship between this cytological evaluation and the standard histological method of assessing specimens, measuring the distance from the tumor to the various anatomical boundaries and disease recurrence in radical retropubic prostatectomy patients. In a prospective study of 91 consecutive clinical stages T1c and T2 cancer cases radical retropubic prostatectomy touch preparation cytology was performed intraoperatively in an anatomical fashion (apex, posterior, lateral right and left, and base). A single blinded cytopathologist reviewed all prostate touch preparation specimens and categorized them as malignant, benign or atypical cells. Benign or atypical cells were classified as negative cytology. Detailed histological margin analysis of the surgical specimens was also done in which distances between the tumor front, and prostate capsule (inner and outer edge) and surgical margins (apex, posterior, right and left lateral, and base) were measured. All specimens were re-staged by the same pathologist. Median followup was 38 months. Disease recurrence was determined biochemically (prostate specific antigen), and with bone scans, prostatic fossa biopsies and digital rectal examinations. Of the 91 specimens 25 were excluded from study because distance measurements could not be made for technical reasons. Multivariate analysis was performed on the remaining 66 patients based on the variables of stage, age, cytology status, distance from tumor to the inner prostatic capsule, distance from tumor to the surgical margin and postoperative Gleason sum. The only variable with independent prognostic value was postoperative Gleason sum (p = 0.04). Cytology status was not statistically significant (p = 0.07) nor were distance data to the inner capsule (p >0.05) and surgical margin (p >0.05). Although touch preparation cytology does not enhance prognostic information already provided by Gleason sum, it does correlate highly with postoperative Gleason sum. Other gross macroscopic variables, that is pathological stage, margin status and distance measurements, although lacking in independent predictive value, correlated with postoperative Gleason sum. The constancy of Gleason sum leads us to believe that the key to predicting prostatic cancer behavior lies not on the macroscopic but on the molecular or cellular level. Of the various factors analyzed in this study postoperative Gleason sum remains the most powerful predictor of recurrence risk.


The interrelations between verbal working memory and visual selection of emotional faces.
Working memory (WM) and visual selection processes interact in a reciprocal fashion based on overlapping representations abstracted from the physical characteristics of stimuli. Here, we assessed the neural basis of this interaction using facial expressions that conveyed emotion information. Participants memorized an emotional word for a later recognition test and then searched for a face of a particular gender presented in a display with two faces that differed in gender and expression. The relation between the emotional word and the expressions of the target and distractor faces was varied. RTs for the memory test were faster when the target face matched the emotional word held in WM (on valid trials) relative to when the emotional word matched the expression of the distractor (on invalid trials). There was also enhanced activation on valid compared with invalid trials in the lateral orbital gyrus, superior frontal polar (BA 10), lateral occipital sulcus, and pulvinar. Re-presentation of the WM stimulus in the search display led to an earlier onset of activity in the superior and inferior frontal gyri and the anterior hippocampus irrespective of the search validity of the re-presented stimulus. The data indicate that the middle temporal and prefrontal cortices are sensitive to the reappearance of stimuli that are held in WM, whereas a fronto-thalamic occipital network is sensitive to the behavioral significance of the match between WM and targets for selection. We conclude that these networks are modulated by high-level matches between the contents of WM, behavioral goals, and current sensory input.


An imperative to offer pregnant and lactating women access to the COVID-19 vaccination roll-out programme.
In view of the continuing worldwide spread of COVID-19 infection, the increased morbidity and mortality from the disease during pregnancy, and the current efficacy and safety of vaccines in non-pregnant individuals, vaccines should not be withheld from women simply because of pregnancy or lactation. All pregnant women, especially healthcare professionals, should be offered vaccination and counselled about its advantages and disadvantages by their maternity care providers. Complete eradication of COVID-19 infection will be possible if potential niduses of the infection, which may act as sources for future outbreaks, are protected against the pathogen. However, if a hypothetical medication is the only means yet proven of limiting severe compromise to maternal health, access to the medication should be at the pregnant woman's discretion. Shared decision-making requires physicians to actively engage with their patients and share their knowledge about the subject matter.


Evaluation of Hospital Discharge Prescriptions in the Elderly and Younger Adults Using the Medication Regimen Complexity Index.
Advances in the clinical management of diseases have been accompanied by increasing complexity of treatment regimens. The complexity of medication regimen is of concern for patients as well as doctors as it may adversely affect patient compliance and treatment outcomes. It may result in medication errors, increased utilization of health resources owing to a reduction in treatment effectiveness, and increased risk of therapeutic failure. This study aimed to assess the complexity of medication regimen prescribed to patients on hospital discharge using the medication regimen complexity index (MRCI). A cross-sectional, descriptive study was conducted. Hospital discharge prescriptions written for patients discharged from the General Medicine wards of a tertiary care teaching hospital in South India were scored for their complexity using MRCI. The correlation of age and gender with the MRCI scores was also assessed. Patients ≥60 years of age were considered elderly. The median MRCI score for 563 prescriptions studied was 14 (Interquartile range, 9-21). Elderly patients received a significantly more complex medication regimen compared with younger patients (p < 0.001) at the time of hospital discharge. Gender variation was seen with higher MRCI scores in females, but this was not statistically significant in the elderly group. MRCI scores are significantly high in elderly patients at the time of hospital discharge. Although a strong correlation is seen between the number of medications and the MRCI score, the latter helps to distinguish regimen complexity between prescriptions with the same number of medications.


A double-blind placebo-controlled trial evaluating the safety and efficacy of acarbose for the treatment of patients with insulin-requiring type II diabetes.
To determine whether a forced titration of acarbose (from 50 to 300 mg three times daily) administered over a 24-week period, in conjunction with diet and insulin therapy, improves glycemic control and reduces daily insulin requirements in insulin-requiring type II diabetes. This multicenter, randomized, double-blind, placebo-controlled trial was 36 weeks in duration. The trial consisted of a 6-week pretreatment period, a 24-week double-blind treatment period, and a 6-week post-treatment follow-up period. The primary efficacy variables were the mean change from baseline in HbA1c levels and the mean percentage change from baseline in total daily insulin dose. Treatment with acarbose was associated with significant reductions in HbA1c levels of 0.40% (P = 0.0001) and in total daily insulin dose of 8.3% (P = 0.0015). There were also significant reductions in all plasma glucose variables measured, including a 0.9 mmol/l reduction in fasting glucose (P = 0.0440), a 2.6 mmol/l reduction in glucose Cmax (P = 0.0001) and a 270 mmol.min-1.l-1 reduction in glucose area under the curve (P = 0.0002). Although acarbose treatment was associated with a greater incidence of adverse events than was placebo treatment, primarily flatulence and diarrhea, these events did not generally prevent patients from completing the study. The results of this study suggest that acarbose is a safe and effective adjunct to diet and insulin therapy for the management of insulin-requiring type II diabetes.


Cutaneous T-cell lymphomas: a review of new discoveries and treatments.
Treatment regimens of patients with CTCL vary widely based on clinician preference and patient tolerance. Skin directed therapies are recommended for patients with early stage IA and IB MF, with combinations used in refractory cases. While no regimen has been proven to prolong survival in advanced stages, immunomodulatory regimens should be used initially to reduce the need for cytotoxic therapies. In more advanced stages of disease, treatment efforts should strive for palliation and improvement of quality of life. With many new therapies and strategies on the horizon, the future looks promising for CTCL patients. Unfortunately, other than allogeneic HCT, there are no potential curative therapies for CTCL. Clinical trials are currently underway to identify new therapies to improve quality of life for patients, and researchers are hard at work to identify novel pathways and genes for prognostication and as targets for therapies. Importantly, collaborative clinical trials to enhance rates of accrual need to be conducted, and improved interpretation of data via standardizing end points and response criteria should be an emphasis. Recently, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) met to develop consensus guidelines to facilitate collaboration on clinical trials. These proposed guidelines consist of: recommendations for standardizing general protocol design; a scoring system for assessing tumor burden in skin, lymph nodes, blood, and viscera; definition of response in skin, nodes, blood, and viscera; a composite global response score; and a definition of end points. Although these guidelines were generated by consensus panels, they have not been prospectively or retrospectively validated through analysis of large patient cohorts.


Conceptual Framework Development for a Double-Walled Aortic Stent-Graft to Manage Blood Pressure.
A double-walled stent-graft (DWSG) design with a compressible gas layer was conceived with the goal of treating hypertension in patients receiving an aortic stent-graft. Early prototypes were developed to evaluate the design concept through static measurements from a finite element (FE) model and quasi-static inflation experiments, and through dynamic measurements from an in vitro flow loop and the three-element Windkessel model. The amount of gas in the gas layer and the properties of the flexible inner wall were the primary variables evaluated in this study. Properties of the inner wall had minimal effect on DWSG behavior, but increased gas charge led to increased fluid capacitance and larger reduction in peak and pulse pressures. In the flow loop, placement of the DWSG decreased pulse pressure by over 20% compared to a rigid stent-graft. Capacitance measurements were consistent across all methods, with the maximum capacitance estimated at 0.07 mL/mmHg for the largest gas charge in the 15 cm long prototype. Windkessel model predictions for in vivo performance of a DWSG placed in the aorta of a hypertensive patient showed pulse pressure reduction of 14% compared to a rigid stent-graft case, but pressures never returned to unstented values. These results indicate that the DWSG design has potential to be developed into a new treatment for hypertensive patients requiring an aortic intervention.


Effects of calcium on flagellar movement in the trypanosome Crithidia oncopelti.
1. The effects of calcium on the motility of different preparations of flagella from Crithidia oncopelti were studied using stroboscopic and high-speed cine photographic techniques. 2. By varying the concentration of calcium in suspensions of chemically treated samples of the organism it was found that changes occurred in bend shape, wave direction and frequency. 3. Waves on the flagellum of the organisms in vivo possess the unusual ability to propagate from tip to base, but reverse in direction during an avoiding response. In chemically extracted and reactivated preparations tip to base propagation was observed only at low concentrations (less than 10(-4) mol m-3) of calcium ion; at high concentrations base to tip propagation only was seen. In cells treated with ion across membranes, tip to base propagation was seen only in the presence of EGTA; when calcium was added the majority of organisms propagated waves from base to tip. 4. At certain values (ca. 10(-3) mol m-3) of the calcium concentration the wave shape had meander-like characteristics, whereas at higher and lower concentrations it was more sinsoidal. At high calcium concentrations only one wave appeared on the flagellum whereas at low values two or three were observed. 5. A reduction in frequency at high calcium concentrations was probably due to competitive inhibition of magnesium ions. 6. The results suggest that wave reversal in living Crithidia is induced by the release of calcium ions within the flagellum following stimulation of the membrane. In terms of the sliding filament model of flagellar activity the effects of calcium suggest that the ion is effective in modifying the interaction between the spoke head and central sheath and may control the relative direction of microtubular sliding.


Outcomes of longitudinal integrated clinical placements for students, clinicians and society.
Longitudinal integrated clerkships (LICs) have been widely implemented in both rural and urban contexts, as is now evident in the wealth of studies published internationally. This narrative literature review aims to summarise current evidence regarding the outcomes of LICs for student, clinician and community stakeholders. Recent literature was examined for original research articles pertaining to outcomes of LICs. Students in LICs achieve academic results equivalent to and in some cases better than those of their counterparts who receive clinical education in block rotations. Students in LICs are reported to have well-developed patient-centred communication skills, demonstrate understanding of the psychosocial contributions to medicine, and report more preparedness in higher-order clinical and cognitive skills in comparison with students in traditional block rotations (TBRs). Students in LICs take on increased responsibility with patients and describe having more confidence in dealing with ethical dilemmas. Continuity of supervision reportedly facilitates incremental knowledge acquisition, and supervisors provide incrementally progressive feedback. Despite early disorientation regarding the organising of their learning, students feel well supported by the continuity of student-preceptor relationships and value the contributions made by these. Students in LICs living and working in rural areas are positively influenced towards primary care and rural career choices. A sound body of knowledge in the field of LIC research suggests it is time to move beyond descriptive or exploratory research that is designed to justify this new educational approach by comparing academic results. As the attributes of LIC alumni are better understood, it is important to conduct explanatory research to develop a more complete understanding of these findings and a foundation for new theoretical frameworks that underpin educational change. Longitudinal integrated clerkships are now recognised as representing credible and effective pedagogical alternatives to TBRs in medical education.


Quantification of ¹³C enrichments and isotopomer abundances for metabolic flux analysis using 1D NMR spectroscopy.
The analysis of stable isotope incorporation following feeding of (13)C-labeled precursors to plant tissues provides the constraints necessary for metabolic flux analysis. This protocol describes the use of one-dimensional (1)H and (13)C nuclear magnetic resonance spectroscopy for the quantification of (13)C enrichments and isotopomer abundances in mixtures of metabolites or hydrolyzed biomass components.


Cortical correlates of illusory hand movement perception in humans: a MEG study.
The present study aimed to investigate cortical activity associated with perception of illusory hand movements elicited by tendon vibration using magnetoencephalography (MEG) in humans. We compared MEG responses in two conditions of stimulation, "illusion" and "no illusion". In the "illusion" condition, covibration at different frequencies applied on the tendons of the right wrist flexor and extensor muscle groups evoked illusory movements of the hand. In the "no illusion" condition, covibration was delivered at the same frequency on both tendon groups and no movement was perceived. In both experimental conditions, equivalent current dipoles (ECD) were identified in each of four time windows: 0-200 ms, 200-400 ms, 400-600 ms and 600-800 ms. Our data showed similar activation in S1, superior parietal gyrus and supramarginal gyrus in both conditions, whereas the supplementary motor area, M1 and the left angular gyrus were found active in the "illusion" condition only. Our results confirmed the role of posterior parietal areas as well as motor areas in the arising of kinesthetic sensations. The hypothesis of an interaction between the angular gyrus and the primary motor area occurring about 400 ms after the beginning of the stimulation is discussed.


Pu'erh tea extract-mediated protection against hepatosteatosis and insulin resistance in mice with diet-induced obesity is associated with the induction of de novo lipogenesis in visceral adipose tissue.
White adipose tissue (WAT) is important for the maintenance of metabolic homeostasis, and metabolic syndrome is sometimes associated with WAT dysfunction in humans and animals. WAT reportedly plays a key, beneficial role in the maintenance of glucose and lipid homeostasis during de novo lipogenesis (DNL). Pu'erh tea extract (PTE) can inhibit harmful, ectopic DNL in the liver, thus protecting against hepatosteatosis, in mice with diet-induced obesity. We examined whether PTE could induce DNL in WAT and consequently protect against hepatosteatosis. C57BL/6 male mice were fed a high-fat diet (HFD) with/without PTE for 16 weeks. Systemic insulin sensitivity was determined using HOMA-IR, insulin- and glucose-tolerance tests, and WAT adipogenesis was evaluated by histological analysis. Adipogenesis-, inflammation-, and DNL-related gene expression in visceral AT (VAT) and subcutaneous AT (SAT) was measured using quantitative reverse transcription-PCR. Regression analysis was used to investigate the association between DNL in WAT and systemic insulin resistance or hepatosteatosis. Pu'erh tea extract significantly reduced the gain of body weight and SAT, but not VAT adiposity, in mice fed the high-fat diet and induced adipogenesis in VAT. The expression of DNL-related genes, including Glut4, encoding an important insulin-regulated glucose transporter (GLUT4), were highly elevated in VAT. Moreover, PTE inhibited VAT inflammation by simultaneously downregulating inflammatory molecules and inducing expression of Gpr120 that encodes an anti-inflammatory and pro-adipogenesis receptor (GPR-120) that recognizes unsaturated long-chain fatty acids, including DNL products. The expression of DNL-related genes in VAT was inversely correlated with hepatosteatosis and systemic insulin resistance. Activation of DNL in VAT may explain PTE-mediated alleviation of hepatosteatosis symptoms and systemic insulin resistance.


PI3K signaling through the dual GTPase-activating protein ARAP3 is essential for developmental angiogenesis.
One function of phosphoinositide 3-kinase α (PI3Kα), which generates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)], is its regulation of angiogenesis in the developing embryo and in pathological situations. ARAP3 is a PtdIns(3,4,5)P(3)- and Rap-activated guanosine triphosphatase (GTPase)-activating protein (GAP) for the small GTPases RhoA and Arf6. Here, we show that deleting Arap3 in the mouse caused embryonic death in mid-gestation due to an endothelial cell-autonomous defect in sprouting angiogenesis. Explants taken at a developmental stage at which no defect was yet present reproduced this phenotype ex vivo, demonstrating that the defect was not secondary to hypoxia, placental defects, or organ failure. In addition, knock-in mice expressing an ARAP3 point mutant that cannot be activated by PtdIns(3,4,5)P(3) had angiogenesis defects similar to those of Arap3(-/-) embryos. Our work delineates a previously unknown signaling pathway that controls angiogenesis immediately downstream of PI3Kα through ARAP3 to the Rho and Arf family of small GTPases.


Pediatric Vesicoureteral Reflux Guidelines Panel Summary Report: Clinical Practice Guidelines for Screening Siblings of Children With Vesicoureteral Reflux and Neonates/Infants With Prenatal Hydronephrosis.
The American Urological Association established the Vesicoureteral Reflux Guideline Update Committee in July 2005 to update the management of primary vesicoureteral reflux in children guideline. The Panel defined the task into 5 topics pertaining to specific vesicoureteral reflux management issues, which correspond to the management of 3 distinct index patients and the screening of 2 distinct index patients. This report summarizes the existing evidence pertaining to screening of siblings and offspring of index patients with vesicoureteral reflux and infants with prenatal hydronephrosis. From this evidence clinical practice guidelines are developed to manage the clinical scenarios insofar as the data permit. The Panel searched the MEDLINE(R) database from 1994 to 2008 for all relevant articles dealing with the 5 chosen guideline topics. The database was reviewed and each abstract segregated into a specific topic area. Exclusions were case reports, basic science, secondary reflux, review articles and not relevant. The extracted article to be accepted should have assessed a cohort of children, clearly stating the number of children undergoing screening for vesicoureteral reflux. Vesicoureteral reflux should have been diagnosed with a cystogram and renal outcomes assessed by nuclear scintigraphy. The screening articles were extracted into data tables developed to evaluate epidemiological factors, patient and renal outcomes, and results of treatment. The reporting of meta-analysis of observational studies elaborated by the MOOSE group was followed. The extracted data were analyzed and formulated into evidence-based recommendations regarding the screening of siblings and offspring in index cases with vesicoureteral reflux and infants with prenatal hydronephrosis. In screened populations the prevalence of vesicoureteral reflux is 27.4% in siblings and 35.7% in offspring. Prevalence decreases at a rate of 1 screened person every 3 months of age. The prevalence is the same in males and females. Bilateral reflux prevalence is similar to unilateral reflux. Grade I-II reflux is estimated to be present in 16.7% and grade III-V reflux in 9.8% of screened patients. The estimate for renal cortical abnormalities overall is 19.3%, with 27.8% having renal damage in cohorts of symptomatic and asymptomatic children combined. In asymptomatic siblings only the rate of renal damage is 14.4%. There are presently no randomized, controlled trials of treated vs untreated screened siblings with vesicoureteral reflux to evaluate health outcomes as spontaneous resolution, decreased rates of urinary infection, pyelonephritis or renal scarring. In screened populations with prenatal hydronephrosis the prevalence of vesicoureteral reflux is 16.2%. Reflux in the contralateral nondilated kidney accounted for a mean of 25.2% of detected cases for a mean prevalence of 4.1%. In patients with a normal postnatal renal ultrasound the prevalence of reflux is 17%. The prenatal anteroposterior renal pelvic diameter was not predictive of reflux prevalence. A diameter of 4 mm is associated with a 10% to 20% prevalence of vesicoureteral reflux. The prevalence of reflux is statistically significantly greater in females (23%) than males (16%) (p=0.022). Reflux grade distribution is approximately a third each for grades I-II, III and IV-V. The estimate of renal damage in screened infants without infection is 21.8%. When stratified by reflux grade renal damage was estimated to be present in 6.2% grade I-III and 47.9% grade IV-V (p <0.0001). The risk of urinary tract infection in patients with and without prenatal hydronephrosis and vesicoureteral reflux could not be determined. The incidence of reported urinary tract infection in patients with reflux was 4.2%. The meta-analysis provided meaningful information regarding screening for vesicoureteral reflux. However, the lack of randomized clinical trials for screened patients to assess clinical health outcomes has made evidence-based guideline recommendations difficult. Consequently, screening guidelines are based on present practice, risk assessment, meta-analysis results and Panel consensus.


Screening HIV-infected patients for non-AIDS-defining malignancies.
The use of antiretroviral therapy has reduced mortality and shifted the spectrum of malignancies affecting people living with HIV/AIDS (PLWH). We review guidelines and evidence for screening PLWH for non-AIDS-defining malignancies as compared with the general population. Cervical cancer screening clearly differs for HIV-seropositive women, with two Pap tests 6 months apart in the first year and then annually if normal. The role of cervical human papillomavirus screening has not yet been defined in HIV-seropositive women. Anal cancer screening consists of an annual digital rectal examination, and some (but not all) guidelines also recommend annual anal Pap tests. Screening for breast and colorectal cancer should follow standard, age-appropriate screening recommendations that apply to the general population. Screening HIV-infected men for prostate cancer, as with the general population, lacks a clear benefit. Despite increasing rates of hepatocellular carcinoma and lung cancers among PLWH, there is insufficient evidence to support routine screening.


Nonsteroidal anti-inflammatory drugs and increased risk of acute urinary retention.
Acute urinary retention (AUR) is characterized by the sudden inability to urinate, which is usually extremely painful and requires catheterization. Prostaglandins play an important role in the genitourinary function as they provoke contractions of the detrusor muscle. Relaxation of the detrusor muscle, via the inhibition of the prostaglandin synthesis, could result in AUR. We conducted a population-based case-control study within the Integrated Primary Care Information project in the Netherlands to investigate whether the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of AUR. All men 45 years or older registered in the database between 1995 and 2002 and with at least 6 months of valid history were included. Cases were all men with a validated diagnosis of AUR. To each case, up to 10 controls were matched on age and calendar time. Within the source population of 72 114 men, we identified 536 cases of AUR and 5348 matched controls. Risk of AUR was 2.02-fold higher in current users of NSAIDs than in nonusers (95% confidence interval, 1.23-3.31). The highest risk for AUR (adjusted odds ratio, 3.3; 95% confidence interval, 1.2-9.2) was observed in patients who recently started using NSAIDs and in those using a dose equal to or higher than the recommended daily dose. This study shows that the risk of AUR is about 2-fold higher in men who use NSAIDs.


Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis.
The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum.


The role of TG2 in regulating S100A4-mediated mammary tumour cell migration.
The importance of S100A4, a Ca(2+)-binding protein, in mediating tumour cell migration, both intracellularly and extracellularly, is well documented. Tissue transglutaminase (TG2) a Ca(2+)-dependent protein crosslinking enzyme, has also been shown to enhance cell migration. Here by using the well characterised non-metastatic rat mammary R37 cells (transfected with empty vector) and highly metastatic KP1 cells (R37 cells transfected with S100A4), we demonstrate that inhibition of TG2 either by TG2 inhibitors or transfection of cells with TG2 shRNA block S100A4-accelerated cell migration in the KP1cells and in R37 cells treated with exogenous S100A4. Cell migration was also blocked by the treatment with the non-cell permeabilizing TG2 inhibitor R294, in the human breast cancer cell line MDA-MB-231 (Clone 16, which has a high level of TG2 expression). Inhibition was paralleled by a decrease in S100A4 polymer formation. In vitro co-immunoprecipitation and Far Western blotting assays and cross-linking assays showed not only the direct interaction between TG2 and S100A4, but also confirmed S100A4 as a substrate for TG2. Using specific functional blocking antibodies, a targeting peptide and a recombinant protein as a competitive treatment, we revealed the involvement of syndecan-4 and α5β1 integrin co-signalling pathways linked by activation of PKCα in this TG2 and S100A4-mediated cell migration. We propose a mechanism for TG2-regulated S100A4-related mediated cell migration, which is dependent on TG2 crosslinking.


Syndromic surveillance using ambulatory electronic health records.
To assess the performance of electronic health record data for syndromic surveillance and to assess the feasibility of broadly distributed surveillance. Two systems were developed to identify influenza-like illness and gastrointestinal infectious disease in ambulatory electronic health record data from a network of community health centers. The first system used queries on structured data and was designed for this specific electronic health record. The second used natural language processing of narrative data, but its queries were developed independently from this health record. Both were compared to influenza isolates and to a verified emergency department chief complaint surveillance system. Lagged cross-correlation and graphs of the three time series. For influenza-like illness, both the structured and narrative data correlated well with the influenza isolates and with the emergency department data, achieving cross-correlations of 0.89 (structured) and 0.84 (narrative) for isolates and 0.93 and 0.89 for emergency department data, and having similar peaks during influenza season. For gastrointestinal infectious disease, the structured data correlated fairly well with the emergency department data (0.81) with a similar peak, but the narrative data correlated less well (0.47). It is feasible to use electronic health records for syndromic surveillance. The structured data performed best but required knowledge engineering to match the health record data to the queries. The narrative data illustrated the potential performance of a broadly disseminated system and achieved mixed results.


Rapid recovery of damaged ecosystems.
Recent reports on the state of the global environment provide evidence that humankind is inflicting great damage to the very ecosystems that support human livelihoods. The reports further predict that ecosystems will take centuries to recover from damages if they recover at all. Accordingly, there is despair that we are passing on a legacy of irreparable damage to future generations which is entirely inconsistent with principles of sustainability. We tested the prediction of irreparable harm using a synthesis of recovery times compiled from 240 independent studies reported in the scientific literature. We provide startling evidence that most ecosystems globally can, given human will, recover from very major perturbations on timescales of decades to half-centuries. Accordingly, we find much hope that humankind can transition to more sustainable use of ecosystems.


Revisiting mu suppression in autism spectrum disorder.
Two aspects of the EEG literature lead us to revisit mu suppression in Autism Spectrum Disorder (ASD). First and despite the fact that the mu rhythm can be functionally segregated in two discrete sub-bands, 8-10 Hz and 10-12/13 Hz, mu-suppression in ASD has been analyzed as a homogeneous phenomenon covering the 8-13 Hz frequency. Second and although alpha-like activity is usually found across the entire scalp, ASD studies of action observation have focused on the central electrodes (C3/C4). The present study was aimed at testing on the whole brain the hypothesis of a functional dissociation of mu and alpha responses to the observation of human actions in ASD according to bandwidths. Electroencephalographic (EEG) mu and alpha responses to execution and observation of hand gestures were recorded on the whole scalp in high functioning subjects with ASD and typical subjects. When two bandwidths of the alpha-mu 8-13 Hz were distinguished, a different mu response to observation appeared for subjects with ASD in the upper sub-band over the sensorimotor cortex, whilst the lower sub-band responded similarly in the two groups. Source reconstructions demonstrated that this effect was related to a joint mu-suppression deficit over the occipito-parietal regions and an increase over the frontal regions. These findings suggest peculiarities in top-down response modulation in ASD and question the claim of a global dysfunction of the MNS in autism. This research also advocates for the use of finer grained analyses at both spatial and spectral levels for future directions in neurophysiological accounts of autism.


[MEDICAL LIBRARIES OF THE SOVIET UNION].
Medical libraries are a part of the Soviet library system. The total number of medical libraries in the country is more than 4,000, with a collection of over 42,000,000 volumes that are used by over a million readers. The State Central Medical Library occupies a special place among these libraries. It carries out the functions of a methodological, bibliographic, and coordinating center. It has a collection of over 1,000,000 units of books and periodicals. All the bibliographic work of medical libraries as well as any other work is provided to help medical institutions. Libraries prepare special bibliographies of medical literature for publication according to a plan. The libraries also conduct reference and information work. The methodological work helps to solve the most important problems that arise in libraries with reference to the specific character of their work and tasks. The chief means of rendering methodological guidance are to analyze the work of various libraries, to hold conferences, to exchange visits with libraries, to give both field and correspondence consultations, and to organize qualification courses for librarians and bibliographers.


Phylogeny of Sabellidae (Annelida) and relationships with other taxa inferred from morphology and multiple genes.
The monophyly of Sabellidae, the phylogenetic relationships of its lineages, and the composition of Sabellida have been debated for many decades. Most studies on sabellid phylogeny have focused on morphological features but little DNA work has been published to date. We performed analyses using maximum-parsimony methods that included 36 sabellids and members of previously related taxa. We integrated morphological and DNA sequence data to resolve relationships at different hierarchical levels (135 morphological features, fragments of the nuclear ribosomal RNA genes 18S and 28S, and the mitochondrial gene 16S). The results indicate the monophyly of Sabellida, including Sabellidae and Serpulidae. Monophyly of Fabriciinae and Serpulidae is assessed and the two groups are recovered as sister taxa, but with weak support. There is no significant support for the monophyly of Sabellinae. Relationships between members of the Sabellidae are still partially unresolved due to incongruence between partitions and low support for most clades. The evolution and transformation of certain characters within Sabellidae is explored. © The Willi Hennig Society 2010.


The Role of Substance Use and Mental Health Problems in Medication Adherence Among HIV-Infected MSM.
Mental health and substance abuse problems are highly prevalent among HIV-infected men who have sex with men (MSM) and frequently interfere with antiretroviral therapy (ART) adherence. Novel interventions that address underlying psychosocial health problems are necessary for improving ART adherence to enhance HIV-related health outcomes and suppress HIV viral load in an effort to prevent transmission to uninfected partners. This brief review describes the mental health problems and specific substances that pose the greatest threat to medication adherence among MSM and summarizes findings from recent intervention trials that simultaneously address ART adherence and comorbid psychosocial factors among HIV-infected MSM.


Medical decision-making capacity: knowledge, attitudes, and assessment practices of physicians in Switzerland.
Decision-making capacity (DMC) is an indispensable prerequisite for patients' informed consent and therefore directly related to the right to self-determination. In view of this ethical implication, valid and reliable assessment of DMC is essential to best practice. In general, and with particular regard to the Swiss context, little is known about healthcare practitioners' knowledge of and attitudes to the concept of DMC, or about their assessment practice. The present study aims to close this gap. A randomised representative sample of 3,500 physicians, including all specialisms and from all parts of Switzerland, were contacted by mail and invited to complete a survey questionnaire, which was specifically designed for the purpose of the study. A total of 763 questionnaires were included for analysis (response rate: 22.15%). Physicians diverged in their general understanding of DMC as either a dichotomous or a gradual concept, and in relation to the conceptual challenges of decisional relativity and risk-relativity. Along with cognitive abilities, emotional, intuitive, or evaluative factors were acknowledged as important criteria. DMC was most often assessed implicitly: explicit assessments, if conducted, depended mainly on unstructured interviews. A discrepancy was identified between physicians' perceptions of responsibility and qualification, indicating a related need for more guidance and training. The conceptual and practical challenges of DMC are far from being resolved. There is a clear need for more guidance in this area in the form of guidelines, tools, and training.


Extra thermo- and water-stable one-dimensional organic-inorganic hybrid perovskite [N-methyldabconium]PbI3 showing switchable dielectric behaviour, conductivity and bright yellow-green emission.
Haloplumbate-based perovskites display promising functionalities for advanced photovoltaic, optoelectronic and other applications with high performances and low costs. Herein, we present a study of variable-temperature crystal structures, dielectrics and conductance at 153-513 K, and luminescence at ambient temperature for a one-dimensional organic-inorganic perovskite, [N-methyldabconium]PbI3 (1). Hybrid 1 shows extra thermo- and water-stability (thermal decomposition at ca. 653 K), switchable dielectric behaviour and conductance at around 348 K, owing to symmetry-breaking structure phase transition from the hexagonal space group P63/mmc in the high-temperature phase to the orthogonal space group Pcba in the low-temperature phase, and bright yellow-green emission at room temperature, originating from the electron transition within the semiconducting {PbI3}∞ chains. This study will broaden the scope of lead halide-based hybrid materials for practical application in optical and electrical devices.


Biobehavioral profiles of arousal and social motivation in autism spectrum disorders.
Children with autism spectrum disorder (ASD) are impaired in social communication and interaction with peers, which may reflect diminished social motivation. Many children with ASD show enhanced stress when playing with other children. This study investigated social and stress profiles of children with ASD during play. We utilized a peer interaction paradigm in a natural playground setting with 66 unmedicated, prepubertal, children aged 8-12 years [38 with ASD, 28 with typical development (TD)]. Salivary cortisol was collected before and after a 20-min playground interaction that was divided into periods of free and solicited play facilitated by a confederate child. Statistical analyses included Wilcoxon rank-sum tests, mixed effects models, and Spearman correlations to assess the between-group differences in social and stress functioning, identify stress responders, and explore associations between variables, respectively. There were no differences between the groups during unsolicited free play; however, during solicited play by the confederate, significant differences emerged such that children with ASD engaged in fewer verbal interactions and more self-play than the TD group. Regarding physiological arousal, children with ASD as a group showed relatively higher cortisol in response to social play; however, there was a broad range of responses. Moreover, those with the highest cortisol levels engaged in less social communication. The social interaction of children with ASD can be facilitated by peer solicitation; however, it may be accompanied by increased stress. The children with ASD that have the highest level of cortisol show less social motivation; yet, it is unclear if it reflects an underlying state of heightened arousal or enhanced reactivity to social engagement, or both.


An approach to functional abdominal pain in children and adolescents.
For children with chronic abdominal pain, the early introduction of stress as a potential cause is likely to improve outcome. Parents underestimate their child's awareness of and capacity to worry about everyday events. Parents, children, and teachers need to be convinced that functional symptoms are a normal feature of life. The need for empathy and quality discussion between doctor, parents, and child concerning potential causes of stress is critical. All reinforcement should be removed including insistence on continued school attendance. Cognitive behavioural therapy appears to be helpful in resistant cases. Medication such as antidepressants should be avoided unless prescribed by a child psychiatrist.


3D printing of layered brain-like structures using peptide modified gellan gum substrates.
The brain is an enormously complex organ structured into various regions of layered tissue. Researchers have attempted to study the brain by modeling the architecture using two dimensional (2D) in vitro cell culturing methods. While those platforms attempt to mimic the in vivo environment, they do not truly resemble the three dimensional (3D) microstructure of neuronal tissues. Development of an accurate in vitro model of the brain remains a significant obstacle to our understanding of the functioning of the brain at the tissue or organ level. To address these obstacles, we demonstrate a new method to bioprint 3D brain-like structures consisting of discrete layers of primary neural cells encapsulated in hydrogels. Brain-like structures were constructed using a bio-ink consisting of a novel peptide-modified biopolymer, gellan gum-RGD (RGD-GG), combined with primary cortical neurons. The ink was optimized for a modified reactive printing process and developed for use in traditional cell culturing facilities without the need for extensive bioprinting equipment. Furthermore the peptide modification of the gellan gum hydrogel was found to have a profound positive effect on primary cell proliferation and network formation. The neural cell viability combined with the support of neural network formation demonstrated the cell supportive nature of the matrix. The facile ability to form discrete cell-containing layers validates the application of this novel printing technique to form complex, layered and viable 3D cell structures. These brain-like structures offer the opportunity to reproduce more accurate 3D in vitro microstructures with applications ranging from cell behavior studies to improving our understanding of brain injuries and neurodegenerative diseases.


Chromium supplementation in non-obese non-diabetic subjects is associated with a decline in insulin sensitivity.
The use of chromium supplements is widespread for the prevention and treatment of diabetes mellitus but there are conflicting reports on efficacy, possibly reflecting discrepant effects across different populations. In the present studies, we test the hypothesis that chromium supplementation raises serum chromium levels and correspondingly improves insulin sensitivity. A double blind placebo-controlled randomized trial was conducted on 31 non-obese, normoglycemic subjects. After baseline studies, the subjects were randomized to placebo or chromium picolinate 500 μg twice a day. The primary endpoint was change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp. Pre-specified secondary endpoints included fasting lipids, blood pressure, weight, body composition measured by DXA scan. After 16 weeks of chromium picolinate therapy there was no significant change in insulin sensitivity between groups (p=0.83). There was, however, a strong association between serum chromium and change in insulin resistance (β = -0.83, p=0.01), where subjects with the highest serum chromium had a worsening of insulin sensitivity. This effect could not be explained by changes in physiological parameters such as body weight, truncal fat and serum lipids with chromium therapy. Chromium therapy did not improve insulin sensitivity in non-obese normoglycemic individuals. Further, subjects who have high serum chromium levels paradoxically had a decline in insulin sensitivity. Caution therefore should be exercised in recommending the use of this supplement. The study was registered on the NIH registry (clinicaltrials.gov) and the identifier is NCT00846248.


Article 4: Impact assessment of supervision performance assessment and recognition strategy (SPARS) to improve supply chain management in health facilities in Uganda: a national pre and post study.
To strengthen medicines management capacity, including supply chain management, at public sector health facilities in Uganda, the Ministry of Health introduced a multipronged supervision, performance assessment, and recognition strategy (SPARS). The aim of this study was to assess the impact of SPARS on improving supply chain management. A series of four papers on SPARS described the SPARS concept, its impact on overall and domain practices and appropriate medicines use, and now in the fourth paper describing the effect on supply chain management. District-based health workers trained as supervisors build facility-level capacity in medicines management using an indicator-based performance assessment followed by targeted supervisory visits. From 2010 to 2013, 1222 SPARS visits were implemented, and the SPARS performance indicator scores determined. This article assesses impact on 13 indicators in three of the five SPARS domains-stock management, storage management, and ordering and reporting quality-using a pre-post design. We also explored factors that may have influenced these outcomes. Between the first and last visit within one year of SPARS implementation, we found an average improvement of 16 percentage points (p < 0.001) in supply chain management measures across all levels of care. The improvement in scores for stock management, storage management, and ordering and reporting was 22 (ns), 16 (p < 0.001), and 11 (p = 0.032) percentage points, respectively. The study identified the key predictors of positive change as a low initial indicator score, frequent supervisory visits, and engagement of the district health officer. The multipronged SPARS approach was effective in building supply chain management capacity in lower-level health care facilities with statistically significant improvements in supply chain management overall and in almost all stock and storage- management and ordering and reporting measures after one year of implementation. We recommend broad dissemination of the SPARS approach as an effective strategy to strengthen supply chain management in low-income countries. The study did not involve or use human participants or identifiable personal data, human tissue, or animals and thus did not require ethical approval or a waiver. It is a study implemented in collaboration with the Ministry of Health and does not require trial registration.


Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors.
The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms. The net effect of neurotransmitter interaction at the mesolimbic brain region induces "reward" when dopamine (DA) is released from the neuron at the nucleus accumbens and interacts with a dopamine D2 receptor. "The reward cascade" involves the release of serotonin, which in turn at the hypothalmus stimulates enkephalin, which in turn inhibits GABA at the substania nigra, which in turn fine tunes the amount of DA released at the nucleus accumbens or "reward site." It is well known that under normal conditions in the reward site DA works to maintain our normal drives. In fact, DA has become to be known as the "pleasure molecule" and/or the "antistress molecule." When DA is released into the synapse, it stimulates a number a DA receptors (D1-D5) which results in increased feelings of well-being and stress reduction. A consensus of the literature suggests that when there is a dysfunction in the brain reward cascade, which could be caused by certain genetic variants (polygenic), especially in the DA system causing a hypodopaminergic trait, the brain of that person requires a DA fix to feel good. This trait leads to multiple drug-seeking behavior. This is so because alcohol, cocaine, heroin, marijuana, nicotine, and glucose all cause activation and neuronal release of brain DA, which could heal the abnormal cravings. Certainly after ten years of study we could say with confidence that carriers of the DAD2 receptor A1 allele have compromised D2 receptors. Therefore lack of D2 receptors causes individuals to have a high risk for multiple addictive, impulsive and compulsive behavioral propensities, such as severe alcoholism, cocaine, heroin, marijuana and nicotine use, glucose bingeing, pathological gambling, sex addiction, ADHD, Tourette's Syndrome, autism, chronic violence, posttraumatic stress disorder, schizoid/avoidant cluster, conduct disorder and antisocial behavior. In order to explain the breakdown of the reward cascade due to both multiple genes and environmental stimuli (pleiotropism) and resultant aberrant behaviors, Blum united this hypodopaminergic trait under the rubric of a reward deficiency syndrome.


The ecology of arsenic.
Arsenic is a metalloid whose name conjures up images of murder. Nonetheless, certain prokaryotes use arsenic oxyanions for energy generation, either by oxidizing arsenite or by respiring arsenate. These microbes are phylogenetically diverse and occur in a wide range of habitats. Arsenic cycling may take place in the absence of oxygen and can contribute to organic matter oxidation. In aquifers, these microbial reactions may mobilize arsenic from the solid to the aqueous phase, resulting in contaminated drinking water. Here we review what is known about arsenic-metabolizing bacteria and their potential impact on speciation and mobilization of arsenic in nature.


A systematic review investigating if genetic or epigenetic markers are associated with postnatal depression.
Postnatal depression (PND) is common, affects the health of the mother, the development of the infant and places a large financial burden on services. Genetic and epigenetic biomarkers for PND could potentially improve the accuracy of current antenatal screening approaches. The aim of this systematic review is to report on the evidence for an association between genetic or epigenetic factors and postnatal depression. A systematic search of five databases (Medline, EMBASE, PILOT, PsychINFO and SCOPUS) was carried out using the following (MeSh) terms and keywords: postpartum, depression, postnatal depression, genetics, genetic polymorphisms and epigenetics. Inclusion criteria were applied and quality of studies was assessed using guidelines from the HuGE Review Handbook (Little and Higgins, 2006). Following removal of duplicate articles, 543 remained; of these 37 met the inclusion criteria. Positive associations have been reported between PND and polymorphisms in the HMNC1, COMT, MAOT, PRKCB, ESR1, SLC6A4 genes in the presence of stressful life events, the BDNF gene when the postnatal period occurs during autumn and winter months and the OXT and OXTR genes in the presence of childhood adversity experienced by the mother. Epigenetic interactions with genotype, estrogen, and childhood adversity were identified that are predictive of PND. The number of studies investigating some of the markers was small and grey literature was not included. This review highlights the importance of examining the interaction between epigenetic, genetic, hormonal and environmental factors in order to fully understand the risk factors for PND and to improve the accuracy of current antenatal and early postnatal screening procedures. Women susceptible to PND appear to have heightened epigenetic sensitivity to the physiological changes of childbirth or to environmental factors conferred by genotype.


Healthcare costs of Staphylococcus aureus and Clostridium difficile infections in veterans: role of vitamin D deficiency.
Clostridium difficile and staphylococcal infections are associated with increased morbidity, mortality and healthcare costs. Vitamin D deficiency may also contribute to increased healthcare costs. There is increasing evidence that vitamin D may have an antimicrobial role. We examined the relationship of serum 25(OH)D levels to staphylococcal and C. difficile infections to determine if vitamin D deficiency was associated with adverse outcomes. In the outpatient setting, vitamin D deficiency in patients with C. difficile and staphylococcal infections were associated with significantly increased total outpatients costs and fee-based consultation. Laboratory expenses had a trend towards higher costs in the vitamin D-deficient group but did not reach statistical significance. The differences were most clearly seen in the in-patient group with enhanced laboratory, pharmacy and radiology costs. These differences resulted in vitamin D-deficient patients with C. difficile or staphylococcal infections having costs more than five times higher than the non-deficient patients. The total length of hospital stay was four times greater in the vitamin D-deficient group. In addition, the total number of hospitalizations was also significantly greater in the vitamin D-deficient group. Surgery costs demonstrated a tendency to be higher in the vitamin D-deficient group but failed to reach statistical significance. Vitamin D deficiency is intimately linked to adverse health outcomes and costs in Veterans with staphylococcal and C. difficile infections in North East Tennessee. We recommend that vitamin D status be checked in patients with these infections and appropriate therapy be instituted to restore vitamin D level to normal in an expeditious manner.


The Shanghai Women's Asthma and Allergy Study: objectives, design, and recruitment results.
The Shanghai Women's Asthma and Allergy Study is the first population-based incidence study designed to assess the associations of dietary antioxidant intake and measures of oxidative stress and antioxidant enzyme activity with development of adult-onset asthma and allergic rhinitis. A total of 65,732 participants in the Shanghai Women's Health Study, an ongoing cohort study in seven districts of Shanghai, People's Republic of China, were recruited to the Shanghai Women's Asthma and Allergy Study from 2003 to 2007. Dietary intake was assessed in the parent study by using a validated and quantitative food frequency questionnaire at baseline recruitment and at the first biennial follow-up survey. Blood and urine samples were collected to measure baseline oxidative stress, antioxidant enzyme activity, and nutrient levels at the baseline survey. Incident asthma and allergic rhinitis were assessed by using a modification of the International Study of Asthma and Allergies in Childhood questionnaire during the biennial in-person survey of the Shanghai Women's Health Study. Diagnosis of asthma was confirmed by either methacholine challenge testing or test of reversibility to beta-agonists. Dietary antioxidant intake, plasma antioxidants, antioxidant enzymes, and urinary isoprostanes, a marker of oxidative stress, were measured prior to disease onset. This paper describes the study objectives, design, population demographics, and recruitment results.


Interventions for sustained healthcare professional behaviour change: a protocol for an overview of reviews.
Failure to successfully implement and sustain change over the long term continues to be a major problem in health and social care. Translating evidence into routine clinical practice is notoriously complex, and it is recognised that to implement new evidence-based interventions and sustain them over time, professional behaviour needs to change accordingly. A number of theories and frameworks have been developed to support behaviour change among health and social care professionals, and models of sustainability are emerging, but few have translated into valid and reliable interventions. The long-term success of healthcare professional behavioural change interventions is variable, and the characteristics of successful interventions unclear. Previous reviews have synthesised the evidence for behaviour change, but none have focused on sustainability. In addition, multiple overlapping reviews have reported inconsistent results, which do not aid translation of evidence into practice. Overviews of reviews can provide accessible succinct summaries of evidence and address barriers to evidence-based practice. We aim to compile an overview of reviews, identifying, appraising and synthesising evidence relating to sustained social and healthcare professional behaviour change. We will conduct a systematic review of Cochrane reviews (an Overview). We plan to systematically search the Cochrane Database of Systematic Reviews. We will include all systematic reviews of randomised controlled trials comparing a healthcare professional targeted behaviour change intervention to a standard care or no intervention control group. Two reviewers will independently assess the eligibility of the reviews and the methodological quality of included reviews using the ROBIS tool. The quality of evidence within each comparison in each review will be judged based on the GRADE criteria. Disagreements will be resolved through discussion. Effects of interventions will be systematically tabulated and the quality of evidence used to determine implications for clinical practice and make recommendations for future research. This overview will bring together the best available evidence relating to the sustainability of health professional behaviour change, thus supporting policy makers with decision-making in this field.


Hepatitis C Virus and Hepatocellular Carcinoma: A Narrative Review.
Hepatocellular carcinoma (HCC) is a leading cause of liver-related death worldwide. Hepatitis C virus (HCV) infection is a major cause of advanced hepatic fibrosis and cirrhosis, with significantly increased risk for development of HCC. The morbidity and mortality of HCV-related HCC remains high, as rates of HCV cirrhosis continue to increase. The long-term goal of antiviral therapy for chronic HCV is to reduce complications from cirrhosis, including HCC. The advent of new direct-acting antivirals with high rates of virological clearance has revolutionized cure of HCV infection. While the development of HCC in HCV patients who achieve disease sustained virologic response is reduced, these patients remain at risk for HCC, particularly those patients with advanced fibrosis and cirrhosis. This review outlines the epidemiology of HCC in chronic HCV, various mechanisms, risk factors and pathophysiology that contribute to this disease process, screening recommendations, and the available data on the impact of new direct-acting antiviral treatment on the development on HCC.


Functional brain networks in the schizophrenia spectrum and bipolar disorder with psychosis.
Psychotic experiences have been proposed to lie on a spectrum, ranging from subclinical experiences to treatment-resistant schizophrenia. We aimed to characterize functional connectivity and brain network characteristics in relation to the schizophrenia spectrum and bipolar disorder with psychosis to disentangle neural correlates to psychosis. Additionally, we studied antipsychotic medication and lithium effects on network characteristics. We analyzed functional connectivity strength and network topology in 487 resting-state functional MRI scans of individuals with schizophrenia spectrum disorder (SCZ), bipolar disorder with a history of psychotic experiences (BD), treatment-naïve subclinical psychosis (SCP), and healthy controls (HC). Since differences in connectivity strength may confound group comparisons of brain network topology, we analyzed characteristics of the minimum spanning tree (MST), a relatively unbiased backbone of the network. SCZ and SCP subjects had a lower connectivity strength than BD and HC individuals but showed no differences in network topology. In contrast, BD patients showed a less integrated network topology but no disturbances in connectivity strength. No differences in outcome measures were found between SCP and SCZ, or between BD patients that used antipsychotic medication or lithium and those that did not. We conclude that functional networks in patients prone to psychosis have different signatures for chronic SCZ patients and SCP compared to euthymic BD patients, with a limited role for medication. Connectivity strength effects may have confounded previous studies, as no functional network alterations were found in SCZ after strict correction for connectivity strength.


Use of light-emitting diode photomodulation to reduce erythema and discomfort after intense pulsed light treatment of photodamage.
This study evaluates the use of light-emitting diode (LED) photomodulation therapy to accelerate resolution of post-intense pulsed light (IPL) erythema. In this split-face study, 15 subjects were randomized to receive LED treatment to one side of the face as determined by computer-generated randomization numbers. All 15 subjects received a single IPL treatment for facial photodamage. Immediately after IPL treatment, one side of the face was treated for 35 s with the LED device. The other side was not treated. Subjects returned 24 h later for a second LED treatment on the same side of the face. Posttreatment erythema was rated on both sides of the face by the blinded investigator and by subjects immediately after IPL treatment, 24 h later, and 1 week later on a scale of 0% (no erythema) to 100% (severe erythema). Patients commented on posttreatment discomfort immediately after IPL treatment. Mean erythema scores on the first visit were significantly higher (P = 0.0054) on the side not treated with LED (52.7 +/- 24.6) than on the LED-treated side (43.3 +/- 21.9). Visit 2 data showed a similar trend (P = 0.0281). The subjects reported similar findings with mean erythema scores on the first visit on the LED-treated side (46.7 +/- 25.3) compared with the untreated side (60.0 +/- 23.3); the difference was significant (P = 0.0382). On the second visit, the mean erythema scores trended lower on the LED-treated side (24.3 +/- 22.1) than on the untreated side (27.9 +/- 25.8), but the difference did not reach statistical significance (P = 0.1365). Erythema scores on both facial sides were 0 for all subjects 1 week after IPL treatment. Four patients commented that posttreatment discomfort was considerably less on the LED-treated side immediately after treatment. LED photomodulation treatment may accelerate the resolution of erythema and reduce posttreatment discomfort in IPL-treated patients with photodamage.


Stable isotope labeling by amino acids in cell culture for quantitative proteomics.
Mass spectrometry (MS)-based quantitative proteomics is an increasingly popular approach to study changes in protein abundances in biological samples. Stable isotope labeling by amino acids in cell culture (SILAC), one of the more widely used methods for quantitative proteomics, is a metabolic-labeling strategy that encodes whole cellular proteomes. Cells are grown in a culture medium where the natural form of an amino acid is replaced with a stable isotope form, such as arginine bearing six 13C atoms. Incorporation of the "heavy" amino acid occurs through cell growth, protein synthesis, and turnover. SILAC allows "light" and "heavy" proteomes to be distinguished by MS while avoiding any chemical derivatization and associated purification. In this chapter, we provide detailed SILAC protocols and explain how to incorporate SILAC into any experiment.