Spatial coding of touch at the fingers: Insights from double simultaneous stimulation within and between hands.
We studied the effect of tactile double simultaneous stimulation (DSS) within and between hands to examine spatial coding of touch at the fingers. Participants performed a go/no-go task to detect a tactile stimulus delivered to one target finger (e.g., right index), stimulated alone or with a concurrent non-target finger, either on the same hand (e.g., right middle finger) or on the other hand (e.g., left index finger=homologous; left middle finger=non-homologous). Across blocks we also changed the unseen hands posture (both hands palm down, or one hand rotated palm-up). When both hands were palm-down DSS interference effects emerged both within and between hands, but only when the non-homologous finger served as non-target. This suggests a clear segregation between the fingers of each hand, regardless of finger side. By contrast, when one hand was palm-up interference effects emerged only within hand, whereas between hands DSS interference was considerably reduced or absent. Thus, between hands interference was clearly affected by changes in hands posture. Taken together, these findings provide behavioral evidence in humans for multiple spatial coding of touch during tactile DSS at the fingers. In particular, they confirm the existence of representational stages of touch that distinguish between body-regions more than body-sides. Moreover, they show that the availability of tactile stimulation side becomes prominent when postural update is required.


Open laparoscopic access technique: review of 2010 patients.
We assessed safety and efficacy of an open laparoscopic entry technique. A retrospective review of all patients undergoing laparoscopy via open laparoscopic access over an 8-year period from January 1, 1998 to December 31, 2006 is presented. During the study period, 2010 consecutive subjects underwent laparoscopy. Recorded intraoperative complications include enterotomy (0.1%) and failure to enter (0.1%). There were no instances of vascular injury related to entry. Recorded postoperative complications include hernia (0.9%), infection (2.5%), hematoma (0.05%), and noncosmetic healing (0.4%). A statistically significant association existed between obesity and postoperative hernia, and between previous abdominal surgery and postoperative infection. Though typically straightforward, initial entry is one of the most common causes of injury in laparoscopy. The predominant entry method of entry in gynecologic surgery remains a closed technique. This technique has unfortunately been demonstrated in multiple series to have the potential for visceral and vascular injury due to its blind insertion of Veress needles and trocars. The open laparoscopic technique is a safe and effective method of obtaining access to the abdominal cavity with no associated vascular injury.


Interleukin 28B gene polymorphisms in hepatitis C virus-related cryoglobulinemic vasculitis.
Single-nucleotide polymorphisms (SNP) in the interleukin 28B (IL-28B) gene region are strongly predictive of the response of infected patients to antiviral therapy for hepatitis C virus (HCV). We sought to determine the prevalence of SNP IL-28B rs12979860 C/C and non-C/C (C/T plus T/T) genotypes in HCV-related cryoglobulinemic vasculitis (CV), as compared with HCV-positive patients without CV. We also searched for their association with peculiar clinical manifestations of CV and potential influence on the complete response (virological, molecular, and immunological) to the therapy. The study cohort comprised 159 and 172 HCV-infected patients with and without CV, respectively, prospectively followed starting from 1990. SNP rs12979860 genotyping was performed by Taq-Man allelic discrimination. In 106 patients (66.6%) with CV, the profile of circulating B cell clonalities was determined as well. All patients with CV were treated with pegylated interferon-α/ribavirin-based antiviral therapy. The T/T IL-28B genotype was more common in patients with CV than in those without (17% vs 8.1%, p = 0.02). In patients with CV, compared with non-C/C variants, the IL-28B C/C genotype was associated with a higher rate of complete response (52.6% vs 39.2%, p = 0.13), whereas a treatment response of 61.4% was demonstrated when solely virological response was considered (p = 0.008). A higher frequency of expanded B cell clonalities in the circulation (84.2% vs 55.9%; p = 0.005), kidney involvement (21% vs 2.9%; p = 0.003), and B cell non-Hodgkin lymphoma (17.5% vs 6.8%; p = 0.048), were also observed. In HCV-positive patients with CV, the IL-28B C/C genotype is distinguished biologically by a higher frequency of restriction of B cell response and clinically by a higher risk of cryoglobulinemic nephropathy and B cell malignancies, while acting as an independent predictor of a sustained virological response to antiviral therapy. In addition, we found that IL-28B T/T variant was more prevalent in patients with CV than in those without.


Climate change and food security.
Dynamic interactions between and within the biogeophysical and human environments lead to the production, processing, distribution, preparation and consumption of food, resulting in food systems that underpin food security. Food systems encompass food availability (production, distribution and exchange), food access (affordability, allocation and preference) and food utilization (nutritional and societal values and safety), so that food security is, therefore, diminished when food systems are stressed. Such stresses may be induced by a range of factors in addition to climate change and/or other agents of environmental change (e.g. conflict, HIV/AIDS) and may be particularly severe when these factors act in combination. Urbanization and globalization are causing rapid changes to food systems. Climate change may affect food systems in several ways ranging from direct effects on crop production (e.g. changes in rainfall leading to drought or flooding, or warmer or cooler temperatures leading to changes in the length of growing season), to changes in markets, food prices and supply chain infrastructure. The relative importance of climate change for food security differs between regions. For example, in southern Africa, climate is among the most frequently cited drivers of food insecurity because it acts both as an underlying, ongoing issue and as a short-lived shock. The low ability to cope with shocks and to mitigate long-term stresses means that coping strategies that might be available in other regions are unavailable or inappropriate. In other regions, though, such as parts of the Indo-Gangetic Plain of India, other drivers, such as labour issues and the availability and quality of ground water for irrigation, rank higher than the direct effects of climate change as factors influencing food security. Because of the multiple socio-economic and bio-physical factors affecting food systems and hence food security, the capacity to adapt food systems to reduce their vulnerability to climate change is not uniform. Improved systems of food production, food distribution and economic access may all contribute to food systems adapted to cope with climate change, but in adopting such changes it will be important to ensure that they contribute to sustainability. Agriculture is a major contributor of the greenhouse gases methane (CH4) and nitrous oxide (N2O), so that regionally derived policies promoting adapted food systems need to mitigate further climate change.


Barriers to optimal antibiotic use for community-acquired pneumonia at hospitals: a qualitative study.
Physician adherence to key recommendations of guidelines for community-acquired pneumonia (CAP) is often not optimal. A better understanding of factors influencing optimal performance is needed to plan effective change. The authors used semistructured interviews with care providers in three Dutch medium-sized hospitals to qualitatively study and understand barriers to appropriate antibiotic use in patients with CAP. They discussed recommendations about the prescription of empirical antibiotic therapy that adheres to the guidelines, timely administration of antibiotics, adjusting antibiotic dosage to accommodate decreased renal function, switching and streamlining therapy, and blood and sputum culturing. The authors then classified the barriers each recommendation faced into categories using a conceptual framework (Cabana). Eighteen interviews were performed with residents and specialists in pulmonology and internal medicine, with medical microbiologists and a clinical pharmacist. Two additional multidisciplinary small group interviews which included nurses were performed. Each guideline recommendation elicited a different type of barrier. Regarding the choice of guideline-adherent empirical therapy, treating physicians said that they worried about patient outcome when prescribing narrow-spectrum antibiotic therapy. Regarding the timeliness of antibiotic administration, barriers such as conflicting guidelines and organisational factors (for example, delayed laboratory results, antibiotics not directly available, lack of time) were reported. Not streamlining therapy after culture results became available was thought to be due to the physicians' attitude of "never change a winning team". Efforts to improve the use of antibiotics for patients with CAP should consider the range of barriers that care providers face. Each recommendation meets its own barriers. Interventions to improve adherence should be tailored to these factors.


Women's experiences of how their recovery process is promoted after a first myocardial infarction: Implications for cardiac rehabilitation care.
A rapid improvement in the care of myocardial infarction (MI) in the emergency services has been witnessed in recent years. There is, however, a lack of understanding of the factors involved in a successful recovery process, after the initial stages of emergency care among patients, and in particular those who are women. Both preventive and promotive perspectives should be taken into consideration for facilitating the recovery process of women after a MI. To explore how women's recovery processes are promoted after a first MI. A qualitative content analysis was used. The women's recovery process is a multidirectional process with a desire to develop and approach a new perspective on life. The women's possibility to approach new perspectives on life incorporates how they handle the three dimensions: behaviour, that is, women's acting and engaging in various activities; social, that is, how women receive and give support in their social environment; and psychological, that is, their way of thinking, reflecting, and appreciating life. The personal recovery of women is a multidirectional process with a desire to develop and approach a new perspective on life. It is important for cardiac rehabilitation nurses to not only focus on lifestyle changes and social support but also on working actively with the women's inner strength in order to promote the recovery of the women.


Meditation training increases brain efficiency in an attention task.
Meditation is a mental training, which involves attention and the ability to maintain focus on a particular object. In this study we have applied a specific attentional task to simply measure the performance of the participants with different levels of meditation experience, rather than evaluating meditation practice per se or task performance during meditation. Our objective was to evaluate the performance of regular meditators and non-meditators during an fMRI adapted Stroop Word-Colour Task (SWCT), which requires attention and impulse control, using a block design paradigm. We selected 20 right-handed regular meditators and 19 non-meditators matched for age, years of education and gender. Participants had to choose the colour (red, blue or green) of single words presented visually in three conditions: congruent, neutral and incongruent. Non-meditators showed greater activity than meditators in the right medial frontal, middle temporal, precentral and postcentral gyri and the lentiform nucleus during the incongruent conditions. No regions were more activated in meditators relative to non-meditators in the same comparison. Non-meditators showed an increased pattern of brain activation relative to regular meditators under the same behavioural performance level. This suggests that meditation training improves efficiency, possibly via improved sustained attention and impulse control.


A modern day holy anorexia? Religious language in advertising and anorexia nervosa in the West.
In this review we comment on the media, in particular advertisements and the internet, using religious and moralistic motifs in connection with eating and their possible role in promoting modern-day 'nutritional' consumerism and fundamentalism (diet, discipline and discipleship). We have reviewed historically the concept of holy anorexia and have analyzed the pictorial and language content of some representative advertisements. Words used include 'temptation', 'decadent', 'heaven' and 'purity' and suggest a connection with eating and moral values. They also imply eating as either heaven or sin, to be yielded to in both circumstances. Such messages identifying eating with guilt or reward could precipitate 'atypical' eating disorders in vulnerable subjects, invoking the historical associations with extreme religiosity and anorexia. It is not clear how these 'fundamentalist' trends developed but health educators should be aware of them in dealing with at-risk subjects for eating disorders.


Effects of sequential infections of Caenorhabditis elegans with Staphylococcus aureus and Proteus mirabilis.
Caenorhabditis elegans can be used to study the dynamics of polymicrobial infections, specifically those between Gram-positive and Gram-negative bacteria. With C. elegans, Proteus mirabilis acts as an opportunistic pathogen and does not kill this host. Hence, in the present study, C. elegans was immunochallenged by pre-infecting it with the pathogen Staphylococcus aureus in order to study the subsequent effect of P. mirabilis on the host. It was found that 12 hrs of S. aureus and 80 hrs of subsequent P. mirabilis infection significantly reduced the life span of exposed C. elegans by 80%. However, preinfection with S. aureus for 8 and 4 hrs reduced the life span of C. elegans by only 60 and 30%, respectively. Further, there was greater production of reactive oxygen species in the sequentially infected samples than in the S. aureus and P. mirabilis controls. Real time PCR analysis indicated regulation of candidate immune regulatory genes, lysozyme (lys-7), CUB-like proteins (F08G5.6), neuropeptide-like factors (nlp-29), transcription factors of mitogen-activated protein kinase (ATF-7) and daf-2-daf-16 (daf-16), insulin-like signaling pathways and C-type lectin (clec-60 and clec-87) family members during S. aureus and subsequent P. mirabilis-mediated infections, indicating possible roles of, and contributions by, the above factors during host immune responses against these sequential infections. The present findings demonstrate that S. aureus infections increase the vulnerability of the C. elegans host by subverting its immune system, which then permits the opportunistic pathogen P. mirabilis to be pathogenic to this host.


Gamma-aminobutyric acid specifically inhibits progression of tubular fibrosis and atrophy in nephrectomized rats.
Gamma-aminobutyric acid (GABA) was administered orally to rats for 60 d after excision of five-sixths of their kidney volume. A decrease in renal function parameters was observed in these nephrectomized rats. However, the administration of GABA ameliorated renal dysfunction, and a longer administration period of GABA increased its protective effect. In addition, tubular fibrosis was markedly increased at 10 and 60 d in nephrectomized control rats, while GABA administration for 10 d reduced tubular fibrosis to the normal level. Tubular atrophy was markedly induced by nephrectomy, and was significantly reduced by the administration of GABA at 60 d. Furthermore, the nephrectomized control rats exhibited an increased expression level of transforming growth factor-beta1, where GABA significantly decreased it after administration for 10 d. The expression of fibronectin in the tubuli of rats administrated GABA for 60 d was completely and dose-dependently reduced as compared with nephrectomized control rats. However, the improvement effects in glomeruli were less. We also found that GABAA and GABAB receptors were specifically localized in tubuli. Specific agonists for GABAA and GABAB receptors improved renal function. These results suggest that GABA may have a beneficial effect on renal function in nephrectomized rats by inhibiting fibrosis and atrophy primarily in tubuli, and that it ameliorates losses of renal function in renal failure.


An Alarm Watch for Daytime Urinary Incontinence: A Randomized Controlled Trial.
Daytime urinary incontinence is disabling and occurs in 17% of school-aged children. Timed-voiding is part of standard therapy. Can an alarm watch to aid timed-voiding improve treatment response to standard therapy? The WATCH (Watch with Alarm for Timed-Voiding in Children) study is a randomized controlled trial. Participants were randomly assigned (1:1) to a vibrating alarm or nonalarming watch for 3-months. The primary outcome was the proportion who achieved a complete response (14 consecutive dry days) after 3-months of treatment. Children aged 5 to 13 years who were prescribed timed-voiding for daytime urinary incontinence. Overall, 243 children, with a mean age of 8 years, were enrolled, with 62% girls. At 3-months, the complete response rates were similar between the 2 groups (22% alarm versus 17% control; difference: 5%; 95% confidence interval (CI): -5% to 16%; P = .42). In the alarm group, treatment adherence was higher (40% vs 10%; difference: 30%; 95% CI: 20% to 40%; P < .001), frequency of incontinence was lower (25% dry; 40% had 1-3 wet days per week, 24% had 4-6 wet days per week, and 12% had daily wetting, compared with 19%, 30%, 35%, and 16%, respectively; P =.05), and fewer had abnormal postvoid residual urine volumes (12% vs 24%; difference: -12%; 95% CI: -21% to -1%; P = .04) compared with the control group. Improvement was transient and did not persist 6 months beyond the treatment period. Alarm watches do not appear to lead to complete resolution of urinary incontinence in children but did promote treatment adherence, normalization of postvoid residual volumes, and reduction in incontinent episodes while being used.


Melatonin prevents postovulatory oocyte aging in the mouse and extends the window for optimal fertilization in vitro.
The quality of metaphase II oocytes deteriorates rapidly following ovulation as the result of an aging process associated with impaired fertilizing potential, disrupted developmental competence, and increased likelihood of embryonic resorption. Because oxidative stress accelerates the onset of apoptosis in oocytes and influences their capacity for fertilization, this study aimed to characterize the significance of such stress in the postovulatory aging of mouse oocytes in vitro. We investigated the ability of the potent antioxidant melatonin to arrest the aging process when used to supplement oocyte culture medium. This study demonstrated that oxidative stress may occur in oocytes after as little as 8 h in culture and coincides with the appearance of early apoptotic markers such as phosphatidylserine externalization, followed 16 h later by caspase activation (P < 0.05) and morphological evidence of oocyte senescence. Importantly, supplementation of oocyte culture medium with 1 mM melatonin was able to significantly relieve the time-dependent appearance of oxidative stress in oocytes (P < 0.05) and, as a result, significantly delay the onset of apoptosis (P < 0.05). Furthermore, melatonin supplementation extended the optimal window for fertilization of oocytes aged for 8 and 16 h in vitro (P < 0.05) and significantly improved the quality of the resulting embryos (P < 0.01). We conclude that melatonin may be a useful tool in a clinical setting to prevent the time-dependent deterioration of oocyte quality following prolonged culture in vitro.


Peroxisome proliferator-activated receptor γ regulates genes involved in insulin/insulin-like growth factor signaling and lipid metabolism during adipogenesis through functionally distinct enhancer classes.
The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPAR induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPAR also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPAR utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process.


Factors affecting the perception of intoxication: dose, tolerance, and setting.
The present experiment was designed to investigate whether changes in internal sensations and affect are used to discriminate intoxication and to determine how the discriminability of these cues is affected by dose, acquired tolerance, and the setting in which alcohol is consumed. Setting varied according to whether subjects were distracted or not distracted from attending to alcohol induced changes. Furthermore, subjects drank either a placebo beverage or one of two doses of alcohol. The results showed an interaction between dose and setting, which suggested that subjects who participated in a distracting task were less accurate in the evaluation of their intoxication and were more easily misled into believing that they had consumed alcohol when they had actually received a placebo. Additional measures suggested that the distracted subjects did not base their intoxication ratings as closely on changes associated with alcohol consumption. Acquired tolerance to alcohol also affected the perception of intoxication and influenced the discriminability of changes in internal sensations and affect. The findings on tolerance are related to motives for increasing alcohol consumption over time and to the inefficacy of blood alcohol level discrimination training with alcoholics.


In vitro alterations do not reflect a requirement for host cell cycle progression during Plasmodium liver stage infection.
Prior to invading nonreplicative erythrocytes, Plasmodium parasites undergo their first obligate step in the mammalian host inside hepatocytes, where each sporozoite replicates to generate thousands of merozoites. While normally quiescent, hepatocytes retain proliferative capacity and can readily reenter the cell cycle in response to diverse stimuli. Many intracellular pathogens, including protozoan parasites, manipulate the cell cycle progression of their host cells for their own benefit, but it is not known whether the hepatocyte cell cycle plays a role during Plasmodium liver stage infection. Here, we show that Plasmodium parasites can be observed in mitotic hepatoma cells throughout liver stage development, where they initially reduce the likelihood of mitosis and ultimately lead to significant acquisition of a binucleate phenotype. However, hepatoma cells pharmacologically arrested in S phase still support robust and complete Plasmodium liver stage development, which thus does not require cell cycle progression in the infected cell in vitro. Furthermore, murine hepatocytes remain quiescent throughout in vivo infection with either Plasmodium berghei or Plasmodium yoelii, as do Plasmodium falciparum-infected primary human hepatocytes, demonstrating that the rapid and prodigious growth of liver stage parasites is accomplished independent of host hepatocyte cell cycle progression during natural infection.


Mixed effects approach to the analysis of the stepped wedge cluster randomised trial-Investigating the confounding effect of time through simulation.
A stepped wedge cluster randomised trial (SWCRT) is a multicentred study which allows an intervention to be rolled out at sites in a random order. Once the intervention is initiated at a site, all participants within that site remain exposed to the intervention for the remainder of the study. The time since the start of the study ("calendar time") may affect outcome measures through underlying time trends or periodicity. The time since the intervention was introduced to a site ("exposure time") may also affect outcomes cumulatively for successful interventions, possibly in addition to a step change when the intervention began. Motivated by a SWCRT of self-monitoring for bipolar disorder, we conducted a simulation study to compare model formulations to analyse data from a SWCRT under 36 different scenarios in which time was related to the outcome (improvement in mood score). The aim was to find a model specification that would produce reliable estimates of intervention effects under different scenarios. Nine different formulations of a linear mixed effects model were fitted to these datasets. These models varied in the specification of calendar and exposure times. Modelling the effects of the intervention was best accomplished by including terms for both calendar time and exposure time. Treating time as categorical (a separate parameter for each measurement time-step) achieved the best coverage probabilities and low bias, but at a cost of wider confidence intervals compared to simpler models for those scenarios which were sufficiently modelled by fewer parameters. Treating time as continuous and including a quadratic time term performed similarly well, with slightly larger variations in coverage probability, but narrower confidence intervals and in some cases lower bias. The impact of misspecifying the covariance structure was comparatively small. We recommend that unless there is a priori information to indicate the form of the relationship between time and outcomes, data from SWCRTs should be analysed with a linear mixed effects model that includes separate categorical terms for calendar time and exposure time. Prespecified sensitivity analyses should consider the different formulations of these time effects in the model, to assess their impact on estimates of intervention effects.


Adjacent segment degeneration in the lumbar spine.
A primary concern after posterior lumbar spine arthrodesis is the potential for adjacent segment degeneration cephalad or caudad to the fusion segment. There is controversy regarding the subsequent degeneration of adjacent segments, and we are aware of no long-term studies that have analyzed both cephalad and caudad degeneration following posterior arthrodesis. A retrospective investigation was performed to determine the rates of degeneration and survival of the motion segments adjacent to the site of a posterior lumbar fusion. Two hundred and fifteen patients who had undergone posterior lumbar arthrodesis were included in this study. The study group included 126 female patients and eighty-nine male patients. The average duration of follow-up was 6.7 years. Radiographs were analyzed with regard to arthritic degeneration at the adjacent levels both preoperatively and at the time of the last follow-up visit. Disc spaces were graded on a 4-point arthritic degeneration scale. Correlation analysis was used to determine the contribution of independent variables to the rate of degeneration. Survivorship analysis was performed to describe the degeneration of the adjacent motion segments. Fifty-nine (27.4%) of the 215 patients had evidence of degeneration at the adjacent levels and elected to have an additional decompression (fifteen patients) or arthrodesis (forty-four patients). Kaplan-Meier analysis predicted a disease-free survival rate of 83.5% (95% confidence interval, 77.5% to 89.5%) at five years and of 63.9% (95% confidence interval, 54.0% to 73.8%) at ten years after the index operation. Although there was a trend toward progression of the arthritic grade at the adjacent disc levels, there was no significant correlation, with the numbers available, between the preoperative arthritic grade and the need for additional surgery. The rate of symptomatic degeneration at an adjacent segment warranting either decompression or arthrodesis was predicted to be 16.5% at five years and 36.1% at ten years. There appeared to be no correlation with the length of fusion or the preoperative arthritic degeneration of the adjacent segment.


Human apolipoprotein A-I-derived amyloid: its association with atherosclerosis.
Amyloidoses constitute a group of diseases in which soluble proteins aggregate and deposit extracellularly in tissues. Nonhereditary apolipoprotein A-I (apoA-I) amyloid is characterized by deposits of nonvariant protein in atherosclerotic arteries. Despite being common, little is known about the pathogenesis and significance of apoA-I deposition. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironment associated with chronic inflammation on the folding and pro-amyloidogenic processing of apoA-I. Results showed that mildly acidic pH promotes misfolding, aggregation, and increased binding of apoA-I to extracellular matrix elements, thus favoring protein deposition as amyloid like-complexes. In addition, activated neutrophils and oxidative/proteolytic cleavage of the protein give rise to pro amyloidogenic products. We conclude that, even though apoA-I is not inherently amyloidogenic, it may produce non hereditary amyloidosis as a consequence of the pro-inflammatory microenvironment associated to atherogenesis.


Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation.
In May 2008, the National Institute for Health and Clinical Excellence (NICE) issued an updated guideline [clinical guideline (CG) 66] for the management of all aspects of type 2 diabetes. This report aims to provide information on new drug developments to support a 'new drugs update' to the 2008 guideline. To review the newer agents available for blood glucose control in type 2 diabetes from four classes: the glucagon-like peptide-1 (GLP-1) analogue exenatide; dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin; the long-acting insulin analogues, glargine and detemir; and to review concerns about the safety of the thiazolidinediones. The following databases were searched: MEDLINE (1990-April 2008), EMBASE (1990-April 2008), the Cochrane Library (all sections) Issue 2, 2008, and the Science Citation Index and ISI Proceedings (2000-April 2008). The websites of the American Diabetes Association, the European Association for the Study of Diabetes, the US Food and Drug Administration, the European Medicines Evaluation Agency and the Medicines and Healthcare Products Regulatory Agency were searched, as were manufacturers' websites. Data extraction was carried out by one person, and checked by a second. Studies were assessed for quality using standard methods for reviews of trials. Meta-analyses were carried out using the Cochrane Review Manager (RevMan) software. Inclusion and exclusion criteria were based on current standard clinical practice in the UK, as outlined in NICE CG 66. The outcomes for the GLP-1 analogues, DPP-4 inhibitors and the long-acting insulin analogues were: glycaemic control, reflected by glycated haemoglobin (HbA1c) level, hypoglycaemic episodes, changes in weight, adverse events, quality of life and costs. Modelling of the cost-effectiveness of the various regimes used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model. Exenatide improved glycaemic control by around 1%, and had the added benefit of weight loss. The gliptins were effective in improving glycaemic control, reducing HbA1c level by about 0.8%. Glargine and detemir were equivalent to Neutral Protamine Hagedorn (NPH) (and to each other) in terms of glycaemic control but had modest advantages in terms of hypoglycaemia, especially nocturnal. Detemir, used only once daily, appeared to cause slightly less weight gain than glargine. The glitazones appeared to have similar effectiveness in controlling hyperglycaemia. Both can cause heart failure and fractures, but rosiglitazone appears to slightly increase the risk of cardiovascular events whereas pioglitazone reduces it. Eight trials examined the benefits of adding pioglitazone to an insulin regimen; in our meta-analysis, the mean reduction in HbA1c level was 0.54% [95% confidence interval (CI) -0.70 to -0.38] and hypoglycaemia was marginally more frequent in the pioglitazone arms [relative risk (RR) 1.27, 95% CI 0.99 to 1.63]. In most studies, those on pioglitazone gained more weight than those who were not. In terms of annual drug acquisition costs among the non-insulin regimes for a representative patient with a body mass index of around 30 kg/m2, the gliptins were the cheapest of the new drugs, with costs of between 386 pounds and 460 pounds. The glitazone costs were similar, with total annual costs for pioglitazone and for rosiglitazone of around 437 pounds and 482 pounds, respectively. Exenatide was more expensive, with an annual cost of around 830 pounds. Regimens containing insulin fell between the gliptins and exenatide in terms of their direct costs, with a NPH-based regimen having an annual cost of around 468 pounds for the representative patient, whereas the glargine and detemir regimens were more expensive, at around 634 pounds and 716 pounds, respectively. Comparisons of sitagliptin and rosiglitazone, and of vidagliptin and pioglitazone slowed clinical equivalence in terms of quality-adjusted life-years (QALYs), but the gliptins were marginally less costly. Exenatide, when compared with glargine, appeared to be cost-effective. Comparing glargine with NPH showed an additional anticipated cost of around 1800 pounds. Within the comparison of detemir and NPH, the overall treatment costs for detemir were slightly higher, at between 2700 pounds and 2600 pounds. The UKPDS Outcomes Model does not directly address aspects of the treatments under consideration, for example the direct utility effects from weight loss or weight gain, severe hypoglycaemic events and the fear of severe hypoglycaemic events. Also, small differences in QALYs among the drugs lead to fluctuations in incremental cost-effectiveness ratios. Exenatide, the gliptins and detemir were all clinically effective. The long-acting insulin analogues glargine and detemir appeared to have only slight clinical advantages over NPH, but had much higher costs and did not appear to be cost-effective as first-line insulins for type 2 diabetes. Neither did exenatide appear to be cost-effective compared with NPH but, when used as third drug after failure of dual oral combination therapy, exenatide appeared cost-effective relative to glargine in this analysis. The gliptins are similar to the glitazones in glycaemic control and costs, and appeared to have fewer long-term side effects. Therefore, it appears, as supported by recent NICE guidelines, that NPH should be the preferred first-line insulin for the treatment of type 2 diabetes. More economic analysis is required to establish when it becomes cost-effective to switch from NPH to a long-acting analogue. Also, long-term follow-up studies of exenatide and the gliptins, and data on combined insulin and exenatide treatment, would be useful.


Next-generation sequencing of nine atrial fibrillation candidate genes identified novel de novo mutations in patients with extreme trait of atrial fibrillation.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Genome-wide association studies (GWAS) have identified common variants in nine genomic regions associated with AF (KCNN3, PRRX1, PITX2, WNT8A, CAV1, C9orf3, SYNE2, HCN4 and ZFHX3 genes); however, the genetic variability of these risk variants does not explain the entire genetic susceptibility to AF. Rare variants missed by GWAS may also contribute to genetic risk of AF. We used an extreme trait design to sequence carefully selected probands with extreme phenotypes and their unaffected parents to identify rare de novo variants or mutations. Based on the hypothesis that common and rare variants may colocate in the same disease susceptibility gene, we used next-generation sequencing to sequence these nine published AF susceptibility genes identified by GWAS (a total of 179 exons) in 20 trios, 200 unrelated patients with AF and 200 non-AF controls. We identified a novel mutation in the 5' untranslated region of the PITX2 gene, which localised in the transcriptionally active enhancer region. We also identified one missense exon mutation in KCNN3, two in ZFHX3 and one in SYNE2. None of these mutations were present in other unrelated patients with AF, healthy controls, unaffected parents and are thus novel and de novo (p<10(-4)). Functional study showed that the mutation in the 5' untranslated region of the PITX2 gene significantly downregulated PITX2 expression in atrial myocytes, either in basal condition or during rapid pacing. In silico analysis showed that the missense mutation in ZFHX3 results in damage of the ZFHX3 protein structure. The genetic architecture of subjects with extreme phenotypes of AF is similar to that of rare or Mendelian diseases, and mutations may be the underlying cause.


Composition of archaeal, bacterial, and eukaryal RuBisCO genotypes in three Western Pacific arc hydrothermal vent systems.
We studied the diversity of all forms of the RuBisCO large subunit-encoding gene cbbL in three RuBisCO uncharacterized hydrothermal vent communities. This diversity included the archaeal cbbL and the forms IC and ID, which have not previously been studied in the deep-sea environment, in addition to the forms IA, IB and II. Vent plume sites were Fryer and Pika in the Mariana arc and the Suiyo Seamount, Izu-Bonin, Japan. The cbbL forms were PCR amplified from plume bulk microbial DNA and then cloned and sequenced. Archaeal cbbL was detected in the Mariana samples only. Both forms IA and II were amplified from all samples, while the form IC was amplified only from the Pika and Suiyo samples. Only the Suiyo sample showed amplification of the form ID. The form IB was not recorded in any sample. Based on rarefaction analysis, nucleotide diversity and average pairwise difference, the archaeal cbbL was the most diverse form in Mariana samples, while the bacterial form IA was the most diverse form in the Suiyo sample. Also, the Pika sample harbored the highest diversity of cbbL phylogenetic lineages. Based on pairwise reciprocal library comparisons, the Fryer and Pika archaeal cbbL libraries showed the most significant difference, while Pika and Suiyo showed the highest similarity for forms IA and II libraries. This suggested that the Fryer supported the most divergent sequences. All archaeal cbbL sequences formed unique phylogenetic lineages within the branches of anaerobic thermophilic archaea of the genera Pyrococcus, Archaeoglobus, and Methanococcus. The other cbbL forms formed novel phylogenetic clusters distinct from any recorded previously in other deep-sea habitats. This is the first evidence for the diversity of archaeal cbbL in environmental samples.


Task relevance differentially shapes ventral visual stream sensitivity to visible and invisible faces.
Top-down modulations of the visual cortex can be driven by task relevance. Yet, several accounts propose that the perceptual inferences underlying conscious recognition involve similar top-down modulations of sensory responses. Studying the pure impact of task relevance on sensory responses requires dissociating it from the top-down influences underlying conscious recognition. Here, using visual masking to abolish perceptual consciousness in humans, we report that functional magnetic resonance imaging (fMRI) responses to invisible faces in the fusiform gyrus are enhanced when they are task-relevant, but suppressed when they are task-irrelevant compared to other object categories. Under conscious perceptual conditions, task-related modulations were also present but drastically reduced, with visible faces always eliciting greater activity in the fusiform gyrus compared to other object categories. Thus, task relevance crucially shapes the sensitivity of fusiform regions to face stimuli, leading from enhancement to suppression of neural activity when the top-down influences accruing from conscious recognition are prevented.


Gene expression dosage regulation in an allopolyploid fish.
How allopolyploids are able not only to cope but profit from their condition is a question that remains elusive, but is of great importance within the context of successful allopolyploid evolution. One outstanding example of successful allopolyploidy is the endemic Iberian cyprinid Squalius alburnoides. Previously, based on the evaluation of a few genes, it was reported that the transcription levels between diploid and triploid S. alburnoides were similar. If this phenomenon occurs on a full genomic scale, a wide functional ''diploidization'' could be related to the success of these polyploids. We generated RNA-seq data from whole juvenile fish and from adult livers, to perform the first comparative quantitative transcriptomic analysis between diploid and triploid individuals of a vertebrate allopolyploid. Together with an assay to estimate relative expression per cell, it was possible to infer the relative sizes of transcriptomes. This showed that diploid and triploid S. alburnoides hybrids have similar liver transcriptome sizes. This in turn made it valid to directly compare the S. alburnoides RNA-seq transcript data sets and obtain a profile of dosage responses across the S. alburnoides transcriptome. We found that 64% of transcripts in juveniles' samples and 44% in liver samples differed less than twofold between diploid and triploid hybrids (similar expression). Yet, respectively 29% and 15% of transcripts presented accurate dosage compensation (PAA/PA expression ratio of 1 instead of 1.5). Therefore, an exact functional diploidization of the triploid genome does not occur, but a significant down regulation of gene expression in triploids was observed. However, for those genes with similar expression levels between diploids and triploids, expression is not globally strictly proportional to gene dosage nor is it set to a perfect diploid level. This quantitative expression flexibility may be a strong contributor to overcome the genomic shock, and be an immediate evolutionary advantage of allopolyploids.


Assessment of Tamsulosin 0.2 mg for Symptomatic Bladder Outlet Obstruction Secondary to Benign Prostatic Enlargement: Data from a Korean Multicenter Cross-Sectional Study.
To estimate efficacy and treatment satisfaction with tamsulosin 0.2 mg in patients with symptomatic bladder outlet obstruction secondary to benign prostatic enlargement and lower urinary tract symptoms in relation to personal satisfaction. The study was conducted in 1,260 subjects who were asked to fill in detailed questionnaires designed to evaluate their satisfaction with the treatment and symptom improvement 8 weeks after receiving tamsulosin 0.2 mg. After being treated with tamsulosin 0.2 mg for 8 weeks, the International Prostate Symptom Score (IPSS) score improved significantly. Among the 1,260 patients, 813 (64.52%) were satisfied, while 447 (35.48%) were dissatisfied with tamsulosin 0.2 mg. The reasons for patient dissatisfaction were efficacy problems (79.87%) and side effects (4.25%). Treatment satisfaction was affected by age, underlying medical disease and baseline IPSS severity (p = 0.020, 0.0427 and <0.001, respectively), but only age and baseline IPSS were risk factors for dissatisfaction. Tamsulosin 0.2 mg was effective in symptomatic improvement, but a relatively high proportion of patients were dissatisfied with the treatment. Efficacy problems were selected by patients as the main reason for dissatisfaction. It is also significant to note that the degree of satisfaction was related to age and baseline IPSS severity.


Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care nephrology Italian collaborative effort (NEFROINT).
Acute kidney injury (AKI) is an independent risk factor for mortality in critically ill patients whose epidemiology has been made unclear in the past by the use of different definitions across various studies. The RIFLE consensus definition has provided a unifying definition for AKI leading to large retrospective studies in different countries. The present study is a prospective observational multicenter study designed to prospectively evaluate all incident admissions in 10 Intensive Care Units (ICUs) in Italy and the relevant epidemiology of AKI. A simple user-friendly web-based data collection tool was created with the scope to serve for this study and to facilitate future multicenter collaborative efforts. We enrolled 601 consecutive patients into the study; 25 patients with End-Stage Renal Disease were excluded leaving 576 patients for analysis. The median age was 66 (IQR 53-76) years, 59.4% were male, while median SAPS II and APACHE II scores were 43 (IQR 35-54) and 18 (IQR 13-24), respectively. The most common diagnostic categories for ICU admission were: respiratory (27.4%), followed by neurologic (17%), trauma (14.4%), and cardiovascular (12.1%). Crude ICU and hospital mortality were 21.7% and median ICU length of stay was 5 days (IQR 3, 14). Of 576 patients, 246 patients (42.7%) had AKI within 24 hours of ICU admission while 133 developed new AKI later during their ICU stay. RIFLE-initial class was Risk in 205 patients (54.1%), Injury in 99 (26.1%) and Failure in 75 (19.8%). Progression of AKI to a worse RIFLE class was seen in 114 patients (30.8% of AKI patients). AKI patients were older, with higher frequency of common risk factors. 116 AKI patients (30.6%) fulfilled criteria for sepsis during their ICU stay, compared to 33 (16.7%) of non-AKI patients (P<0.001). 48 patients (8.3%) were treated with renal replacement therapy (RRT) in the ICU. Patients were started on RRT a median of 2 (IQR 0-6) days after ICU admission. Among AKI patients, they were started on RRT a median of 1 (IQR 0-4) days after fulfilling criteria for AKI. Median duration of RRT was 5 (IQR 2-10) day. AKI patients had a higher crude ICU mortality (28.8% vs. non-AKI 8.1%, P<0.001) and longer ICU length of stay (median 7 days vs. 3 days [non-AKI], P<0.001). Crude ICU mortality and ICU length of stay increased with greater severity of AKI. Two hundred twenty five patients (59.4% of AKI patients) had complete recovery of renal function, with a SCr at time of ICU discharge which was ≤120% of baseline; an additional 51 AKI patients (13.5%) had partial renal recovery, while 103 (27.2%) had not recovered renal function at the time of death or ICU discharge. Septic patients had more severe AKI, and were more likely to receive RRT with less frequency of renal function recovery. Patients with sepsis had higher ICU mortality and longer ICU stay. The study confirms previous analyses describing RIFLE as an optimal classification system to stage AKI severity. AKI is indeed a deadly complication for ICU patients where the level of severity correlated with mortality and length of stay. The tool developed for data collection resulted user friendly and easy to implement. Some of its features including a RIFLE class alert system, may help the treating physician to collect systematically AKI data in the ICU and possibly may guide specific decision on the institution of renal replacement therapy.


Minority women victims of recent sexual violence: disparities in incident history.
The aims of this descriptive study were to (1) describe assault and care characteristics and (2) determine differences in assault and care characteristics between black women and white women who sought emergency care following sexual violence. A retrospective, cross-sectional design was used to examine forensic examination data characterizing the incident history reported by women victims of sexual violence at the time of a forensic nurse examination. Examinations occurred at an urban university-affiliated hospital emergency department (ED) over a 2-year period. Of the women (n = 173) seeking care in the ED, 58.4% were black and 41.6% were white. When compared with white women, black women were more likely to have weapons used in their assaults (42.6% vs. 16.7%, p < 0.00) and to be assaulted in the city rather than the suburbs (82.8% vs. 56.5%, p < 0.00). In general, substance use prior to the assault was reported to have occurred in 49.1% of the victims and 41% of the assailants; however, differences existed in the type and pattern of substance use by race/ethnicity. Black victims were more likely to report use of illicit drugs (28.7% vs. 12.5%, p = 0.01). White women were more likely than black women to report personal alcohol use prior to their assault, with significant differences for drinking by victims (47.2% vs. 23.8%, p = 0.01) or assailant use of alcohol (47.2% vs. 23.8%, p = 0.00). White women were more likely than black women to report both they and the assailant had used some type of substance (38.9 vs. 21.8, p = 0.01). Black women were more likely to arrive to the ED via EMS services (45.5% vs. 29.2%, p = 0.03). There were no reported differences in care characteristics by race. Findings from this study suggest that differences exist in assault characteristics between black and white women. Use of substances, including alcohol, plays an important role in sexual violence in women and should be a focus of preventive intervention initiatives when conducting a forensic examination. Both coordinated responses and comprehensive, individualized care by specially trained providers are important in the emergency care of minority women who are victims of recent sexual violence.


Effect of liver failure on the ventilatory response to hypoxia in man and the goat.
1. The ventilatory responses to transient and steady-state hypoxia were measured in ten patients with hepatic cirrhosis and in ten healthy control subjects. Successive measurements of these responses were also obtained in six goats before and after the experimental production of liver failure. Changes in the effect of steady-state hypoxia on the ventilatory response to hypercapnia were evaluated by successive studies in another goat. 2. In spite of a respiratory alkalosis during liver failure, the response to transient hypoxia was greater in the patients than in the control subjects. This response was increased after the onset of liver failure in all the goats. 3. In healthy humans and goats the responses to transient and steady-state hypoxia were similar in magnitude. During liver failure there was a disparity between the size of these responses, since the ventilatory increment evoked by steady-state hypoxia was unchanged in spite of the increase in response to transient hypoxia. Steady-state hypoxia consistently enhanced the ventilatory response to hypercapnia in a healthy goat, but frequently depressed the response to hypercapnia during liver failure. 4. The findings suggest that liver failure heightens the sensitivity of the peripheral chemoreceptors to the hypoxic stimulus, but may increase the tendency of the medullary centres to become depressed in hypoxia.


Alcohol intake and Parkinson's disease risk in the million women study.
Alcohol intake may be associated with a lower risk of Parkinson's disease (PD), but findings from previous studies have been inconclusive. To determine the association between alcohol intake and PD risk in the Million Women Study, a large, prospective study of women in the UK. Between 1996 and 2001, approximately 1.3 million women in the UK, mean age 56 (standard deviation, 5) years, were recruited into the Million Women Study. Information on alcohol intake, lifestyle factors, and medical history was collected at recruitment by questionnaire. Information on incident cases of PD was ascertained by record linkage to national hospital admission records and death registrations. We estimated multivariable-adjusted relative risks and corresponding 95% confidence intervals using Cox proportional hazards models according to categories of alcohol intake. During an average of 17.9 years of follow-up, 11,009 women had a new record of PD among 1,309,267 women. In drinkers, the multivariable-adjusted relative risk comparing women who drank more than 14 drinks of alcohol per week with women who drank 1 to 2 drinks of alcohol per week was 0.99 (95% confidence interval: 0.90, 1.10). Results did not materially change after excluding the first 10 years of follow-up (relative riskadjusted = 1.01; 95% confidence interval: 0.90, 1.13). There were no significant trends in alcohol-related PD risk among never smokers. Additionally, examining this association by type of alcohol intake also yielded null findings. These results do not support an association between alcohol intake and PD risk in women. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Enhanced production and dendritic growth of new dentate granule cells in the middle-aged hippocampus following intracerebroventricular FGF-2 infusions.
Declined production and diminished dendritic growth of new dentate granule cells in the middle-aged and aged hippocampus are correlated with diminished concentration of fibroblast growth factor-2 (FGF-2). This study examined whether increased FGF-2 concentration in the milieu boosts both production and dendritic growth of new dentate granule cells in the middle-aged hippocampus. The FGF-2 or vehicle was infused into the posterior lateral ventricle of middle-aged Fischer (F)344 rats for 2 weeks using osmotic minipumps. New cells born during the first 12 days of infusions were labeled via daily intraperitoneal injections of 5'-bromodeoxyuridine (BrdU) and analysed at 10 days after the last BrdU injection. Measurement of BrdU(+) cells revealed a considerably enhanced number of new cells in the subgranular zone (SGZ) and granule cell layer (GCL) of the dentate gyrus (DG) ipsilateral to FGF-2 infusions. Characterization of beta-III tubulin(+) neurons among newly born cells suggested an increased addition of new neurons to the SGZ/GCL ipsilateral to FGF-2 infusions. Quantification of DG neurogenesis at 8 days post-infusions via doublecortin (DCX) immunostaining also revealed the presence of an enhanced DG neurogenesis ipsilateral to FGF-2 infusions. Furthermore, DCX(+) neurons in FGF-2-infused rats exhibited enhanced dendritic growth compared with their counterparts in vehicle-infused rats. Thus, subchronic infusion of FGF-2 is efficacious for stimulating an enhanced DG neurogenesis from neural stem/progenitor cells in the middle-aged hippocampus. As dentate neurogenesis is important for hippocampal-dependent learning and memory and DG long-term potentiation, strategies that maintain increased FGF-2 concentration during ageing may be beneficial for thwarting some of the age-related cognitive impairments.


Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution.
The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.


Hedgehog controls hepatic stellate cell fate by regulating metabolism.
The pathogenesis of cirrhosis, a disabling outcome of defective liver repair, involves deregulated accumulation of myofibroblasts derived from quiescent hepatic stellate cells (HSCs), but the mechanisms that control transdifferentiation of HSCs are poorly understood. We investigated whether the Hedgehog (Hh) pathway controls the fate of HSCs by regulating metabolism. Microarray, quantitative polymerase chain reaction, and immunoblot analyses were used to identify metabolic genes that were differentially expressed in quiescent vs myofibroblast HSCs. Glycolysis and lactate production were disrupted in HSCs to determine if metabolism influenced transdifferentiation. Hh signaling and hypoxia-inducible factor 1α (HIF1α) activity were altered to identify factors that alter glycolytic activity. Changes in expression of genes that regulate glycolysis were quantified and localized in biopsy samples from patients with cirrhosis and liver samples from mice following administration of CCl(4) or bile duct ligation. Mice were given systemic inhibitors of Hh to determine if they affect glycolytic activity of the hepatic stroma; Hh signaling was also conditionally disrupted in myofibroblasts to determine the effects of glycolytic activity. Transdifferentiation of cultured, quiescent HSCs into myofibroblasts induced glycolysis and caused lactate accumulation. Increased expression of genes that regulate glycolysis required Hh signaling and involved induction of HIF1α. Inhibitors of Hh signaling, HIF1α, glycolysis, or lactate accumulation converted myofibroblasts to quiescent HSCs. In diseased livers of animals and patients, numbers of glycolytic stromal cells were associated with the severity of fibrosis. Conditional disruption of Hh signaling in myofibroblasts reduced numbers of glycolytic myofibroblasts and liver fibrosis in mice; similar effects were observed following administration of pharmacologic inhibitors of Hh. Hedgehog signaling controls the fate of HSCs by regulating metabolism. These findings might be applied to diagnosis and treatment of patients with cirrhosis.


Exposure to dideoxynucleosides is reflected in lowered mitochondrial DNA in subcutaneous fat.
Nucleoside reverse transcriptase inhibitors (NRTIs), particularly dideoxynucleoside analogs (ddNs), used in the treatment of HIV, inhibit mitochondrial DNA polymerase gamma in vitro. Mitochondrial DNA (mtDNA) depletion is proposed as the underlying mechanism of many of the in vivo side effects of these agents. A reliable and valid laboratory test to detect this is not yet available. The objective of this study was to correlate tissue mtDNA quantification in HIV-infected patients with exposure to nucleoside analogs. 60 HIV-infected adults underwent detailed clinical assessment and blood and tissue sampling. Clinical and antiretroviral treatment details were correlated with results of plasma lactate assays, and real-time polymerase chain reaction quantification of mtDNA in peripheral blood mononuclear cells (PBMCs) and subcutaneous fat from the lower limb. Forty-nine (82%) subjects were on combination antiretroviral therapy. Of these, 33 (55%) were currently receiving one or more ddNs (stavudine, didanosine, or zalcitabine). mtDNA in subcutaneous fat was lower in subjects currently on ddNs than in those not taking ddNs (mean [log10] 2.47 vs. 2.74, p =.002). Plasma lactate was somewhat higher in subjects currently taking ddNs than those on no antiretroviral treatment (median 1.5 vs. 1.0, p =.03), but was not significantly different in either of these groups compared with subjects on other NRTIs. mtDNA in PBMCs did not vary with treatment status. mtDNA in subcutaneous fat was significantly reduced in patients currently taking ddNs. mtDNA in PBMCs was independent of patient exposure to NRTIs.


LC-MS based stability-indicating method for studying the degradation of lonidamine under physical and chemical stress conditions.
Lonidamine is a hexokinase II inhibitor, works as an anticancer molecule, and is extensively explored in clinical trials. Limited information prevails about the stability-indicating methods which could determine the forced degradation of lonidamine under stressed conditions. Hence, we report the use of a rapid, sensitive, reproducible, and highly accurate liquid chromatography and mass spectrometry method to analyze lonidamine degradation. The Xbridge BEH shield reverse phase C18 column (2.5 μm, 4.6 × 75 mm) using isocratic 50:50 water: acetonitrile with 0.1% formic acid can detect lonidamine with help of mass spectrometer in tandem with an ultraviolet (UV) detector at 260 nm wavelength. A linear curve with r2 > 0.99 was obtained for tandem liquid chromatography-mass spectrometry (LC-MS)-UV based detections. This study demonstrated (in the present set up of isocratic elution) that LC-MS based detection has a relatively high sensitivity (S/N (10 ng/mL): 220 and S/N (20 ng/mL): 945) and accuracy at lower detection and quantitation levels, respectively. In addition to developing the LC-MS method, we also report that the current method is stability-indicating and shows that lonidamine gets degraded over time under all three stress conditions; acidic, basic, and oxidative. LC-MS based quantitation of lonidamine proved to be a better method compared to high-performance liquid chromatography (HPLC)-UV detections for mapping lonidamine degradation. This is the first report on the stability-indicating method for studying the forced degradation of lonidamine using LC-MS method.


Attention alters decision criteria but not appearance: a reanalysis of Anton-Erxleben, Abrams, and Carrasco (2010).
Paying attention to a stimulus affords it many behavioral advantages, but whether attention also changes its subjective appearance is controversial. K. A. Schneider and M. Komlos (2008) demonstrated that the results of previous studies suggesting that attention increased perceived contrast could also be explained by a biased decision mechanism. This bias could be neutralized by altering the methodology to ask subjects whether two stimuli were equal in contrast or not rather than which had the higher contrast. K. Anton-Erxleben, J. Abrams, and M. Carrasco (2010) claimed that, even using this equality judgment, attention could still be shown to increase perceived contrast. In this reply, we analyze their data and conclude that the effects that they reported resulted from fitting symmetric functions that poorly characterized the individual subject data, which exhibited significant asymmetries between the high- and low-contrast tails. The strength of the effect attributed to attentional enhancement in each subject was strongly correlated with this skew. By refitting the data with a response model that included a non-zero asymptotic response in the low-contrast regime, we show that the reported attentional effects are better explained as changes in subjective criteria. Thus, the conclusion of Schneider and Komlos that attention biases the decision mechanism but does not alter appearance is still valid and is in fact supported by the data from Anton-Erxleben et al.


ORIGINAL ARTICLE: Taxonomy and diversity of Afroalpine Chironomidae (Insecta: Diptera) on Mount Kenya and the Rwenzori Mountains, East Africa.
Aim Anthropogenic climate change is expected to result in the complete loss of glaciers from the high mountains of tropical Africa, with profound impacts on the hydrology and ecology of unique tropical cold-water lakes located downstream from them. This study examines the biodiversity of Chironomidae (Insecta: Diptera) communities in these scarce Afroalpine lake systems, in order to determine their uniqueness in relation to lowland African lakes and alpine lakes in temperate regions, and to evaluate the potential of Afroalpine Chironomidae as biological indicators to monitor future changes in the ecological integrity of their habitat. Location Mount Kenya (Kenya) and Rwenzori Mountains (Uganda). Methods The species composition of Afroalpine chironomid communities was assessed using recent larval death assemblages extracted from the surface sediments of 11 high-mountain lakes between 2900 and 4575 m. Results were compared with similar faunal data from 68 East African lakes at low and middle elevation (750-2760 m), and with literature records of Chironomidae species distribution in sub-Saharan Africa, the Palaearctic region and elsewhere. All recovered taxa were fully described and illustrated. Results The 11-lake analysis yielded 1744 subfossil chironomid larvae belonging to 16 distinct taxa of full-grown larvae, and three taxa of less differentiated juveniles. Eleven of these 16 are not known to occur in African lakes at lower elevation, and eight taxa (or 50% of total species richness) appear restricted to the specific habitat of cold lakes above 3900 m, where night-time freezing is frequent year-round. The faunal transition zone coincides broadly with the Ericaceous zone of terrestrial vegetation (c. 3000-4000 m). Snowline depression during the Quaternary ice ages must have facilitated dispersion of cold-stenothermous species among the high mountains of equatorial East Africa, but less so from or to the Palaearctic region via the Ethiopian highlands. Main conclusions Chironomid communities in glacier-fed lakes on Africa's highest mountains are highly distinct from those of lowland African lakes, and potentially unique on a continental scale. By virtue of excellent preservation and their spatial and temporal integration of local community dynamics, chironomid larval death assemblages extracted from surface sediments are powerful biological indicators for monitoring the hydrological and ecological changes associated with the current retreat and loss of Africa's glaciers.


Curcumol inhibits the proliferation and metastasis of melanoma via the miR-152-3p/PI3K/AKT and ERK/NF-κB signaling pathways.
Melanoma is the most aggressive and treatment-resistant form of skin cancer. Curcumol is a Chinese medicinal herb traditionally used as a cancer remedy. However, the molecular mechanisms underlying the anticancer activity of curcumol in melanoma remains largely unknown. In the present study, we observed that Curcumol decreased mouse melanoma B16 cell proliferation and migration. The xenograft tumor assay showed that curcumol reduced melanoma volume and lung metastasis. Curcumol upregulated the expression of E-cadherin and downregulated the expression of N-cadherin, MMP2 and MMP9 in mouse melanoma B16 cell. Western blot analysis revealed that curcumol reduced the translocation of p65 to the nucleus and decreased p-ERK. Furthermore, curcumol attenuated c-MET, P13K and p-AKT protein expression and upregulated miR-152-3p gene expression. The dual-luciferase reporter assay indicated that c-MET was a target gene of miR-152-3p. Reduced expression of miR-152-3p partially attenuated the effect of curcumol on mouse melanoma B16 cell proliferation and migration. The decrease in c-MET, P13K and p-AKT protein expression following curcumol treatment in mouse melanoma B16 cells was notably attenuated by the miR-152-3p inhibitor. Taken together, our findings suggested that curcumol attenuated melanoma progression and concomitantly suppressed ERK/NF-κB signaling and promoted miR-152-3p expression to inactivate the c-MET/PI3K/AKT signaling pathway.


Direct demonstration of increased expression of Thomsen-Friedenreich (TF) antigen in colonic adenocarcinoma and ulcerative colitis mucin and its concealment in normal mucin.
Increased binding of the lectin peanut agglutinin is a common feature in epithelial malignancy and hyperplasia. This may have considerable functional importance in the intestine by allowing interaction between the epithelium and mitogenic lectins of dietary or microbial origin. Peanut agglutinin binds the disaccharide Thomsen-Friedenreich (TF, T or core 1) blood group antigen, Gal beta (1-3) GalNAc alpha-, but is not totally specific for this site. Consequently, there has been controversy about the presence of this structure in colon cancer; studies with anti-TF monoclonal antibodies have failed to detect it. We have examined the presence of TF antigen in colonic mucus glycoprotein (mucin) using endo-alpha-N-acetylgalactosaminidase (O-Glycanase), which specifically catalyzes the hydrolysis of TF antigen from glycoconjugates. Samples of adenocarcinoma, inflammatory bowel disease (ulcerative colitis), and normal mucin were treated with O-glycanase, the liberated disaccharide was separated from the glycoprotein and analyzed using dual CarboPac PA-100 column high performance anion-exchange chromatography coupled with pulsed amperometric detection. O-Glycanase treatment released increased amounts of TF antigen from both colonic adenocarcinoma (8.0 +/- 3.9 ng/micrograms protein, n = 11; P < 0.0001 ANOVA) and ulcerative colitis mucin (3.3 +/- 0.3 ng/micrograms protein, n = 5; P = 0.04) compared with mucin samples from histologically normal mucosa distant from carcinoma (1.5 +/- 1.1 ng/micrograms protein, n = 9). However, after mild acid treatment to remove sialic acids and fucose, releasable TF antigen was increased in all nine of these histologically normal mucin samples (5.5 +/- 2.6 ng/micrograms protein, P < 0.0002). We conclude that TF antigen is an oncofetal antigen which is expressed in colon cancer, but is concealed by further glycosylation (sialylation and/or fucosylation) in the normal colonic mucosa.


Effect of a dental water jet with orthodontic tip on plaque and bleeding in adolescent patients with fixed orthodontic appliances.
Effective self-care is difficult for people with orthodontic appliances because of the inherent design of brackets and archwires. It is not uncommon to have increases in plaque and gingivitis after placement of fixed appliances. The purpose of this study was to evaluate the effect of using a dental water jet (DWJ) with a specialized tip (orthodontic) on plaque and bleeding in adolescent orthodontic patients with fixed appliances. One hundred six subjects were enrolled in this single blind, parallel clinical study. They were randomly assigned to 1 of 3 treatment groups: group 1, once daily irrigation with a DWJ and orthodontic jet tip plus a manual toothbrush; group 2, once daily flossing (FL) plus a manual toothbrush; group 3, manual toothbrush (MT) only. Plaque index (PI) and bleeding index (BI) scores were recorded at baseline, and at 2 and 4 weeks. All groups showed statistically significant reductions in PI (whole mouth and interproximal) at 2 and 4 weeks (P <.001). In group 1, the DWJ was statistically more effective at reducing whole-mouth and interproximal plaque than the methods in the other groups (P >.001) at both 2 and 4 weeks, whereas the FL protocol in group 2 was significantly more effective than the MT protocol in group 3 at 4 weeks (P =.025) for whole-mouth plaque and at 2 and 4 weeks (P = .011 and P = .028, respectively) for interproximal plaque. All groups showed statistically significant reductions in BI (whole mouth and interproximal) at 2 and 4 weeks (P <.001). The DWJ in group 1 was statistically more effective at reducing whole-mouth bleeding than the protocols of the other groups at 2 and 4 weeks (P <.001), and the FL was statistically more effective than the MT at both times (P <.001). Both the DWJ and the FL were significantly more effective than the MT at 2 weeks (P <.001 and P <.016, respectively) for interproximal bleeding, but there were no differences between the groups at 4 weeks. A DWJ with a specialized orthodontic jet tip is effective for adolescents in fixed orthodontic appliances; it demonstrated beneficial results for the reduction of plaque and bleeding.


Learning curve for the anterior approach total hip arthroplasty.
The anterior approach to total hip arthroplasty has the advantages of using intermuscular and internervous planes, but it is technically demanding. We evaluated the learning curve for this approach with regard to operative parameters and immediate outcomes. From November 2005 through May 2007, 73 patients underwent 81 consecutive primary anterior-approach total hip arthroplasties. We grouped the hips into three consecutive groups of 20 and one of 21, and surgical and fluoroscopy times, estimated blood loss, intraoperative and postoperative complications, patient comorbidities, component position, and leg-length discrepancy were compared (statistical significance, p < 0.05). Comparing Groups 1 and 4, there were only two significant differences: operative time, 124 to 98 minutes, respectively, and estimated blood loss, 596 to 347 mL, respectively. Proficiency improved after Group 2 (40 cases) and was more marked after Group 3 (60 cases), with no major complications. Surgeons considering this approach should expect a substantial learning period.


Fixation to features and neural processing of facial expressions in a gender discrimination task.
Early face encoding, as reflected by the N170 ERP component, is sensitive to fixation to the eyes. Whether this sensitivity varies with facial expressions of emotion and can also be seen on other ERP components such as P1 and EPN, was investigated. Using eye-tracking to manipulate fixation on facial features, we found the N170 to be the only eye-sensitive component and this was true for fearful, happy and neutral faces. A different effect of fixation to features was seen for the earlier P1 that likely reflected general sensitivity to face position. An early effect of emotion (∼120 ms) for happy faces was seen at occipital sites and was sustained until ∼350 ms post-stimulus. For fearful faces, an early effect was seen around 80 ms followed by a later effect appearing at ∼150 ms until ∼300 ms at lateral posterior sites. Results suggests that in this emotion-irrelevant gender discrimination task, processing of fearful and happy expressions occurred early and largely independently of the eye-sensitivity indexed by the N170. Processing of the two emotions involved different underlying brain networks active at different times.


Heavy-Metal-Free Flexible Hybrid Polymer-Nanocrystal Photodetectors Sensitive to 1.5 μm Wavelength.
Photodetection in the short-wave infrared (SWIR) wavelength window represents one of the core technologies allowing for many applications. Most current photodetectors suffer from high cost due to the epitaxial growth requirements and the ecological issue due to the use of highly toxic heavy-metal elements. Toward alternative SWIR photodetection strategies, in this work, high-performance heavy-metal-free flexible photodetectors sensitive to λ = 1.5 μm photons are presented based on the formation of a solution-processed hybrid composed of a conjugated diketopyrrolopyrrole-base polymer/PC70BM bulk heterojunction organic host together with inorganic guest NaYF4:15%Er3+ upconversion nanoparticles (UCNPs). Under the illumination of λ = 1.5 μm SWIR photons, optimized hybrid bulk-heterojunction (BHJ)/UCNP photodetectors exhibit a photoresponsivity of 0.73 and 0.44 mA/W, respectively, for devices built on rigid indium tin oxide (ITO)/glass and flexible ITO/polyethylene terephthalate substrates. These hybrid photodetectors are capable of performing SWIR photodetection with a fast operation speed, characterized by a short photocurrent rise time down to 80 μs, together with an excellent mechanical robustness for flexible applications. Exhibiting simultaneously multiple advantages including solution-processability, flexibility, and the absence of toxic heavy metal elements together with a fast operation speed and good photoresponsivity, these hybrid BHJ(DPPTT-T/PC70BM)/UCNP photodetectors are promising candidates for next-generation low-cost and high-performance SWIR photodetectors.


Narrow-Line Cooling and Imaging of Ytterbium Atoms in an Optical Tweezer Array.
Engineering controllable, strongly interacting many-body quantum systems is at the frontier of quantum simulation and quantum information processing. Arrays of laser-cooled neutral atoms in optical tweezers have emerged as a promising platform because of their flexibility and the potential for strong interactions via Rydberg states. Existing neutral atom array experiments utilize alkali atoms, but alkaline-earth atoms offer many advantages in terms of coherence and control, and also open the door to new applications in precision measurement and time keeping. In this Letter, we present a technique to trap individual alkaline-earth-like ytterbium (Yb) atoms in optical tweezer arrays. The narrow ^{1}S_{0}-^{3}P_{1} intercombination line is used for both cooling and imaging in a magic-wavelength optical tweezer at 532 nm. The low Doppler temperature allows for imaging near the saturation intensity, resulting in a very high atom detection fidelity. We demonstrate the imaging fidelity concretely by observing rare (<1 in 10^{4} images) spontaneous quantum jumps into and out of a metastable state. We also demonstrate stochastic loading of atoms into a two-dimensional, 144-site tweezer array. This platform will enable advances in quantum information processing, quantum simulation, and precision measurement. The demonstrated narrow-line Doppler imaging may also be applied in tweezer arrays or quantum gas microscopes using other atoms with similar transitions, such as erbium and dysprosium.


Barriers to influenza immunization in a low-income urban population.
Although influenza immunization significantly reduces mortality from influenza, over one third of elderly Americans are not immunized each year. Low rates of immunization are particularly concerning among African-American low-income populations. Preliminary interviews suggested that fear of undisclosed ingredients in the influenza vaccine may impede vaccine acceptance in this vulnerable population. To assess the role of concern about vaccine contents and other factors in the use of influenza immunization among a predominantly African-American low-income urban population. Cross-sectional, health-system-population-based, telephone survey of a random sample of West Philadelphia residents aged > or =65 years. Of 659 eligible individuals, 486 (73.8%) were successfully interviewed. Concern about undisclosed shot contents was reported by 132 (20%) respondents and was inversely associated with vaccine receipt (OR 0. 49, 95% CI 0.26-0.91). This association was similar among African Americans and Caucasians. In addition, receipt of influenza vaccine was inversely associated with belief that immunization is inconvenient (OR 0.14, 95% CI 0.05-0.36), belief that immunization is painful (OR 0.21, 95% CI 0.08-0.54), and history of previous side effects (OR 0.33, 95% CI 0.18-0.60), and positively associated with physician recommendation (OR 3.22, 95% CI 1.76-5.93). In a low-income urban population, concern about undisclosed vaccine contents appears to impede acceptance of influenza immunization among both African Americans and Caucasians. Directly addressing this concern offers a new approach to increasing immunization in this vulnerable population.


On the origin of pattern and form in early Metazoans.
The 'Cambrian explosion', about 540 million years ago, may have occurred within 10 to 50 million years. Almost all of the modern phyla, a very restricted group and many groups that may represent extinct phyla, suddenly appear near that time in the fossil record. Numerous extensive periods of mass extinction since that time led to no new phyla. This is taken as an impetus to examine a possible source, beyond Darwinian adaptation, of the apparently restricted number of phyla. Such a postulated constraint or restriction beyond adaptation is proposed to be based on a mutation or mutations allowing single celled or colonial precursors to begin forming into epithelial sheets and gene activation patterns of a particular kind, those giving rise to the very earliest metazoans. The interaction of signaling pathways in pairs, with different pairs acting sequentially are proposed as key to this earliest patterning, such patterning being extensively elaborated over the last approximately 550 million years. Restrictions on the very large set of possible forms and patterns on which adaptation acts are discussed.


Unusual manifestations of acute Q fever: autoimmune hemolytic anemia and tubulointerstitial nephritis.
Q fever is a worldwide zoonotic infection that caused by Coxiella burnetii, a strict intracellular bacterium. It may be manifested by some of the autoimmune events and is classified into acute and chronic forms. The most frequent clinical manifestation of acute form is a self-limited febrile illness which is associated with severe headache, muscle ache, arthralgia and cough. Meningoencephalitis, thyroiditis, pericarditis, myocarditis, mesenteric lymphadenopathy, hemolytic anemia, and nephritis are rare manifestations. Here we present a case of acute Q fever together with Coombs' positive autoimmune hemolytic anemia (AIHA) and tubulointerstitial nephritis treated with chlarithromycin, steroids and hemodialysis. Clinicians should be aware of such rare manifestations of the disease.


Acute and chronic structural effects of pilocarpine on monkey outflow tissues.
Determine the effects of supraclinical topical doses of pilocarpine on the structure of the trabecular meshwork (TM), ciliary muscle (CM), and ciliary processes in monkeys. Cynomolgus monkeys received topical pilocarpine hydrochloride doses of 1 to 2 mg unilaterally once or twice daily for 1 to 211 days. Both eyes were examined by light and electron microscopy. After 1 dose, the TM was expanded and the flow pathways open. Some elastic anterior CM tendons were disconnected from the muscle tips and/or the tips themselves were disrupted; macrophage-like cells accumulated in these regions. In eyes that had long-term treatment, scar tissue at the muscle tips and disruption of myofibrils within muscle cells indicated regions of previous disconnection. Most collagen tendons inserting into the peripheral cornea were unaffected. With increasing treatment duration in younger monkeys, there was anteroposterior shortening of Schlemm's canal, TM densification due to collapse, and increased cellularity in the subendothelial region of Schlemm's canal. TM densification and Schlemm's canal shortening were not found in older monkeys, implicating posterior movement of the elastic young limbal region induced by strong CM contraction, rather than pilocarpine toxicity. In the ciliary body we found vasodilation, Greeff's vesicles, and blood-aqueous barrier breakdown in the anterior ciliary processes and vasodilation, edema, and round-cell infiltration in the posterior pars plana. Large pilocarpine doses induce morphologic changes in the monkey anterior segment, likely consequent to intense CM contraction. Changes in the TM and Schlemm's canal are seen only in young monkeys, apparently owing to mechanical deformation of the elastic limbal region.


Interval-level measurement with visual analogue scales in Internet-based research: VAS Generator.
The present article describes VAS Generator (www.vasgenerator.net), a free Web service for creating a wide range of visual analogue scales that can be used as measurement devices in Web surveys and Web experimentation, as well as for local computerized assessment. A step-by-step example for creating and implementing a visual analogue scale with visual feedback is given. VAS Generator and the scales it generates work independently of platforms and use the underlying languages HTML and JavaScript. Results from a validation study with 355 participants are reported and show that the scales generated with VAS Generator approximate an interval-scale level. In light of previous research on visual analogue versus categorical (e.g., radio button) scales in Internet-based research, we conclude that categorical scales only reach ordinal-scale level, and thus visual analogue scales are to be preferred whenever possible.


A probabilistic model of cross-categorization.
Most natural domains can be represented in multiple ways: we can categorize foods in terms of their nutritional content or social role, animals in terms of their taxonomic groupings or their ecological niches, and musical instruments in terms of their taxonomic categories or social uses. Previous approaches to modeling human categorization have largely ignored the problem of cross-categorization, focusing on learning just a single system of categories that explains all of the features. Cross-categorization presents a difficult problem: how can we infer categories without first knowing which features the categories are meant to explain? We present a novel model that suggests that human cross-categorization is a result of joint inference about multiple systems of categories and the features that they explain. We also formalize two commonly proposed alternative explanations for cross-categorization behavior: a features-first and an objects-first approach. The features-first approach suggests that cross-categorization is a consequence of attentional processes, where features are selected by an attentional mechanism first and categories are derived second. The objects-first approach suggests that cross-categorization is a consequence of repeated, sequential attempts to explain features, where categories are derived first, then features that are poorly explained are recategorized. We present two sets of simulations and experiments testing the models' predictions about human categorization. We find that an approach based on joint inference provides the best fit to human categorization behavior, and we suggest that a full account of human category learning will need to incorporate something akin to these capabilities.


The antiquity of the Rhine River: stratigraphic coverage of the dinotheriensande (eppelsheim formation) of the Mainz Basin (Germany).
Mammalian fossils from the Eppelsheim Formation (Dinotheriensande) have been a benchmark for Neogene vertebrate palaeontology since 200 years. Worldwide famous sites like Eppelsheim serve as key localities for biochronologic, palaeobiologic, environmental, and mammal community studies. So far the formation is considered to be of early Late Miocene age (~9.5 Ma, Vallesian), representing the oldest sediments of the Rhine River. The stratigraphic unity of the formation and of its fossil content was disputed at times, but persists unresolved. Here we investigate a new fossil sample from Sprendlingen, composed by over 300 mammalian specimens and silicified wood. The mammals comprise entirely Middle Miocene species, like cervids Dicrocerus elegans, Paradicrocerus elegantulus, and deinotheres Deinotherium bavaricum and D. levius. A stratigraphic evaluation of Miocene Central European deer and deinothere species proof the stratigraphic inhomogenity of the sample, and suggest late Middle Miocene (~12.5 Ma) reworking of early Middle Miocene (~15 Ma) sediments. This results agree with taxonomic and palaeoclimatic analysis of plant fossils from above and within the mammalian assemblage. Based on the new fossil sample and published data three biochronologic levels within the Dinotheriensand fauna can be differentiated, corresponding to early Middle Miocene (late Orleanian to early Astaracian), late Middle Miocene (late Astaracian), and early Late Miocene (Vallesian) ages. This study documents complex faunal mixing of classical Dinotheriensand fauna, covering at least six million years, during a time of low subsidence in the Mainz Basin and shifts back the origination of the Rhine River by some five million years. Our results have severe implications for biostratigraphy and palaeobiology of the Middle to Late Miocene. They suggest that turnover events may be obliterated and challenge the proposed 'supersaturated' biodiversity, caused by Middle Miocene superstites, of Vallesian ecosystems in Central Europe.


Pilot study of intracranial venous physiology in craniosynostosis.
OBJECTIVE In addition to craniocerebral disproportion, other factors, such as Chiari malformation type I, obstructive sleep apnea, and venous outflow obstruction, are considered to have a role in the occurrence of intracranial hypertension in craniosynostosis. This pilot study examined cerebral venous flow velocity to better characterize the complex intracranial venous physiology of craniosynostosis. METHODS The authors performed a prospective cohort study of craniosynostosis patients (n = 34) referred to a single national (tertiary) craniofacial unit. Controls (n = 28) consisted of children who were referred to the unit's outpatient clinic and did not have craniosynostosis. Transfontanelle ultrasound scans with venous Doppler flow velocity assessment were performed at the first outpatient clinic visit and after each surgery, if applicable. Mean venous blood flow velocities of the internal cerebral vein (ICVv) and the superior sagittal sinus (SSSv) were recorded and blood flow waveform was scored. RESULTS Preoperatively, SSSv was decreased in craniosynostosis patients compared with controls (7.57 vs 11.31 cm/sec, p = 0.009). ICVv did not differ significantly between patients and controls. Postoperatively, SSSv increased significantly (7.99 vs 10.66 cm/sec, p = 0.023). Blood flow waveform analyses did not differ significantly between patients and controls. CONCLUSIONS Premature closure of cranial sutures was associated with decreased SSSv but not ICVv; indicating an effect on the superficial rather than deep venous drainage. Further Doppler ultrasound studies are needed to test the hypothesis that at an early stage of craniosynostosis pathology SSSv, but not pulsatility, is abnormal, and that abnormality in both SSSv and the superficial venous waveform reflect a more advanced stage of evolution in suture closure.


Decreased total serum adiponectin and its isoforms in women with acute ischemic stroke.
An association between cerebral infarct risk factors and serum adiponectin levels (both total and separate isoforms) has previously been identified. The aim of this study was to assess circulating levels of all forms of adiponectin in the course of an ischemic stroke. Adiponectin and its isoforms (HMW, MMW and LMW) were measured in serum samples taken from 38 women in the first 24 hours of cerebral infarct and 38 controls matched for gender, body mass index (BMI) and age. In addition, biochemical parameters (glucose, insulin, lipid profile) and clinical data (blood pressure, weight, and height) were evaluated. A significant reduction in serum levels of adiponectin and all examined fractions of this adipokine was observed in women suffering from acute ischemic stroke, compared with the matched controls. Differences in the serum adiponectin array between stroke subjects and controls were identified and further studies are required to investigate the clinical implications of this finding.


Perfusion MRI of brain tumours: a comparative study of pseudo-continuous arterial spin labelling and dynamic susceptibility contrast imaging.
The purpose of this study was to compare the non-invasive 3D pseudo-continuous arterial spin labelling (PC ASL) technique with the clinically established dynamic susceptibility contrast perfusion magnetic resonance imaging (DSC-MRI) for evaluation of brain tumours. A prospective study of 28 patients with contrast-enhancing brain tumours was performed at 3 T using DSC-MRI and PC ASL with whole-brain coverage. The visual qualitative evaluation of signal enhancement in tumour was scored from 0 to 3 (0 = no signal enhancement compared with white matter, 3 = pronounced signal enhancement with equal or higher signal intensity than in grey matter/basal ganglia). The extent of susceptibility artefacts in the tumour was scored from 0 to 2 (0 = no susceptibility artefacts and 2 = extensive susceptibility artefacts (maximum diameter > 2 cm)). A quantitative analysis was performed with normalised tumour blood flow values (ASL nTBF, DSC nTBF): mean value for region of interest (ROI) in an area with maximum signal enhancement/the mean value for ROIs in cerebellum. There was no difference in total visual score for signal enhancement between PC ASL and DSC relative cerebral blood flow (p = 0.12). ASL had a lower susceptibility-artefact score than DSC-MRI (p = 0.03). There was good correlation between DSC nTBF and ASL nTBF values with a correlation coefficient of 0.82. PC ASL is an alternative to DSC-MRI for the evaluation of perfusion in brain tumours. The method has fewer susceptibility artefacts than DSC-MRI and can be used in patients with renal failure because no contrast injection is needed.


The cervical spine of Australopithecus sediba.
Cervical vertebrae are rare in the early hominin fossil record, presenting a challenge for understanding the evolution of the neck and head carriage in hominin evolution. Here, we examine the cervical vertebrae of Australopithecus sediba, which unlike other South African taxa is known from associated cervical vertebrae. The A. sediba cervical vertebrae exhibit human-like values for wedging, pedicle cross-sectional areas, and articular facet heights, indicating reduced ventral loading relative to African apes. These features combine with a pattern of vertebral body bone distribution and caudally progressive size expansion suggesting a mode of cervical lordosis, load mitigation, and head carriage similar to humans and distinct from the cantilevered mode of head carriage of the extant African great apes. Yet these derived features in A. sediba are accompanied by ape-like vertebral body and dorsal pillar sizes, articular facet orientation, and uncinate process morphology signaling reduced lateral and rotational coupled movements between vertebral elements and indicate a considerably stiffer neck than in humans. A primitively long and horizontally-oriented C7 spinous process is likely related to a prognathic viscerocranium, although the complimentary C3 spinous process is short, implying large moments emanating from scapular and shoulder elevators rather than large muscles of head stabilization. Cross-sectional spinous process shape and robust anterior tubercles similarly signal increased arm elevation consistent with climbing behavior in corroboration with arboreal signatures previously observed in the shoulder, arms, and hand of A. sediba. Spinal canal shape and size suggests that A. sediba lacked the cervical spinal cord enlargement of Homo that confers humans with enhanced motor control to the upper limbs. The cervical spine of A. sediba thus presents a mosaic of primitive and derived characters, with anatomical features relating to neck posture and head carriage mirroring humans juxtaposed with most other aspects of functional anatomy that resemble chimpanzees.


Comparative dynamics, seasonality in transmission, and predictability of childhood infections in Mexico.
The seasonality and periodicity of infections, and the mechanisms underlying observed dynamics, can have implications for control efforts. This is particularly true for acute childhood infections. Among these, the dynamics of measles is the best understood and has been extensively studied, most notably in the UK prior to the start of vaccination. Less is known about the dynamics of other childhood diseases, particularly outside Europe and the United States. In this paper, we leverage a unique dataset to examine the epidemiology of six childhood infections - measles, mumps, rubella, varicella, scarlet fever and pertussis - across 32 states in Mexico from 1985 to 2007. This dataset provides us with a spatio-temporal probe into the dynamics of six common childhood infections, and allows us to compare them in the same setting over the same time period. We examine three key epidemiological characteristics of these infections - the age profile of infections, spatio-temporal dynamics, and seasonality in transmission - and compare them with predictions from existing theory and past findings. Our analysis reveals interesting epidemiological differences between the six pathogens, and variations across space. We find signatures of term-time forcing (reduced transmission during the summer) for measles, mumps, rubella, varicella, and scarlet fever; for pertussis, a lack of term-time forcing could not be rejected.