Subclinical diabetic neuropathy. A common complication in Saudi diabetics.
To determine the prevalence of sub clinical diabetic neuropathy in Saudi diabetics and the risk factors associated with symptomatic diabetic neuropathy. A prospective study of Saudi diabetics attending King Abdulaziz University Hospital out patient clinic from January 1998 until April 1999. Detailed information of each patients` age, sex, body mass index, type and duration of diabetes mellitus, mode of treatment, degree of blood glucose control, presence of hypertension, hyperlipidemia, smoking, family history of diabetes mellitus and hypertension were recorded. Patients were assessed for diabetic neuropathy using the Michigan Neuropathy Program. Patients who were asymptomatic and scored less than 2 on simple clinical examination were referred to a neurologist for a complete neurological examination and nerve conduction studies. A total of 237 patients were studied with a mean age of 54.19 years and mean duration of diabetes 10.6 years. Symptomatic diabetic neuropathy was present in 132 (56%) patients while subclinical neuropathy was present in 58 (57%) of asymptomatic patients. Old age, type II diabetes with long duration, poor control and smoking were risk factors associated with symptomatic diabetic neuropathy (p<0.001, p=0.09, p<0.001, p=0.04, p=0.08). Subclinical diabetic neuropathy is common. Early diagnosis is important for possible prevention of late neuropathic complications (foot ulcers and infections). Prolonged poorly controlled diabetes mellitus, old age and smoking are risk factors for symptomatic diabetic neuropathy. Meticulous blood glucose control is important for nerve function protection. Researches are urgently needed for satisfactory therapy.


Podocyte-specific RAP1GAP expression contributes to focal segmental glomerulosclerosis-associated glomerular injury.
Injury to the specialized epithelial cells of the glomerulus (podocytes) underlies the pathogenesis of all forms of proteinuric kidney disease; however, the specific genetic changes that mediate podocyte dysfunction after injury are not fully understood. Here, we performed a large-scale insertional mutagenic screen of injury-resistant podocytes isolated from mice and found that increased expression of the gene Rap1gap, encoding a RAP1 activation inhibitor, ameliorated podocyte injury resistance. Furthermore, injured podocytes in murine models of disease and kidney biopsies from glomerulosclerosis patients exhibited increased RAP1GAP, resulting in diminished glomerular RAP1 activation. In mouse models, podocyte-specific inactivation of Rap1a and Rap1b induced massive glomerulosclerosis and premature death. Podocyte-specific Rap1a and Rap1b haploinsufficiency also resulted in severe podocyte damage, including features of podocyte detachment. Over-expression of RAP1GAP in cultured podocytes induced loss of activated β1 integrin, which was similarly observed in kidney biopsies from patients. Furthermore, preventing elevation of RAP1GAP levels in injured podocytes maintained β1 integrin-mediated adhesion and prevented cellular detachment. Taken together, our findings suggest that increased podocyte expression of RAP1GAP contributes directly to podocyte dysfunction by a mechanism that involves loss of RAP1-mediated activation of β1 integrin.


Functional NMDA receptors are transiently active and support the survival of Purkinje cells in culture.
Conflicting evidence exists concerning the activity of NMDA receptors (NMDARs) in cerebellar Purkinje cells and their possible functions. To investigate the activity of NMDARS, we used whole-cell recording on immunocytochemically identified Purkinje cells in primary culture. In addition, we used mice with a disrupted NMDAR1 gene that lack functional NMDARs (NR1-/-) to assess the physiological role of NMDARs. In cultures from normal mice, NMDA-medicated currents were detected in all identified Purkinje cells at 4 d in vitro (div). After 14 d, however, NMDA responses were reduced in amplitude, whereas the responses to kainate and glutamate increased steadily in amplitude. In addition, the NMDA-induced current displayed a pronounced desensitization at these later stages; peak current declined to zero during steady application of NMDA. At 7 div, the number of surviving Purkinje cells was less in cultures treated with NMDA antagonists, and their survival was dose-dependent. Purkinje cell survival was correspondingly poorer in cultures from the NR1-/- mice than in wild-type controls, suggesting that NMDAR activity enhances the survival of Purkinje cells in vitro. The addition of moderate doses of NMDA promoted the survival of wild-type Purkinje cells in the presence of tetrodotoxin. Feeder layers of cerebellar granule cells derived from wild-type or NR1-/- mice promoted survival of Purkinje cells to a similar degree, suggesting that the NMDAR in Purkinje cells, but not in other cells, is directly involved in Purkinje cell viability. The results demonstrate that NMDARs transiently produce membrane current in Purkinje cells and may serve as one of the epigenetic factors that support the survival of Purkinje cells in vitro.


Inhibition of the activation and troponin calcium binding of dog cardiac myofibrils by acidic pH.
The aim of experiments described here was to test whether deactivation of cardiac myofibrils in acidic pH is associated with decreases in amounts of calcium bound to myofilament troponin. We determined the amounts of myofibrillar bound calcium attributable to troponin, from measurements of calcium binding to myofibrils and to myosin and from determination of the troponin C content of the myofibrillar preparations (0.40 nmol troponin C/mg protein). In measurements done at 2 mM free magnesium, 2 mM (magnesium-adenosine triphosphate, ionic strength 0.12, 22 degrees C, the pCa50 (-log of the half maximally activating molar free calcium) for myofibrillar magnesium-adenosine triphosphatase activity was 5.87 at pH 7.0, 5.49 at pH 6.5, and 5.04 at pH 6.2. This change in calcium sensitivity of myofibrillar magnesium-adenosine triphosphatase activity was present whether or not ethyleneglycol-bis(beta-aminoethyl ether)-N, N'-tetraacetic acid, was used to buffer the free calcium and whether or not myofibrillar troponin I had been phosphorylated by cyclic adenosine 3',5'-monophosphate-dependent protein kinase. However, the change in pCa50 of myofibrillar adenosine triphosphatase activity induced by acidic pH, was greater when free magnesium was reduced from 2.0 to 0.05 mM, and less when free magnesium was increased from 2.0 mM to 10 and 15 mM. The change in pCa50 with acidic pH was less if the ionic strength was reduced from 0.12 to 0.035 M. The magnesium-adenosine triphosphatase activity of troponin/tropomyosin-free myofibrils was independent of pCa and unaffected by a reduction of pH from 7.0 to 6.5. The affinity of myofibrillar troponin C for calcium decreased as pH was reduced from 7.0 to 6.5 and to 6.2 with and without ethyleneglycolbis(beta-aminoethyl ether)-N,N'-tetraacetic acid, and in a manner predicted from the effect of acidic pH on pCa50 for myofibrillar activation. Our results are consistent with the idea that at least part of the mechanism responsible for deactivation of the adenosine triphosphatase activity of cardiac myofilaments in acidic pH is a reduction in the affinity of myofibrillar troponin C for calcium.


The DUNDRUM Quartet: validation of structured professional judgement instruments DUNDRUM-3 assessment of programme completion and DUNDRUM-4 assessment of recovery in forensic mental health services.
Moving a forensic mental health patient from one level of therapeutic security to a lower level or to the community is influenced by more than risk assessment and risk management. We set out to construct and validate structured professional judgement instruments for consistency and transparency in decision making Two instruments were developed, the seven-item DUNDRUM-3 programme completion instrument and the six item DUNDRUM-4 recovery instrument. These were assessed for all 95 forensic patients at Ireland's only forensic mental health hospital. The two instruments had good internal consistency (Cronbach's alpha 0.911 and 0.887). Scores distinguished those allowed no leave or accompanied leave from those with unaccompanied leave (ANOVA F = 38.1 and 50.3 respectively, p < 0.001). Scores also distinguished those in acute/high security units from those in medium or in low secure/pre-discharge units. Each individual item distinguished these levels of need significantly. The DUNDRUM-3 and DUNDRUM-4 correlated moderately with measures of dynamic risk and with the CANFOR staff rated unmet need (Spearman r = 0.5, p < 0.001). The DUNDRUM-3 programme completion items distinguished significantly between levels of therapeutic security while the DUNDRUM-4 recovery items consistently distinguished those given unaccompanied leave outside the hospital and those in the lowest levels of therapeutic security. This data forms the basis for a prospective study of outcomes now underway.


DNA fingerprinting and anastomosis grouping reveal similar genetic diversity in Rhizoctonia species infecting turfgrasses in the transition zone of USA.
Rhizoctonia blight is a common and serious disease of many turfgrass species. The most widespread causal agent, Thanatephorus cucumeris (anamorph: R. solani), consists of several genetically different subpopulations. In addition, Waitea circinata varieties zeae, oryzae and circinata (anamorph: Rhizoctonia spp.) also can cause the disease. Accurate identification of the causal pathogen is important for effective management of the disease. It is challenging to distinguish the specific causal pathogen based on disease symptoms or macroscopic and microscopic morphology. Traditional methods such as anastomosis reactions with tester isolates are time consuming and sometimes difficult to interpret. In the present study universally primed PCR (UP-PCR) fingerprinting was used to assess genetic diversity of Rhizoctonia spp. infecting turfgrasses. Eighty-four Rhizoctonia isolates were sampled from diseased turfgrass leaves from seven distinct geographic areas in Virginia and Maryland. Rhizoctonia isolates were characterized by ribosomal DNA internal transcribed spacer (rDNA-ITS) region and UP-PCR. The isolates formed seven clusters based on ITS sequences analysis and unweighted pair group method with arithmetic mean (UPGMA) clustering of UP-PCR markers, which corresponded well with anastomosis groups (AGs) of the isolates. Isolates of R. solani AG 1-IB (n = 18), AG 2-2IIIB (n = 30) and AG 5 (n = 1) clustered separately. Waitea circinata var. zeae (n = 9) and var. circinata (n = 4) grouped separately. A cluster of six isolates of Waitea (UWC) did not fall into any known Waitea variety. The binucleate Rhizoctonia-like fungi (BNR) (n = 16) clustered into two groups. Rhizoctonia solani AG 2-2IIIB was the most dominant pathogen in this study, followed by AG 1-IB. There was no relationship between the geographic origin of the isolates and clustering of isolates based on the genetic associations. To our knowledge this is the first time UP-PCR was used to characterize Rhizoctonia, Waitea and Ceratobasidium isolates to their infra-species level.


A role for mesenchyme-derived tachykinins in tooth and mammary gland morphogenesis.
Tachykinin peptides such as substance P (SP) function as neurotransmitters and neuromodulators in the mammalian central and peripheral nervous systems. Here, we provide evidence that they may also play an important role in the morphogenesis of some nonneural organs where epithelial-mesenchymal interactions are involved. We show the following. (1) mRNA encoding tachykinin precursor proteins is expressed transiently in condensing mesenchyme during the development of mouse tooth germ, mammary gland, limb bud, external auditory meatus and genital tubercle. (2) In developing tooth germ and mammary gland; mRNA encoding the neutral endopeptidase (NEP) that degrades secreted tachykinins is spatially and temporally co-expressed with tachykinin precursor mRNA. (3) SP and the mRNA encoding SP receptors are also expressed in the developing tooth germ. (4) Tooth development in explant cultures is blocked both by tachykinin-precursor-specific antisense oligonucleotide and by an SP receptor antagonist: in both cases the block is relieved by exogenous SP. Together, these findings suggest a surprising new role for tachykinins in tooth and mammary gland morphogenesis, and possibly also in limb, ear and external genitalia morphogenesis.


Fetal-maternal outcomes and complications in pregnant women with polycystic ovary syndrome.
Earlier studies have shown that polycystic ovary syndrome (PCOS) is associated with cardiovascular disease as well as pregnancy complications. We examined whether women with PCOS have an increased risk of complications in pregnancy compared with healthy women, and if there are any correlations between complications and clinical/demographic variables before and/or in early pregnancy. This retrospective cohort study comprised 37 women with PCOS and 126 healthy women whose birth was recorded at Sundsvall County Hospital, Sweden, from 2009 to 2014. Medical records were searched to identify pregnancy complications, maternal outcomes, and neonatal outcomes. Compared with healthy women, the women with PCOS were more likely to have a history of miscarriage (42.9% vs. 19.8% P=0.005) and undergo caesarean section (41.2% vs. 21.4%, P=0.019). They were also at increased risk of developing a complication (odds ratio 2.38, 95% CI: 1.05-5.38) or having multiple concurrent complications (odds ratio 8.27, 95% CI: 1.45-47.3). The rates of premature birth, birth weight and Apgar score at 5 min were similar between the two groups. The preconception serum testosterone concentration was positively correlated with the complication rate and negatively correlated with gestational age. We found that women with PCOS are at greater risk of complications during pregnancy than healthy women, consistent with the results of earlier studies. High testosterone concentrations could be an aggravating factor in the risk of complications. Therefore, women with PCOS may require more careful monitoring during pregnancy than healthy women.


Sequence diversity of TT virus in geographically dispersed human populations.
TT virus (TTV) is a newly discovered DNA virus originally classified as a member of the Parvoviridae. TTV is transmitted by blood transfusion where it has been reported to be associated with mild post-transfusion hepatitis. TTV can cause persistent infection, and is widely distributed geographically; we recently reported extremely high prevalences of viraemia in individuals living in tropical countries (e.g. 74% in Papua New Guinea, 83% in Gambia; Prescott & Simmonds, New England Journal of Medicine 339, 776, 1998). In the current study we have compared nucleotide sequences from the N22 region of TTV (222 bases) detected in eight widely dispersed human populations. Some variants of TTV, previously classified as genotypes 1a, 1b and 2, were widely distributed throughout the world, while others, such as a novel subtype of type 1 in Papua New Guinea, were confined to a single geographical area. Five of the 122 sequences obtained in this study (from Gambia, Nigeria, Papua New Guinea, Brazil and Ecuador) could not be classified as types 1, 2 or 3, with the variant from Brazil displaying only 46-50% nucleotide (32-35% amino acid) sequence similarity to other variants. This study provides an indication of the extreme sequence diversity of TTV, a characteristic which is untypical of parvoviruses.


Use of sedative drugs at reducing the side effects of voiding cystourethrography in children.
Imaging of the kidneys and urinary tract has a significant and critical role for diagnosis of genitourinary system diseases. Although technological progress goes toward less invasive approaches, some of the current methods are still invasive and annoying. Voiding cystourethrography (VCUG) is the best and most accurate method for diagnosis and grading of vesicoureteral reflux. VCUG is a distressful procedure that gives serious anxiety and pain in a large proportion of children and fear for parents; therefore, using effective sedative drugs with the least side effects is necessary and should be considered. In this review article, importance and efficacy of different drugs before catheterization VCUG be compared in the base of literature survey on EMBASE, PubMed, and Cochrane source. We found that the treatment should be based on nonpharmacological and pharmacological methods; nonpharmacological treatment includes the psychological preparation before procedures as a safety precaution with little or no risk modality, as well as reassuring support. The presence of parents during painful procedures cannot alleviate children distress. Pharmacological methods include oral midazolam (0.5 mg/kg) and intranasal use (0.2 mg/kg) that had been used 10 min before the procedure can effect on anterograde amnesia and sedation without considerable effect on accuracy and grade of reflux. Nitric oxide has a shorter recovery time versus midazolam but has a potential risk for deep sedation and may interfere with the child's voiding phase. In summary, oral midazolam of 0.5-0.6 mg/kg or 0.2 mg/kg intranasal is acceptable drug that can be used before VCUG.


Rationale, design, and sample characteristics of a practical randomized trial to assess a weight loss intervention for low-income women: the Weight-Wise II Program.
Obesity is common among low-income mid-life women, yet most published weight loss studies have not focused on this population and have been highly resourced efficacy trials. Thus, practical type 2 translational studies are needed to evaluate weight loss interventions for low-income women. In this paper, we present the rationale, study design, and baseline characteristics of a type 2 translational study that evaluates both the processes and outcomes of a weight loss intervention for low-income women given at 6 county health departments in North Carolina. Key features of this study include random selection of study sites, intervention delivery by current staff at study sites, efforts to integrate the intervention with local community resources, a focus on evaluating the processes of translation using the RE-AIM framework, use of an evidence-based weight loss intervention, a detailed description of participant recruitment and representativeness, and a practical randomized trial designed to assess the effectiveness of the intervention. Of 81 health departments invited to participate, 30 (37%) were eligible and willing, and 6 were selected at random to deliver the intervention. Of 432 potential participants screened by phone, 213 (49%) were eligible and of these, 189 (89%) completed baseline measures and were randomized to receive a 5-month weight loss intervention or a delayed intervention. The mean age was 51, mean BMI 37 kg/m(2), 53% were African American, and 43% had no health insurance. The results of this study should be informative to key stakeholders interested in real world weight loss interventions for low-income mid-life women.


Beaten and poor? A study of the long-term economic situation of women victims of severe violence.
This 10-year follow-up study based on Swedish national registers compares the economic situation of women victims of violence leading to hospitalization (n = 6,085) to nonexposed women (n = 55,016) in 1992 to 2005. Women exposed to severe violence had a poorer financial situation prior to the assault. Violence seems to heavily reinforce this pattern, indicating a continued need of support from the social work profession. Assaulted women had a worse income development, lower odds for being in employment, and higher odds for having low incomes and means tested social assistance during the 10-year follow-up, independent of having children or not.


The German East-West Mortality Difference: Two Crossovers Driven by Smoking.
Before the fall of the Berlin Wall, mortality was considerably higher in the former East Germany than in West Germany. The gap narrowed rapidly after German reunification. The convergence was particularly strong for women, to the point that Eastern women aged 50-69 now have lower mortality despite lower incomes and worse overall living conditions. Prior research has shown that lower smoking rates among East German female cohorts born in the 1940s and 1950s were a major contributor to this crossover. However, after 1990, smoking behavior changed dramatically, with higher smoking intensity observed among women in the eastern part of Germany. We forecast the impact of this changing smoking behavior on East-West mortality differences and find that the higher smoking rates among younger East German cohorts will reverse their contemporary mortality advantage. Mortality forecasting methods that do not account for smoking would, perhaps misleadingly, forecast a growing mortality advantage for East German women. Experience from other countries shows that smoking can be effectively reduced by strict anti-smoking policies. Instead, East Germany is becoming an example warning of the consequences of weakening anti-smoking policies and changing behavioral norms.


Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis.
To evaluate the associations between (1) antidrug antibody (ADAb) and therapeutic response, (2) ADAb and serum drug trough levels and (3) serum drug levels and therapeutic responses in rheumatoid arthritis (RA) patients receiving adalimumab or etanercept. Secondarily, we aim (1) to evaluate the concordance between radioimmunoassay and bridging ELISA for ADAb assessment and to evaluate the correlation between two different ELISA methods for detecting drug levels, and (2) to determine the optimal cut-off drug levels for good European League Against Rheumatism (EULAR) response. ADAb levels were determined by bridging ELISA and radioimmunoassay, and drug levels evaluated using sandwich ELISA among 36 adalimumab-treated patients and 34 etanercept-treated patients at the 6th and 12th month. The optimal cut-off drug levels for EULAR responses were determined by receiver-operating characteristic curve analysis. ADAb was detected in 10 (27.8%) and 13 (36.1%) of adalimumab-treated patients after 12-month therapy using bridging ELISA and radioimmunoassay respectively, but not detected in any of etanercept-treated patients. The presence of ADAb was associated with lower EULAR response and lower drug levels compared with those without ADAb (both p<0.001). Drug trough levels were positively associated with DAS28 decrement (ΔDAS28) (all p<0.001). The optimal cut-off trough levels for adalimumab were 1.274 μg/mL and 1.046 μg/mL, and those for etanercept were 1.242 μg/mL and 0.800 μg/mL for good EULAR response assessed at the 6th and 12th month, respectively. ADAb levels were inversely correlated with therapeutic response and drug levels. The positive correlation between drug levels and ΔDAS28 indicates that drug monitoring would be useful to evaluate therapeutic response of TNF-α inhibitors.


Spectrin tethers and mesh in the biosynthetic pathway.
The paradox of how the Golgi and other organelles can sort a continuous flux of protein and lipid but maintain temporal and morphological stability remains unresolved. Recent discoveries highlight a role for the cytoskeleton in guiding the structure and dynamics of organelles. Perhaps one of the more striking, albeit less expected, of these discoveries is the recognition that a spectrin skeleton associates with many organelles and contributes to the maintenance of Golgi structure and the efficiency of protein trafficking in the early secretory pathway. Spectrin interacts directly with phosphoinositides and with membrane proteins. The small GTPase ARF, a key player in Golgi dynamics, regulates the assembly of the Golgi spectrin skeleton through its ability to control phosphoinositide levels in Golgi membranes, whereas adapter molecules such as ankyrin link spectrin to other membrane proteins. Direct interactions of spectrin with actin and centractin (ARP1) provide a link to dynein, myosin and presumably other motors involved with intracellular transport. Building on the recognized ability of spectrin to organize macromolecular complexes of membrane and cytosolic proteins into a multifaceted scaffold linked to filamentous structural elements (termed linked mosaics), recent evidence supports a similar role for spectrin in organelle function and the secretory pathway. Two working models accommodate much of the available data: the Golgi mesh hypothesis and the spectrin ankyrin adapter protein tethering system (SAATS) hypothesis.


Dynamics of Transcription Factor Binding Site Evolution.
Evolution of gene regulation is crucial for our understanding of the phenotypic differences between species, populations and individuals. Sequence-specific binding of transcription factors to the regulatory regions on the DNA is a key regulatory mechanism that determines gene expression and hence heritable phenotypic variation. We use a biophysical model for directional selection on gene expression to estimate the rates of gain and loss of transcription factor binding sites (TFBS) in finite populations under both point and insertion/deletion mutations. Our results show that these rates are typically slow for a single TFBS in an isolated DNA region, unless the selection is extremely strong. These rates decrease drastically with increasing TFBS length or increasingly specific protein-DNA interactions, making the evolution of sites longer than ∼ 10 bp unlikely on typical eukaryotic speciation timescales. Similarly, evolution converges to the stationary distribution of binding sequences very slowly, making the equilibrium assumption questionable. The availability of longer regulatory sequences in which multiple binding sites can evolve simultaneously, the presence of "pre-sites" or partially decayed old sites in the initial sequence, and biophysical cooperativity between transcription factors, can all facilitate gain of TFBS and reconcile theoretical calculations with timescales inferred from comparative genomics.


Right coronary artery from the left sinus of valsalva: Multislice CT and transradial PCI.
A 42-year-old-woman presented with de novo crescendo angina. Thallium-scintigraphy showed inferior ischemia. Coronary angiogram revealed a right coronary artery (RCA), originating from the left sinus of Valsalva with a severe proximal systolic compression. She underwent successful transradial percutaneous coronary intervention with stent implantation. Multislice-computed tomography (MSCT) is usually used to evaluate coronary artery anomalies and can effectively show the anomalous RCA and the inter-arterial trajectory between the aorta and pulmonary arteries. Anomalies of the origin of the coronary arteries are rare, but can produce specific clinicopathological entities that should be diagnosed with accuracy. This case report illustrates the role of MSCT in the detailed description of an abnormal coronary artery and the use of stenting for symptoms relief.


Social epidemiology of hypertension in Buffalo City Metropolitan Municipality (BCMM): cross-sectional study of determinants of prevalence, awareness, treatment and control among South African adults.
This study examined hypertension prevalence, awareness, treatment and control and their determinants among adults attending health facilities in Buffalo City Metropolitan Municipality (BCMM) in the Eastern Cape. A cross-sectional analytical study. The three largest outpatient clinics in BCMM. Ambulatory adults (aged 18 years and over) attending the study settings during the study period (n=998). The prevalence of hypertension (systolic blood pressure (BP) of ≥140 mm Hg and/or a diastolic BP of ≥90 mm Hg or current medication for hypertension), the awareness of it (prior diagnosis of it) and its treatment and control (Eighth Joint National Committee Criteria of BP <140/90/90 mm Hg). Associated factors of hypertension, hypertension unawareness and uncontrolled hypertension. Of the 998 participants included, the prevalence of hypertension was 49.2%. Hypertension unawareness was reported by 152 participants (23.1%) with significant gender difference (p=0.005). Male sex, age <45 years, higher level of education, single status, current employment, higher monthly income, current smoking, alcohol usage, absence of diabetes and non-obese were significantly associated (p<0.05) with hypertension unawareness.Of the participants who were aware of having hypertension (n=339), nearly all (91.7%, n=311) were on antihypertensive medication and only 121 participants (38.9%) achieved the BP treatment target. In the multivariate logistic regression model analysis, ageing (95% CI 1.9 to 4.4), being married (95% CI 1.0 to 2.0), male sex (95% CI 1.2 to 2.3), concomitant diabetes (95% CI 1.9 to 3.9), lower monthly income (95% CI 1.2 to 2.2), being unemployed (95% CI 1.0 to 1.9) and central obesity (95% CI 1.5 to 2.8) were the significant and independent determinants of prevalent hypertension. The prevalence and awareness of hypertension was high in the study population. In addition, the suboptimal control of BP among treated individuals, as well as the significant cardiovascular risk factors, warrant the attention of health authorities of BCMM and the country.


Early-onset axonal pathology in a novel P301S-Tau transgenic mouse model of frontotemporal lobar degeneration.
Tau becomes hyperphosphorylated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-tau), resulting in functional deficits of neurones, neurofibrillary tangle (NFT) formation and eventually dementia. Expression of mutant human tau in the brains of transgenic mice has produced different lines that recapitulate various aspects of FTLD-tau and AD. In this study, we characterized the novel P301S mutant tau transgenic mouse line, TAU58/2. Both young and aged TAU58/2 mice underwent extensive motor testing, after which brain tissue was analysed with immunohistochemistry, silver staining, electron microscopy and Western blotting. Tissue from various FTLD subtypes and AD patients was also analysed for comparison. TAU58/2 mice presented with early-onset motor deficits, which became more pronounced with age. Throughout the brains of these mice, tau was progressively hyperphosphorylated resulting in increased NFT formation with age. In addition, frequent axonal swellings that stained intensively for neurofilament (NF) were present in young TAU58/2 mice prior to NFT formation. Similar axonal pathology was also observed in human FTLD-tau and AD. Interestingly, activated microglia were found in close proximity to neurones harbouring transgenic tau, but were not associated with NF-positive axonal swellings. In TAU58/2 mice, early tau pathology induces functional deficits of neurones associated with NF pathology. This appears to be specific to tau, as similar changes are observed in FTLD-tau, but not in FTLD with TDP-43 inclusions. Therefore, TAU58/2 mice recapitulate aspects of human FTLD-tau and AD pathology, and will become instrumental in studying disease mechanisms and therapeutics in the future.


BRIEF: Computing a Local Binary Descriptor Very Fast.
Binary descriptors are becoming increasingly popular as a means to compare feature points very fast while requiring comparatively small amounts of memory. The typical approach to creating them is to first compute floating-point ones, using an algorithm such as SIFT, and then to binarize them. In this paper, we show that we can directly compute a binary descriptor, which we call BRIEF, on the basis of simple intensity difference tests. As a result, BRIEF is very fast both to build and to match. We compare it against SURF and SIFT on standard benchmarks and show that it yields comparable recognition accuracy, while running in an almost vanishing fraction of the time required by either.


Principles that underpin effective school-based drug education.
This study identifies the conceptual underpinnings of effective school-based drug education practice in light of contemporary research evidence and the practical experience of a broad range of drug education stakeholders. The research involved a review of the literature, a national survey of 210 Australian teachers and others involved in drug education, and structured interviews with 22 key Australian drug education policy stakeholders. The findings from this research have been distilled and presented as a list of 16 principles that underpin effective drug education. In broad terms, drug education should be evidence-based, developmentally appropriate, sequential, and contextual. Programs should be initiated before drug use commences. Strategies should be linked to goals and should incorporate harm minimization. Teaching should be interactive and use peer leaders. The role of the classroom teacher is central. Certain program content is important, as is social and resistance skills training. Community values, the social context of use, and the nature of drug harm have to be addressed. Coverage needs to be adequate and supported by follow-up. It is envisaged that these principles will provide all those involved in the drug education field with a set of up-to-date, research-based guidelines against which to reference decisions on program design, selection, implementation, and evaluation.


Medication adherence challenges among HIV positive substance abusers: the role of food and housing insecurity.
This study examines the prevalence of food/housing insecurity and its association with psychological, behavioral, and environmental factors impacting antiretroviral (ARV) medication adherence and diversion among substance using HIV+ patients in South Florida. Five hundred and three HIV+ substance abusers were recruited through targeted sampling. Participants completed a standardized instrument assessing demographics, mental health status, sex risk behaviors, HIV diagnosis, treatment history and access, ARV adherence and diversion, and attitudes toward health-care providers. Chi-square and t-tests were used to examine differences by food/housing status and a multivariate linear regression model examined food/housing insecurity and its associations to ARV adherence. Food/housing insecurity was reported by 43.3% of the sample and was associated with higher likelihood of severe psychological distress and substance dependence. Nearly 60% reported recent ARV diversion; only 47.2% achieved 95% medication adherence over one week. Food/housing insecure participants had deficits in their HIV care, including less time in consistent care, lower access to medical care, and less favorable attitudes toward care providers. Multivariate linear regression showed food/housing insecurity demonstrated significant main effects on adherence, including lower past week adherence. Medication diversion was also associated with reduced adherence. Our findings suggest that food/housing insecurity operates as a significant driver of ARV non-adherence and diversion in this population. In the pursuit of better long-term health outcomes for vulnerable HIV+ individuals, it is essential for providers to understand the role of food and housing insecurity as a stressor that negatively impacts ARV adherence and treatment access, while also significantly contributing to higher levels of distress and substance dependence.


The utility of the historical record for assessing the transient climate response to cumulative emissions.
The historical observational record offers a way to constrain the relationship between cumulative carbon dioxide emissions and global mean warming. We use a standard detection and attribution technique, along with observational uncertainties to estimate the all-forcing or 'effective' transient climate response to cumulative emissions (TCRE) from the observational record. Accounting for observational uncertainty and uncertainty in historical non-CO2 radiative forcing gives a best-estimate from the historical record of 1.84°C/TtC (1.43-2.37°C/TtC 5-95% uncertainty) for the effective TCRE and 1.31°C/TtC (0.88-2.60°C/TtC 5-95% uncertainty) for the CO2-only TCRE. While the best-estimate TCRE lies in the lower half of the IPCC likely range, the high upper bound is associated with the not-ruled-out possibility of a strongly negative aerosol forcing. Earth System Models have a higher effective TCRE range when compared like-for-like with the observations over the historical period, associated in part with a slight underestimate of diagnosed cumulative emissions relative to the observational best-estimate, a larger ensemble mean-simulated CO2-induced warming, and rapid post-2000 non-CO2 warming in some ensemble members.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.


Detecting coalitions by optimally partitioning signed networks of political collaboration.
We propose new mathematical programming models for optimal partitioning of a signed graph into cohesive groups. To demonstrate the approach's utility, we apply it to identify coalitions in US Congress since 1979 and examine the impact of polarized coalitions on the effectiveness of passing bills. Our models produce a globally optimal solution to the NP-hard problem of minimizing the total number of intra-group negative and inter-group positive edges. We tackle the intensive computations of dense signed networks by providing upper and lower bounds, then solving an optimization model which closes the gap between the two bounds and returns the optimal partitioning of vertices. Our substantive findings suggest that the dominance of an ideologically homogeneous coalition (i.e. partisan polarization) can be a protective factor that enhances legislative effectiveness.


Aggravation of necrotic death of glucose-deprived cells by the MEK1 inhibitors U0126 and PD184161 through depletion of ATP.
The extracellular-regulated kinases (ERK) modulate cell proliferation and survival in response to several different stimuli and are therefore important drug targets. ERKs are activated by the dual phosphorylation kinase MEK1 and MEK1 inhibitors PD98059, U0126 and CI-1040 are now widely used to inhibit ERKs in cell and animal studies. In an analysis of ERK functions in astrocytes we found that PD98059 (100microM) failed to inhibit ERK phosphorylation but U0126 (50microM) inhibited ERK phosphorylation to approximately 80%. Surprisingly, U0126 also caused profound depletion of ATP in glucose-deprived cells, leading to death by necrosis. Since glucose-deprived cells depend mainly on mitochondrial ATP-synthase for ATP production, we tested whether U0126 or PD184161, a derivative of CI-1040, might inhibit ATP synthase activity, using 143B(Rho0) cells (which lack a functional F0 subunit) to further parse this effect. We found that the F1F0ATPase activity extracted from U0126- or PD184161-treated parental 143B cells or astrocytes was indeed inhibited by >or=80% suggesting a covalent change in the enzyme. However, F1F0ATPase activity extracted from similarly treated 143B(Rho0) cells was spared. Because F1F0ATPase activity in isolated mitochondria was not inhibited directly, we propose that U0126 and PD184161 inhibit ATP-synthase via an indirect action on F0. The MEK1 inhibitors also induced necrosis of other glucose-deprived cell types including primary neurons at the same concentrations required for inhibition of ERK phosphorylation. Thus, the MEK1/ERK signalling pathway may modulate ATP synthase function, and its inhibition may cause cells unable to perform glycolysis to die by necrosis.


Investigation of interface states in single-negative metamaterial layered structures based on the phase properties.
The physical mechanism of the interface states in layered structures consisting of single-negative metamaterials is investigated using a simple resonant cavity model. We found that the interface states and their corresponding tunneling transmission modes appeared when the resonant condition is satisfied. Such resonant condition depends on the phase changes inside the resonant cavity. Based on these results, we proposed an efficient method to precisely predict the frequencies of the tunneling interface states inside the single-negative metamaterial layers. Our method is effective for interface states corresponding to perfect or imperfect tunneling transmission. Composite right/left-handed transmission lines were used to realize the pair and sandwich metamaterial layered structures in the microwave region. Electromagnetic tunneling interface states were observed in the measurements, which agreed well with the theory. Our study offers a way for effectively designing metamaterial devices with novel electromagnetic tunneling properties.


Flow cytometric analysis of transmembrane phospholipid movement in bull sperm.
Fluorescent phospholipids are useful to investigate phospholipid dynamics in biological membranes. We used flow cytometry to investigate transbilayer phospholipid movement in live sperm cells. Acyl-labeled N-4-nitrobenzo-2-oxa-1,3-diazole (NBD) -phosphatidylcholine (-PC), -phosphatidylethanolamine (-PE), or -phosphatidylserine (-PS) were incorporated into sperm cells, and the transbilayer location was determined by extraction of probe from cell with excess bovine serum albumin (BSA) or by chemical destruction of probe by sodium dithionite. Using these methods, we have measured the head group specific outer leaflet to inner leaflet movement (flip) of the aminophospholipids NBD-PS and NBD-PE. The fluorescent phospholipids moved inward across the plasma membrane with half-times of 1.8, 2.5, and 11.2 min, for NBD-PS, NBD-PE, and NBD-PC and reached apparent equilibrium levels of 88%, 94%, and 32% inside, respectively. The inward movement of NBD-PE was inhibited by sulfhydryl reagents, elevated intracellular Ca2+, and depletion of cellular ATP. Analysis of the kinetics of NBD-PE and -PS extraction by BSA allows determination of the rates for outward movement (flop) across the plasma membrane. Half-times for flop were 4.7 and 4.5 min for NBD-PS and -PE, respectively. Based on these measurements, a simple model of NBD-phospholipid equilibria was developed and fit to the kinetic data. Computer-generated fits reflected major features of the experimental data and provide a potential tool for predicting the dynamics of endogenous lipids.


Theoretical and experimental investigation of compatible SSB modulation for single channel long-distance optical OFDM transmission.
We present the first experimental demonstration of compatible single-sideband (compatible-SSB) modulated OFDM optical system at 11.1Gb/s data rate for long distance transmission over 675 km uncompensated standard single-mode fiber. Compatible-SSB modulation employing a simple dual-drive Mach-Zehnder modulator (MZM) in the transmitter and direct-detection at the receiver provides an OFDM system implementation with reduced complexity. It does not require a guard-band between the carrier and the OFDM sideband and so makes full use of available digital-to-analog converter (DAC) bandwidth. We demonstrate digital pre-compensation applied in the transmitter to correct MZM nonlinear transfer function and to improve the system transmission performance. We show that optimum modulation index value decreases with increasing transmission distance. We have also investigated the impact of self-phase modulation (SPM) on the system performance, and show that a compatible-SSB modulated system is less vulnerable to SPM in comparison to the conventional offset-SSB modulation at the same data rate.


Plasma cannabinoid concentrations during dronabinol pharmacotherapy for cannabis dependence.
Recently, high-dose oral synthetic delta-9-tetrahydrocannabinol (THC) was shown to alleviate cannabis withdrawal symptoms. The present data describe cannabinoid pharmacokinetics in chronic, daily cannabis smokers who received high-dose oral THC pharmacotherapy and later a smoked cannabis challenge. Eleven daily cannabis smokers received 0, 30, 60, or 120 mg/d THC for four 5-day medication sessions, each separated by 9 days of ad libitum cannabis smoking. On the fifth day, participants were challenged with smoking one 5.9% THC cigarette. Plasma collected on the first and fifth days was quantified by two-dimensional gas chromatography mass spectrometer for THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). Linear ranges (ng/mL) were 0.5-100 for THC, 1-50 for 11-OH-THC, and 0.5-200 for THCCOOH. During placebo dosing, THC, 11-OH-THC, and THCCOOH concentrations consistently decreased, whereas all cannabinoids increased dose dependently during active dronabinol administration. THC increase over time was not significant after any dose, 11-OH-THC increased significantly during the 60- and 120-mg/d doses, and THCCOOH increased significantly only during the 120-mg/d dose. THC, 11-OH-THC, and THCCOOH concentrations peaked within 0.25 hours after cannabis smoking, except after 120 mg/d THC when THCCOOH peaked 0.5 hours before smoking. The significant withdrawal effects noted during placebo dronabinol administration were supported by significant plasma THC and 11-OH-THC concentration decreases. During active dronabinol dosing, significant dose-dependent increases in THC and 11-OH-THC concentrations support withdrawal symptom suppression. THC concentrations after cannabis smoking were only distinguishable from oral THC doses for 1 hour, too short a period to feasibly identify cannabis relapse. THCCOOH/THC ratios were higher 14 hours after overnight oral dronabinol abstinence but cannot distinguish oral THC dosing from the smoked cannabis intake.


Signal sequence analysis of protein sequences from the filarial nematode parasite Brugia malayi and the evolution of secreted proteins in parasites.
Taking a genomic approach to characterize potential secreted products, we analyzed putative protein sequences from Brugia malayi whole-genome shotgun sequencing project. SignalP analysis was applied to predict protein sequences and to identify potential signal peptides and anchors. We randomly analyzed 552 sequences, of which 88 (15.9%) bear predicted signal sequence coding regions. Through comparisons of sequences with homologs from other species, we found that although some of the sequences with signal sequences have no homologs with others, there are almost the same amounts of the sequences with signals which are highly conserved. Considering the distribution of secretory proteins of B. malayi in three categories has not made big differences, and most of the homologues of free-living nematodes of these secretory proteins also contained either N-signal signal peptides or signal anchors; we speculated that secretory proteins may be in the same evolutional status as the non-secretory proteins.


Cutaneous inputs from the back abolish locomotor-like activity and reduce spastic-like activity in the adult cat following complete spinal cord injury.
Spasticity is a condition that can include increased muscle tone, clonus, spasms, and hyperreflexia. In this study, we report the effect of manually stimulating the dorsal lumbosacral skin on spontaneous locomotor-like activity and on a variety of reflex responses in 5 decerebrate chronic spinal cats treated with clonidine. Cats were spinalized 1 month before the terminal experiment. Stretch reflexes were evoked by stretching the left triceps surae muscles. Crossed reflexes were elicited by electrically stimulating the right tibial or superficial peroneal nerves. Wind-up of reflex responses was evoked by electrically stimulating the left tibial or superficial peroneal nerves. We found that pinching the skin of the back abolished spontaneous locomotor-like activity. We also found that back pinch abolished the rhythmic activity observed during reflex testing without eliminating the reflex responses. Some of the rhythmic episodes of activity observed during reflex testing were consistent with clonus with an oscillation frequency greater than 3 Hz. Pinching the skin of the back effectively abolished rhythmic activity occurring spontaneously or evoked during reflex testing, irrespective of oscillation frequency. The results are consistent with the hypothesis that locomotion and clonus are produced by common central pattern-generators. Stimulating the skin of the back could prove helpful in managing undesired rhythmic activity in spinal cord-injured humans.


Solid-state characterization of nevirapine.
The purpose of this investigation is to characterize nevirapine from commercial samples and samples crystallized from different solvents under various conditions. The solid-state behavior of nevirapine samples was investigated using a variety of complementary techniques such as microscopy (optical, polarized, hot stage microscopy), differential scanning calorimeter, thermogravimetric analysis, Fourier transform infrared spectroscopy and powder X-ray diffractometry. The commercial samples of nevirapine had the same polymorphic crystalline form with an anhedral crystal habit. Intrinsic dissolution of nevirapine was similar for both the commercial batches. Powder dissolution showed pH dependency, with maximum dissolution in acidic pH and there was no significant effect of particle size. The samples recrystallized from different solvent systems with varying polarity yielded different crystal habits. Stirring and degrees of supersaturation influenced the size and shape of the crystals. The recrystallized samples did not produce any new polymorphic form, but weak solvates with varying crystal habit were produced. Recrystallized samples showed differences in the x-ray diffractograms. However, all the samples had the same internal crystal lattice as revealed from their similar melting points and heat of fusion. The intrinsic dissolution rate of recrystallized samples was lower than the commercial sample. It was found that the compression pressure resulted in desolvation and partial conversion of the crystal form. After compression, the recrystallized samples showed similar x-ray diffractograms to the commercial sample. Amorphous form showed slightly higher aqueous solubility than the commercial crystalline form.


Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study.
To determine if intravenous thiamine would reduce lactate in patients with septic shock. Randomized, double-blind, placebo-controlled trial. Two US hospitals. Adult patients with septic shock and elevated (> 3 mmol/L) lactate between 2010 and 2014. Thiamine 200 mg or matching placebo twice daily for 7 days or until hospital discharge. The primary outcome was lactate levels 24 hours after the first study dose. Of 715 patients meeting the inclusion criteria, 88 patients were enrolled and received study drug. There was no difference in the primary outcome of lactate levels at 24 hours after study start between the thiamine and placebo groups (median: 2.5 mmol/L [1.5, 3.4] vs. 2.6 mmol/L [1.6, 5.1], p = 0.40). There was no difference in secondary outcomes including time to shock reversal, severity of illness and mortality. 35% of the patients were thiamine deficient at baseline. In this predefined subgroup, those in the thiamine treatment group had statistically significantly lower lactate levels at 24 hours (median 2.1 mmol/L [1.4, 2.5] vs. 3.1 [1.9, 8.3], p = 0.03). There was a statistically significant decrease in mortality over time in those receiving thiamine in this subgroup (p = 0.047). Administration of thiamine did not improve lactate levels or other outcomes in the overall group of patients with septic shock and elevated lactate. In those with baseline thiamine deficiency, patients in the thiamine group had significantly lower lactate levels at 24 hours and a possible decrease in mortality over time.


Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study.
Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients. Histologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score. Serum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available. Treatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.


Modulation of the ligand-independent traffic of Notch by Axin and Apc contributes to the activation of Armadillo in Drosophila.
There is increasing evidence for close functional interactions between Wnt and Notch signalling. In many instances, these are mediated by convergence of the signalling events on common transcriptional targets, but there are other instances that cannot be accounted for in this manner. Studies in Drosophila have revealed that an activated form of Armadillo, the effector of Wnt signalling, interacts with, and is modulated by, the Notch receptor. Specifically, the ligand-independent traffic of Notch serves to set up a threshold for the amount of this form of Armadillo and therefore for Wnt signalling. In the current model of Wnt signalling, a complex assembled around Axin and Apc allows GSK3 (Shaggy) to phosphorylate Armadillo and target it for degradation. However, genetic experiments suggest that the loss of function of any of these three elements does not have the same effect as elevating the activity of β-catenin. Here, we show that Axin and Apc, but not GSK3, modulate the ligand-independent traffic of Notch. This finding helps to explain unexpected differences in the phenotypes obtained by different ways of activating Armadillo function and provides further support for the notion that Wnt and Notch signalling form a single functional module.


Intramembrane glycine mediates multimerization of Insig-2, a requirement for sterol regulation in Chinese hamster ovary cells.
Sterol-induced binding of endoplasmic reticulum (ER) membrane proteins Insig-1 and Insig-2 to SREBP cleavage-activating protein (Scap) and HMG-CoA reductase triggers regulatory events that limit cholesterol synthesis in animal cells. Binding of Insigs to Scap prevents proteolytic activation of sterol-regulatory element binding proteins (SREBPs), membrane-bound transcription factors that enhance cholesterol synthesis, by trapping Scap-SREBP complexes in the ER. Insig binding to reductase causes ubiquitination and subsequent proteasome-mediated degradation of the enzyme from ER membranes, slowing a rate-limiting step in cholesterol synthesis. Here, we report the characterization of mutant Chinese hamster ovary cells, designated SRD-20, that are resistant to 25-hydroxycholesterol, which potently inhibits SREBP activation and stimulates degradation of reductase. SRD-20 cells were produced by mutagenesis of Insig-1-deficient SRD-14 cells, followed by selection in 25-hydroxycholesterol. DNA sequencing reveals that SRD-20 cells harbor a point mutation in one Insig-2 allele that results in production of a truncated, nonfunctional protein, whereas the other allele contains a point mutation that results in substitution of glutamic acid for glycine-39. This glycine residue localizes to the first membrane-spanning segment of Insig-2 and is also present in the corresponding region of Insig-1. Mutant forms of Insig-1 and Insig-2 containing the Glu-to-Gly substitution fail to confer sterol regulation upon overexpressed Scap and reductase. These studies identify the intramembrane glycine as a key residue for normal sterol regulation in animal cells.


Influence of genetic factors on the development of breast cancer in the older woman.
Although the major part of the burden of disease for female breast cancer occurs at older age, less is known about the development and progression in this age group than in women under 60 years of age. As the world population continues to age, the percentage of elderly is increasing in all communities and the incidence of breast cancer will rise accordingly. Improving detection and diagnosis, and a better understanding of the mechanisms that play a role in this age group, will not only improve quality of life in older sufferers but could also contribute to the management of this disease in the adult population as well. Development of breast cancer in the older woman is influenced by many variables that may differ from the risk factors that are involved in younger women. In addition to well-described variables at younger ages such as family history, hormonal exposure, lifestyle factors and pre-existing benign breast disease, in older women age-related changes in breast tissue, biochemistry, inflammatory responses and the immune system, as well as accumulation of DNA damage and spontaneous mutations are suspected to contribute to the complex relationship between ageing and breast cancer. We review the available data on the role of age-related changes and genetic mutations in the development of breast cancer in older women as well as their effects on estrogen metabolism and free oxygen radical inactivation.


PACE: Data-Driven Virtual Agent Interaction in Dense and Cluttered Environments.
We present PACE, a novel method for modifying motion-captured virtual agents to interact with and move throughout dense, cluttered 3D scenes. Our approach changes a given motion sequence of a virtual agent as needed to adjust to the obstacles and objects in the environment. We first take the individual frames of the motion sequence most important for modeling interactions with the scene and pair them with the relevant scene geometry, obstacles, and semantics such that interactions in the agents motion match the affordances of the scene (e.g., standing on a floor or sitting in a chair). We then optimize the motion of the human by directly altering the high-DOF pose at each frame in the motion to better account for the unique geometric constraints of the scene. Our formulation uses novel loss functions that maintain a realistic flow and natural-looking motion. We compare our method with prior motion generating techniques and highlight the benefits of our method with a perceptual study and physical plausibility metrics. Human raters preferred our method over the prior approaches. Specifically, they preferred our method 57.1% of the time versus the state-of-the-art method using existing motions, and 81.0% of the time versus a state-of-the-art motion synthesis method. Additionally, our method performs significantly higher on established physical plausibility and interaction metrics. Specifically, we outperform competing methods by over 1.2% in terms of the non-collision metric and by over 18% in terms of the contact metric. We have integrated our interactive system with Microsoft HoloLens and demonstrate its benefits in real-world indoor scenes. Our project website is available at https://gamma.umd.edu/pace/.


Relapse-Free Survival and PD-L1 Expression in First High- and Low-Grade Relapsed Luminal, Basal and Double-Negative P53-Mutant Non-Muscular Invasive Bladder Cancer Depending on Previous Chemo- and Immunotherapy.
The goal of this study was to assess how PD-L1 expression in tissue specimens of patients with main molecular subtypes of NMIBC (luminal, basal and double-negative p53-mutant) associates with relapsed-free survival in dependence on the tumor grade and prior treatment of primary bladder cancer. PD-L1 expressions on the membrane of neoplastic and CD8+ immune cells were assessed in tumor specimens (n = 240) of primary and relapsed luminal, basal and double-negative p53-mutant NMIBC. Association between relapse-free survival and PD-L1 expression was estimated for high- and low-grade relapsed NMIBC according to previous treatment and their molecular profile, using the Kaplan-Meier method, and assessed by using the log-rank test. Potential confounders were adjusted by Cox regression models. In a group of patients who underwent only TUR without intravesical therapy, there were significant differences in relapse time between high- and low-grade tumors in basal and luminal molecular subtypes; for basal relapsed carcinoma, RFS was shorter in cases where tumors were less malignant. Both intravesical mitomycin and Bacillus Calmette-Guerin (BCG) therapy significantly extended the time of recurrence of low-grade luminal and basal bladder malignancies with no intergroup differences in double-negative NMIBC. PD-L1 expression status was associated with RFS for luminal relapsed NMIBCs in the group without previous frontline intervention, and with RFS in the group of patients with luminal relapsed bladder cancer previously utilized BCG. Obtained results may be considered as a promising approach for further clinical implementation.


Defining heterochromatin in C. elegans through genome-wide analysis of the heterochromatin protein 1 homolog HPL-2.
Formation of heterochromatin serves a critical role in organizing the genome and regulating gene expression. In most organisms, heterochromatin flanks centromeres and telomeres. To identify heterochromatic regions in the heavily studied model C. elegans, which possesses holocentric chromosomes with dispersed centromeres, we analyzed the genome-wide distribution of the heterochromatin protein 1 (HP1) ortholog HPL-2 and compared its distribution to other features commonly associated with heterochromatin. HPL-2 binding highly correlates with histone H3 mono- and dimethylated at lysine 9 (H3K9me1 and H3K9me2) and forms broad domains on autosomal arms. Although HPL-2, like other HP1 orthologs, binds H3K9me peptides in vitro, the distribution of HPL-2 in vivo appears relatively normal in mutant embryos that lack H3K9me, demonstrating that the chromosomal distribution of HPL-2 can be achieved in an H3K9me-independent manner. Consistent with HPL-2 serving roles independent of H3K9me, hpl-2 mutant worms display more severe defects than mutant worms lacking H3K9me. HPL-2 binding is enriched for repetitive sequences, and on chromosome arms is anticorrelated with centromeres. At the genic level, HPL-2 preferentially associates with well-expressed genes, and loss of HPL-2 results in up-regulation of some binding targets and down-regulation of others. Our work defines heterochromatin in an important model organism and uncovers both shared and distinctive properties of heterochromatin relative to other systems.


Measuring women's experiences of maternity care: protocol for a systematic review of self-report survey instruments.
The use of survey instruments to measure women's experiences of their maternity care is regarded internationally as an indicator of the quality of care received. To ensure the credibility of the data arising from these instruments, the methodological quality of development must be high. This paper reports the protocol for a systematic review of self-report instruments used to measure women's experiences of their maternity care. Citation databases CINAHL, Ovid MEDLINE and EMBASE will be searched from 2002 to 2018 using keywords including women, experience, maternity care, questionnaires, surveys, and self-report. Citations will be screened by two reviewers, in two rounds, for inclusion as per predetermined inclusion and exclusion criteria. Data extraction forms will be populated with data, extracted from each study, to evaluate the methodological quality of each survey instrument and the criteria for good measurement properties using quality criteria. Data will also be extracted to categorise the items included in each survey instrument. A combination of a structured narrative synthesis and quantitate summaries in tabular format will allow for recommendations to be made on the use, adaptation and development of future survey instruments. The value of survey instruments that evaluate women's experiences of their maternity care, as a marker of quality care, has been recognised internationally with many countries employing the use of such instruments to inform policy and practice. The development of these instruments must be methodologically sound and the instrument itself fit for the purpose and context in which it is used. This protocol describes the methods that will be used to complete a systematic review that will serve as a guide for choosing the most appropriate existing instruments to use or adapt so that they are fit for purpose, in addition to informing the development of new instruments. PROSPERO CRD42018105325.


Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression.
Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to immunomodulate cells from both the innate and the adaptive immune systems promoting an anti-inflammatory environment. During the last decade, MSCs have been intensively studied in vitro and in vivo in experimental animal model of autoimmune and inflammatory disorders. Based on these studies, MSCs are currently widely used for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) characterized by complex deregulation of the immune systems. However, the therapeutic properties of MSCs in arthritis are still controverted. These controversies might be due to the diversity of MSC sources and isolation protocols used, the time, the route and dose of MSC administration, the variety of the mechanisms involved in the MSCs suppressive effects, and the complexity of arthritis pathogenesis. In this review, we discuss the role of the interactions between MSCs and the different immune cells associated with arthritis pathogenesis and the possible means described in the literature that could enhance MSCs therapeutic potential counteracting arthritis development and progression.


Comparison of basophil histamine release induced by the cross-linking of IgE receptors.
Basophil histamine release induced by allergens (house dust and Candida albicans) and anti-IgE was examined in 31 patients with bronchial asthma in relation to patient age, age at onset of the disease and serum IgE levels. Basophils from patients under 40 years of age generally released a significantly large amount of histamine by stimulation with house dust and anti-IgE. On the other hand, histamine release from patients over 41 years of age was generally not marked when the cells were incubated with house dust and anti-IgE, although, in some cases, the release induced by C. albicans was fairly marked. Basophils from patients under 30 years of age at onset were reactive to house dust and anti-IgE, while the cells from patients over 41 years of age at onset tended to be reactive only to C. albicans. Basophils from patients with low serum IgE levels were less reactive than the cells from patients with high levels of IgE to house dust and anti-IgE. C. albicans-induced release of histamine did not correlate with serum IgE levels.


Synaptojanin1 is required for temporal fidelity of synaptic transmission in hair cells.
To faithfully encode mechanosensory information, auditory/vestibular hair cells utilize graded synaptic vesicle (SV) release at specialized ribbon synapses. The molecular basis of SV release and consequent recycling of membrane in hair cells has not been fully explored. Here, we report that comet, a gene identified in an ENU mutagenesis screen for zebrafish larvae with vestibular defects, encodes the lipid phosphatase Synaptojanin 1 (Synj1). Examination of mutant synj1 hair cells revealed basal blebbing near ribbons that was dependent on Cav1.3 calcium channel activity but not mechanotransduction. Synaptojanin has been previously implicated in SV recycling; therefore, we tested synaptic transmission at hair-cell synapses. Recordings of post-synaptic activity in synj1 mutants showed relatively normal spike rates when hair cells were mechanically stimulated for a short period of time at 20 Hz. In contrast, a sharp decline in the rate of firing occurred during prolonged stimulation at 20 Hz or stimulation at a higher frequency of 60 Hz. The decline in spike rate suggested that fewer vesicles were available for release. Consistent with this result, we observed that stimulated mutant hair cells had decreased numbers of tethered and reserve-pool vesicles in comparison to wild-type hair cells. Furthermore, stimulation at 60 Hz impaired phase locking of the postsynaptic activity to the mechanical stimulus. Following prolonged stimulation at 60 Hz, we also found that mutant synj1 hair cells displayed a striking delay in the recovery of spontaneous activity. Collectively, the data suggest that Synj1 is critical for retrieval of membrane in order to maintain the quantity, timing of fusion, and spontaneous release properties of SVs at hair-cell ribbon synapses.


Ethyl glucuronide hair testing: A review.
Ethyl glucuronide (EtG) is a minor, non-oxidative ethanol metabolite that can be detected in several matrices (e.g. blood, urine, hair, meconium) for variable periods of time. Quantification of EtG in hair (hEtG) has established itself, over recent years, as one of the most reliable biomarkers of long-term alcohol consumption habits, with the Society of Hair Testing (SoHT) offering cut-off values for assessment of both abstinence and heavy drinking (>60 g/day). Despite its high diagnostic performance, however, issues concerning inter- and intra-laboratory variability as well as data interpretation are still being investigated and represent the ultimate barrier to widespread acceptance of hEtG in the forensic context. The aim of this review is to summarize currently available analytical methods of hEtG testing, provide a framework to understand current hEtG cut-offs and their possible upcoming changes (in particular, a lower abstinence cut-off has been proposed for the 2019 revision of the SoHT consensus), and offer a schematic but exhaustive overview of the pitfalls in result reproducibility and interpretation that may limit applications of hEtG testing in the forensic context. Ultimately, the purpose of the authors is not to undermine the reliability of hEtG as an alcohol use marker, but rather to enhance it by promoting familiarization with all aspects related to it, from ethanol pharmacokinetics and EtG incorporation into hair, to sample preparation and analytical methods, to specific cases warranting close attention and additional tests for correct interpretation of hEtG results.


A metabolism perspective on alternative urban water servicing options using water mass balance.
Urban areas will need to pursue new water servicing options to ensure local supply security. Decisions about how best to employ them are not straightforward due to multiple considerations and the potential for problem shifting among them. We hypothesise that urban water metabolism evaluation based a water mass balance can help address this, and explore the utility of this perspective and the new insights it provides about water servicing options. Using a water mass balance evaluation framework, which considers direct urban water flows (both 'natural' hydrological and 'anthropogenic' flows), as well as water-related energy, we evaluated how the use of alternative water sources (stormwater/rainwater harvesting, wastewater/greywater recycling) at different scales influences the 'local water metabolism' of a case study urban development. New indicators were devised to represent the water-related 'resource efficiency' and 'hydrological performance' of the urban area. The new insights gained were the extent to which alternative water supplies influence the water efficiency and hydrological performance of the urban area, and the potential energy trade-offs. The novel contribution is the development of new indicators of urban water resource performance that bring together considerations of both the 'anthropogenic' and 'natural' water cycles, and the interactions between them. These are used for the first time to test alternative water servicing scenarios, and to provide a new perspective to complement broader sustainability assessments of urban water.


The face of negative affect: trial-by-trial corrugator responses to negative pictures are positively associated with amygdala and negatively associated with ventromedial prefrontal cortex activity.
The ability to simultaneously acquire objective physiological measures of emotion concurrent with fMRI holds the promise to enhance our understanding of the biological bases of affect and thus improve our knowledge of the neural circuitry underlying psychiatric disorders. However, the vast majority of neuroimaging studies to date examining emotion have not anchored the examination of emotion-responding circuitry to objective measures of emotional processing. To that end, we acquired EMG activity of a valence-sensitive facial muscle involved in the frowning response (corrugator muscle) concurrent with fMRI while twenty-six human participants viewed negative and neutral images. Trial-by-trial increases in corrugator EMG activity to negative pictures were associated with greater amygdala activity and a concurrent decrease in ventromedial PFC activity. Thus, this study highlights the reciprocal relation between amygdalar and ventromedial PFC in the encoding of emotional valence as reflected by facial expression.


Computational and neural mechanisms of statistical pain learning.
Pain invariably changes over time. These fluctuations contain statistical regularities which, in theory, could be learned by the brain to generate expectations and control responses. We demonstrate that humans learn to extract these regularities and explicitly predict the likelihood of forthcoming pain intensities in a manner consistent with optimal Bayesian inference with dynamic update of beliefs. Healthy participants received probabilistic, volatile sequences of low and high-intensity electrical stimuli to the hand during brain fMRI. The inferred frequency of pain correlated with activity in sensorimotor cortical regions and dorsal striatum, whereas the uncertainty of these inferences was encoded in the right superior parietal cortex. Unexpected changes in stimulus frequencies drove the update of internal models by engaging premotor, prefrontal and posterior parietal regions. This study extends our understanding of sensory processing of pain to include the generation of Bayesian internal models of the temporal statistics of pain.


Graph Matching: Relax at Your Own Risk.
Graph matching-aligning a pair of graphs to minimize their edge disagreements-has received wide-spread attention from both theoretical and applied communities over the past several decades, including combinatorics, computer vision, and connectomics. Its attention can be partially attributed to its computational difficulty. Although many heuristics have previously been proposed in the literature to approximately solve graph matching, very few have any theoretical support for their performance. A common technique is to relax the discrete problem to a continuous problem, therefore enabling practitioners to bring gradient-descent-type algorithms to bear. We prove that an indefinite relaxation (when solved exactly) almost always discovers the optimal permutation, while a common convex relaxation almost always fails to discover the optimal permutation. These theoretical results suggest that initializing the indefinite algorithm with the convex optimum might yield improved practical performance. Indeed, experimental results illuminate and corroborate these theoretical findings, demonstrating that excellent results are achieved in both benchmark and real data problems by amalgamating the two approaches.


Proteinase inhibitory activities of two two-domain Kazal proteinase inhibitors from the freshwater crayfish Pacifastacus leniusculus and the importance of the P(2) position in proteinase inhibitory activity.
Serine proteinase inhibitors are found ubiquitously in living organisms and involved in homeostasis of processes using proteinases as well as innate immune defense. Two two-domain Kazal-type serine proteinase inhibitors (KPIs), KPI2 and KPI8, have been identified from the hemocyte cDNA library of the crayfish Pacifastacus leniusculus. Unlike other KPIs from P. leniusculus, they are found specific to the hemocytes and contain an uncommon P(2) amino acid residue, Gly. To unveil their inhibitory activities, the two KPIs and their domains were over-expressed. By testing against subtilisin, trypsin, chymotrypsin and elastase, the KPI2 was found to inhibit strongly against subtilisin and weakly against trypsin, while the KPI8 was strongly active against only trypsin. With their P(1) Ser and Lys residues, the KPI2_domain2 and KPI8_domain2 were responsible for strong inhibition against subtilisin and trypsin, respectively. Mutagenesis of KPI8_domain1 at P(2) amino acid residue from Gly to Pro, mimicking the P(2) residue of KPI8_domain2, rendered the KPI8_domain1 strongly active against trypsin, indicating the important role of P(2) residue in inhibitory activities of the Kazal-type serine proteinase inhibitors. Only the KPI2 was found to inhibit against the extracellular serine proteinases from the pathogenic oomycete of the freshwater crayfish, Aphanomyces astaci.


Ear, nose, and throat manifestations of gastroesophageal reflux disease. Complaints can be telltale signs.
GERD is one of the most common gastrointestinal conditions in the general US population. ENT become more commonly recognized or suspected by physicians, although the direct association between symptoms and acid reflux has been difficult to establish. Most patients with suspected supraesophageal GERD do not have the typical symptoms of heartburn and acid regurgitation. Possible mechanisms of GERD-mediated damage to extraesophageal structures include direct-contact damage of mucosal surfaces by acid-pepsin exposure and a vagal reflex arc between the esophagus and the upper aerodigestive tract, triggered by acid reflux. Dual-channel ambulatory pH monitoring is the most sensitive and specific diagnostic test for determining transient reflux episodes, although demonstrating the presence of acid reflux alone does not prove that it is the cause of suspected GERD-related signs or symptoms. Therefore, physicians must sometimes resort to an empirical treatment strategy for both diagnosis and treatment. High-dose PPI therapy for 9 to 12 weeks is the recognized first-line therapy; operative therapy is reserved for patients who have severe complications or whose condition incompletely responds to treatment. Complete lack of response should prompt reconsideration of alternative diagnoses. Controlled, well-designed clinical trials to assess treatment and more sophisticated techniques to quantify acid reflux are needed to help determine which patients with suspected extraesophageal complications actually have GERD as the primary cause.


The Burden of Pneumocystis Pneumonia Infection among HIV Patients in Ethiopia: A Systematic Review.
Pneumocystis pneumonia (PCP) is a leading cause of death among patients with AIDS worldwide, but its burden is difficult to estimate in low- and middle-income countries, including Ethiopia. This systematic review aimed to estimate the pooled prevalence of PCP in Ethiopia, the second most densely populated African country. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used to review published and unpublished studies conducted in Ethiopia. Studies that reported on the prevalence of PCP among HIV-infected patients were searched systematically. Variations between the studies were assessed by using forest plot and I-squared heterogeneity tests. Subgroup and sensitivity analyses were carried out when I2 > 50. The pooled estimate prevalence with 95% CI was computed using a random-effects model of analysis. Thirteen articles, comprising studies of 4847 individuals living with HIV, were included for analysis. The pooled prevalence of PCP was 5.65% (95% CI [3.74-7.56]) with high heterogeneity (I2 = 93.6%, p < 0.01). To identify the source of heterogeneity, subgroup analyses were conducted by study design, geographical region, diagnosis methods, and year of publication. PCP prevalence differed significantly when biological diagnostic methods were used (32.25%), in studies published before 2010 (32.51%), in cross-sectional studies (8.08%), and in Addis Ababa (14.05%). PCP prevalence differences of 3.25%, 3.07%, 3.23%, and 2.29% were recorded in studies based on clinical records, published since 2017, follow-up studies, and north-west Ethiopian studies, respectively. The prevalence of PCP is probably underestimated, as the reports were mainly based on clinical records. An expansion of biological diagnostic methods could make it possible to estimate the exact burden of PCP in Ethiopia.


Overlay measurement using angular scatterometer for the capability of integrated metrology.
Angular scatterometry, which has the advantage of good measurement precision, is an optical measurement technology based on the analysis of light scattered from periodic features, such as a linear grating, and is proposed as an alternative solution for overlay metrology. We present overlay measurements using an angular scatterometer and a bright-field microscope. A theoretical library based on rigorous coupled wave theory was created, and the reflected signatures measured by angular scatterometer were matched to the library to obtain structure parameters, including overlay, critical dimension (CD), and sidewall angle at the same time. The results reveal that angular scatterometer has a good precision and low tool-induced shift for overlay measurements, and has the potential for integrated metrology.


Human neural learning depends on reward prediction errors in the blocking paradigm.
Learning occurs when an outcome deviates from expectation (prediction error). According to formal learning theory, the defining paradigm demonstrating the role of prediction errors in learning is the blocking test. Here, a novel stimulus is blocked from learning when it is associated with a fully predicted outcome, presumably because the occurrence of the outcome fails to produce a prediction error. We investigated the role of prediction errors in human reward-directed learning using a blocking paradigm and measured brain activation with functional magnetic resonance imaging. Participants showed blocking of behavioral learning with juice rewards as predicted by learning theory. The medial orbitofrontal cortex and the ventral putamen showed significantly lower responses to blocked, compared with nonblocked, reward-predicting stimuli. In reward-predicting control situations, deactivation in orbitofrontal cortex and ventral putamen occurred at the time of unpredicted reward omissions. Responses in discrete parts of orbitofrontal cortex correlated with the degree of behavioral learning during, and after, the learning phase. These data suggest that learning in primary reward structures in the human brain correlates with prediction errors in a manner that complies with principles of formal learning theory.


Multislice CT angiography in the follow-up of fenestrated endovascular grafts: effect of slice thickness on 2D and 3D visualization of the fenestration stents.
To investigate the effect of multislice computed tomography (CT) protocols on the visualization of target vessel stents in patients with abdominal aortic aneurysm (AAA) treated with fenestrated endovascular grafts. Twenty-one patients (19 men; mean age 75 years, range 63-86) undergoing fenestrated endovascular repair of AAA were retrospectively studied. Multislice CT angiography was performed with several protocols, and the section thicknesses used in each were compared to identify any relationship between slice thickness and target vessel stents visualized on 2-dimensional (2D) axial, multiplanar reformatted (MPR), and 3-dimensional (3D) virtual intravascular endoscopy (VIE) images. Image quality was assessed based on the degree of artifacts and their effect on the ability to visualize the configuration, intra-aortic location, and intraluminal appearance of the target vessel stents and measure their protrusion into the aortic lumen. There were 7 different multislice CT scanning protocols employed in the 21 patients (25 datasets, with 2 sets of follow-up images in 4 patients). The slice thicknesses and numbers (n) of studies included were 0.5 (n=3), 0.625 (n=6), 1.0 (n=1), 1.25 (n=9), 2.5 (n=3), 3.0 (n=1), and 5.0 mm (n=2). Of these CT protocols, images (especially 2D/3D reconstructions) acquired at 2.5, 3.0, and 5.0 mm were significantly compromised by interference from artifacts. Images acquired with a slice thickness of 1.0 or 1.25 mm were scored equal to or lower than those acquired with a submillimeter section thickness (0.5 or 0.625 mm), with minor degrees of artifacts resulting in acceptable image quality. Visualization of the target vessel stents depends on the appropriate selection of multislice CT scanning protocols. Our results showed that studies performed with a slice thickness of 1.0 or 1.25 mm produced similar image quality to those with a thickness of 0.5 or 0.625 mm. Submillimeter slices are not recommended in imaging patients treated with fenestrated stent-grafts, as they did not add additional information to the visualization.


Estimating achievable signal-to-noise ratios of MRI transmit-receive coils from radiofrequency power measurements: applications in quality control.
The inverse relationship between the radiofrequency (RF) power needed to transmit a 90 degree RF pulse, and the signal-to-noise ratio (SNR) available from a transmit-receive RF coil is well known. The theory is restated and a formula given for the signal-to-noise ratio from water, achievable from a single-shot MRI experiment, in terms of the net forward RF power needed for a rectangular 90 degree RF pulse of known shape and duration. The result is normalized to a signal bandwidth of 1 Hz and a sample mass of 1 g. The RF power information needed is available on most commercial scanners, as it is used to calculate specific absorption rates for RF tissue heating. The achievable SNR figure will normally be larger that that actually observed, mainly because of receiver noise, but also because of inaccuracies in setting RF pulse angles, and relaxation effects. Phantom experiments were performed on the transmit-receive RF head coil of a commercial MRI system at 0.95 T using a projection method. The measured SNR agreed with that expected from the formula for achievable SNR once a correction was made for the noise figure of the receiving chain. Comparisons of measured SNR figures with those calculated from RF power measurements are expected to be of value in acceptance testing and quality control.


Effect of Polymerization Time and Home Bleaching Agent on the Microhardness and Surface Roughness of Bulk-Fill Composites: A Scanning Electron Microscopy Study.
The aim of this study is to evaluate the microhardness and surface roughness of two different bulk-fill composites polymerized with light-curing unit (LCU) with different polymerization times before and after the application of a home bleaching agent. For both microhardness and surface roughness tests, 6 groups were prepared with bulk-fill materials (SonicFill, Filtek Bulk Fill) according to different polymerization times (10, 20, and 30 s). 102 specimens were prepared using Teflon molds (4 mm depth and 5 mm diameter) and polymerized with LCU. 30 specimens (n = 5) were assessed for microhardness. Before home bleaching agent application, the bottom/top (B/T) microhardness ratio was evaluated. After bleaching agent application, the microhardness measurements were performed on top surfaces. Roughness measurements were performed in 72 specimens (n = 12) before and after bleaching application. Additionally, for SEM analyses, two specimens from all tested groups were prepared before and after bleaching agent application. The data B/T microhardness ratio before bleaching was analyzed by two-way ANOVA and Tukey's HSD test. The data from the top surface of specimens' microhardness before and after bleaching were analyzed using Wilcoxon signed-rank test, Kruskal-Wallis, Mann-Whitney U tests. The data from surface roughness tests were statistically analyzed by multivariate analysis of variance and Bonferroni test (p < 0.05). The B/T microhardness ratio results revealed no significant differences between groups (p > 0.05). Comparing the microhardness values of the composites' top surfaces before and after bleaching, a significant decrease was observed exclusively in FB30s (p < 0.05). No significant differences in surface roughness values were observed when the groups were compared based on bulk-fill materials (p > 0.05) while the polymerization time affected the surface roughness of the SF20s and SF30s groups (p < 0.05). After bleaching, surface roughness values were significantly increased in the SF20s and SF30s groups (p < 0.05). The clinicians should adhere to the polymerization time recommended by the manufacturer to ensure the durability of the composite material in the oral environment.


Mechanisms of tumour cell metastasis.
Abercrombie and his colleagues have accumulated evidence that changes in the heterotypic contact-inhibition response are largely responsible for the invasiveness of cells, at least in culture. We have identified a 37,000 Mr protein on the surface of mouse fibrosarcoma cells that is involved in their in vitro invasion. Blocking this protein with specific antibodies inhibits the invasion of chicken heart fibroblasts by the tumour cells and normal heterotypic contact inhibition is restored. These results are presented in the general framework of metastatic mechanisms and we review a selection of more recent studies aimed at describing the metastatic phenotype in molecular terms.


Assessing the Veterans Affairs Surgical Quality Improvement Program Risk Calculator in Cholecystectomy.
The Veterans Affairs Surgical Quality Improvement Program (VASQIP) risk calculator has been validated for several operations but has not been assessed specifically for cholecystectomy. Our aim was to externally validate the VASQIP calculator's accuracy in predicting 30-day morbidity and mortality (M&M) for patients undergoing cholecystectomy. A retrospective review of patients undergoing cholecystectomy at the North Texas Veterans Affairs hospital was performed. The VASQIP risk calculator was used to determine predicted 30-day M&M, which was compared with actual M&M. The predictive accuracy of the Veterans Affairs risk calculator was assessed using the C-statistic and a graphical assessment of a locally weighted least squares regression smoother. Overall, 848 patients were included in the study. Actual M&M were 6.3 and 0.94 per cent, respectively, whereas predicted M&M were 6.0 and 0.54 per cent. The C-statistic was 0.75 for morbidity and 0.78 for mortality. In our analysis, the VASQIP risk calculator reasonably predicted 30-day M&M.


A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates.
Utilizing the CEPH reference panel and genotypic data for 53 markers, we have constructed a 20-locus multipoint genetic map of human chromosome 4. New RFLPs are reported for four loci. The map integrates a high-resolution genetic map of 4p16 into a continuous map extending to 4q31 and an unlinked cluster of three loci at 4q35. The 20 linked markers form a continuous linkage group of 152 cM in males and 202 cM in females. Likely genetic locations are provided for 25 polymorphic anonymous sequences and 28 gene-specific RFLPs. The map was constructed employing the LINKAGE and CRIMAP computational methodologies to build the multipoint map via a stepwise algorithm. A detailed 10-point map of the 4p16 region constructed from the CEPH panel provides evidence for heterogeneity in the linkage maps constructed from families segregating for Huntington disease (HD). It additionally provides evidence for position-specific recombination frequencies in the telomeric region of 4p.


RF up/down-conversion based on optically injection-locked VCSEL.
All-optical radio frequency conversion is proposed by directly modulated optically injection-locked vertical-cavity surface-emitting lasers. The enhancement effect of second order products of RF signals by OIL technique is analyzed based on reflection-mode OIL model. Simulation results show that high injection ratio and large wavelength detuning of OIL condition lead to a high RF conversion gain. Compared with free running condition, more than 20 dB RF conversion gain enhancement is achieved in the simulation. The experimental results of the RF conversion gain improvement (+ 18 dB) by OIL show excellent agreement with our simulation results. The spurious free dynamic range improvement (+ 15 dB) of conversion signals by OIL is also experimentally demonstrated.


3D structure determination of native mammalian cells using cryo-FIB and cryo-electron tomography.
Cryo-electron tomography (cryo-ET) has enabled high resolution three-dimensional(3D) structural analysis of virus and host cell interactions and many cell signaling events; these studies, however, have largely been limited to very thin, peripheral regions of eukaryotic cells or to small prokaryotic cells. Recent efforts to make thin, vitreous sections using cryo-ultramicrotomy have been successful, however,this method is technically very challenging and with many artifacts. Here, we report a simple and robust method for creating in situ, frozen-hydrated cell lamellas using a focused ion beam at cryogenic temperature (cryo-FIB), allowing access to any interior cellular regions of interest. We demonstrate the utility of cryo-FIB with high resolution 3D cellular structures from both bacterial cells and large mammalian cells. The method will not only facilitate high-throughput 3D structural analysis of biological specimens, but is also broadly applicable to sample preparation of thin films and surface materials without the need for FIB "lift-out".


Milrinone Pharmacokinetics and Pharmacodynamics in Neonates with Persistent Pulmonary Hypertension of the Newborn.
Objective To describe the pharmacokinetics and pharmacodynamics of milrinone in infants with persistent pulmonary hypertension of the newborn (PPHN) and to explore the impact of age on milrinone disposition. Design Randomized, open label pilot study. Setting Multicenter; level 3 and level 4 neonatal intensive care units. Patients Six infants ≥34 weeks' gestational age and <10 days of life with persistent hypoxemia receiving inhaled nitric oxide. Intervention Intravenous milrinone lactate in one of two dosing regimens: (1) low dose, 20 mcg/kg bolus followed by 0.2 mcg/kg/minute, and (2) standard dose, 50 mcg/kg bolus followed by 0.5 mcg/kg/minute. Measurements and Main Results The final structural model was a two-compartment disposition model with interindividual variability estimated on clearance (CL). The estimated value of CL is 7.65 mL/minute/3.4 kg (3.05 mL/minute/kg). The addition of age improved the precision of the CL estimate, and CL increased with chronological age in days. The oxygenation index was highly variable within each participant and improved with time. There were no observed safety concerns in either dosing group. Conclusion The CL of milrinone in newborns with PPHN is reduced and increases with age. In this pilot study, we did not see significant pharmacodynamic or safety effects associated with drug exposure.


Joint modelling of repeated measurements and time-to-event outcomes: the fourth Armitage lecture.
In many longitudinal studies, the outcomes recorded on each subject include both a sequence of repeated measurements at pre-specified times and the time at which an event of particular interest occurs: for example, death, recurrence of symptoms or drop out from the study. The event time for each subject may be recorded exactly, interval censored or right censored. The term joint modelling refers to the statistical analysis of the resulting data while taking account of any association between the repeated measurement and time-to-event outcomes. In this paper, we first discuss different approaches to joint modelling and argue that the analysis strategy should depend on the scientific focus of the study. We then describe in detail a particularly simple, fully parametric approach. Finally, we use this approach to re-analyse data from a clinical trial of drug therapies for schizophrenic patients, in which the event time is an interval-censored or right-censored time to withdrawal from the study due to adverse side effects.


Mammalian cochlea as a physics guided evolution-optimized hearing sensor.
Nonlinear physics plays an essential role in hearing. We demonstrate on a mesoscopic description level that during the evolutionary perfection of the hearing sensor, nonlinear physics led to the unique design of the cochlea observed in mammals, and that this design requests as a consequence the perception of pitch. Our insight challenges the view that mostly genetics is responsible for the uniformity of the construction of the mammalian hearing sensor. Our analysis also suggests that scaleable and non-scaleable arrangements of nonlinear sound detectors may be at the origin of the differences between hearing sensors in amniotic lineages.