Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study.
There is considerable interindividual variation in sulfonylurea response in type 2 diabetes. Transcription factor 7-like 2 (TCF7L2) variants have been identified to be strongly associated with type 2 diabetes risk, probably due to decreased beta-cell function. We hypothesized that variation in TCF7L2 would influence response to sulfonylureas but not metformin. We studied the effect of TCF7L2 rs12255372 and rs7903146 genotypes on glycemic response. The DARTS/MEMO (Diabetes Audit and Research Tayside/Medicines Monitoring Unit) collaboration database includes prescribing, biochemistry, and clinical phenotype of all patients with diabetes within Tayside, Scotland, from 1992. Of these, the TCF7L2 genotype was determined in 4,469 patients with type 2 diabetes recruited to GoDARTS (Genetics of Diabetes Audit and Research Tayside) between 1997 and July 2006. A total of 901 incident sulfonylurea users and 945 metformin users were identified. A logistic regression was used with treatment failure defined as an A1C >7% within 3-12 months after treatment initiation. Covariates included the TCF7L2 genotype, BMI, sex, age diagnosed, drug adherence, and drug dose. A1C pretreatment was available in a subset of patients (sulfonylurea n = 579; metformin n = 755). Carriers of the risk allele were less likely to respond to sulfonylureas with an odds ratio (OR) for failure of 1.95 (95% CI 1.23-3.06; P = 0.005), comparing rs12255372 T/T vs. G/G. Including the baseline A1C strengthened this association (OR 2.16 [95% CI 1.21-3.86], P = 0.009). A similar, although slightly weaker, association was seen with rs7903146. No association was seen between metformin response and either single nucleotide polymorphism, after adjustment for baseline A1C. TCF7L2 variants influence therapeutic response to sulfonylureas but not metformin. This study establishes that genetic variation can alter response to therapy in type 2 diabetes.


Intervention planning for Antibiotic Review Kit (ARK): a digital and behavioural intervention to safely review and reduce antibiotic prescriptions in acute and general medicine.
Hospital antimicrobial stewardship strategies, such as 'Start Smart, Then Focus' in the UK, balance the need for prompt, effective antibiotic treatment with the need to limit antibiotic overuse using 'review and revise'. However, only a minority of review decisions are to stop antibiotics. Research suggests that this is due to both behavioural and organizational factors. To develop and optimize the Antibiotic Review Kit (ARK) intervention. ARK is a complex digital, organizational and behavioural intervention that supports implementation of 'review and revise' to help healthcare professionals safely stop unnecessary antibiotics. A theory-, evidence- and person-based approach was used to develop and optimize ARK and its implementation. This was done through iterative stakeholder consultation and in-depth qualitative research with doctors, nurses and pharmacists in UK hospitals. Barriers to and facilitators of the intervention and its implementation, and ways to address them, were identified and then used to inform the intervention's development. A key barrier to stopping antibiotics was reportedly a lack of information about the original prescriber's rationale for and their degree of certainty about the need for antibiotics. An integral component of ARK was the development and optimization of a Decision Aid and its implementation to increase transparency around initial prescribing decisions. The key output of this research is a digital and behavioural intervention targeting important barriers to stopping antibiotics at review (see http://bsac-vle.com/ark-the-antibiotic-review-kit/ and http://antibioticreviewkit.org.uk/). ARK will be evaluated in a feasibility study and, if successful, a stepped-wedge cluster-randomized controlled trial at acute hospitals across the NHS.


Evidence for a predominantly central hypotensive effect of alpha-methyldopa in humans.
We examined the time course and extent to which central and peripheral mechanisms contribute to the short-term effects of a 500-mg oral dose of alpha-methyldopa on supine mean arterial pressure, cardiac output, and total peripheral resistance, as well as its effects on total urinary excretion of norepinephrine and its metabolites, in five subjects with essential hypertension. Total peripheral resistance was reduced significantly 1 hour after alpha-methyldopa administration and remained so for the ensuing 7 hours of the study (p less than 0.05). A small but significant reduction in mean arterial pressure occurred 7 hours after the dose (p less than 0.05), while cardiac output did not change significantly. Total 24-hour urinary norepinephrine and metabolite excretion was reduced by 8.1 mumol (35% compared with placebo). The relative distribution of urinary norepinephrine metabolites was unaffected by alpha-methyldopa, and the catecholamine metabolites of alpha-methyldopa, alpha-methylnorepinephrine and alpha-methylnormetanephrine did not account for this reduction. Competitive inhibition of methyldopa transport across the blood-brain barrier and into the central nervous system by large oral doses of isoleucine antagonized most of the effect of alpha-methyldopa. The effects on total peripheral resistance were completely abolished, and small, insignificant changes during the 7-hour study were similar to those observed after placebo. Changes in mean arterial pressure were not significant; however, 24-hour total urinary norepinephrine and metabolite excretion increased by 6.1 mumol to 22.7 mumol (24.7 mumol excreted after placebo). Adding benserazide to the alpha/methyldopa-isoleucine dose regimen in an attempt to inhibit any residual, presumably peripheral, effects of alpha-methyldopa caused little, if any, further antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)


Nonlinear generation of very high-order UV modes in microstructured fibers.
Cobweb microstructured optical fibers are often strongly multimode in the visible and near infrared regions. This may lead to a number of intermodally phase-matched nonlinear processes. Here we describe a process of nonlinear generation of very high-order UV modes by pumping such fibers with 100 fs Ti:sapphire pulses. Wavelengths as short as 260 nm are generated through a mechanism distinct from supercontinuum generation.


Impact of zidovudine-based triple combination therapy on an AIDS drug assistance program.
A static deterministic model was used to estimate the effect of the shift to a triple combination therapeutic standard on the annual AIDS Drug Assistance Program (ADAP) budget, total medical care expenditures, and population health outcomes for New York (NY) state ADAP enrollees. The model used opportunistic disease incidence data from the Multicenter AIDS Cohort Study (MACS) and other studies. Costs of treating opportunistic infections (OIs) and other HIV complications with each type of therapy were derived from treatment algorithms and standard unit costs. CD4+ cell counts were used as an index of need for OI prophylaxis and for determining OI incidence. Treatment with zidovudine-based combination therapy has been shown to increase CD4+ cell counts and reduce OI incidence. The model estimated that a change from monotherapy to triple therapy would have increased NY ADAP budget expenditures per enrollee by 115%. However, total medical system costs per ADAP enrollee (including ADAP costs) would decrease by 0.4% in the base case as a result of reduction in OIs and other HIV sequelae and associated costs. Results are sensitive to the assumed percentage of people taking combination therapy as well as to the assumptions made about the impact of the combination therapy on CD4+ cell count. Total ADAP budget impacts will depend on the growth in ADAP enrollment as a result of the availability of more effective therapies. In conclusion, this model demonstrates how access to newer, more effective HIV drug treatments can reduce the costs of treating OIs and provide major health benefits for ADAP enrollees.


Detection of Gluteal Changes Using Ultrasound Imaging During Phases of Gait in Individuals With Medial Knee Displacement.
Context: Medial knee displacement (MKD) is a common risk factor for lower-extremity injury and is related to altered gluteal muscle activity. Ultrasound imaging (USI) is a reliable means to explore mechanical muscle activity; however, no information exists regarding USI of the gluteals during gait in an MKD population. Objective: To determine differences in USI gluteal muscle activity during gait in individuals with and without MKD. Design: Descriptive laboratory study. Setting: University research laboratory. Participants: Out of 28 participants, 14 exhibiting MKD unilaterally during a single-leg squat (19.36 [1.51] y, 169.73 [7.50] cm, and 62.01 [10.57] kg; 10 females) and 14 matched non-MKD subjects (20.29 [1.73] y, 167.24 [9.07] cm, and 67.53 [16.03] kg). Interventions: Bilateral B-mode USI of the gluteus maximus (Gmax) and gluteus medius (Gmed) muscles during quiet stance, heel strike, and a 10-second treadmill walking clip. Main Outcome Measures: Gluteal thickness measures normalized to quiet stance yielded activity ratios, and percentage of muscle thickness change was assessed between heel strike and quiet stance. Differences between groups were assessed with Cohen's d effect sizes with 95% confidence intervals. Activity ratios with 90% confidence intervals plotted on 10% intervals from 0% to 100% of gait were used to compare groups and limbs. A subsample of images was measured to determine intertester reliability. Results: USI revealed decreased Gmax and Gmed percent change at heel strike (%change = -9.57% [7.15%] and -8.76% [4.26%], respectively). The MKD limb compared with the contralateral limb exhibited decreased Gmed activity ratio at 30% of gait (MKD = 0.89 [0.056]; non-MKD = 1.01 [.052]). Intertester reliability was excellent for gluteus maximus (intraclass correlation coefficient = .987 [.014]) and Gmed (intraclass correlation coefficient = .989 [.013]) measurements. Conclusions: USI highlighted gluteal activity differences of MKD limbs during gait, which may contribute to inadequate hip stabilization during this daily repetitive task. These findings potentiate the use of USI as an intervention- or screening-based visual tool.


Salmonella and Vibrio cholerae in brackishwater cultured tropical prawns.
The occurrence of Salmonella and Vibrio cholerae in brackishwater ponds was monitored over a 2-year period in one of the major prawn exporting countries in Southeast Asia. The principal production areas were identified and regular samples taken for Salmonella and V. cholerae analysis. Results demonstrated that brackishwater ponds and cultured prawns were inherently contaminated with both bacterial pathogens. Salmonella spp. were present in 16.0% of prawns and 22.1% of mud/water samples from ponds; and V. cholerae present in 1.5% of prawns and 3.1% of mud/water samples. Culturing by intensive methods tended to favour contamination by these pathogens, which is most likely due to the accumulation of waste and increase in the volume of sediments in ponds. Typical environmental factors such as water temperature, pH, and salinity were all favourable for growth of microorganisms. The incidence of the pathogens increased during the wet season and was marginally higher when ponds were located close to urban areas. S. weltevreden was identified as the principal serotype found in ponds, and to a lesser extent S. anatum (11%) S. wandsworth (8%) and S. potsdam (8%). The V. cholerae belonged to the non-O1 serogroup.


A framework for grouping nanoparticles based on their measurable characteristics.
There is a need to take a broader look at nanotoxicological studies. Eventually, the field will demand that some generalizations be made. To begin to address this issue, we posed a question: are metal colloids on the nanometer-size scale a homogeneous group? In general, most people can agree that the physicochemical properties of nanomaterials can be linked and related to their induced toxicological responses. The focus of this study was to determine how a set of selected physicochemical properties of five specific metal-based colloidal materials on the nanometer-size scale - silver, copper, nickel, iron, and zinc - could be used as nanodescriptors that facilitate the grouping of these metal-based colloids. The example of the framework pipeline processing provided in this paper shows the utility of specific statistical and pattern recognition techniques in grouping nanoparticles based on experimental data about their physicochemical properties. Interestingly, the results of the analyses suggest that a seemingly homogeneous group of nanoparticles could be separated into sub-groups depending on interdependencies observed in their nanodescriptors. These particles represent an important category of nanomaterials that are currently mass produced. Each has been reputed to induce toxicological and/or cytotoxicological effects. Here, we propose an experimental methodology coupled with mathematical and statistical modeling that can serve as a prototype for a rigorous framework that aids in the ability to group nanomaterials together and to facilitate the subsequent analysis of trends in data based on quantitative modeling of nanoparticle-specific structure-activity relationships. The computational part of the proposed framework is rather general and can be applied to other groups of nanomaterials as well.


Association of post-operative CEA with survival and oxaliplatin benefit in patients with stage II colon cancer: a post hoc analysis of the MOSAIC trial.
Adjuvant treatment for stage II colon cancer (CC) can be proposed to patients with high-risk disease. Recently, 2.35 ng/mL carcinoembryonic antigen (CEA) was identified as the best cut-off value. This post hoc analysis of the MOSAIC trial assessed post-operative CEA prognostic value for survival outcomes and predictive value for the addition of oxaliplatin to adjuvant treatment. Prognostic and predictive values of post-operative CEA in patients with stage II CC were evaluated with Kaplan-Meier survival curves and Cox model with interaction terms. Disease-free survival (DFS) and overall survival (OS) were estimated. Among 899 stage II CC patients, post-operative CEA was available in 867 (96.4%); and 434 (48.65%) had a high-risk stage II disease. The 3-year DFS rate was 88.5% and 78.7% in the ≤ 2.35 ng/mL and > 2.35 ng/mL group, respectively (P = 0.006). Use of oxaliplatin showed survival benefit only in patients with high-risk stage II CC and post-operative CEA > 2.35 ng/ml (interaction term P = 0.09 and 0.03 for DFS and OS). CEA is a strong prognostic factor for DFS and OS in stage II CC. In the MOSAIC trial, only high-risk stage II CC patients with post-operative CEA > 2.35 ng/mL benefited from the addition of oxaliplatin to LV5FU2. NCT00275210 (January 11, 2006).


Identification of a functional glucocorticoid response element in the phenylethanolamine N-methyltransferase promoter using fusion genes introduced into chromaffin cells in primary culture.
The rat gene encoding phenylethanolamine N-methyltransferase (PNMT) was cloned and a consensus sequence for a glucocorticoid response element (GRE) was found at -513 bp, 5' to the transcriptional start site. In order to define the function of this element, fusion genes containing the PNMT promoter and a chloramphenicol acetyltransferase (CAT) reporter gene were constructed. These constructs did not express after transfection into any of 7 continuous cell lines, none of which endogenously produce PNMT. A system for transfecting chromaffin cells in primary culture was therefore devised using constructs containing 200 bp of the proenkephalin (ENK) promoter, whose expression characteristics are well known. pENK beta GAL-1, containing the ENK promoter with a lac Z reporter, was introduced into these cells and beta-galactosidase activity was visualized in situ. Approximately 90% of cells transfected were chromaffin; transfection efficiency was 5%. High levels of CAT activity were measured in chromaffin cells transfected with pENKAT12, possessing a CAT reporter. In contrast to tumor cell lines, pENKAT12 induction in these cells by forskolin and phorbol esters did not require a phosphodiesterase inhibitor. In this chromaffin system, both basal and regulated expression of the PNMT fusion genes were detected. Dexamethasone (dex) induced expression of pPNMT3000 and pPNMT900, containing the putative GRE and 3000 bp or 863 bp of PNMT promoter sequence, 4- to 10-fold. Expression of pPNMT300 and pPNMT100, which lack the GRE and contain 273 bp or 99 bp of PNMT promoter sequence, was unaffected by dex. Addition of the PNMT region spanning -490 to -863 bp conferred full dex responsiveness to a thymidine kinase promoter. Deletion of the putative GRE sequence by site-directed mutagenesis abolished the dex response. These data identify the sequence at -513 bp in the rat PNMT gene as a functional, positively acting GRE. Primary cultures of bovine chromaffin cells provide a biologically relevant expression system for transcriptional studies of catecholamine genes and their related neuropeptides.


Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults.
Vitamin D supplements are widely recommended for bone health in the general population, but data on whether they prevent fractures have been inconsistent. In an ancillary study of the Vitamin D and Omega-3 Trial (VITAL), we tested whether supplemental vitamin D3 would result in a lower risk of fractures than placebo. VITAL was a two-by-two factorial, randomized, controlled trial that investigated whether supplemental vitamin D3 (2000 IU per day), n-3 fatty acids (1 g per day), or both would prevent cancer and cardiovascular disease in men 50 years of age or older and women 55 years of age or older in the United States. Participants were not recruited on the basis of vitamin D deficiency, low bone mass, or osteoporosis. Incident fractures were reported by participants on annual questionnaires and adjudicated by centralized medical-record review. The primary end points were incident total, nonvertebral, and hip fractures. Proportional-hazards models were used to estimate the treatment effect in intention-to-treat analyses. Among 25,871 participants (50.6% women [13,085 of 25,871] and 20.2% Black [5106 of 25,304]), we confirmed 1991 incident fractures in 1551 participants over a median follow-up of 5.3 years. Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96). There was no modification of the treatment effect according to baseline characteristics, including age, sex, race or ethnic group, body-mass index, or serum 25-hydroxyvitamin D levels. There were no substantial between-group differences in adverse events as assessed in the parent trial. Vitamin D3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; VITAL ClinicalTrials.gov number, NCT01704859.).


Research with older people in a world with COVID-19: identification of current and future priorities, challenges and opportunities.
Older people are disproportionately affected by the COVID-19 pandemic, which has had a profound impact on research as well as clinical service delivery. This commentary identifies key challenges and opportunities in continuing to conduct research with and for older people, both during and after the current pandemic. It shares opinions from responders to an international survey, a range of academic authors and opinions from specialist societies. Priorities in COVID-19 research include its specific presentation in older people, consequences for physical, cognitive and psychological health, treatments and vaccines, rehabilitation, supporting care homes more effectively, the impact of social distancing, lockdown policies and system reconfiguration to provide best health and social care for older people. COVID-19 research needs to be inclusive, particularly involving older people living with frailty, cognitive impairment or multimorbidity, and those living in care homes. Non-COVID-19 related research for older people remains of critical importance and must not be neglected in the rush to study the pandemic. Profound changes are required in the way that we design and deliver research for older people in a world where movement and face-to-face contact are restricted, but we also highlight new opportunities such as the ability to collaborate more widely and to design and deliver research efficiently at scale and speed.


Acute Coronary Syndrome During Pregnancy: A Case Report and Literature Review.
A 32-year-old multiparous woman who presented with chest pain at seven weeks gestation was admitted to our hospital 35 minutes after the onset of symptoms. Sudden cardiac arrest developed while the patient was waiting in the triage room. Cardiopulmonary resuscitation was performed, and the patient was immediately intubated. Electrocardiography revealed an inferior myocardial infarction. The patient underwent coronary angiography, which revealed slow coronary flow of the circumflex and left anterior descending coronary arteries. For treatment, the combination of aspirin with clopidogrel and unfractionated heparin was initiated. She had previously had three healthy children and hadn't had any problems during her previous pregnancies. She had a history of family and smoking, but no history of other coronary risk factors such as diabetes mellitus, hypertension, or dyslipidemia. She was discharged home on day five after admission with clopidogrel, aspirin and a beta-blocker with close outpatient follow-up. Elective abortion was planned for two weeks after the myocardial infarction.


Early HIV disclosure and nondisclosure among men and women on antiretroviral treatment in Uganda.
Efforts to expand access to HIV care and treatment often stress the importance of disclosure of HIV status to aid adherence, social support, and continued resource mobilization. We argue that an examination of disclosure processes early in the process of seeking testing and treatment can illuminate individual decisions and motivations, offering insight into potentially improving engagement in care and adherence. We report on baseline data of early HIV disclosure and nondisclosure, including reasons for and responses to disclosure from a cohort of men and women (n=949) currently accessing antiretroviral treatment in two regions of Uganda. We found early disclosures at the time of suspicion or testing positive for HIV by men and women to be largely for the purposes of emotional support and friendship. Responses to these selected disclosures were overwhelmingly positive and supportive, including assistance in accessing treatment. Nonetheless, some negative responses of worry, fear, or social ostracism did occur. Individuals deliberately chose to not disclose their status to partners, relatives, and others in their network, for reasons of privacy or not wanting to cause worry from the other person. These data demonstrate the strategic choices that individuals make early in the course of suspicion, testing, and treatment for HIV to mobilize resources and gain emotional or material support, and similarly their decisions and ability to maintain privacy regarding their status.


The Effect of Postoperative Complications After Minimally Invasive Esophagectomy on Long-term Survival: An International Multicenter Cohort Study.
Esophagectomy is a technically challenging procedure, associated with significant morbidity. The introduction of minimally invasive esophagectomy (MIE) has reduced postoperative morbidity. Although the short-term effect on complications is increasingly being recognized, the impact on long-term survival remains unclear. This study aims to investigate the association between postoperative complications following MIE and long-term survival. Data were collected from the EsoBenchmark Collaborative composed by 13 high-volume, expert centers routinely performing MIE. Patients operated between June 1, 2011 and May 31, 2016 were included. Complications were graded using the Clavien-Dindo (CD) classification. To correct for short-term effects of postoperative complications on mortality, patients who died within 90 days postoperative were excluded. Primary endpoint was 5-year overall survival. A total of 915 patients were included with a mean follow-up time of 30.8 months (standard deviation 17.9). Complications occurred in 542 patients (59.2%) of which 50.2% had a CD grade ≥III complication [ie, (re)intervention, organ dysfunction, or death]. The incidence of anastomotic leakage (AL) was 135 of 915 patients (14.8%) of which 84 patients were classified as a CD grade ≥III. Multivariable analysis showed a significantly deteriorated long-term survival in all patients with AL [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.25-2.24]. This inverse relation was most distinct when AL was scored as a CD grade ≥III (HR 1.83, 95% CI 1.30-2.58). For all other complications, no significant association with long-term survival was found. The occurrence and severity of AL, but not overall complications, after MIE negatively affect long-term survival of esophageal cancer patients.


Validating the colloid model to optimise the design and operation of both moving-bed biofilm reactor and integrated fixed-film activated sludge systems.
The paper presents a systematic study of simulations, using a previously calibrated Colloid model, from which it was found that: (i) for pure moving-bed biofilm reactor (MBBR) processes with tertiary nitrification conditions (no influent chemical oxygen demand (COD)), dissolved oxygen = 5 mg/L and residual NH4-N > 4 mgN/L, a nitrification rate of 1.2 gN/(m(2)d) was obtained at 10 °C. This rate decreases sharply when residual NH4-N is lower than 2 mgN/L, (ii) for MBBR systems with predenitrification-nitrification zones and COD in the influent (soluble and particulate), the nitrification rate (0.6 gN/(m(2)d)) is half of that in tertiary nitrification due to the effect of influent colloidal XS (particulate slowly biodegradable COD) and (iii) for integrated fixed-film activated sludge (IFAS) processes the nitrification rate in the biofilm (0.72 gN/(m(2)d)) is 20% higher than for the pure MBBR due to the lower effect of influent XS since it is adsorbed onto flocs. However, it is still 40% lower than the tertiary nitrification rate. In the IFAS, the fraction of the nitrification rate in suspension ranges from 10 to 70% when the aerobic solids retention time varies from 1.4 to 6 days.


Social costs of untreated opioid dependence.
Using cost-of-illness methodology applied to a comprehensive survey of 114 daily opiate users not currently in or seeking treatment for their addiction, we estimated the 1996 social costs of untreated opioid dependence in Toronto (Ontario, Canada). The survey collected data on social and demographic characteristics, drug use history, physical and mental health status, the use of health care and substance treatment services, drug use modality and sex-related risks of infectious diseases, sources of income, as well as criminality and involvement with the law enforcement system. The annual social cost generated by this sample, calculated at Canadian $5.086 million, is explained mostly by crime victimization (44.6%) and law enforcement (42.4%), followed by productivity losses (7.0%) and the utilization of health care (6.1%). Applying the $13,100 cost to the estimated 8,000 to 13,000 users and 2.456 million residents living in Toronto yields a range of social cost between $43 and $69 per capita.


Management importance of common treatments: contribution of top 20 procedures to surgical workload and cost.
To assess the contribution of the most frequently performed procedures to surgical workload and to evaluate the financial implications. Analysis of data held on the department's computerised clinical information system. Department of surgery in a district general hospital. 4845 patients were treated by surgeons in three consultant firms over an 18 month period and 5346 patients by surgeons in a single firm over a five year period. Percentage and cumulative percentage contribution to workload in order of frequency by procedure. Costs of the commonest and costliest treatments. Half of the workload of the department was encompassed by eight procedures. Twenty procedures accounted for 70% of the work. For a single firm 20 procedures represented over 80% of all the surgical work. Transurethral prostatectomy was the treatment that consumed most resources (pounds 240,900 for 198 patients in 18 months). The costliest patients were those who had undergone complicated large bowel surgery, vascular reconstructions, or amputation. Clinicians and managers need to appreciate the importance of the most common surgical procedures. It is vital that performance and costing of these procedures are optimum as they contribute disproportionately to overall results and finance.


The effect of a haptic biofeedback system on postural control in patients with stroke: An experimental pilot study.
Impaired balance in patients with hemiparesis caused by stroke is frequently related to deficits in the central integration of afferent inputs, and traditional rehabilitation reinforces excessive visual reliance by focusing on visual compensation. The present study investigated whether a balance task involving a haptic biofeedback (BF) system, which provided supplementary vibrotactile sensory cues associated with center-of-foot-pressure displacement, improved postural control in patients with stroke. Seventeen stroke patients were assigned to two groups: the Vibrotactile BF and Control groups. During the balance task (i.e., standing on a foam mat), participants in the Vibrotactile BF group tried to stabilize their postural sway while wearing the BF system around the pelvic girdle. In the Control group, participants performed an identical postural task without the BF system. Pre- and post-test measurements of postural control using a force plate revealed that the stability of bipedal posture in the Vibrotactile BF group was markedly improved compared with that in the Control group. A balance task involving a vibrotactile BF system improved postural stability in patients with stroke immediately. This confirms the potential of a haptic-based BF system for balance training, both in routine clinical practice and in everyday life.


The electronic properties of Au clusters on CeO2 (110) surface with and without O-defects.
We use density functional theory with Hubbard corrections (DFT+U) to understand the local electronic properties of Au adatom and Au2 dimer adsorption on the CeO2 (110) surface. We show that, based on the initial geometries, we can observe Au species in a variety of charge states including Au+, Au-, Auδ- and Auδ+-Auδ-. We present a detailed discussion using Bader charge analysis and partial density of states to support our observations. We also discuss the influence of solvent on the adsorption of Au adatoms adsorbed on top of an O-vacancy, which shows interesting geometrical and electronic properties.


A Fractal-Based Authentication Technique Using Sierpinski Triangles in Smart Devices.
The prevalence of smart devices in our day-to-day activities increases the potential threat to our secret information. To counter these threats like unauthorized access and misuse of phones, only authorized users should be able to access the device. Authentication mechanism provide a secure way to safeguard the physical resources as well the information that is processed. Text-based passwords are the most common technique used for the authentication of devices, however, they are vulnerable to a certain type of attacks such as brute force, smudge and shoulder surfing attacks. Graphical Passwords (GPs) were introduced as an alternative for the conventional text-based authentication to overcome the potential threats. GPs use pictures and have been implemented in smart devices and workstations. Psychological studies reveal that humans can recognize images much easier and quicker than numeric and alphanumeric passwords, which become the basis for creating GPs. In this paper a novel Fractal-Based Authentication Technique (FBAT) has been proposed by implementing a Sierpinski triangle. In the FBAT scheme, the probability of password guessing is low making system resilient against abovementioned threats. Increasing fractal level makes the system stronger and provides security against attacks like shoulder surfing.


Effects of recombinant human growth hormone (rhGH) replacement therapy on detailed immunologic parameters in somatotropine--deficient paediatrics patients prior and after 6 months of rhGH treatment.
This study aims at assessing how recombinant human growth hormone treatment of children and young people suffering from isolated growth hormone deficiency affects some selected parameters of the immune system: a percentage of lymphocytes, granulocytes, monocytes, concentrations of A, G, and M immunoglobulins, a percentage of T lymphocytes divided into subpopulations CD4 and CD8, a percentage of NK and B lymphocytes, and phagocytic activity of granulocytes and monocytes. The study comprised 30 children and young people aged 4.2-18 years with isolated growth hormone deficiency both prior to and 6 months after rhGH (recombinant human growth hormone) treatment with a dose of 0.093 IU/kg every 24 hr. The control group comprised 25 healthy children with normal height in the respective age bracket. Labelling was conducted by flow cytometry FACS manufactured by Becton-Dickinson using both labelled antibodies and PHAGOTEST® commercial kit (Orpegen). Concentrations of A, G and M immunoglobulins in blood serum were assessed by means of immunoturbidimetric method using COBAS (manufactured by Roche). The lowest percentage of active granulocytes in PHAGOTEST® was found in a group examined prior to treatment compared to the control group. The percentage increased after 6 months of rhGH treatment to values comparable with the control group. Although mean concentrations of IgM and IgA after 6 months of treatment with rhGH significantly decreased in comparison with those determined prior to treatment, they still remained within the baseline norm. No significant differences in the phagocytic activity of monocytes, IgG concentration, % of NK lymphocytes, T lymphocytes divided into CD4 and CD8 lymphocytes, B lymphocytes and CD4/CD8 lymphocytic index were found. None of the patients exhibited any clinical symptoms of immune disorders. rhGH treatment of patients with isolated growth hormone deficiency can have positive influence on the phagocytic activity of scavenger cells, mainly granulocytes, which in children with isolated growth hormone deficiency seems to be lower than in their health peers. Growth hormone treatment of children with isolated growth hormone deficiency does not significantly affect the activity of the immune system expressed by the phagocytic activity of monocytes, the percentage of B, T and NK lymphocytes and IgG concentration in blood serum.


The GENCODE exome: sequencing the complete human exome.
Sequencing the coding regions, the exome, of the human genome is one of the major current strategies to identify low frequency and rare variants associated with human disease traits. So far, the most widely used commercial exome capture reagents have mainly targeted the consensus coding sequence (CCDS) database. We report the design of an extended set of targets for capturing the complete human exome, based on annotation from the GENCODE consortium. The extended set covers an additional 5594 genes and 10.3 Mb compared with the current CCDS-based sets. The additional regions include potential disease genes previously inaccessible to exome resequencing studies, such as 43 genes linked to ion channel activity and 70 genes linked to protein kinase activity. In total, the new GENCODE exome set developed here covers 47.9 Mb and performed well in sequence capture experiments. In the sample set used in this study, we identified over 5000 SNP variants more in the GENCODE exome target (24%) than in the CCDS-based exome sequencing.


Characterizing a System for Measuring Limb Tourniquet Pressures.
Pressure is an important variable in emergency use limb tourniquet science. This study characterizes one system for measuring tourniquet-applied pressure. A neonatal blood pressure cuff bladder was inflated to target pressures over atmospheric. Unconstrained or constrained within 1-inch tubular polyester webbing, the neonatal cuff was placed in a 500mL Erlenmeyer flask. A 3-hole stopper provided connections to flask interior (chamber) and bladder pressure sensors and a 60mL syringe for altering chamber pressure: atmospheric to >1500mmHg absolute to atmospheric. Within a finite range of chamber pressures, the neonatal cuffbased system accurately indicates applied pressure (minimum and maximum 95% confidence interval linear regression slopes of 0.9871 to 0.9953 and y-intercepts of -0.1144 to 2.157). The visually defined linear response ranges for bladder inflation pressures were as follows for unconstrained/ constrained: 100 to 400mmHg unconstrained/450mmHg constrained for 10mmHg, 150 unconstrained/100 constrained to 450mmHg for 12mmHg, 150 to 500mmHg for 15mmHg, 150 to 500mmHg unconstrained/550mmHg constrained for 18mmHg, 150 to 550mmHg for 21mmHg. Below the linear response range, the inflated bladder system indicated higher pressures than chamber pressures. Above the linear response range, the system indicated progressively lower pressures than chamber pressures. Within the linear response range, the bladder pressure accurately indicates surface-applied pressure.


Managing hepatitis B coinfection in HIV-infected patients.
Since viral hepatitis is one of the most common causes of morbidity and mortality in HIV, it is critical to recognize and treat these patients appropriately. Hepatitis B infection is particularly difficult to manage as it changes with shifts in immune status. Inactive infection may flare up with restoration of CD4 cell count. In addition, many drugs used to treat HIV are also active against hepatitis B. Thus, patients may require therapy for both diseases or only for hepatitis B. The practicing physician must be aware of which drug to use with antiretrovirals and which can be used for hepatitis B alone. Current therapies for HIV that have hepatitis B activity include lamivudine, emtricitabine, and tenofovir. Therapies for hepatitis B without HIV activity are adefovir and entecavir. The major advances in the past year include emerging data on epidemiology, occult infection, genotypes, and newer therapies. Long-term management of hepatitis B includes monitoring for hepatocellular carcinoma. Two recent consensus conferences have provided excellent reviews of management of coinfection .


Cyclosporin protects the eyelid skin from injury after injection of doxorubicin.
The myotoxic drug doxorubicin can treat blepharospasm and hemifacial spasm permanently when injected directly into the eyelid of patients. One side effect of this treatment is the dose-related occurrence of injury to the skin overlying the injection site. The purpose of this study was to determine if injection of the immunosuppressive agent cyclosporin into rabbit eyelids before doxorubicin treatment could reduce the occurrence of injury to the overlying skin and to determine the effect of cyclosporin pretreatment on doxorubicin-induced muscle fiber loss. Anesthetized rabbits received injections of varying doses of cyclosporin 20 minutes before injection of either 0.5, 1, or 2 mg doxorubicin. The rabbits were examined daily, and epithelial changes were recorded as to duration, time of onset, and healing. When the skin was completely healed, the animals were killed and eyelid tissue was prepared for morphometric determination of muscle fiber number. Acute inflammation was quantitatively assessed using an Evans blue assay. At specified doses, cyclosporin improved the doxorubicin chemomyectomy protocol in three ways. It delayed the onset of skin injury at the higher doses of doxorubicin, and it markedly decreased the duration of skin injury. At some doses, cyclosporin completely prevented the formation of epithelial defects. The combination, however, did not increase muscle loss compared to doxorubicin alone; in fact, it had a slightly myoprotective effect. A dose range for cyclosporin administration was determined that resulted in a quantitative and dose-dependent reduction in inflammation at the injection site. The injection of cyclosporin into the eyelids before doxorubicin treatment delayed the onset, reduced the duration, and limited the extent of development of eyelid skin injury. Perhaps by limiting cytokine release, cyclosporin decreased the inflammatory reaction compared to that seen with doxorubicin alone. This combination has the potential to improve patient acceptance of doxorubicin chemomyectomy for the treatment of blepharospasm and hemifacial spasm.


Increased inhaled bronchodilator vs increased inhaled corticosteroid in the control of moderate asthma.
Undertreatment of chronic asthma may reflect uncertainty as to how it may be best controlled. We compared the effects of increased inhaled corticosteroid vs regular inhaled bronchodilator in 32 adult asthmatics. During three 16-week treatment periods, comprising baseline inhaled corticosteroid (mean 505 micrograms daily) and on-demand beta-agonist, baseline inhaled corticosteroid and increased (regularly scheduled four times daily) beta-agonist, and increased inhaled corticosteroid (mean 1478 micrograms daily) and on-demand beta-agonist, subjects recorded symptoms, morning and evening peak flow, and additional medication. Of 25 subjects whose control differed significantly between treatments with baseline vs increased corticosteroid, 22 (88 percent) favored the increased dosage (p < 0.001). Of 28 subjects whose control differed between treatments with regular beta-agonist vs increased corticosteroid, 24 (86 percent) were better controlled with increased inhaled corticosteroid and were worse with regular beta-agonist (p < 0.001). Only one quarter the number of exacerbations were experienced during treatment with increased inhaled corticosteroid. Upper airway adverse effects were minor and easily controlled. Hence, asthma with persistent symptoms was better controlled by increased inhaled corticosteroid therapy than by increased use of inhaled beta-agonist.


Coherent diffractive imaging of microtubules using an X-ray laser.
X-ray free electron lasers (XFELs) create new possibilities for structural studies of biological objects that extend beyond what is possible with synchrotron radiation. Serial femtosecond crystallography has allowed high-resolution structures to be determined from micro-meter sized crystals, whereas single particle coherent X-ray imaging requires development to extend the resolution beyond a few tens of nanometers. Here we describe an intermediate approach: the XFEL imaging of biological assemblies with helical symmetry. We collected X-ray scattering images from samples of microtubules injected across an XFEL beam using a liquid microjet, sorted these images into class averages, merged these data into a diffraction pattern extending to 2 nm resolution, and reconstructed these data into a projection image of the microtubule. Details such as the 4 nm tubulin monomer became visible in this reconstruction. These results illustrate the potential of single-molecule X-ray imaging of biological assembles with helical symmetry at room temperature.


Rapid movement of axonal neurofilaments interrupted by prolonged pauses.
Axonal cytoskeletal and cytosolic proteins are synthesized in the neuronal cell body and transported along axons by slow axonal transport, but attempts to observe this movement directly in living cells have yielded conflicting results. Here we report the direct observation of the axonal transport of neurofilament protein tagged with green fluorescent protein in cultured nerve cells. Live-cell imaging of naturally occurring gaps in the axonal neurofilament array reveals rapid, intermittent and highly asynchronous movement of fluorescent neurofilaments. The movement is bidirectional, but predominantly anterograde. Our data indicate that the slow rate of slow axonal transport may be the result of rapid movements interrupted by prolonged pauses.


A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia.
The purpose of the study was to assess the efficacy and safety of pregabalin monotherapy in patients with fibromyalgia in a randomized, double-blinded, placebo-controlled trial. After 1 week of single-blinded administration of placebo, 750 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to pregabalin (300 mg/d, 450 mg/d, 600 mg/d) or placebo, administered twice daily for 14 weeks. The primary outcome variable was comparison of end point mean pain scores, derived from daily diary ratings of pain intensity (0 to 10 scale), between each of the pregabalin groups and the placebo group. If positive, additional primary efficacy parameters included the Patient Global Impression of Change (PGIC) and the Fibromyalgia Impact Questionnaire (FIQ) total score. Compared with placebo-treated patients, mean changes in pain scores at the end point in pregabalin-treated patients were significantly greater (P < .001: 300 mg/d, -0.71; 450 mg/d, -0.98; 600 mg/d, -1.00). Compared with placebo, significantly more pregabalin-treated patients reported improvement on PGIC (P < .01 for all 3 pregabalin doses) and significant improvements in total FIQ score for the 450 mg/d (P = .004) and the 600 mg/d (P = .003) doses. Compared with placebo, all 3 doses of pregabalin were associated with significant improvement in sleep. The most commonly reported pregabalin-related adverse events were dizziness and somnolence, which tended to be dose-related. This randomized, placebo-controlled trial of 300, 450, and 600 mg/d of pregabalin monotherapy demonstrated that all 3 doses were efficacious for up to 14 weeks for the treatment of fibromyalgia and were well tolerated by most patients. These results provide evidence that pregabalin is an important treatment option for patients with fibromyalgia.


Diabetic and nondiabetic patients with left main and/or 3-vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel-eluting stents.
This study was designed to compare contemporary surgical revascularization (coronary artery bypass graft surgery [CABG]) versus TAXUS Express (Boston Scientific, Natick, Massachusetts) paclitaxel-eluting stents (PES) in diabetic and nondiabetic patients with left main and/or 3-vessel disease. Although the prevalence of diabetes mellitus is increasing, the optimal coronary revascularization strategy in diabetic patients with complex multivessel disease remains controversial. The SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) study randomly assigned 1,800 patients (452 with medically treated diabetes) to receive PES or CABG. The overall 1-year major adverse cardiac and cerebrovascular event rate was higher among diabetic patients treated with PES compared with CABG, but the revascularization method did not impact the death/stroke/myocardial infarction rate for nondiabetic patients (6.8% CABG vs. 6.8% PES, p = 0.97) or for diabetic patients (10.3% CABG vs. 10.1% PES, p = 0.96). The presence of diabetes was associated with significantly increased mortality after either revascularization treatment. The incidence of stroke was higher among nondiabetic patients after CABG (2.2% vs. PES 0.5%, p = 0.006). Compared with CABG, mortality was higher after PES use for diabetic patients with highly complex lesions (4.1% vs. 13.5%, p = 0.04). Revascularization with PES resulted in higher repeat revascularization for nondiabetic patients (5.7% vs. 11.1%, p < 0.001) and diabetic patients (6.4% vs. 20.3%, p < 0.001). Subgroup analyses suggest that the 1-year major adverse cardiac and cerebrovascular event rate is higher among diabetic patients with left main and/or 3-vessel disease treated with PES compared with CABG, driven by an increase in repeat revascularization. However, the composite safety end point (death/stroke/myocardial infarction) is comparable between the 2 treatment options for diabetic and nondiabetic patients. Although further study is needed, these exploratory results may extend the evidence for PES use in selected patients with less complex left main and/or 3-vessel lesions. (SYNergy Between PCI With TAXus and Cardiac Surgery [SYNTAX]; NCT00114972).


Environmental factors associated with toxic cyanobacterial blooms across 20 drinking water reservoirs in a semi-arid region of Brazil.
Cyanobacteria are known to produce a wide variety of bioactive, toxic secondary metabolites generally described as hepatotoxins, neurotoxins, cytotoxins, or dermatoxins. In Brazil, the regular monitoring of cyanobacterial toxins has intensified after the death of 65 patients in a hemodialysis clinic in Caruaru in the state of Pernambuco due to microcystin exposure. The primary objective of this study was to use multivariate statistics that incorporated environmental parameters (both biotic and abiotic) to forecast blooms of cyanobacteria and their toxic secondary metabolites in 20 drinking water reservoirs managed by the Water Treatment Company of Ceará (CAGECE) in the semi-arid region of Ceará, Brazil. Across four years (January 2013 to January 2017), 114 different phytoplankton taxa were identified, including 24 cyanobacterial taxa. In general, Ceará reservoirs were dominated by cyanobacteria due to eutrophication but also because of the dry and warm climate found throughout the region. Interestingly, specific cyanobacterial taxa were influenced by different biotic and abiotic factors. For example, nitrogen-to-phosphorus (N:P) and evaporation were positively related to saxitoxin-producing taxa, especially Raphidiopsis raciborskii, while temperature, electrical conductivity, total phosphorus, and transparency (measured as Secchi depth) were positively associated with microcystin-producing taxa, such as Microcystis aeruginosa. Climate forecasts predict higher evaporation and temperatures in the semi-arid Ceará region, which will likely magnify droughts and water scarcity as well as promote toxic cyanobacterial blooms in reservoirs in the future. Therefore, understanding the factors associated with algal blooms dominated by specific taxa is paramount for water resource management.


Image quality in abdominal CT using an iodine contrast reduction algorithm employing patient size and weight and low kV CT technique.
Low tube potential-high tube current computed tomography (CT) imaging allows reduction in iodine-based contrast dose and may extend the benefit of routine contrast-enhanced CT exams to patients at risk of nephrotoxicity. To determine the ability of an iodine contrast reduction algorithm to maintain diagnostic image quality for contrast-enhanced abdominal CT. CT exams with iodine contrast reduction were prescribed for patients at risk for renal dysfunction. The iodine contrast reduction algorithm combines weight-based contrast volume reduction with patient width-based low tube potential selection and bolus-tracking. Control exams with routine iodine dose were selected based on weight, width, and scan protocol. Three radiologists evaluated image quality and diagnostic confidence using a 4-point scale (<2 acceptable). Another radiologist assessed contrast reduction indications and measured portal vein and liver contrast-to-noise ratios. Forty-six contrast reduction algorithm and control exams were compared (mean creatinine 1.6 vs. 1.2 mg/dL, P ≤ 0.0001). Thirty-nine contrast reduction patients had an eGFR <60 mL/min/1.73m2 and 15 had single or transplanted kidney. Mean iodine contrast dose was lower in the contrast reduction group (20.9 vs. 39.4 g/mL, P < 0.0001). Diagnostic confidence was rated as acceptable in 95% (131/138) of contrast reduction and 100% of control exams (1.18-1.28 vs. 1.02-1.13, respectively; P > 0.06). Liver attenuation and contrast-to-noise ratio (CNR) were similar (P = 0.08), but portal vein attenuation and CNR were lower with contrast-reduction (mean 176 vs. 198 HU, P = 0.02; 13 vs. 16, P = 0.0002). This size-based contrast reduction algorithm using low kV and bolus tracking reduced iodine contrast dose by 50%, while achieving acceptable image quality in 95% of exams.


A comparison of gray matter density in restless legs syndrome patients and matched controls using voxel-based morphometry.
Restless legs syndrome (RLS) is a common neurological disorder the pathophysiology of which is incompletely understood. Four studies have examined structural differences between the brains of RLS patients and healthy controls, using voxel-based morphometry (VBM). All 4 studies have provided different results. Optimized VBM was used to search for structural differences in gray matter density. Sixteen RLS patients naïve to dopaminergic drugs and 16 age- and sex-matched controls received structural T1-weighted MR scans. Structural data were analyzed using FSL-VBM. No difference in gray matter density was detected between the two groups (voxel-wise significance: no significant voxels at P= .89 (whole brain Family Wise Error (FWE) corrected); no significant voxels at P < .05 (whole brain False Discovery Rate (FDR) corrected; smallest achievable FDR threshold .99). The present study did not replicate (confirm) previous findings of structural brain changes in RLS, but instead supported the findings of a recent study showing a lack of gray matter alteration in an elderly RLS population. More specifically, the results do not support neuronal loss as an underlying disease mechanism in RLS. Potential limitations in the application of VBM are also discussed.


Biogenesis and the regulation of the maturation of miRNAs.
Regulation of gene expression is a fundamental process in both prokaryotic and eukaryotic organisms. Multiple regulatory mechanisms are in place to control gene expression at the level of transcription, post-transcription and post-translation to maintain optimal RNA and protein expressions in cells. miRNAs (microRNAs) are abundant short 21-23 nt non-coding RNAs that are key regulators of virtually all eukaryotic biological processes. The levels of miRNAs in an organism are crucial for proper development and sustaining optimal cell functions. Therefore the processing and regulation of the processing of these miRNAs are critical. In the present chapter we highlight the most important steps of miRNA processing, describe the functions of key proteins involved in the maturation of miRNAs, and discuss how the generation and the stability of miRNAs are regulated.


Decreased sexual function in partners after patients' first-time myocardial infarction.
A myocardial infarction event affects not only patients but also partners, although how it affects the partners' sexual function is not studied. The purpose of this study was to describe and compare how partners experienced their sexual function one year before with one year after first-time myocardial infarction of their partner. A longitudinal and comparative design was used. Self-reported data on Watts Sexual Function Questionnaire was collected retrospectively at two occasions from 123 partners (87 women and 36 men), measuring the year prior to the first-time myocardial infarction and the year after. Data were analysed using descriptive and inferential statistics. The total score for Watts Sexual Function Questionnaire showed a significant decrease over time. In all four subscales a decrease was found, which were statistically significant in three out of the four subscales (sexual desire, 19.39 vs 18.61; p<0.001, orgasm, 14.11 vs 13.64; p=0.027 and satisfaction, 12.61 vs 12.31; p=0.042). Twenty-six partners reported that their intercourse frequencies decreased over time, while six partners reported an increased intercourse frequency. Partners' sexual function decreased after patients' first-time myocardial infarction. It is important for health personnel to offer information and discussion about sexual function and concerns with both patients and partners after a first-time myocardial infarction.


A voltage and current measurement dataset for plug load appliance identification in households.
This paper presents the Plug-Load Appliance Identification Dataset (PLAID), a labelled dataset containing records of the electrical voltage and current of domestic electrical appliances obtained at a high sampling frequency (30 kHz). The dataset contains 1876 records of individually-metered appliances from 17 different appliance types (e.g., refrigerators, microwave ovens, etc.) comprising 330 different makes and models, and collected at 65 different locations in Pittsburgh, Pennsylvania (USA). Additionally, PLAID contains 1314 records of the combined operation of 13 of these appliance types (i.e., measurements obtained when multiple appliances were active simultaneously). Identifying electrical appliances based on electrical measurements is of importance in demand-side management applications for the electrical power grid including automated load control, load scheduling and non-intrusive load monitoring. This paper provides a systematic description of the measurement setup and dataset so that it can be used to develop and benchmark new methods in these and other applications, and so that extensions to it can be developed and incorporated in a consistent manner.


Relation between lung cancer, chronic bronchitis, and airways obstruction.
Since cigarette smoking is an important cause of lung cancer and chronic bronchitis both conditions should occur together more often in cigarette smokers than would result from chance. If they do commonly occur together then severe airways obstruction, which is often associated with chronic bronchitis, should also be often associated with lung cancer. To discover whether this were so three groups of patients were studied at the London Chest Hospital. Two hundred men and 43 women who presented with lung cancer provided information on the prevalence of defined chronic bronchitis and airways obstruction in those suffering from lung cancer. The third group consisted of 233 men presenting with defined chronic bronchitis who were kept under observation to discover how many would die from lung cancer. The results suggested that simple bronchitis and lung cancer often occur together but that obstructive bronchitis and lung cancer do not often occur together. The lack of association between lung cancer and severe airways obstruction requires an explanation.


The Wisdom of Individuals: Exploring People's Knowledge About Everyday Events Using Iterated Learning.
Determining the knowledge that guides human judgments is fundamental to understanding how people reason, make decisions, and form predictions. We use an experimental procedure called ''iterated learning,'' in which the responses that people give on one trial are used to generate the data they see on the next, to pinpoint the knowledge that informs people's predictions about everyday events (e.g., predicting the total box office gross of a movie from its current take). In particular, we use this method to discriminate between two models of human judgments: a simple Bayesian model (Griffiths & Tenenbaum, 2006) and a recently proposed alternative model that assumes people store only a few instances of each type of event in memory (MinK; Mozer, Pashler, & Homaei, 2008). Although testing these models using standard experimental procedures is difficult due to differences in the number of free parameters and the need to make assumptions about the knowledge of individual learners, we show that the two models make very different predictions about the outcome of iterated learning. The results of an experiment using this methodology provide a rich picture of how much people know about the distributions of everyday quantities, and they are inconsistent with the predictions of the MinK model. The results suggest that accurate predictions about everyday events reflect relatively sophisticated knowledge on the part of individuals.


Outcome of unilateral and bilateral pallidotomy for Parkinson's disease: patient assessment.
Pallidotomy has recently regained acceptance as a safe and effective treatment for Parkinson's disease symptoms. The goal of this study was to obtain the patients' perspective on their results after undergoing this procedure. Special attention was focused on the potential complications and the respective advantages and risks of unilateral versus bilateral pallidotomy. Fifty-six patients were studied during a 2-year period; 44 completed the evaluation, with a median follow-up of 7 months. Of these patients, 22 underwent unilateral pallidotomy, and 17 had bilateral simultaneous pallidotomy. Five patients who underwent staged bilateral pallidotomy were excluded from the statistical analysis, because the number of patients was considered too small for analysis. The procedures were performed with magnetic resonance imaging determination of the target, combined with physiological confirmation, including microelectrode recording. According to Visual Analog Scale scores, unilateral pallidotomy significantly improved dyskinesias (P < 0.05) but no other symptoms. Simultaneous bilateral pallidotomy improved slowness, rigidity, tremor, and dyskinesias (P < 0.05) but worsened speech function (P < 0.05). According to the patients' most frequently chosen answers to multiple-choice questions, unilateral pallidotomy improved night sleep, muscle pain, freezing, overall "on," overall "off," and the duration of "off periods," but it worsened the volume of the voice and articulation, increased drooling, and reduced concentration. Bilateral pallidotomy improved night sleep, muscle pain, freezing, overall "on," overall "off," duration of "off periods," and the amount of medication taken, but it increased drooling and worsened the volume of the voice, articulation, and writing. Subjective visual disturbance was noted in 36 and 41% of patients who underwent unilateral and simultaneous bilateral pallidotomy, respectively. Globally, the result of the procedure was rated "good" or "excellent" by 64% of the patients who underwent unilateral pallidotomy and by 76% of the patients who underwent bilateral pallidotomy. An age less than 70 years was a positive prognostic factor for the global outcome (P < 0.05), as were severe preoperative dyskinesias (P < 0.05). This study confirms that, from a patient standpoint, unilateral and simultaneous bilateral pallidotomy can reduce all the key symptoms of Parkinson's disease (i.e., akinesia, tremor, and rigidity) and the side effects of L-dopa treatment (i.e., dyskinesias). Preoperative severe dyskinesias and younger age are positive prognostic factors for a successful outcome. Simultaneous bilateral pallidotomy was more effective than unilateral pallidotomy regarding tremor, rigidity, and dyskinesias, but it conferred a higher risk of postoperative speech deterioration.


Skeletal development in the Chinese soft-shelled turtle Pelodiscus sinensis (Testudines: Trionychidae).
We investigated the development of the whole skeleton of the soft-shelled turtle Pelodiscus sinensis, with particular emphasis on the pattern and sequence of ossification. Ossification starts at late Tokita-Kuratani stage (TK) 18 with the maxilla, followed by the dentary and prefrontal. The quadrate is the first endoskeletal ossification and appears at TK stage 22. All adult skull elements have started ossification by TK stage 25. Plastral bones are the first postcranial bones to ossify, whereas the nuchal is the first carapacial bone to ossify, appearing as two unstained anlagen. Extensive examination of ossification sequences among autopodial elements reveals much intraspecific variation. Patterns of ossification of cranial dermal elements are more variable than those of endochondral elements, and dermal elements ossify before endochondral ones. Differences in ossification sequences with Apalone spinifera include: in Pelodiscus sinensis the jugal develops relatively early and before the frontal, whereas it appears later in A. spinifera; the frontal appears shortly before the parietal in A. spinifera whereas in P. sinensis the parietal appears several stages before the frontal. Chelydrids exhibit an early development of the postorbital bone and the palatal elements as compared to trionychids. Integration of the onset of ossification data into an analysis of the sequence of skeletal ossification in cryptodirans using the event-pairing and Parsimov methods reveals heterochronies, some of which reflect the hypothesized phylogeny considered taxa. A functional interpretation of heterochronies is speculative. In the chondrocranium there is no contact between the nasal capsules and planum supraseptale via the sphenethmoid commissurae. The pattern of chondrification of forelimb and hind limb elements is consistent with a primary axis and digital arch. There is no evidence of anterior condensations distal to the radius and tibia. A pattern of quasi- simultaneity is seen in the chondrogenesis of the forelimb and the hind limb.


Ineffective morphine treatment regimen for the control of Neonatal Abstinence Syndrome in buprenorphine- and methadone-exposed infants.
This study aimed to determine if morphine is effective in ameliorating Neonatal Abstinence Syndrome (NAS) symptoms to non-opioid-exposed control levels in methadone- and buprenorphine-exposed infants. A prospective, non-randomized comparison study with flexible dosing was undertaken in a large teaching maternity hospital in Australia. Twenty-five infants in the groups of buprenorphine-, methadone- and control non-opioid-exposed infants were compared (total n = 75 infants). Oral morphine sulphate (1 mg/ml) was administered every 4 h to opioid agonist-exposed infants. Modified Finnegan Withdrawal Scale (MFWS) scores determined dosing: score of 8-10: 0.5 mg/kg/day, 11-13: 0.7 mg/kg/day and 14+: 0.9 mg/kg/day. Withdrawal score, amount of morphine administered and length of hospital stay, were used to assess NAS over a 4-week follow-up period. No controls achieved a score higher than 7 on the MFWS. There was no significant difference in the percentage of infants requiring treatment between methadone (60%) and buprenorphine (48%) infants. For treated infants, significantly (P < 0.01) more morphine was administered to methadone (40.07 ± 3.95 mg) compared with buprenorphine infants (22.77 ± 4.29 mg) to attempt to control NAS. Following treatment initiation, significantly more (P < 0.01) methadone (87%) compared with buprenorphine infants (42%) continued to exceed scoring thresholds for morphine treatment requirement, and non-opioid-exposed control infant scores. For treated infants, there was no significant difference in length of hospital stay between methadone and buprenorphine infants. Morphine treatment was not entirely effective in ameliorating NAS to non-opioid-exposed control symptom levels in methadone or buprenorphine infants. The regimen may be less effective in methadone compared with buprenorphine infants.


IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus.
High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease. 1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African-American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay. In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR>2.56, p<1.9×10(-14) for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained >70% of the genetic risk of SLE due to IRF5. In African-American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African-American subjects and absent in African patients with SLE. The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements. SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population. These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness and are likely pathogenic in SLE.


A genetic screen identifies new steps in oocyte maturation that enhance proteostasis in the immortal germ lineage.
Somatic cells age and die, but the germ-cell lineage is immortal. In Caenorhabditis elegans, germline immortality involves proteostasis renewal at the beginning of each new generation, when oocyte maturation signals from sperm trigger the clearance of carbonylated proteins and protein aggregates. Here, we explore the cell biology of this proteostasis renewal in the context of a whole-genome RNAi screen. Oocyte maturation signals are known to trigger protein-aggregate removal via lysosome acidification. Our findings suggest that lysosomes are acidified as a consequence of changes in endoplasmic reticulum activity that permit assembly of the lysosomal V-ATPase, which in turn allows lysosomes to clear the aggregates via microautophagy. We define two functions for mitochondria, both of which appear to be independent of ATP generation. Many genes from the screen also regulate lysosome acidification and age-dependent protein aggregation in the soma, suggesting a fundamental mechanistic link between proteostasis renewal in the germline and somatic longevity.


Thermophilic bio-electro carbon dioxide recycling harnessing renewable energy surplus.
Renewable energies will represent an increasing share of the electricity supply, while flue and gasification-derived gases can be a promising CO2 feedstock with a heat load. In this study, microbial electrosynthesis of organic compounds from CO2 at high temperature was proposed as an alternative for valorising energy surplus and decarbonizing the economy. The unremitting fluctuation of renewable energy sources was assessed using two bioreactors at 50 °C, under circumstances of continuous and intermittent power supply (ON-OFF; 8-16 h), simulating an off-grid photovoltaic system. Results highlighted that maximum acetate production rate (43.27 g m-2 d-1) and columbic efficiency (98%) were achieved by working with an intermittent energy supply, while current density was reduced three times. This boosted the production of acetate per unit of electricity provided up to 138 g kWh-1 and reinforced the robustness of the technology by showing resilience to tolerate perturbations and returning to its initial state.


Spatial and behavioral correlates of hippocampal neuronal activity.
The firing rate of hippocampal neurons in rats was related both to spatial location and to multiple behavioral variables as rats performed 2 kinds of tasks that rely on hippocampal function: a spatial navigation task similar in performance demands to the radial-arm maze task and a simultaneous cue odor-discrimination task. In the place task, most cells had distinct single or multiple place fields, that is, neurons increased firing when the rat was in a particular location or locations. However, in most of these cells, firing rate also varied systematically in relation to behavioral variables, including the speed, direction, and turning angle of the rat as it moved through the place field. In addition, the activity of most cells was time-locked to task-relevant approach movements. In the odor task, most cells fired as the rat sampled discriminative cues or when it executed specific, task-relevant approach movements. Some cells fired selectively in relation to which odors were presented, the configuration of odor cues, the locus of the response, or a combination of these variables. Many cells with spatial correlates in the place task also had striking behavioral correlates when rats performed the odor task in the same environment, and the locus of the increased firing associated with behavior in the odor task was not the same as the place field in the place task. Thus, while the complex stimuli that compose spatial cues are reflected in hippocampal neuronal activity, hippocampal processing is not limited to the representation of spatial location. Rather, the domain of hippocampal representation includes both spatial and nonspatial relations among multiple cues and the actions directed in relation to these cues, across cue modalities, and across behavioral paradigms.


Mobile marine predators: an understudied source of nutrients to coral reefs in an unfished atoll.
Animal movements can facilitate important ecological processes, and wide-ranging marine predators, such as sharks, potentially contribute significantly towards nutrient transfer between habitats. We applied network theory to 4 years of acoustic telemetry data for grey reef sharks (Carcharhinus amblyrhynchos) at Palmyra, an unfished atoll, to assess their potential role in nutrient dynamics throughout this remote ecosystem. We evaluated the dynamics of habitat connectivity and used network metrics to quantify shark-mediated nutrient distribution. Predator movements were consistent within year, but differed between years and by sex. Females used higher numbers of routes throughout the system, distributing nutrients over a larger proportion of the atoll. Extrapolations of tagged sharks to the population level suggest that prey consumption and subsequent egestion leads to the heterogeneous deposition of 94.5 kg d-1 of nitrogen around the atoll, with approximately 86% of this probably derived from pelagic resources. These results suggest that sharks may contribute substantially to nutrient transfer from offshore waters to near-shore reefs, subsidies that are important for coral reef health.


Short-chain dehydrogenases/reductases (SDR): the 2002 update.
Short-chain dehydrogenases/reductases (SDR) form a large, functionally heterogeneous protein family presently with about 3000 primary and about 30 3D structures deposited in databases. Despite low sequence identities between different forms (about 15-30%), the 3D structures display highly similar alpha/beta folding patterns with a central beta-sheet, typical of the Rossmann-fold. Based on distinct sequence motifs functional assignments and classifications are possible, making it possible to build a general nomenclature system. Recent mutagenetic and structural studies considerably extend the knowledge on the general reaction mechanism, thereby establishing a catalytic tetrad of Asn-Ser-Tyr-Lys residues, which presumably form the framework for a proton relay system including the 2'-OH of the nicotinamide ribose, similar to the mechanism found in horse liver ADH. Based on their cellular functions, several SDR enzymes appear as possible and promising pharmacological targets with application areas spanning hormone-dependent cancer forms or metabolic diseases such as obesity and diabetes, and infectious diseases.


Isometric strength and dynamic back extensor endurance are unrelated in children ages 6-10 years: a pilot study.
This study assessed the correlation between back extensor isometric force and dynamic endurance in 69 children 6-10 years of age. Subjects were positioned prone with legs and hips supported and restrained on two folded 6-in. mats. 42 subjects (20 girls; 22 boys) performed three 5-sec. isometric back extension efforts against a calibrated dynamometer and peak force values were averaged. An additional 27 subjects (9 girls; 18 boys) also performed a dynamic (0 degrees --> 45 degrees flexion-->0 degrees) back extension test at a frequency of 20 per minute, and the number of repetitions was recorded. Both tests were repeated at a 1-wk. interval. Pearson correlations for the endurance, the isometric force test, and test-retest, and between the functional concentric endurance vs isometric force were .55, .79 (both p<.01), and .03, respectively. These tests have moderate to high reliability but they examine different aspects of back muscle fitness. They should not be used interchangeably to assess back extensor muscle fitness. Further investigation must determine whether different dynamic test frequencies and mat heights yield different results.


Legionella pathogenicity: genome structure, regulatory networks and the host cell response.
Legionella spp. the causative agent of Legionnaires' disease is naturally found in fresh water where the bacteria parasitize intracellularly within protozoa. Upon aerosol formation via man-made water systems, Legionella can enter the human lung and cause a severe form of pneumonia. Here we review results from systematic comparative genome analysis of Legionella species with different pathogenic potentials. The complete genomes reveal that horizontal gene transfer has played an important role during the evolution of Legionella and indicate the importance of secretion machineries for the intracellular lifestyle of this pathogen. Moreover, we highlight recent findings on the in vivo transcriptional program of L. pneumophila and the regulatory networks involved in the biphasic life cycle. In order to understand how Legionella effectively subvert host cell functions for its own benefit the transcriptional host cell response upon infection of the model amoeba Dictyostelium discoideum was studied. The use of this model organism made it possible to develop a roadmap of host cell factors which significantly contribute to the uptake of L. pneumophila and the establishment of an ER-associated replicative vacuole.


Autism, Asperger's syndrome and semantic-pragmatic disorder: where are the boundaries?
The diagnostic criteria for autism have been refined and made more objective since Kanner first described the syndrome, so there is now reasonable consistency in how this diagnosis is applied. However, many children do not meet these criteria, yet show some of the features of autism. Where language development is impaired, such children tend to be classed as cases of developmental dysphasia (or specific language impairment) whereas those who learn to talk at the normal age may be diagnosed as having Asperger's syndrome. It is argued that rather than thinking in terms of rigid diagnostic categories, we should recognise that the core syndrome of autism shades into other milder forms of disorder in which language or non-verbal behaviour may be disproportionately impaired.


Aphrodisiac properties of Tribulus Terrestris extract (Protodioscin) in normal and castrated rats.
Tribulus terrestris (TT) has long been used in the traditional Chinese and Indian systems of medicine for the treatment of various ailments and is popularly claimed to improve sexual functions in man. Sexual behaviour and intracavernous pressure (ICP) were studied in both normal and castrated rats to further understand the role of TT containing protodioscin (PTN) as an aphrodisiac. Adult Sprague-Dawley rats were divided into five groups of 8 each that included distilled water treated (normal and castrated), testosterone treated (normal and castrated, 10 mg/kg body weight, subcutaneously, bi-weekly) and TT treated (castrated, 5 mg/kg body weight, orally once daily). Decreases in body weight, prostate weight and ICP were observed among the castrated groups of rats compared to the intact group. There was an overall reduction in the sexual behaviour parameters in the castrated groups of rats as reflected by decrease in mount and intromission frequencies (MF and IF) and increase in mount, intromission, ejaculation latencies (ML, IL, EL) as well as post-ejaculatory interval (PEI). Compared to the castrated control, treatment of castrated rats (with either testosterone or TT extract) showed increase in prostate weight and ICP that were statistically significant. There was also a mild to moderate improvement of the sexual behaviour parameters as evidenced by increase in MF and IF; decrease in ML, IL and PEI. These results were statistically significant. It is concluded that TT extract appears to possess aphrodisiac activity probably due to androgen increasing property of TT (observed in our earlier study on primates).


Moderate prenatal alcohol exposure impairs performance by adult male rats in an object-place paired-associate task.
Memory impairments, including spatial and object processing, are often observed in individuals with Fetal Alcohol Spectrum Disorders. The neurobiological basis of memory deficits after prenatal alcohol exposure (PAE) is often linked to structural and functional alterations in the medial temporal lobe, including the hippocampus. Recent evidence suggests that the medial temporal lobe plays a critical role in processing high-order sensory stimuli such as complex objects and their associated locations in space. In the first experiment, we tested male rat offspring with moderate PAE in a medial temporal-dependent object-place paired-associate (OPPA) task. The OPPA task requires a conditional discrimination between an identical pair of objects presented at two spatial locations 180° opposite arms of a radial arm maze. Food reinforcement is contingent upon selecting the correct object of the pair for a given spatial location. Adult rats were given a total of 10 trials per day over 14 consecutive days of training. PAE male rats made significantly more errors than male saccharin (SACC) control rats during acquisition of the OPPA task. In Experiment 2, rats performed an object-discrimination task in which a pair of objects were presented in a single arm of the maze. Moderate PAE and SACC control rats exhibited comparable performance. The results suggest that moderate PAE rats can learn to discriminate objects, but are impaired when required to discriminate between objects on the basis of spatial location in the environment.


Dietary supplementation with S-adenosyl methionine delays the onset of motor neuron pathology in a murine model of amyotrophic lateral sclerosis.
The full range of causative factors in Amyotrophic lateral sclerosis (ALS) remains elusive, but oxidative stress is recognized as a contributing factor. Mutations in Cu/Zn superoxide dismutase 1 (SOD-1), associated with familial ALS, promote widespread oxidative damage. Mice-expressing G93A mutant human SOD-1 mice display multiple pathological changes characteristic of ALS and are therefore useful for therapeutic development. Dietary supplementation with S-adenosyl methionine (SAM) has provided multiple neuroprotective effects in mouse models of age-related cognitive pathology. We examined herein whether SAM supplementation could affect the course of motor neuron pathology in mice-expressing mutant human SOD-1. SAM delayed disease onset by 2-3 weeks. SAM also delayed hallmarks of neurodegeneration in these mice and in ALS, including preventing loss of motor neurons, and reducing gliosis, SOD-1 aggregation, protein carbonylation, and induction of antioxidant activity. SAM did not increase survival time. These preliminary findings, using a single concentration of SAM, suggest that SAM supplementation maybe useful as part of a comprehensive therapeutic approach for ALS.


TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40.
TNF receptor-associated factor (TRAF) proteins are candidate signal transducers that associate with the cytoplasmic domains of members of the tumor necrosis factor (TNF) receptor superfamily. The role of TRAFs in the TNF-R2 and CD40 signal transduction pathways, which result in the activation of transcription factor NF-kappa B, was investigated. Overexpression of TRAF2, but not TRAF1 or TRAF3, was sufficient to induce NF-kappa B activation. A truncated derivative of TRAF2 lacking an amino-terminal RING finger domain was a dominant-negative inhibitor of NF-kappa B activation mediated by TNF-R2 and CD40. Thus, TRAF2 is a common mediator of TNF-R2 and CD40 signaling.


Is it really important to form a big bubble in DALK to enhance the visual acuity?
The aim of this study was to investigate the prognosis of visual acuity (VA) in the patients with keratoconus, who underwent deep anterior lamellar keratoplasty (DALK) with a successful big bubble or lamellar dissection. Sixty-eight eyes of 60 patients with keratoconus, who underwent DALK using the big-bubble technique, were enrolled in this retrospective comparative study. The VA and refractive errors were assessed before the operation and, thereafter, at months 1, 3, 6, and 12 after the operation (1) in the patients who achieved a big-bubble formation, and in those who required layer-by-layer lamellar dissection (2) to reach the Descemet membrane. Successful big bubble was achieved in 50 eyes (73.5 %) (group 1), and lamellar dissection was performed in 18 eyes (26.5 %) (group 2). The mean follow-up period was 22.4±6.2 months in group 1 and 23.7±7.8 months in group 2 (P=0.562). Although best-corrected visual acuity (BCVA) values observed at months 1 and 3 were significantly higher in group 1 than in group 2 (P=0.016 and P=0.024, respectively), there was no statistically significant difference between the two groups for BCVA values observed at months 6 and 12 (P=0.412 and P=0.528, respectively). Although the visual recovery was delayed in the early postoperative follow-up because of residual stroma in lamellar dissection, the final results were comparable between the achievement of big-bubble formation and lamellar dissection.


The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17.
To develop a fundus photographic severity scale for age-related macular degeneration (AMD). In the Age-Related Eye Disease Study, stereoscopic color fundus photographs were taken at baseline, at the 2-year follow-up visit, and annually thereafter. Photographs were graded for drusen characteristics (size, type, area), pigmentary abnormalities (increased pigment, depigmentation, geographic atrophy), and presence of abnormalities characteristic of neovascular AMD (retinal pigment epithelial detachment, serous or hemorrhagic sensory retinal detachment, subretinal or sub-retinal pigment epithelial hemorrhage, subretinal fibrous tissue). Advanced AMD was defined as presence of 1 or more neovascular AMD abnormalities, photocoagulation for AMD, or geographic atrophy involving the center of the macula. We explored associations among right eyes of 3212 participants between severity of drusen characteristics and pigmentary abnormalities at baseline and development of advanced AMD within 5 years of follow-up. A 9-step severity scale that combines a 6-step drusen area scale with a 5-step pigmentary abnormality scale was developed, on which the 5-year risk of advanced AMD increased progressively from less than 1% in step 1 to about 50% in step 9. Among the 334 eyes that had at least a 3-step progression on the scale between the baseline and 5-year visits, almost half showed stepwise progression through intervening severity levels at intervening visits. Replicate gradings showed agreement within 1 step on the scale in 87% of eyes. The scale provides convenient risk categories and has acceptable reproducibility. Progression along it may prove to be useful as a surrogate for progression to advanced AMD.


Accumulation of p27(kip1) is associated with cyclin D3 overexpression in the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma.
The down regulation of protein p27(kip1) (p27) in most cases of thyroid cancer has relevant diagnostic and prognostic implications. However, the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma expresses more p27 than benign oxyphilic lesions do. To evaluate the mechanism underlying this difference in expression of p27. Because high levels of cyclin D3 lead to p27 accumulation in cell lines and clinical samples of thyroid cancer, the immunocytochemical pattern of cyclin D3 in oxyphilic (n = 47) and non-oxyphilic (n = 70) thyroid neoplasms was investigated. In the whole study sample, there was a significant correlation between p27 and cyclin D3 expression (Spearman's r: 0.64; p<0.001). The expression of cyclin D3 and p27 was significantly higher in the oxyphilic variant of follicular carcinomas than in non-oxyphilic carcinomas (p<0.001). In the former, cyclin D3 overexpression and p27 accumulation were observed in a median of 75% and 55% of cells, respectively. In co-immunoprecipitation experiments, the level of p27-bound cyclin D3 was much higher in oxyphilic neoplasias than in normal thyroids and other thyroid tumours. These results show that increased p27 expression in the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma results from cyclin D3 overexpression.


Use of oral contraceptives in pregnancy and major structural birth defects in offspring.
Oral contraceptives (OCs) are the most commonly used reversible contraceptive method among US women. Although the majority of previous studies have reported no association between OC use during pregnancy and birth defects, some studies have reported increased occurrence of neural tube defects, limb reduction defects, and urinary tract anomalies. We assessed OC use among mothers who participated in the multisite, case-control, National Birth Defects Prevention Study. Mothers of 9986 infants with 32 types of birth defects and 4000 infants without birth defects were included. Maternal OC use during the first 3 months of pregnancy was associated with an increased odds ratio for 2 of 32 birth defects: hypoplastic left heart syndrome (adjusted odds ratio = 2.3 [95% confidence interval = 1.3-4.3) and gastroschisis (1.8 [1.3-2.7]). Previous reports of associations between OC use and specific types of anomalies were not corroborated. Given that associations were assessed for 32 types of birth defects, our findings of 2 increased associations between OC use and gastroschisis and hypoplastic left heart syndrome should be interpreted as hypotheses until they can be evaluated further. Overall, our findings are consistent with the majority of previous studies that found women who use OCs during early pregnancy have no increased risk for most types of major congenital malformations.


Designing a sensitive and quantifiable nanocolloid assay with dielectrophoretic crossover frequencies.
Dielectrophoretic nanocolloid assay is a promising technique for sensitive molecular detection and identification, as target molecule hybridization onto the probe-functionalized nanocolloids can change their surface conductance and consequently their dielectrophoretic crossover frequencies. Thus, instead of relying on surface charge density increase after hybridization, as in many capacitive and field effect transistor impedance sensing techniques, the current assay utilizes the much larger surface conductance (and dielectrophoresis crossover frequency) changes to effect sensitive detection. Herein, we present a Poisson-Boltzmann theory for surfaces with finite-size molecular probes that include the surface probe conformation, their contribution to surface charge with a proper delineation of the slip and Stern planes. The theory shows that the most sensitive nanocolloid molecular sensor corresponds to a minimum in the dielectrophoretic crossover frequency with respect to the bulk concentration of the molecular probes (oligonucleotides in our case) during nanocolloid functionalization. This minimum yields the lowest number of functionalized probes that are also fully stretched because of surface probe-probe interaction. Our theory provides the surface-bulk oligonucleotide concentration isotherm and a folding number for the surface oligonucleotide conformation from the crossover frequency, the zeta potential, and the hydrodynamic radius data.


Integrative analysis of large scale transcriptome data draws a comprehensive landscape of Phaeodactylum tricornutum genome and evolutionary origin of diatoms.
Diatoms are one of the most successful and ecologically important groups of eukaryotic phytoplankton in the modern ocean. Deciphering their genomes is a key step towards better understanding of their biological innovations, evolutionary origins, and ecological underpinnings. Here, we have used 90 RNA-Seq datasets from different growth conditions combined with published expressed sequence tags and protein sequences from multiple taxa to explore the genome of the model diatom Phaeodactylum tricornutum, and introduce 1,489 novel genes. The new annotation additionally permitted the discovery of extensive alternative splicing in diatoms, including intron retention and exon skipping, which increase the diversity of transcripts generated in changing environments. In addition, we have used up-to-date reference sequence libraries to dissect the taxonomic origins of diatom genes. We show that the P. tricornutum genome is enriched in lineage-specific genes, with up to 47% of the gene models present only possessing orthologues in other stramenopile groups. Finally, we have performed a comprehensive de novo annotation of repetitive elements showing novel classes of transposable elements such as SINE, MITE and TRIM/LARD. This work provides a solid foundation for future studies of diatom gene function, evolution and ecology.


Healthcare Access and PrEP Continuation in San Francisco and Miami After the US PrEP Demo Project.
Pre-exposure prophylaxis (PrEP) for prevention of HIV infection has demonstrated efficacy in randomized controlled trials and in demonstration projects. For PrEP implementation to result in significant reductions in HIV incidence for men who have sex with men in the United States, sufficient access to PrEP care and continued engagement outside of demonstration projects is required. We report the results of a follow-up survey of 173 former participants from the Miami and San Francisco sites of the US PrEP Demo Project, administered 4-6 months after study completion. Survey respondents continued to frequently access medical care and had a high incidence of sexually transmitted infections after completion of the Demo Project, indicating ongoing sexual risk behavior. Interest in continuing PrEP was high with 70.8% indicating that they were "very interested" in continuing PrEP. Among respondents, 39.9% reported continuation of PrEP after completion of the Demo Project, largely through their primary care providers and frequently at low or no cost. Variability in access and engagement was seen, with participants from the San Francisco site, those with medical insurance, and those with a primary care provider at the end of the Demo Project more likely to successfully obtain PrEP medication. Two respondents reported HIV seroconversion in the period between study completion and the follow-up survey. Additional effort to increase equitable access to PrEP outside of demonstration projects is needed to realize the potential impact of this evidence-based prevention intervention.


Familial hypercholesterolemia in children and adolescents.
This review provides an update and highlights the controversies regarding recent advances and recommendations regarding screening, diagnosis and treatment of children and adolescents with familial hypercholesterolemia. Both general cardiovascular risk and specific familial hypercholesterolemia guidelines for children and adolescents have recently been released. Universal lipid screening of children has been recommended, in addition to targeted screening. The role of genetic testing for targeted screening and diagnostic confirmation is less clear. Although lifestyle therapy remains of key importance, increasing evidence of safety and efficacy support the use of statin therapy. Early therapy has been associated with improvements in noninvasive measures of early atherosclerosis in children, which likely can be extrapolated to improved freedom from cardiovascular disease events over the lifespan, as has been observed in adults. The new guidelines provide general and specific recommendations as to how family history and additional risk factors and risk conditions should be incorporated in decisions regarding initiation of statin therapy at LDL-cholesterol cutpoints. Emerging evidence from observational studies are beginning to address concerns regarding the initiation at young ages and longer-term efficacy and safety. Children and adolescents with familial hypercholesterolemia can be identified and effective therapy with a statin initiated with consideration of the patients' overall cardiovascular risk profile, remaining mindful of the uncertainties regarding long-term safety.