[Lack of low-threshold calcium channels in the membrane of cultured cells of the heart ventricle of newborn rats].
In isolated, cultured neonatal rat ventricular myocytes calcium current was investigated by whole-cell patch clamp technique. The shift of holding potential values from -100-80 mV to -40 mV caused no significant changes in calcium current potential-dependent and kinetic properties. No calcium current component with preferential steady-state inactivation at membrane potentials ranged between -100 and -60 mV was observed. Calcium current component resistant to classic Ca-antagonists action was not found either. All data listed above permit a conclusion on lack of the low-threshold calcium channels in the membrane of single cultured neonatal rat ventricular myocytes. Possible reasons of the absence of this type of calcium are discussed.


Two-Step Adsorption of a Switchable Tertiary Amine Surfactant Measured Using a Quartz Crystal Microbalance with Dissipation.
The adsorption of a switchable cationic surfactant, N, N, N'-trimethyl- N'-tallow-1,3-diaminopropane (DTTM, Duomeen TTM), at the silica/aqueous solution interface is characterized using a quartz crystal microbalance with dissipation (QCM-D). The adsorption isotherms reveal that changes in the solution pH or salinity affect surfactant adsorption in competing ways. In particular, the combination of the degree of protonation of the surfactant and electrostatic interactions is responsible for surfactant adsorption. The kinetics of adsorption is carefully measured using the real-time measurement of a QCM-D, allowing us to fit the experimental data with analytical models. At pH values of 3 and 5, where the DTTM is protonated, DTTM exhibits two-step adsorption. This is representative of a fast step in which the surfactant molecules are adsorbed with head-groups orientated toward the surface, followed by a slower second step corresponding to formation of interfacial surfactant aggregates on the silica surface.


Value of micro-flow imaging and high-definition micro-flow imaging in differentiating malignant and benign breast lesions.
To evaluate the value of non-contrast micro-flow imaging (MFI) and high-definition micro-flow imaging (HD-MFI) in differentiating malignant and benign breast lesions. One hundred and thirty-three patients with 138 breast lesions (80 benign and 58 malignant lesions) were examined using colour Doppler flow imaging (CDFI), MFI, and HD-MFI before biopsy, with blood flow signals graded into four types (grade 0, 1, 2, and 3) and penetrating vessels evaluated. The micro-vascular patterns of MFI and HD-MFI were evaluated and classified into five patterns: avascular, line-like, tree-like, root hair-like, and crab claw-like pattern. The diagnostic efficiency of micro-vascular patterns was analysed. Moreover, ultrasound Breast Imaging Reporting and Data System (BI-RADS) 4A lesions were also re-assessed according to the micro-vascular patterns of MFI or HD-MFI. The capability of detecting blood flow and penetrating vessels from high to low was HD-MFI, MFI, and CDFI, respectively (p<0.05). Rich blood flow signals, penetrating vessels, and root hair-like or crab claw-like pattern were more likely in malignant breast lesions, while few blood flow signals, tree-like pattern were mostly in benign lesions (p<0.05). The diagnostic efficiency of HD-MFI and MFI were higher than CDFI (p>0.05). MFI could reduce unnecessary biopsy of 52 US BI-RADS 4A lesions but with two malignancies missed, while 56 ultrasound BI-RADS 4A lesions could be downgraded by HD-MFI with none malignancies missed. MFI and HD-MFI can detect more blood flow in breast lesions than CDFI, and could help distinguish benign and malignant breast lesions. HD-MFI could reduce the unnecessary biopsy of US BI-RADS 4A lesions without missed malignancy.


Endoport Assisted Endoscopic Surgery for Hypertensive Basal Ganglia Hemorrhage by Transsylvian Approach: Technical Nuances and Preliminary Clinical Results.
There is no clear evidence on the indication and surgical approaches on evacuating basal ganglia hemorrhage caused by hypertensive bleeding. Some studies have shown that minimally invasive approaches have therapeutic potentials, but its benefits remain inconclusive. We describe an endoport assisted endoscopic transsylvian approach for basal ganglia hemorrhage evacuation. We evaluate the safety and efficacy of this approach in a cohort study. We included 19 patients (mean age 57 years) who underwent the surgery at a single county-level hospital in Yunan Province, China. The majority had a Glasgow coma scale between 9 and 12 on admission. The midline shift ranged from 16-29 mm (mean 19 mm). Hematoma volume ranged from 46 to 106 ml (mean 67 ml). Six patients (31.6%) presented with intraventricular hemorrhage. All patients achieved greater than 90% decrease in hematoma volume at postoperative computed tomography scan. The average operative time was 115 minutes and average blood loss of 44 ml. The most common postoperative complication was pulmonary infection (63.2%). No rebleeding, seizure, infectious meningitis, or postoperative mortality was observed. A total of 17 patients (89.5%) achieved good functional recovery at follow up within 90 days after surgery (Glasgow outcome scale 4-5) and 2 patients had severe disability (Glasgow outcome scale 3). Endoport assisted endoscopic surgery through transsylvian approach is safe and effective treatment for hypertensive basal ganglia hemorrhage. The majority of patients have good functional recovery and the rate of severe complications is low.


Cardiovascular dysfunction caused by cecal ligation and puncture is attenuated in CD8 knockout mice treated with anti-asialoGM1.
The present study was designed to assess hemodynamics and myocardial function at 18 h after injury caused by cecal ligation and puncture (CLP) in CD8-knockout mice treated with anti-asialoGM1 (CD8KO/alphaAsGM1 mice). Arterial pressure was measured by carotid artery cannulation, and left ventricular pressure-volume measurements were obtained by use of a 1.4-Fr conductance catheter. Blood acid-base balance and indexes of hepatic, renal, and pulmonary injury were also measured. CD8KO/alphaAsGM1 mice exhibited higher mean arterial pressure and increased systemic vascular resistance compared with wild-type mice. Cardiac output was significantly decreased in wild-type, but not CD8KO/alphaAsGM1, mice compared with sham controls. Myocardial function was better preserved in CD8KO/alphaAsGM1 mice as indicated by less impairment of left ventricular pressure development over time, time varying maximum elastance, end-systolic pressure-volume relationship, and preload recruitable stroke work. The impairment in myocardial function was associated with induction of proinflammatory cytokine mRNAs in the hearts of wild-type mice. The hemodynamic derangements in wild-type mice were coupled with significant metabolic acidosis and elevated serum creatinine levels. Overall, this study shows that cardiovascular collapse and shock characterized by hypotension, myocardial depression, low systemic vascular resistance, and metabolic acidosis occurs after CLP in wild-type mice but is attenuated in CD8KO/alphaAsGM1 mice. These observations likely explain, in part, the previously observed survival advantage of CD8KO/alphaAsGM1 mice following CLP.


Academic outcomes and cognitive performance in problematic Internet users.
Only few studies have examined the relationship between problematic Internet use (PIU) and cognitive and academic performance in adolescents. The aim of this study was to analyze the differences in academic and cognitive performance (perception, attention, memory, verbal fluency and abstract reasoning) between adolescents with and without PIU. A total of 575 students from different high schools of the region of Alicante participated. Students were divided into two groups: adolescents with and without PIU (PIU and NPIU, respectively). Several questionnaires were administered to assess problematic Internet use, as well as students' academic performance. Substance use (alcohol / cannabis) was also assessed as exclusion criteria. A battery of neuropsychological tests was used to assess cognitive abilities. On the one hand, PIU users group obtained poorer academic results than NPIU, in terms of lower marks and more failed subjects. On the other hand, PIU group had a better hit ratio in the perception test than NPIU group. However, PIU adolescents got higher error rates for the abstract reasoning test. This greater number of errors, plus a similar number of hits compared to the NPIU group, could indicated a higher response rate for the PIU group, which may might be associated with greater impulsivity. As occurs in other addictive and non-substance-related problems studies, these results could mean difficulties in impulse control and regulation of response inhibition circuits in PIU users group. Future research is needed to analyze in depth the results presented in this paper.


Mechanism and kinetics of metalloenzyme phosphomannose isomerase: measurement of dissociation constants and effect of zinc binding using ESI-FTICR mass spectrometry.
Electrospray ionization Fourier transform ion cyclotron resonance (ESI-FTICR) mass spectrometry was used to study the noncovalent complexation of a metalloenzyme, phosphomannose isomerase (PMI), which catalyzes the interconversion of mannose 6-phosphate and fructose 6-phosphate. The zinc cofactor binding effect and the noncovalent interactions of the holoenzyme with its two natural substrates and two inhibitors, erythrose 4-phosphate and mannitol 1-phosphate, were investigated. Under nondenaturing conditions, the intact zinc-containing monomeric protein ions were reproducibly observed with no dissociation. Molecular ions corresponding to apo-PMI monomer were obtained by dialyzing the holoenzyme against EDTA. The binding/release of the metal ion did not alter the charge-state distributions of the protein to any significant extent, but changed the binding affinity of the substrates by at least 5-fold. Using ESI-FTICR mass spectrometry, the binding stoichiometry and specificity of the enzyme-substrate and enzyme-inhibitor complexes were directly determined. The first time report of the apparent dissociation constant for the isomeric substrates of PMI was measured to be 88.8 microM. The relative dissociation constant of the two inhibitors derived from gas-phase noncovalent complexation was very similar to the relative inhibition constant derived from solution phase kinetics.


Wild Tech: Exploring South Africa's unique robotics landscape.
South Africa's location-specific opportunities have enabled local researchers to establish a niche in the robotics community.


Laser heating tunability by off-resonant irradiation of gold nanoparticles.
Temperature changes in the vicinity of a single absorptive nanostructure caused by local heating have strong implications in technologies such as integrated electronics or biomedicine. Herein, the temperature changes in the vicinity of a single optically trapped spherical Au nanoparticle encapsulated in a thermo-responsive poly(N-isopropylacrylamide) shell (Au@pNIPAM) are studied in detail. Individual beads are trapped in a counter-propagating optical tweezers setup at various laser powers, which allows the overall particle size to be tuned through the phase transition of the thermo-responsive shell. The experimentally obtained sizes measured at different irradiation powers are compared with average size values obtained by dynamic light scattering (DLS) from an ensemble of beads at different temperatures. The size range and the tendency to shrink upon increasing the laser power in the optical trap or by increasing the temperature for DLS agree with reasonable accuracy for both approaches. Discrepancies are evaluated by means of simple models accounting for variations in the thermal conductivity of the polymer, the viscosity of the aqueous solution and the absorption cross section of the coated Au nanoparticle. These results show that these parameters must be taken into account when considering local laser heating experiments in aqueous solution at the nanoscale. Analysis of the stability of the Au@pNIPAM particles in the trap is also theoretically carried out for different particle sizes.


What are the main symptoms and concerns reported by patients with advanced chronic heart failure?-a secondary analysis of the Palliative care Outcome Scale (POS) and Integrated Palliative care Outcome Scale (IPOS).
There is a lack of valid disease-specific patient-reported outcome measures (PROMs) for detecting symptoms and concerns in patients with advanced chronic heart failure (CHF). The Palliative care Outcome Scale (POS) and Integrated Palliative care Outcome Scale (IPOS) are specifically developed to capture the main symptoms and concerns of people severely affected by advanced disease. The aim of this study was to determine whether POS and IPOS captures the main symptoms and concerns self-reported by patients with advanced CHF. A secondary analysis of existing POS/IPOS data collected in three longitudinal studies was conducted. POS and IPOS start with an open-ended question for patients to report their main problems and concerns, followed by subsequent closed questions on a range of symptoms and other concerns. Descriptive statistics were used to report the results. The 102 participants from the three datasets had median age 81 years (SD ±9.84 years); 62% male; 87% white. A total of 107 concerns were reported in the first, open POS/IPOS question seeking the patient's main concerns. Of these, 83 (77%) were reflected in the subsequent IPOS/POS closed questions. The high correspondence between the free-text responses and the closed questions indicates that most issues are captured by the POS/IPOS items. In conclusion, the generic versions of POS and IPOS do capture the main problems and concerns of patients with advanced CHF. Minor adaptations and further psychometric validation of POS and IPOS are needed in this population.


Structural evolution of La2Ti2O7 at elevated temperatures.
Structural evolution of a La2Ti2O7 ferroelectric compound possessing perovskite-type slabs at elevated temperatures was investigated using the single-crystal X-ray diffraction technique. The monoclinic low-temperature phase (L) transformed into the orthorhombic high-temperature phase (H) via an incommensurately modulated phase (IC) between ∼989 and ∼1080 K. The L-IC transition was considered to be of the first order, with the L+IC two-phase co-existing region between ∼989 and ∼1027 K. The structure of IC was determined from the (3+1)-dimensional superspace representation with a modulation vector q = αao (α ≃ 0.49), where ao is the a-axis vector of the basic cell. The structural modulation originated from the variation of the tilt angle of the TiO6 octahedra in the perovskite-type slab in association with small positional displacements of La atoms. The IC-H transition took place at ∼1080 K and was close to the second order. During the IC-H transition, nanoscale flat plate domains having either a cell twin of the L-type structural modules or a cell twin of the alternating H- and L-type structural modules began to appear in the approximant structure of IC. The thickness of the flat plate domains then grew rapidly along the modulation vector in proportion to (½ - α)-1 as α approached ½ with decreasing temperature. In the two-phase L+IC co-existing region, the IC phase consisting of the two types of cell twins was gradually replaced with the low-temperature monoclinic phase L, which is not cell twinned but rather twinned macroscopically by the L-type structural modules.


Fulfilling the social contract between medical schools and the public.
To gain a better understanding of the effects of medical schools related to transformations in medical practice, science, and public expectations, the Association of American Medical Colleges (AAMC) established the Advisory Panel on the Mission and Organization of Medical Schools (APMOMS) in 1994. Recognizing the privileges academic medicine enjoys as well as the power of and the strain on its special relationship with the American public, APMOMS formed the Working Group on Fulfilling the Social Contract. That group focused on the question: What are the roles and responsibilities involved in the social contract between medical schools and various interested communities and constituencies? This article reports the working group's findings. The group describes the historical and philosophical reasons supporting the concept of a social contract and asserts that medical schools have individual and collective social contracts with various subsets of the public, referred to as "stakeholders." Obligations derive implicitly from the generous public funding and other benefits medical school receive. Schools' primary obligation is to improve the nation's health. This obligation is carried out most directly by educating the next generation of physicians and biomedical scientists in a manner that instills appropriate professional attitudes, values, and skills. Group members identified 27 core stakeholders (e.g., government, patients, local residents, etc.) and outlined the expectations those stakeholders have of medical schools and the expectations medical schools have of those stakeholders. The group conducted a survey to test how leaders at medical schools responded to the notion of a social contract, to gather data on school leaders' perceptions of what groups they considered their schools' most important stakeholders, and to determine how likely it was that the schools' and the stakeholders expectations of each other were being met. Responses from 69 deans suggested that the survey provoked thinking about the broad issue of the social contract and stakeholders. Leaders on the same campuses disagreed about what groups were the most important stakeholders. Similarly, the responses revealed a lack of national consensus about the most important stakeholders, although certain groups were consistently included in the responses. The group concludes that medical school leaders should examine their assumptions and perspectives about their institutions' stakeholders and consider the interests of the stakeholders in activities such as strategic planning, policymaking, and program development.


Detection of serum tumor markers in the diagnosis and treatment of patients with pancreatic cancer.
Although a variety of tumor markers are available for diagnosis of pancreatic cancer, their sensitivity and specificity have not yet been ideal. The aims of this study was to detect a panel of serum tumor markers and to evaluate their significance in the diagnosis and prognosis of pancreatic cancer patients. Eight serum tumor markers including AFP, CEA, CA-50, CA72-4, CA-125, CA153, CA19-9 and CA242 were detected in 129 patients with pancreatic cancer by using chemiluminescence immunoassay, immunofluorescence assay and immunoradiometric assay, respectively. The levels of these markers were compared in 99 patients with non-pancreatic malignant tumor, 63 patients with other benign diseases, and 27 patients with pancreatic cancer after pancreatectomy. Among the 8 tumor markers, CA19-9, CA242, CA-50, and CA72-4 were more sensitive in the diagnosis of pancreatic cancer. Parallel combined testing could increase the diagnostic sensitivity to 89.2%, and serial combined examination could increase the diagnostic specificity to 92.3%. The serum tumor markers levels were decreased significantly after radical tumor resection. Serum CA19-9, CA242, CA-50, and CA72-4 are the preferred tumor markers to be used in the diagnosis and follow-up of operated cases of pancreatic cancer. Testing of a panel of multiple serum tumor markers may increase the sensitivity and specificity in the diagnosis of pancreatic cancer.


Biological and behavioural explanations of social inequalities in coronary heart disease: the Whitehall II study.
We determined the degree to which metabolic syndrome components, inflammation and health behaviours account for the social gradient in CHD. A total of 5312 men, initially aged 39 to 63 years, were followed for 13.1 years for incident coronary death or non-fatal myocardial infarction according to socioeconomic position (employment grade). The contribution of explanatory factors to socioeconomic differences in CHD was assessed by the reduction in hazard ratios computed using Cox models. The effects of measurement error were taken into account. Coronary events were more common in lower employment grades than in higher, with a hazard ratio (relative index of inequality) of 2.2 (95% CI 1.3-3.7), after adjustment for age and ethnic group. Behavioural risk factors (mainly smoking and diet) explained a third of the socioeconomic gradient in CHD incidence. Components of the metabolic syndrome and inflammatory markers predicted CHD incidence and also explained a third of the gradient. Combined, these two groups of predictors, i.e. behavioural and biological, accounted for over half of the socioeconomic gradient in incident CHD. Adding body height as a marker of the effects of early life increased this figure to about 60%. A major question has been how someone's socioeconomic position can lead to increased risk of CHD. Socioeconomic differences in components of the metabolic syndrome (and inflammatory markers) provide part of the answer. This was, to an important degree, independent of the contribution of health behaviours to the socioeconomic differentials in CHD.


Studies on the valyl-h-tRNA synthetase of chick embryo brain irradiated with 60Co gamma-rays, in vivo.
18-day-old chick embryos (Leghorn) were irradiated in vivo with 1,2,3,4,5 or 7 Gy 60Co gamma-rays (dose rate = 0.9 Gy/min). Twenty-four hours after irradiation the activity of valyl-tRNA synthetase isolated from the brains was determined and compared with that of the non-irradiated control. The aminoacylation activity was found to decrease exponentially as a function of the dose (D37 = 6 Gy). Irradiation caused a more pronounced decrease in valyl-tRNA synthetase activity in 18-day-old than in 14-day-old chick embryos and induced in the valine-dependent ATP-PPi exchange reaction less change than in the valyl-tRNA FORMATion. The exposure of 15-day-old chick embryos to a dose of 4 or 5 Gy induced, respectively, a 40 or 20 per cent increase in enzyme activity of VRS (prepared on day 19 of embryonic life) relative to the control. In these experiments a decrease of Km value for tRNA has been found. The change in the number of sulfhydryl groups was also investigated.


Telephone smoking cessation quitline use among pregnant and non-pregnant women.
To describe characteristics, referrals, service utilization, and self-reported quit rates among pregnant and non-pregnant women enrolled in a smoking cessation quitline. This information can be used to improve strategies to increase pregnant and non-pregnant smokers' use of quitlines. We examined tobacco use characteristics, referral sources, and use of services among 1,718 pregnant and 24,321 non-pregnant women aged 18-44 years enrolled in quitline services in 10 states during 2006-2008. We examined self-reported 30-day quit rates 7 months after enrollment among 246 pregnant and 4,123 non-pregnant women and, within groups, used Chi-square tests to compare quit rates by type of service received. The majority of pregnant and non-pregnant callers, respectively, smoked ≥10 cigarettes per day (62 %; 83 %), had recently attempted to quit (55 %; 58 %), smoked 5 or minutes after waking (59 %; 55 %), and lived with a smoker (63 %; 48 %). Of callers, 24.3 % of pregnant and 36.4 % of non-pregnant women were uninsured. Pregnant callers heard about the quitline most often from a health care provider (50 %) and non-pregnant callers most often through mass media (59 %). Over half of pregnant (52 %) and non-pregnant (57 %) women received self-help materials only, the remainder received counseling. Self-reported quit rates at 7 months after enrollment in the subsample were 26.4 % for pregnant women and 22.6 % for non-pregnant women. Quitlines provide needed services for pregnant and non-pregnant smokers, many of whom are uninsured. Smokers should be encouraged to access counseling services.


Comparative expression of matrix-associated genes and inflammatory cytokines-associated genes according to disc degeneration: analysis of living human nucleus pulposus.
The 2 groups of living human nucleus pulposus were prospectively compared according to disc degeneration. This study was conducted to investigate the expressions of various genes associated with matrix synthesis and expressions of inflammatory cytokines-associated genes according to degrees of disc degeneration in human discs. Degenerated discs were obtained from 18 patients who underwent discectomy for lumbar disc herniation. Disc degeneration was graded by T2-weighted magnetic resonance imaging using Pfirrmann's grading system. Discs were allocated to 2 groups: group I (9 patients)-mildly degenerated discs (grades II and III) and group II (9 patients)-severely degenerated discs (grades IV and V). Cells from the nucleus pulposus were isolated and then cultured as monolayers. The mRNA expressions of aggrecan, type II collagen, Sox9, type I collagen, alkaline phosphatase, osteocalcin, tumor necrosis factor-α, and interleukin-1β in the 2 groups were compared by real-time polymerase chain reaction, and production of matrix-associate proteins (aggrecan, type II collagen, Sox9, type I collagen, alkaline phosphatase, and osteocalcin) were compared by Western blotting. mRNA expressions in group I were upregulated versus group II to the following extents: 1.83 times for aggrecan, 1.82 times for type II collagen, 1.80 times for Sox9, 1.41 times for type I collagen, 1.38 times for alkaline phosphatase, and 1.80 times for osteocalcin. Furthermore, Western blotting showed that aggrecan, type II collagen, Sox9, type I collagen, alkaline phosphatase, and osteocalcin were higher in group I. However, the mRNA levels of tumor necrosis factor-α and interleukin-1β were 1.26 and 1.11-fold, respectively, upregulated in group II. Mildly degenerated discs showed greater matrix, chondrogenic, and osteoblastic gene expressions than severely degenerated discs, indicating that the ability to produce matrix-associated proteins is greater for cells in mildly degenerated than in severely degenerated discs. However, inflammatory cytokine genes associated with disc degeneration were expressed at higher levels in the severely degenerated group. This study shows that a reduction in matrix synthesis and an increase of inflammatory cytokine levels occurs during disc degeneration at the same time.


A comparison of magnetostrictive and piezoelectric ultrasonic scaling devices: an in vitro study.
The effects of magnetostrictive and piezoelectric devices on tooth surfaces seem to differ with regard to the root surface roughness they produce. This study aimed to compare the results of scaling using magnetostrictive and piezoelectric devices on extracted teeth. Forty-four human extracted teeth were assigned to four study groups (n=11). In two groups (C100 and C200), the teeth were scaled using a magnetostrictive device and two different lateral forces: 100 g and 200 g, respectively. In the other two groups (P100 and P200), the teeth were scaled with a piezoelectric device with 100 g and 200 g of lateral force, respectively. he teeth were scaled and the data on the duration of scaling and the amount of surface were collected and analyzed using the t-test. The mean time needed for instrumentation for the piezoelectric and magnetostrictive devices was 50:54 and 41:10, respectively, but their difference was not statistically significant (P=0.171). For root surface roughness, we only found a statistically significantly poorer result for the C200 group in comparison to the P200 group (P=0.033). This study revealed that applying a piezoelectric scaler with 200 g of lateral force leaves smoother surfaces than a magnetostrictive device with the same lateral force.


Bone and joint symptoms in Paget's disease.
Fifty patients with Paget's disease of bone were reviewed with regard to the basis of their symptoms and the long-term results of treatment. Twenty-four patients (48%) presented with pain localised within bone, while 17 (34%) presented with symptoms of degenerative joint disease. Three patients presented with bone pain and arthritis and the remaining six with fractures, ataxia, or painless deformity. Symptomatic osteoarthritis of the hip (OA) developed in 25 patients (50%) with approximately half developing radiological changes identical to those of idiopathic OA. Among the other patients those with coxa vara tended to show medial (rather than superior) joint space narrowing and severe Paget's disease on both sides of the joint. Arthritic pain, stiffness, and reduced mobility in other joints (knee, ankle, and wrist) were associated clinically with bone deformity adjacent to the affected joint and radiologically with distorted articular surfaces and narrowed joint spaces; sclerosis, subarticular cyst formation, and osteophytosis were usually absent. Fifteen patients were treated with calcitonin for bone pain alone; all claimed long-term 'good to complete' relief. By contrast, none of the 14 with arthritic symptoms responded to calcitonin when assessed retrospectively. Results of surgical and other medical treatment were analysed. Careful clinical evaluation is a prerequisite for optimal treatment in Paget's disease.


Effects of short-term isolated zinc deficiency on intestinal growth and activities of several brush border enzymes in weaning rats.
To determine whether zinc has a specific role on intestinal growth and function, three groups of male weanling Sprague-Dawley rats were fed a semipurified zinc-deficient diet: ad libitum fed group received powdered diet and water containing 25 ppm of zinc; force fed (ZN, ZD) groups were fed identical amounts of diet to the ad libitum fed group by intragastric infusion three times per day. The diets were aqueous suspensions made with either deionized water (ZD) or water containing 25 ppm of zinc (ZN), and additional drinking water with (ZN) or without zinc (ZD) was offered ad libitum. Rats were sacrificed after 8 days of feeding. The ZD group showed growth arrest, perioral and periorbital dermal lesions, and abdominal distention within 8 days of feeding. Mucosal DNA, protein, sucrase, maltase, lactase, leucine aminopeptidase, and alkaline phosphatase were significantly decreased in the ZD group, whereas intestinal length, weight, and mucosal weight were unaltered. These results suggest that short-term isolated zinc deficiency impairs growth, digestion, and absorption in the rat small intestine, even in the absence of associated protein calorie malnutrition.


Intracranial hydatid cyst: a report of five cases and review of literature.
The authors present five cases of intracranial hydatid cysts managed at the department of Neurosurgery, King Edward Memorial Hospital, Mumbai, between 1984-1997. The mean age of presentation was 13.4 years. Four patients (80%) were in the first decade of life. All patients presented with focal neurological deficit and clinical features of raised intracranial pressure. Radiological investigations included computerised tomography (CT) scan in three cases, CT and magnetic resonance (MR) scan in one case and accidental cystogram in one case. Two patients had multiple intracranial cysts. One patient had a solitary cyst in the lateral ventricle. Commonest location was in the parietal lobe (3 cases). Total excision of the cyst was done in all five cases. Recurrence was seen in two cases, probably as a result of rupture of the cyst during first surgery. The features of this rare disease are retrospectively analyzed in this presentation and the literature is reviewed.


Are There Only Fold Catastrophes in the Diels-Alder Reaction Between Ethylene and 1,3-Butadiene?
This work revisits the topological characterization of the Diels-Alder reaction between 1,3-butadiene and ethylene. In contrast to the currently accepted rationalization, we here provide strong evidence in support of a representation in terms of seven structural stability domains separated by a sequence of 10 elementary catastrophes, but all are only of the fold type (F and F†), that is, C4H6 + C2H4:1-7-[FF]F[F†F†][F†F†][FF]F†-0: C6H10. Such an unexpected finding provides fundamental new insights opening simplifying perspectives concerning the rationalization of the CC bond formation in pericyclic reactions in terms of the simplest Thom's elementary catastrophe, namely, the one-(state) variable, one-(control) parameter function.


Longitudinal host transcriptional responses to SARS-CoV-2 infection in adults with extremely high viral load.
Current understanding of viral dynamics of SARS-CoV-2 and host responses driving the pathogenic mechanisms in COVID-19 is rapidly evolving. Here, we conducted a longitudinal study to investigate gene expression patterns during acute SARS-CoV-2 illness. Cases included SARS-CoV-2 infected individuals with extremely high viral loads early in their illness, individuals having low SARS-CoV-2 viral loads early in their infection, and individuals testing negative for SARS-CoV-2. We could identify widespread transcriptional host responses to SARS-CoV-2 infection that were initially most strongly manifested in patients with extremely high initial viral loads, then attenuating within the patient over time as viral loads decreased. Genes correlated with SARS-CoV-2 viral load over time were similarly differentially expressed across independent datasets of SARS-CoV-2 infected lung and upper airway cells, from both in vitro systems and patient samples. We also generated expression data on the human nose organoid model during SARS-CoV-2 infection. The human nose organoid-generated host transcriptional response captured many aspects of responses observed in the above patient samples, while suggesting the existence of distinct host responses to SARS-CoV-2 depending on the cellular context, involving both epithelial and cellular immune responses. Our findings provide a catalog of SARS-CoV-2 host response genes changing over time.


N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer.
Identification of hypermethylated tumor suppressor genes in body fluids is an appealing strategy for the noninvasive detection of colorectal cancer. Here we examined the role of N-Myc downstream-regulated gene 4 (NDRG4) as a novel tumor suppressor and biomarker in colorectal cancer. NDRG4 promoter methylation was analyzed in human colorectal cancer cell lines, colorectal tissue, and noncancerous colon mucosa by using methylation-specific polymerase chain reaction (PCR) and bisulfite sequencing. NDRG4 mRNA and protein expression were studied using real-time-PCR and immunohistochemistry, respectively. Tumor suppressor functions of NDRG4 were examined by colony formation, cell proliferation, and migration and invasion assays in colorectal cancer cell lines that were stably transfected with an NDRG4 expression construct. Quantitative methylation-specific PCR was used to examine the utility of NDRG4 promoter methylation as a biomarker in fecal DNA from 75 colorectal cancer patients and 75 control subjects. All P values are two-sided. The prevalence of NDRG4 promoter methylation in two independent series of colorectal cancers was 86% (71/83) and 70% (128/184) compared with 4% (2/48) in noncancerous colon mucosa (P < .001). NDRG4 mRNA and protein expression were decreased in colorectal cancer tissue compared with noncancerous colon mucosa. NDRG4 overexpression in colorectal cancer cell lines suppressed colony formation (P = .014), cell proliferation (P < .001), and invasion (P < .001). NDRG4 promoter methylation analysis in fecal DNA from a training set of colorectal cancer patients and control subjects yielded a sensitivity of 61% (95% confidence interval [CI] = 43% to 79%) and a specificity of 93% (95% CI = 90% to 97%). An independent test set of colorectal cancer patients and control subjects yielded a sensitivity of 53% (95% CI = 39% to 67%) and a specificity of 100% (95% CI = 86% to 100%). NDRG4 is a candidate tumor suppressor gene in colorectal cancer whose expression is frequently inactivated by promoter methylation. NDRG4 promoter methylation is a potential biomarker for the noninvasive detection of colorectal cancer in stool samples.


Clinical features, laboratory findings and management of meningococcal meningitis in England and Wales: report of a 1997 survey. Meningococcal meningitis: 1997 survey report.
To describe the epidemiological, clinical and laboratory features of meningococcal meningitis and the effects of antibiotics on laboratory investigations under current clinical practices in England and Wales. Using a telephone questionnaire, information was gathered on 103 cases with a clinical diagnosis of meningococcal meningitis. Included were cases with samples submitted to the Public Health Laboratory Service (PHLS), Meningococcal Reference Unit (MRU) over a 5-month period in 1997. Tests included microscopic examination, latex agglutination and culture for Neisseria meningitidis, and at MRU confirmation of identification and characterization of isolates and meningococcal polymerase chain reaction (PCR) analysis on blood and cerebrospinal fluids (CSF). Clinically 45% of the cases had predominantly meningitis and 55% had septicaemia and meningitis. Only 29% of the cases received pre-admission benzylpenicillin, and 66% were given antibiotics within an hour of hospital attendance. Microbiological confirmation was achieved in 97 cases, 46 (44%) by traditional tests and 92 (89%) by PCR assay, including some with both. The blood culture positive rate was 23 (22%), but in predominant meningitis the rate was only 10% (5/46). PCR was the sole method of confirmation in 48 cases. Seventy percent of the plasma samples referred were reactive by PCR assay, but all samples taken more than 24 h after hospital antibiotics were non-reactive. PCR-based techniques increased the overall number of cases with a serogroup identified by 44%. Lumbar punctures were performed in 73 of the cases and microbiological confirmation was achieved in 67 (92%) of these cases, compared to 26/30 without lumbar puncture (LP). Eighty-nine percent of the CSF samples referred were reactive by PCR; 50% of the CSF samples taken more than 24 h after hospital antibiotics were reactive, whilst none were positive by culture or microscopy. Due to variable clinical manifestations, early diagnosis and treatment was difficult. Laboratory confirmation has been improved by the introduction of PCR-based techniques. Meningococcal DNA was detected by molecular methods in CSF samples taken up to 72 h after commencement of antibiotics. During this period patients could be stabilized and the chances of complications attendant upon early LP reduced. In addition to providing accurate epidemiological information, confirming the diagnosis may alter the extent and length of follow-up.


ROS-dependent HIF1α activation under forced lipid catabolism entails glycolysis and mitophagy as mediators of higher proliferation rate in cervical cancer cells.
In the last decades, the concept of metabolic rewiring as a cancer hallmark has been expanded beyond the "Warburg effect" and the importance of other metabolic routes, including lipid metabolism, has emerged. In cancer, lipids are not only a source of energy but are also required for the formation of membranes building blocks, signaling and post-translational modification of proteins. Since lipid metabolism contributes to the malignancy of cancer cells, it is an attractive target for therapeutic strategies. Over-expression of the adipose triglyceride lipase (ATGL) was used to boost lipid catabolism in cervical cancer cells. The cervical cancer cell line HeLa was employed as the primary experimental model for all subsequent studies. The lipolytic activity of ATGL was mimicked by caproate, a short-chain fatty acid that is efficiently oxidized in mitochondria. Here, we provide evidence of the association between boosted lipid catabolism and the increased proliferation and migration capability of cervical cancer cells. These pro-tumoral effects were ascribed to the reactive oxygen species (ROS)-mediated induction of hypoxia-inducible factor-1α (HIF1α) triggered by the increased mitochondrial fatty acids (FAs) oxidation. HIF1α activation increases glycolytic flux and lactate production, promoting cell proliferation. At the same time, HIF1α increases protein and mRNA levels of its known target BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), which in turn activates mitophagy as a pro-survival process, as demonstrated by the induction of apoptosis upon inhibition of mitophagy. These effects were mimicked by the short-chain fatty acid caproate, confirming that forcing lipid catabolism results in HIF1α induction. Boosting lipid catabolism by ATGL over-expression has a pro-tumor role in cervical cancer cells, dependent on ROS production and HIF1α induction. Together with the bioinformatics evidence of the correlation of ATGL activity with the aggressiveness of cervical cancer cells, our data suggest that ATGL could be a promising prognostic marker for cervical cancer and highlight the need of further investigations on the role of this lipase in cancer cells. This evidence could be exploited to develop new personalized therapy, based on the functionality of the antioxidant equipment of cancer cells, considering that ROS content could affect ATGL role.


A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis.
Nationwide fortification of enriched uncooked cereal grains with folic acid began in the United States and Canada in 1996 and 1997, respectively, and became mandatory in 1998. The rationale was to reduce the number of births complicated by neural tube defects. Concurrently, the United States and Canada experienced abrupt reversals of the downward trend in colorectal cancer (CRC) incidence that the two countries had enjoyed in the preceding decade: absolute rates of CRC began to increase in 1996 (United States) and 1998 (Canada), peaked in 1998 (United States) and 2000 (Canada), and have continued to exceed the pre-1996/1997 trends by 4 to 6 additional cases per 100,000 individuals. In each country, the increase in CRC incidence from the prefortification trend falls significantly outside of the downward linear fit based on nonparametric 95% confidence intervals. The statistically significant increase in rates is also evident when the data for each country are analyzed separately for men and women. Changes in the rate of colorectal endoscopic procedures do not seem to account for this increase in CRC incidence. These observations alone do not prove causality but are consistent with the known effects of folate on existing neoplasms, as shown in both preclinical and clinical studies. We therefore hypothesize that the institution of folic acid fortification may have been wholly or partly responsible for the observed increase in CRC rates in the mid-1990s. Further work is needed to definitively establish the nature of this relationship. In the meantime, deliberations about the institution or enhancement of fortification programs should be undertaken with these considerations in mind.


Two functionally independent pathways for lipopolysaccharide-dependent activation of mouse peritoneal macrophages.
We have investigated the effects of human LPS-binding protein (LBP) and human bactericidal/permeability-increasing protein (BPI) on LPS-dependent activation of mouse thioglycolate-elicited peritoneal macrophages in vitro, in comparison with human PBMCs. Confirming earlier published studies, BPI inhibited, and LBP enhanced, the ability of LPS to stimulate PBMC production of the cytokines TNF-alpha and IL-6. In marked contrast to these results, under identical conditions of in vitro culture, both LBP and BPI suppressed, in a dose-dependent manner, the ability of LPS to stimulate cytokine production in mouse macrophages. Further, while human BPI also suppressed LPS-dependent NO secretion in mouse macrophages, human LBP had no inhibitory effect on NO secretion under conditions that inhibited TNF-alpha secretion. These data provide the first direct evidence that mouse macrophages may utilize two independent pathways in response to LPS, thus leading to different phenotypic responses.


Dexamethasone induce osteoblast apoptosis in a duration- and dose-dependent manner.
Osteoblasts play an important role in the process of osteogenesis and prevention of osteonecrosis. Dexamethasone, a type of glucocorticoids (GCs), induce apoptosis of osteoblasts and lead to the occurrence of non-traumatic osteonecrosis. This study aimed to explore the effects of different doses and duration of Dexamethasone on osteoblast apoptosis of rats in vitro. Proliferation and apoptosis of osteoblasts after Dexamethasone treatment were detected using cell counting kit-8 (CCK-8) assay and FITC-Annexin V/PI staining. The expressions of caspase-3 and -9 in osteoblasts after Dexamethasone treatment were analyzed using western blotting and qRT-PCR. Dexamethasone remarkably inhibited proliferation and induced apoptosis of osteoblasts in a dose-and duration-dependent manner. As the intervention time extended, the expression of caspase-3 mRNA and caspase-9 mRNA in different Dexamethasone groups gradually increased in a duration-dependent manner. With the same time of intervention (12h, 24h, 48h), the expression of caspase-3 and -9 mRNA gradually increased in a dose-dependent manner. After treated with 5 * 10-8M, 5 * 10-7M, 5 * 10-6M and 5 * 10-5M Dexamethasone for 24 hours, the expression of cleaved caspase-3 and -9 protein increased in a dose-dependent manner. Dexamethasone can induce osteoblast apoptosis in a duration- and dose-dependent manner.


Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study.
Alterations in dopaminergic neurotransmission and function of the prefrontal cortex are thought to be central to the pathophysiology of schizophrenia, but the relationship between these factors in the development of psychosis is unclear. To investigate the relationship between striatal dopamine activity and prefrontal function in people at ultra high risk of psychosis. Subjects were studied using functional magnetic resonance imaging while performing a working memory (N-back) task. Positron emission tomography with fluorine 18-labeled fluorodopa was used to investigate presynaptic striatal dopamine activity. Outpatient service for people with prodromal signs of psychosis. Thirty-four subjects participated in the study: 14 healthy volunteers and 20 subjects with an at-risk mental state (ARMS). Regional brain activation (blood oxygen level-dependent response), Ki for [(18)F]fluorodopa uptake, and objective ratings of psychopathology at the time of scanning. In the associative part of the striatum, the Ki for [(18)F]fluorodopa was higher in the ARMS group than in the controls. During the N-back task, ARMS subjects displayed less activation in the right middle frontal gyrus, the medial frontal gyri, and the left superior parietal lobule than controls. The Ki for [(18)F]fluorodopa was positively correlated with activation in the right middle frontal gyrus in controls but negatively correlated with activation in this region in the ARMS group. In people with prodromal signs of psychosis, there are direct correlations between altered prefrontal cortical function and subcortical dopamine synthesis capacity, consistent with the notion that frontostriatal interactions play a critical role in the pathoetiology of schizophrenia.


A Radiolabeling-Free, qPCR-Based Method for Locus-Specific Pseudouridine Detection.
Pseudouridine (Ψ) is the most abundant post-transcriptional RNA modification. Methods have been developed for locus-specific Ψ detection; however, they often involve radiolabeling of RNA, require advanced experimental skills, and can be time-consuming. Herein we report a radiolabeling-free, qPCR-based method to rapidly detect locus-specific Ψ. Pseudouridine residues were labeled chemically, and the resulting adducts induced mutation/deletion during reverse transcription (RT) to generate qPCR products with different melting temperatures and hence altered melting curves. We validated our method on known Ψ sites in rRNA and then used it to sensitively detect Ψ residues in lncRNA and mRNA of low abundance. Finally, we applied our method to pseudouridine synthase identification and showed that Ψ616 in PSME2 mRNA is dependent on PUS7. Our facile and cost-effective method takes only 1.5 days to complete, and with slight adjustment it can be applied to the detection of other epitranscriptomic marks.


Sickle cell acute chest syndrome: pathogenesis and rationale for treatment.
Acute chest syndrome (ACS) is a leading cause of death in sickle cell disease (SCD). Our previous work showed that hypoxia enhances the ability of sickle erythrocytes to adhere to human microvessel endothelium via interaction between very late activation antigen-4 (VLA4) expressed on sickle erythrocytes and the endothelial adhesion molecule vascular cell adhesion molecule-1 (VCAM-1). Additionally, hypoxia has been shown to decrease the production of nitric oxide (NO) which inhibits VCAM-1 upregulation. Based on these observations, we hypothesize that during ACS, the rapidly progressive clinical course that can occur is caused by initial hypoxia-induced pulmonary endothelial VCAM-1 upregulation that is not counterbalanced by production of cytoprotective mediators, including NO, resulting in intrapulmonary adhesion. We assessed plasma NO metabolites and soluble VCAM-1 in 36 patients with SCD and 23 age-matched controls. Patients with SCD were evaluated at baseline (n = 36), in vaso-occlusive crisis (VOC; n = 12), and during ACS (n = 7). We observed marked upregulation of VCAM-1 during ACS (1,290 +/- 451 ng per mL; mean +/- 1 SD) with values significantly higher than controls (P <.0001) or patients either in steady state or VOC (P <. 01). NO metabolites were concomitantly decreased during ACS (9.2 +/- 1.5 nmol/mL) with values lower than controls (22.2 +/- 5.5), patients during steady state (21.4 +/- 5.5), or VOC (14.2 +/- 1.2) (P <.0001). Additionally, the ratio of soluble VCAM-1 to NO metabolites during ACS (132.9 +/- 46.5) was significantly higher when compared with controls (P <.0001) or patients either in steady state or VOC (P <.0001). Although hypoxia enhanced in vitro sickle erythrocyte-pulmonary microvessel adhesion, NO donors inhibited this process with concomitant inhibition of VCAM-1. We suggest that in ACS there is pathologic over expression of endothelial VCAM-1. Our investigations also provide a rationale for the therapeutic use in ACS of cytoprotective modulators including NO and dexamethasone, which potentially exert their efficacy by an inhibitory effect on VCAM-1 and concomitant inhibition of sickle erythrocyte-endothelial adhesion.


Effect of hypoxemia on tissue glycogen content and glycolytic enzyme activities in fetal sheep.
We have tested the hypothesis that prolonged fetal hypoxemia causes a reduction in glycogenolytic enzyme activities and/or a depletion of fetal glycogen stores. We compared the effects of short (4 h) and prolonged (24 h) periods of reduced maternal uterine blood flow (RUBF) on glycogen content and on the activities of glucose-6-phosphatase (G-6-Pase), glycogen phosphorylase (GPase), and glycogen synthase (GSase) in selected fetal tissues. RUBF was reduced in 10 pregnant sheep at 135 days of gestation (term approximately 146 days) for either 4 h (n = 5) or 24 h (n = 5); 5 other fetuses were used as controls. During RUBF, fetal SaC2 was decreased from 61.6 +/- 3.9 to 22.0 +/- 1.4% at 4 h and to 26.7 +/- 1.2% at 24 h. Hepatic glycogen content was significantly reduced at 4 h of RUBF, but was not reduced further at 24 h. Fetal liver GPase (active and total enzyme activity) and G-6-Pase activities were reduced at 4 h of RUBF but tended to return toward control values at 24 h. Similarly, hepatic GSase activity tended to decrease at 4 h of RUBF, although the reduction was not quite significant (P = 0.08). We conclude that RUBF causes a reduction of fetal glycogen stores and a reduction in G-6-Pase and GPase activity at 4 h. Fetal tissue glycogen contents were not reduced further at 24 h, compared with 4 h of RUBF, which indicates that fetal glycogenolysis is reduced during this time, probably because of the inhibition of GPase and G-6-Pase. It is not known why the activities of these enzymes are reduced during prolonged RUBF, when circulating epinephrine and norepinephrine concentrations are high.


Corneal melt as the initial presentation of primary Sjögren's syndrome.
Corneal melting is a rare complication of S ogren's syndrome (SS). Previously reported cases of corneal ulceration occurred in patients with established SS, usually secondary to RA. We describe the first case of corneal ulceration with stromal melting as the initial presentation of primary SS. A 79-year-old man without prior sicca symptoms developed a large sterile corneal ulcer that required extensive treatment over several months with ocular lubricants, systemic immunosuppressives, and surgical repair. Evaluation for an underlying connective tissue disease revealed positive antinuclear antibodies (1:640 speckled) and anti-SSA antibody. A lip biopsy established the diagnosis of SS. Ulceration later occurred in the contralateral eye. Two years after the last corneal ulcer and no longer taking prednisone, the patient's ocular disease remained quiescent taking azathioprine 175 mg and hydroxychloroquine 400 mg daily. This case highlights the potential for primary SS to present with serious ocular complications despite lack of a priori sicca symptoms, as well as the importance of immunosuppressive therapy in the treatment of this complication.


Regulation of BDNF expression by cocaine.
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors. It is expressed throughout the nervous system. A unique feature of the BDNF gene is the existence of multiple mRNA transcripts, all of which are translated into BDNF protein, suggesting a multilevel regulation of expression. In particular, the BDNF exon IV promoter region is a preferential target for epigenetic alterations, as it contains binding sites for CREB and MeCP2, two transcriptional regulators known to mediate epigenetic changes. Exposure to drugs of abuse is known to modulate epigenetic regulation of BDNF gene expression. This review will discuss how exposure to cocaine, one of the most addictive drugs known to mankind, can produce alterations in BDNF gene expression, especially in the mesolimbic dopaminergic system, which lead to alterations in the reward-mediated behaviors involved in addiction.


Passively mode-locked Yb3+:Sc2SiO5 laser with reflection-type single-walled carbon nanotube absorber.
A reflection-type single-walled carbon nanotube saturable absorber fabricated by a vertical evaporation method was to our knowledge first used in a passively mode-locked Yb(3+):Sc(2)SiO(5)(Yb:SSO) laser. The laser operated at a repetition frequency of 94 MHz with a central wavelength of 1062.6 nm. A short pulse duration of 1.8 ps was produced with an average power of 349 mW; and the highest pulse energy of 3.7 nJ, corresponding to its maximum peak power, can reach 2.1 kW.


Determinants of stunting and overweight among young children and adolescents in sub-Saharan Africa.
Stunting and overweight are nutritional problems affecting most of sub-Saharan Africa. The region now has the world's highest rate of stunting among children (43%), while overweight and obesity are becoming a global epidemic, and Africa is not spared. The past two decades have seen a dramatic increase in obesity in sub-Saharan Africa. The purpose of this systematic review is to explore the determinants of stunting and overweight in sub-Saharan Africa. A literature search was conducted in PubMed using the key words stunting, overweight, obesity, Africa, sub-Saharan Africa, determinants, and prevalence. Limits were set to include articles published between 1990 and 2012. The systematic review resulted in 38 studies, and after selection based on title, content, and country of the study, 18 studies were eligible for this review. Data were analyzed by the chi-square test. The prevalence rates of stunting and overweight were dependent on socioeconomic, demographic, and environmental factors. Many studies indicate that male children and those living in a rural setting are more likely to be stunted, whereas overweight among children depends more on age, household composition, occupation of the mother, and the mother's body mass index. Stunting occurred together with overweight among both boys and girls from 1 to 5 years of age. Stunting was more prevalent among boys than among girls. Indicators of socioeconomic status, such as mother's education, mother's occupation, and household income, were some of the determinants directly linked to stunting, whereas environmental factors, such as rural or urban setting and sanitation, influenced both stunting and overweight. Concurrent stunting and overweight is influenced by maternal and household factors, such as maternal height, age, and education, large household size, and lower socioeconomic status. Although socioeconomic, demographic, and environmental factors were significant in determining stunting and overweight, other factors, such as nutrition and lifestyle, were important risk factors. Stunting in childhood is a risk factor that may result in overweight and obesity later in adolescence and adulthood, indicating the need to screen children below 1 year of age to identify stunting early in life. Promoting exclusive breastfeeding is reported to be important in preventing both stunting and overweight among children. More research is needed to explore the relationship between stunting and overweight and to explore policy guidelines to address the phenomenon.


Nanoparticle technology and its implications in endodontics: a review.
The era of Nanomaterials has had a long lasting impression in the field of medical science. It's excellent use in medicine has led to its application in dental science. Serious concerns regarding the eradication of microbial biofilms from the root canal system still exists in the field of endodontics. Nanoparticles have proven to be much more efficient with good bonding capabilities and surface chemistry as compared to the conventional materials. The practical applications of nanotechnology in endodontics has led to future prospects in research in this field. Nanoparticles in endodontics have shown promising results. The various nanoaprticles like graphene, silver nanoparticles, chitosan, hydroxyapaptite nanoparticles, Iron compound, zirconia, Poly (lactic) co-glycolic acid, bioactive glass, mesoporous calcium silicate, titanium dioxide nanoparticles, Magnesium, Calcium oxide and Copper oxide have been discussed. These nanoparticles have fetched and shown great results in various application in endodontics like incorporation of nanoparticles in selaers, obturating materials, irrigation, and intracanal medicament. The application of nanoparticles from natural and synthetic materials is rapidly evolving in dentistry. These biomaterials have helped in treatment of oral diseases, in eradication of smear layer and biofilms, have been incorporated in various dental materials for their antimicrobial effects. Combining all their beneficial aspects, these nanoparticles will provide new paradigm shift in dentistry. This review on nanoparticles will provide the reader with the latest knowledge of these materials, their mechanism of action and its implications in endodontics.


In-line Fourier-transform infrared spectroscopy as a versatile process analytical technology for preparative protein chromatography.
Fourier-transform infrared spectroscopy (FTIR) is a well-established spectroscopic method in the analysis of small molecules and protein secondary structure. However, FTIR is not commonly applied for in-line monitoring of protein chromatography. Here, the potential of in-line FTIR as a process analytical technology (PAT) in downstream processing was investigated in three case studies addressing the limits of currently applied spectroscopic PAT methods. A first case study exploited the secondary structural differences of monoclonal antibodies (mAbs) and lysozyme to selectively quantify the two proteins with partial least squares regression (PLS) giving root mean square errors of cross validation (RMSECV) of 2.42 g/l and 1.67 g/l, respectively. The corresponding Q2 values are 0.92 and, respectively, 0.99, indicating robust models in the calibration range. Second, a process separating lysozyme and PEGylated lysozyme species was monitored giving an estimate of the PEGylation degree of currently eluting species with RMSECV of 2.35 g/l for lysozyme and 1.24 g/l for PEG with Q2 of 0.96 and 0.94, respectively. Finally, Triton X-100 was added to a feed of lysozyme as a typical process-related impurity. It was shown that the species could be selectively quantified from the FTIR 3D field without PLS calibration. In summary, the proposed PAT tool has the potential to be used as a versatile option for monitoring protein chromatography. It may help to achieve a more complete implementation of the PAT initiative by mitigating limitations of currently used techniques.


Sorafenib ameliorates renal fibrosis through inhibition of TGF-β-induced epithelial-mesenchymal transition.
This study was to investigate whether sorafenib can inhibit the progression of renal fibrosis and to study the possible mechanisms of this effect. Eight-week-old rats were subjected to unilateral ureteral obstruction (UUO) and were intragastrically administered sorafenib, while control and sham groups were administered vehicle for 14 or 21 days. NRK-52E cells were treated with TGF-β1 and sorafenib for 24 or 48 hours. HE and Masson staining were used to visualize fibrosis of the renal tissue in each group. The expression of α-SMA and E-cadherin in kidney tissue and NRK-52E cells were performed using immunohistochemistry and immunofluorescence. The apoptosis rate of NRK-52E cells was determined by flow cytometry analysis. The protein levels of Smad3 and p-Smad3 in kidney tissue and NRK-52E cells were detected by western blot analysis. HE staining demonstrated that kidney interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration in the sorafenib-treated-UUO groups were significantly decreased compared with the vehicle-treated-UUO group (p<0.05). Masson staining showed that the area of fibrosis was significantly decreased in the sorafenib-treated-UUO groups compared with vehicle-treated-UUO group (p<0.01). The size of the kidney did not significantly increase; the cortex of the kidney was thicker and had a richer blood supply in the middle-dose sorafenib group compared with the vehicle-treated-UUO group (p<0.05). Compared with the vehicle-treated-UUO and TGF-β-stimulated NRK-52E groups, the expression of a-SMA and E-cadherin decreased and increased, respectively, in the UUO kidneys and NRK-52E cells of the sorafenib-treated groups (p<0.05). The apoptotic rate of NRK-52E cells treated with sorafenib decreased for 24 hours in a dose-dependent manner (p<0.05). Compared with the vehicle-treated UUO and TGF-β-stimulated NRK-52E groups, the ratio of p-Smad3 to Smad3 decreased in the sorafenib-treated groups (p<0.05). Our results suggest that sorafenib may useful for the treatment of renal fibrosis through the suppression of TGF-β/Smad3-induced EMT signaling.


Pharmacological treatment of Parkinson disease: a review.
Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life. To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea. References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic. Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, β-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies. Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established.


Rhinosporidiosis presenting as recurrent nasal polyps.
Rhinosporidiosis is a chronic granulomatous disease of the mucous membrane, predominantly of the nose and nasopharynx. It is uncommon in Malaysia but has been seen in immigrant workers from endemic areas like India and Sri Lanka. A case seen in Johor is reported here to highlight the need of awareness among clinicians at a time where there is increasing numbers of immigrant workers in our country. The causative organism of this disease is Rhinosporidium seeberi, which is found in stagnant waters. Sporangia and endospores of R. seeberi are seen in the granulomatous polypoidal lesions. The patients commonly present with epistaxis and nasal blockage. Complete excision is the treatment of choice for this disease. Recurrences are common despite anti-microbial treatment.


Normative corrections for the Halstead Reitan Neuropsychological Battery.
This article investigates the adequacy of the Heaton-Grant-Matthews norms in correcting age and education effects in the Halstead Reitan Neuropsychological Battery. Two hundred and ninety neurological and 346 psychiatric patients were administered the Halstead Reitan Neuropsychological Battery. Raw scores were converted to standard scores using the Heaton-Grant-Matthews norms. Ten percent of the variance in standard score profiles could be predicted by patient age and education. The primary effect of age was to decrease the overall level of the profile; the primary effect of education was to increase relative scores on the Aphasia test. When these standard scores were converted to age- and education-corrected T-scores, less than 1% of the variance could be predicted by age and education. When individual tests were examined, the Heaton-Grant-Matthews norms failed to correct 2% of the variance in the Speech Sounds test. Discussion focuses on the usefulness of the Heaton-Grant-Matthews norms in interpreting performance on the Halstead Reitan Neuropsychological Battery.


Superior recognition performance for happy masked and unmasked faces in both younger and older adults.
In the aging literature it has been shown that even though emotion recognition performance decreases with age, the decrease is less for happiness than other facial expressions. Studies in younger adults have also revealed that happy faces are more strongly attended to and better recognized than other emotional facial expressions. Thus, there might be a more age independent happy face advantage in facial expression recognition. By using a backward masking paradigm and varying stimulus onset asynchronies (17-267 ms) the temporal development of a happy face advantage, on a continuum from low to high levels of visibility, was examined in younger and older adults. Results showed that across age groups, recognition performance for happy faces was better than for neutral and fearful faces at durations longer than 50 ms. Importantly, the results showed a happy face advantage already during early processing of emotional faces in both younger and older adults. This advantage is discussed in terms of processing of salient perceptual features and elaborative processing of the happy face. We also investigate the combined effect of age and neuroticism on emotional face processing. The rationale was previous findings of age-related differences in physiological arousal to emotional pictures and a relation between arousal and neuroticism. Across all durations, there was an interaction between age and neuroticism, showing that being high in neuroticism might be disadvantageous for younger, but not older adults' emotion recognition performance during arousal enhancing tasks. These results indicate that there is a relation between aging, neuroticism, and performance, potentially related to physiological arousal.


Effects of delay in the snap freezing of colorectal cancer tissues on the quality of DNA and RNA.
The success of basic molecular research using biospecimens strongly depends on the quality of the specimen. In this study, we evaluated the effects of delayed freezing time on the stability of DNA and RNA in fresh frozen tissue from patients with colorectal cancer. Tissues were frozen at 10, 30, 60, and 90 minutes after extirpation of colorectal cancer in 20 cases. Absorbance ratio of 260 to 280 nm (A(260)/A(280)) and agarose gel electrophoresis were evaluated. In addition, the RNA integrity number (RIN) was assayed for the analysis of the RNA integrity. Regardless of delayed freezing time, all DNA and RNA samples revealed A(260)/A(280) ratios of more than 1.9, and all DNA samples showed a discrete, high-molecular-weight band on agarose gel electrophoresis. The RINs were 7.53 ± 2.04, 6.70 ± 1.88, 6.47 ± 2.58, and 4.22 ± 2.34 at 10, 30, 60, and 90 minutes, respectively. Though the concentration of RNA was not affected by delayed freezing, the RNA integrity was decreased with increasing delayed freezing time. According to the RIN results, we recommend that the collection of colorectal cancer tissue should be done within 10 minutes for studies requiring RNA of high quality and within 30 minutes for usual RNA studies.


Current clinical application of intracardiac flow analysis using echocardiography.
In evaluating the cardiac function, it is important to have a comprehensive assessment of structural factors, such as the myocardial or valvular function and intracardiac flow dynamics that pass the heart. Vortex flow that form during left ventricular filling have specific geometry and anatomical location that are critical determinants of directed blood flow during ejection. The formation of abnormal vortices relates to the abnormal cardiac function. Therefore, vortex flow may offer a novel index of cardiac dysfunction. Intracardiac flow visualization using ultrasound technique has definite advantages with a higher temporal resolution and availability in real time clinical setting. Vector flow mapping based on color-Doppler and contrast echocardiography using particle image velocimetry is currently being used for visualizing the intracardiac flow. The purpose of this review is to provide readers with an update on the current method for analyzing intracardiac flow using echocardiography and its clinical applications.


Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer.
Hedgehog (Hh) and epidermal growth factor receptor (EGFR) signaling are involved in pancreatic cancer progression. Targeting these pathways simultaneously with cyclopamine (Hh inhibitor) and gefitinib (EGFR inhibitor) is a promising approach for treating pancreatic cancer. However, the major limitation for effective clinical translation of these molecules is their low aqueous solubility. We have previously demonstrated that methoxy polyethyleneglycol-b-poly(carbonate-co-lactic acid) {mPEG-b-P(CB-co-LA)} copolymer solubilizes hydrophobic anticancer drugs and has the potential to deliver to tumors by an enhanced permeability and retention (EPR) effect. In this study, using the nanoprecipitation method, cyclopamine and gefitinib were efficiently loaded into mPEG-b-P(CB-co-LA) micelles with encapsulation efficiencies of 94.4 and 88.6%, respectively. These micelles had a narrow particle size distribution with a mean particle size of 54.3 nm and a PDI of 0.14. Combination therapy showed a synergistic effect against L3.6pl cells but an additive effect against MIA PaCa-2 cells. Caspase 3/7 activity was also increased when this combination therapy was used, indicating apoptotic cell death. Gene and protein expression analysis indicated cross-talk between Hh and EGFR signaling. Furthermore, the combination decreased tumor growth rate in L3.6pl-derived xenograft mouse tumors. These data suggest the applicability of our micellar system to effectively load and deliver cyclopamine and gefitinib for combination chemotherapy.


Hydergine for dementia.
Currently hydergine is used almost exclusively for treating patients with either dementia, or 'age-related' cognitive symptoms. Since the early eighties there have been over a dozen more clinical trials, yet hydergine's efficacy remains uncertain. Although previous reviews offer generally favorable support for hydergine's efficacy, they were, however, limited by a bias with respect to the particular clinical studies chosen (eg, the inclusion of case reports, and uncontrolled trials), and by authors' impressionistic assessments of results. Not surprisingly, there has been a lack of consensus among reviewers with regard to the efficacy of hydergine. In 1994, a meta-analysis was published by the present reviewers who reported that overall, hydergine was more effective than placebo. However they also observed that the statistical evidence for efficacy in 'possible or probable Alzheimer's disease' patients was so modest that one additional statistically non-significant trial would have reduced the results to non significance. Because of uncertainty surrounding the efficacy of hydergine, the goals of this overview were to assess its overall effect in patients with possible dementia, and to investigate potential moderators of an effect. The Cochrane Dementia Group Register of Clinical Trials was searched using the terms 'hydergine', 'ergoloids,' 'ergoloid mesylates,' 'dihydroergocristine,' 'dihydroergocryptine,' 'dihydroergotoxine,' and 'dihydroergocornine. MEDLINE, EMBASE, and two proprietary databases were searched also. Published reviews were inspected for further sources. Trials to be included must be randomized, double-blind, parallel-group, and unconfounded comparisons of hydergine with placebo for a treatment duration of greater than 1 week in subjects with dementia or symptoms consistent with dementia. Data were extracted independently by the reviewers, pooled where appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used. Outcomes of interest included clinical global impressions of change and comprehensive rating scales. Potential moderating variables of a treatment effect included: inpatient/outpatient status, trial duration, age, sex, medication dose, publication year, and diagnostic grouping. There were a total of nineteen trials that met inclusion criteria and that had data sufficient for analysis. Thirteen trials reported sufficient information to use a global rating of improvement and nine trials provided information on a comprehensive rating scale. Three trials provided both outcome measures. It was not possible to use many of the published results in a combined analysis owing to the lack of sufficient data to perform statistical analyses. For the twelve trials that used global ratings, there was a significant effect favoring hydergine (OR 3.78, 95%CI, 2.72-5.27). For the nine trials that used comprehensive ratings, there was a significant mean difference favoring hydergine (WMD 0.96, 95%CI, 0. 54-1.37). Hydergine was well tolerated in these trials, with 78% of randomized subjects available for data analyses. Greater effect sizes on global ratings were associated with younger age, and possibly higher dose, although most of the subgroup analyses were statistically insignificant. As in an earlier systematic review, we found hydergine to show significant treatment effects when assessed by either global ratings or comprehensive rating scales (based here on a smaller set of trials than in the earlier published systematic review because trials were required to have data that could conform with MetaView, the Cochrane Collaboration statistics software). The small number of trials available for analysis, however, limited the ability of subgroup analyses to identify statistically significant modera


Characterization of the prandial plasma corticosterone peak in the freely moving rat.
To characterize the prandial plasma corticosterone peak, three experiments were done on adult male Wistar rats: (1) the prandial hormone peak was followed at three different times of day, 0800 h, 1900 h, and 0100 h, in starved rats; (2) a 20% glucose solution was infused into the jugular vein or was given as a drinking solution after a 24-h starvation; (3) in order to determine the role of vagal proprioceptive inputs, the hormone peak was examined at two times of day, 0800 h and 0100 h, in starved vagotomized rats. The prandial hormone peak was more conspicuous at midnight than in the daytime. Exposure to food pellets without feeding failed to induce a hormone rise. The peak appeared after oral ingestion, but not after intravenous infusion, of glucose solution. Ingestion of water alone was without effect. The peak was not affected by bilateral vagotomy. Thus, as far as glucose as a metabolite is concerned, the possibility that glucose per se works directly on the brain or indirectly through glucoreceptors in the gut was excluded. Possible modes of action of glucose ingestion are discussed.


Characterization of mouse peroxiredoxin I genomic DNA and its expression.
Peroxiredoxins (Prxs) are a newly defined family of anti-oxidant proteins that have been implicated, via their anti-oxidant activity, in a number of cellular functions, including cell proliferation and differentiation, protection of other proteins from oxidative damage, and intracellular signaling. We isolated genomic DNA sequences of the Prx I genes from the mouse, and characterized their molecular genetic features. Prx I was found to form a small gene family with two and three members; one functional and two pseudogenes. The Prx I-1 gene has splice donor/acceptor site sequences and five or six exons, whereas the Prx I-2 clone has several structural features characteristic of a typical retroposon found to have ORF sequences. We analyzed the expression of pseudogenes, which were not expressed on the transcription levels in the investigated organs. The functional copy of the Prx I-1 gene was expressed abundantly in liver and kidney of the adult, as well as in early developing embryos. This report, together with amino acid/nucleotide sequence similarity between human and mice, provides a basis for speculating on an even earlier event in the evolution of the Prx I gene family, i.e. the Prx I gene was well conserved in human and mice via its anti-oxidant activity.


Survivin regulates intracellular stiffness and extracellular matrix production in vascular smooth muscle cells.
Vascular dysfunction is a common cause of cardiovascular diseases characterized by the narrowing and stiffening of arteries, such as atherosclerosis, restenosis, and hypertension. Arterial narrowing results from the aberrant proliferation of vascular smooth muscle cells (VSMCs) and their increased synthesis and deposition of extracellular matrix (ECM) proteins. These, in turn, are modulated by arterial stiffness, but the mechanism for this is not fully understood. We found that survivin is an important regulator of stiffness-mediated ECM synthesis and intracellular stiffness in VSMCs. Whole-transcriptome analysis and cell culture experiments showed that survivin expression is upregulated in injured femoral arteries in mice and in human VSMCs cultured on stiff fibronectin-coated hydrogels. Suppressed expression of survivin in human VSMCs significantly decreased the stiffness-mediated expression of ECM components related to arterial stiffening, such as collagen-I, fibronectin, and lysyl oxidase. By contrast, expression of these ECM proteins was rescued by ectopic expression of survivin in human VSMCs cultured on soft hydrogels. Interestingly, atomic force microscopy analysis showed that suppressed or ectopic expression of survivin decreases or increases intracellular stiffness, respectively. Furthermore, we observed that inhibiting Rac and Rho reduces survivin expression, elucidating a mechanical pathway connecting intracellular tension, mediated by Rac and Rho, to survivin induction. Finally, we found that survivin inhibition decreases FAK phosphorylation, indicating that survivin-dependent intracellular tension feeds back to maintain signaling through FAK. These findings suggest a novel mechanism by which survivin potentially modulates arterial stiffness.


Intimate partner violence and anal intercourse in young adult heterosexual relationships.
Although intimate partner violence and anal intercourse are common in young adult relationships, few studies have examined whether these behaviors are associated with each other. Data from 6,280 women aged 18-28 who took part in Wave 3 of the National Longitudinal Study of Adolescent Health were used to examine the association between physical and sexual intimate partner violence and anal intercourse in 10,462 relationships. Multivariate hierarchical random effects models were used to adjust for the clustered survey design and for the multiple relationships reported per participant. Physical violence occurred in 29% of relationships, sexual violence in 11% and anal intercourse in 14%. The odds that a couple had had anal intercourse were greater among relationships that included physical violence perpetrated by both partners or only by the woman than among nonviolent relationships (odds ratios, 1.7 and 1.9, respectively). The odds of anal intercourse were also elevated among sexually abusive relationships, although only if the woman was the sole victim or the sole perpetrator (1.3 and 2.0, respectively). In relationships that included anal intercourse, the odds of condom use were lower if the woman was a victim of physical violence than if no violence occurred (0.2). Sexual violence was not associated with condom use. Women in physically violent relationships may be at increased risk for STDs because of their elevated exposure to unprotected anal intercourse. More information on the context surrounding anal intercourse and intimate partner violence is needed to understand the nuances of this association.


In vivo studies of upstream regulatory cis-acting elements of the alcR gene encoding the transactivator of the ethanol regulon in Aspergillus nidulans.
The alcR gene of Aspergillus nidulans, which encodes the specific transactivator of the ethanol utilization pathway, is positively autoregulated and carbon catabolite repressed. Regulation by these two circuits occurs at the transcriptional level via the binding of the two regulators, AlcR and CreA, to their cognate targets respectively. We demonstrate here that out of two clustered putative AlcR repeated consensus sequences, only the palindromic target is functional in vivo. Hence, it is solely responsible for the alcR positive autogenous activation loop. Transcript mapping of the alcR gene showed that transcription initiation can occur at 553 bp and at or near 86 bp upstream of the start codon. These transcription start sites yield a transcript of 3.0 kb, which appears only under induced growth conditions, and of 2.6 kb, which is present under both induced and non-induced growth conditions respectively. Nine CreA consensus sites are present in the alcR promoter but only two pairs of two sites are functional in vivo. One of them is located in close proximity to the AlcR functional target. Within this pair, both sites are necessary to mediate a partial repression of alcR transcription. Disruption of either site results in an overexpression of alcR due to the absence of direct competition between AlcR and CreA for the same DNA region. The second functional pair of CreA sites is located between the two transcription initiation sites. Disruption of either of the two sites results in a totally derepressed alcR transcription, showing that they work as a pair constituting the more efficient repression mechanism. Thus, CreA acts by two different mechanisms: by competing with AlcR for the same DNA region and by an efficient direct repression. The latter mechanism presumably interfers with the general transcriptional machinery.


Hsp90-Sgt1 and Skp1 target human Mis12 complexes to ensure efficient formation of kinetochore-microtubule binding sites.
The formation of functional kinetochores requires the accurate assembly of a large number of protein complexes. The Hsp90-Sgt1 chaperone complex is important for this process; however, its targets are not conserved and its exact contribution to kinetochore assembly is unclear. Here, we show that human Hsp90-Sgt1 interacts with the Mis12 complex, a so-called keystone complex required to assemble a large fraction of the kinetochore. Inhibition of Hsp90 or Sgt1 destabilizes the Mis12 complex and delays proper chromosome alignment due to inefficient formation of microtubule-binding sites. Interestingly, coinhibition of Sgt1 and the SCF subunit, Skp1, increases Mis12 complexes at kinetochores and restores timely chromosome alignment but forms less-robust microtubule-binding sites. We propose that a balance of Mis12 complex assembly and turnover is required for the efficient and accurate assembly of kinetochore-microtubule binding sites. These findings support a novel role for Hsp90-Sgt1 chaperones in ensuring the fidelity of multiprotein complex assembly.


Belimumab for the treatment of recalcitrant cutaneous lupus.
Background Belimumab is a monoclonal antibody that reduces B lymphocyte survival by blocking the binding of soluble human B lymphocyte stimulator (BLyS) to its B cell receptors. The utility of belimumab for management of resistant systemic lupus erythematosus (SLE) skin manifestations has not been reported. We present our experience of using this novel molecule for the successful management of cutaneous lupus at our center. Methods We studied five patients with significant SLE skin manifestations. All patients met 1997 American College of Rheumatology (ACR) SLE criteria and had failed multiple medications to control their skin disease. SLE disease activity indexes (SLEDAI), Cutaneous LE disease Area and Severity Index (CLASI) and patient's global assessment (PGA) were recorded before and 16 weeks after belimumab treatment. Belimumab was added to concomitant standard therapy. Results All five patients demonstrated marked clinical improvement subsequent to belimumab treatment. The average time to clinical improvement after treatment initiation was 8-12 weeks. SLEDAI scores (median, range) improved in all the patients ((2, 2-6) to (0, 0-4); p = 0.025). PGA scores (median, range) were better in all patients ((3, 2-3) to (1, 0-1); p = 0.039). CLASI activity scores (median, range) improved dramatically in all patients ((17, 9-31) to (3, 2-14); p = 0.043). There was no worsening of the CLASI damage scores. The mean daily prednisone dose decreased significantly from 31 mg (±18.8) at baseline to 3 mg (± 2.7) ( p = 0.042). Conclusion In this case series, the addition of belimumab to standard therapy improved the signs and symptoms of refractory cutaneous lupus. This is one of the first reports highlighting the potential utility of this medication for the treatment of severe skin involvement in SLE refractory to conventional therapies. Additional studies need to be performed to assess the use of belimumab in the treatment of cutaneous lupus.


Administering design fluency tests in school-aged children: analyses of design productivity over time, clustering, and switching.
This study investigated the effects of child-related factors (age, sex, and intellectual abilities) upon design fluency (DF) test scores. A DF test, a semantic verbal fluency (VF) test, and a Block Design test, as a proxy of intelligence, were administered to N = 80 healthy native Dutch-speaking children aged 8.45-12.82 years. Three components of DF performance were examined, i.e., design productivity over time, clustering (i.e., generating designs that share visual-spatial similarities, such as addition, deletion, or rotation), and switching (i.e., shifting between strategies that children use to draw the designs). The relation between DF design productivity over time and age was curvilinear, that is, improvements in test scores were much more pronounced for younger children than for older children. No (curvi)linear age effects were found in DF productivity scores, clustering, and switching. Also, our results did not reveal a relation between intellectual abilities and DF test scores. Furthermore, DF test scores and VF test scores were only partially significant, i.e., only significant positive correlations were found between the productivity scores of the VF test and the DF test. Finally, higher order sex by age interactions were found in all DF test scores, i.e., girls <10.5 years produced more designs, made longer clusters, and switched less than boys. Opposite sex differences were found for children >10.5 years. This illustrates the utility of combining quantitative scoring procedures with in-depth clustering and switching to understand interactions between age and sex during DF tests.


Challenges in the counseling and management of older kidney transplant candidates.
Patients aged 60 years and older represent the fastest-growing population with chronic kidney disease and end-stage renal disease (ESRD). In 2002, a total of 137,000 patients aged 65 years and older were on dialysis therapy in the United States, but only a highly selected minority of them (5%) were on the waiting list for a kidney transplant. The majority of older patients on dialysis therapy are not being referred for the waiting list, presumably because of comorbid diseases and lower life expectancy. However, kidney transplantation clearly has been shown to improve survival compared with dialysis, even for older patients. Because both patient age and time on the transplant waiting list increase the risk for death, older patients (ie, > or =60 years) who already have a shorter life expectancy than younger patients are more likely to die with a functioning graft. The limited supply of deceased-donor kidneys and increasing number of patients who would benefit from transplantation have created a dilemma about how to fairly allocate donor kidneys among patients of all ages while meeting the needs of the increasing number of older patients with ESRD. Although older dialysis patients receive fewer kidney transplants than younger patients, their patient and graft survival rates are good. Instead of applying rigid age limits, the "biological," rather than "chronological," age of individual patients should be assessed carefully to help clinicians select the most appropriate candidates for kidney transplantation and reduce morbidity and mortality in older transplant recipients.


SVmine improves structural variation detection by integrative mining of predictions from multiple algorithms.
Structural variation (SV) is an important class of genomic variations in human genomes. A number of SV detection algorithms based on high-throughput sequencing data have been developed, but they have various and often limited level of sensitivity, specificity and breakpoint resolution. Furthermore, since overlaps between predictions of algorithms are low, SV detection based on multiple algorithms, an often-used strategy in real applications, has little effect in improving the performance of SV detection. We develop a computational tool called SVmine for further mining of SV predictions from multiple tools to improve the performance of SV detection. SVmine refines SV predictions by performing local realignment and assess quality of SV predictions based on likelihoods of the realignments. The local realignment is performed against a set of sequences constructed from the reference sequence near the candidate SV by incorporating nearby single nucleotide variations, insertions and deletions. A sandwich alignment algorithm is further used to improve the accuracy of breakpoint positions. We evaluate SVmine on a set of simulated data and real data and find that SVmine has superior sensitivity, specificity and breakpoint estimation accuracy. We also find that SVmine can significantly improve overlaps of SV predictions from other algorithms. SVmine is available at https://github.com/xyc0813/SVmine. firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Role of longitudinal diffusion in the extravascular pulmonary space on parameter estimates derived from data of multiple indicator dilution.
A mathematical model of transcapillary exchange has been developed that considers in detail the role of axial diffusion in the extravascular tissue region on estimates of such physiological parameters as lung water (VE) and pulmonary capillary permeability-surface area products (PS), obtained from multiple indicator dilution studies. The experimental cases considered correspond to two animal models of pulmonary oedema in which the integrity of the pulmonary capillary membrane is disrupted and the effects of extravascular axial diffusion may be important. A novel feature of the computational scheme is the use of an Array Processor in the solution of the governing equations, initial and boundary conditions. Computer time is reduced to 2-3 min for parameter identification, thereby allowing a wide range of values for extravascular axial diffusion coefficients (D'/L2) to be studied at little computational expense. The results indicate that diffusion in the extravascular region does not influence parameter estimates for PS to urea. A statistical correlation is suggested between values for VE, PS to water, and D'/L2.


Sociodemographic, clinical, and work characteristics associated with return-to-work outcomes following surgery for work-related knee injury.
This study examined the association between return-to-work (RTW) outcomes and sociodemographic, clinical, and work characteristics among a cohort of injured workers who underwent knee surgery between 2001-2005 in British Columbia, Canada. Workers' compensation databases were used to identify the retrospective cohort and abstract the study variables. Multinomial logistic regression provided odds ratios (OR) and 95% confidence intervals (95% CI) for the association between RTW (unspecified, partial, full, or non-RTW) and the independent variables. Data was abstracted for 1394 injured workers. Compared to men, women were more likely to have partial RTW (OR 2.55, 95% CI 1.53-4.23) and non-RTW (OR 2.61, 95% CI 1.35-5.03) than full RTW; low income earners were more likely than high income earners to have partial RTW (OR 3.05, 95% CI 1.86-4.99) and non-RTW (OR 4.07, 95% CI 2.19-7.57). Moreover, workers in trade, primary resource, and processing/manufacturing occupations were more likely than those in management occupations to have non-RTW than full RTW by the end of follow-up (OR 2.97, 95% CI 1.32-6.68; OR 9.31, 95% CI 3.41-25.41, and OR 2.71, 95% CI 1.07-6.5, respectively). Surgical and clinical factors were not associated with RTW outcomes. Using population-based data, our study found a link between sociodemographic and work characteristics and the type of RTW outcome following knee surgery for a work-related injury. Women and lower income earners tended not to have full RTW, after controlling for covariates. Workers in physically demanding occupations also tended not to have full RTW, suggesting that factors beyond clinical and surgical characteristics influence disability outcomes. RTW programs need to take into consideration these broader determinants of worker health.