Liver-lung interactions following Escherichia coli bacteremic sepsis and secondary hepatic ischemia/reperfusion injury.
We hypothesized that ischemia/reperfusion (I/R) injury of the liver during normotensive gram-negative bacteremic sepsis alters the kinetics of circulating endotoxin, tumor necrosis factor-alpha (TNF-alpha), and coinduced mediators, thereby exacerbating sepsis-induced lung inflammation. Liver and lung dysfunction were studied after hematogenous infection of Sprague-Dawley rats with 10(9) Escherichia coli serotype O55:B5 (EC) and 90 min of secondary hepatic ischemia in EC + I/R and saline-infused (normal saline NS) x I/R rats, followed by brief (1 h) or longer reperfusion (24 h). TNF- alpha:leukotriene interactions in this model were examined using the 5-lipoxygenase-activating protein inhibitor MK-886. Compared with sham-operated EC + Sham animals, peak serum endotoxin, TNF-alpha, alanine aminotransferase, interleukin-6 (IL-6), and hepatic neutrophil (PMN) influx were higher in EC + I/R rats through 24 h (p < 0.05) despite comparable arterial pressure. Lung PMN influx and wet/dry weight ratios were likewise enhanced in EC + I/R versus EC + Sham or NS + I/R rats. MK-886 attenuated TNF-alpha concentrations and ischemic liver injury but not mortality. Thus, focal hepatic I/R augments circulating endotoxin, TNF-alpha, and postbacteremic lung inflammation early after normotensive E. coli bacteremic sepsis.


Real-time evaluation of p53 oscillatory behavior in vivo using bioluminescent imaging.
p53 is a key mediator of cellular response to stress, and, although its function has been carefully evaluated in vitro, noninvasive evaluation of the transcriptional activity of p53 in live animals has not been reported. To this end, we developed a transgenic mouse model wherein the firefly luciferase gene expression was dependent on the p53-responsive P2 promoter from the murine double minute 2 (MDM2) gene. Bioluminescence activity following ionizing radiation was shown to be dose, time, and p53 dependent. In addition, expression of both p53 and its activated form as well as the expression of p53 target genes (MDM2 and p21) correlated with bioluminescence activity. Temporal evaluation of p53 activity following ionizing radiation showed a distinct oscillatory pattern, which confirmed the oscillations observed previously in cultured cells. In addition, the kinetics of oscillations were altered by pretreatment with radiation-modifying agents. These results show the use of this mouse model in enhancing our understanding of the transcriptional role of p53 in vivo.


[Changes in the lymphocyte membrane lipids during immunization and staphylococcal infection].
The relationship between the state of the lipid complex of lymphocyte membranes and their functional activity has been studied in normal mice after immunization and in mice with staphylococcal infection. The study has revealed essential differences in the dynamics of free-radical processes under normal conditions and in the presence of pathology, as well as their relationship to changes in the functional state of lymphocytes and, in particular, to the development of immunodeficiency.


[Traffic accidents: a qualitative approach from Campinas, São Paulo, Brazil].
This article takes an interdisciplinary qualitative approach to the problem of traffic accidents in Campinas, São Paulo, Brazil. The authors begin by analyzing the "municipalization" (i.e., decentralization to the municipal level) of transport and traffic management in Campinas based on social representations by members of the local government's technical staff. Data demonstrate a significant drop in traffic accident mortality in Campinas in the last ten years. The findings illustrate how new transport and traffic policies had several positive effects. Special attention is given to the objectives, strategies, and obstacles dealt with by local government in the "municipalization" of traffic. The paper concludes by emphasizing the need for specific public policies to revitalize urban mass transportation, including special traffic safety educational programs.


Magnetic-field effect in atomic ionization by intense laser fields.
Numerical integrations of the two-dimensional Schr"dinger equation that describes a flat atom interacting with an intense and linearly polarized laser field are presented. Simulations show the influence of the drift that is due to the magnetic field in situations in which a strong dichotomy of the wave function would otherwise have been expected.


Single-sequence and profile-based prediction of RNA solvent accessibility using dilated convolutional neural network.
RNA solvent accessibility, similar to protein solvent accessibility, reflects the structural regions that are accessible to solvents or other functional biomolecules, and plays an important role for structural and functional characterization. Unlike protein solvent accessibility, only a few tools are available for predicting RNA solvent accessibility despite the fact that millions of RNA transcripts have unknown structures and functions. Also, these tools have limited accuracy. Here, we have developed RNAsnap2 that uses a dilated convolutional neural network with a new feature, based on predicted base-pairing probabilities from LinearPartition. Using the same training set from the recent predictor RNAsol, RNAsnap2 provides an 11% improvement in median Pearson Correlation Coefficient (PCC) and 9% improvement in mean absolute errors for the same test set of 45 RNA chains. A larger improvement (22% in median PCC) is observed for 31 newly deposited RNA chains that are non-redundant and independent from the training and the test sets. A single-sequence version of RNAsnap2 (i.e. without using sequence profiles generated from homology search by Infernal) has achieved comparable performance to the profile-based RNAsol. In addition, RNAsnap2 has achieved comparable performance for protein-bound and protein-free RNAs. Both RNAsnap2 and RNAsnap2 (SingleSeq) are expected to be useful for searching structural signatures and locating functional regions of non-coding RNAs. Standalone-versions of RNAsnap2 and RNAsnap2 (SingleSeq) are available at https://github.com/jaswindersingh2/RNAsnap2. Direct prediction can also be made at https://sparks-lab.org/server/rnasnap2. The datasets used in this research can also be downloaded from the GITHUB and the webserver mentioned above. Supplementary data are available at Bioinformatics online.


Restoration of tRNA3Lys-primed(-)-strand DNA synthesis to an HIV-1 reverse transcriptase mutant with extended tRNAs. Implications for retroviral replication.
The mechanism for the initiation of reverse transcription in human immunodeficiency virus type 1 (HIV-1) was studied utilizing a unique reverse transcriptase (RT) mutant altered in its noncatalytic p51 subunit. This mutant (p66/p51Delta13) retains full DNA- and RNA-dependent DNA polymerase activity but has reduced affinity for tRNA3Lys, the cognate HIV primer. When the ability to support(-)-strand DNA synthesis on a viral RNA template was evaluated, this mutant initiated from an 18-nucleotide (nt) oligoribo- or oligodeoxyribonucleotide primer complementary to the primer binding site (pbs). However, it failed to do so from natural and synthetic versions of tRNA3Lys. tRNA-primed(-)-strand synthesis could, however, be rescued by substituting the 76-nt tRNA3Lys with 81- and 107-nt tRNA-DNA chimeras, i.e. tRNA3Lys extended by 5 and 31 deoxyribonucleotides complementary to the viral genome upstream of the pbs. These findings imply that through interactions involving its p51 subunit, RT may be required to disrupt additional tRNA-viral RNA duplexes outside the pbs to proceed into productive(-)-strand DNA synthesis. Alternatively, specific interactions between tRNA3Lys and HIV-1 RT may be necessary for efficient initiation of(-)-strand DNA synthesis.


Seasonal variations in the onset and healing rates of venous leg ulcers.
As many vascular pathologies exhibit circannual fluctuation, the aim of this study was to assess the chronobiological features of venous ulcers. Based on a retrospective survey of the case histories of 391 venous ulcer patients, the rates of ulcer onset and healing in each month were analysed statistically; a time series was constructed to evaluate the seasonality. There was a significantly higher frequency of ulcer onset during the warmer part of the year (April-October), and onset showed strong seasonality. Healing rates were also unequally and statistically significantly distributed throughout the year: ulcers that appeared or that were treated with specialized treatment in the winter or summer healed slower in comparison to ulcers that began in the spring or autumn. Venous ulcers exhibit circannual fluctuations in their onset and healing rates. Hypothetically, in addition to exacerbation of chronic venous insufficiency, seasonal variations in immune system activity might potentially be responsible for this phenomenon.


Experimental design matters for statistical analysis: how to handle blocking.
Nowadays, evaluation of the effects of pesticides often relies on experimental designs that involve multiple concentrations of the pesticide of interest or multiple pesticides at specific comparable concentrations and, possibly, secondary factors of interest. Unfortunately, the experimental design is often more or less neglected when analysing data. Two data examples were analysed using different modelling strategies. First, in a randomized complete block design, mean heights of maize treated with a herbicide and one of several adjuvants were compared. Second, translocation of an insecticide applied to maize as a seed treatment was evaluated using incomplete data from an unbalanced design with several layers of hierarchical sampling. Extensive simulations were carried out to further substantiate the effects of different modelling strategies. It was shown that results from suboptimal approaches (two-sample t-tests and ordinary ANOVA assuming independent observations) may be both quantitatively and qualitatively different from the results obtained using an appropriate linear mixed model. The simulations demonstrated that the different approaches may lead to differences in coverage percentages of confidence intervals and type 1 error rates, confirming that misleading conclusions can easily happen when an inappropriate statistical approach is chosen. To ensure that experimental data are summarized appropriately, avoiding misleading conclusions, the experimental design should duly be reflected in the choice of statistical approaches and models. We recommend that author guidelines should explicitly point out that authors need to indicate how the statistical analysis reflects the experimental design. © 2017 Society of Chemical Industry.


Fatigue and Durability of Laminated Carbon Fibre Reinforced Polymer Straps for Bridge Suspenders.
Steel cables and suspenders in bridges are at high risk of corrosion-fatigue and in some cases of fretting-fatigue in their anchorages. These factors greatly limit the service stresses of a specific cable system and involve expensive protection measures. In order to investigate the above limitations, the fretting fatigue behaviour of pin-loaded carbon fibre reinforced polymer (CFRP) straps was studied as models for corrosion-resistant bridge suspenders. Two types of straps were tested: small model straps with a sacrificial CFRP ply and large full-scale straps. In a first phase, five fully laminated and carbon pin-loaded CFRP model straps were subjected to an ultimate tensile strength test. Thereafter, and in order to assess their durability, 20 model straps were subjected to a fretting fatigue test, which was successfully passed by 4 straps. An S-N curve was generated for a load ratio of 0.1 and a frequency of 10 Hz. In a second phase, one full-scale strap was tested for its ultimate tensile strength and two full-scale straps were fatigue-tested. The influence of fretting fatigue loading on the residual mechanical properties of the straps was also assessed, and although fretting fatigue represented an important limitation for laminated CFRP straps, it could be shown that the investigated CFRP tension members can compete with the well-established steel suspenders.


Can We Further Improve the Quality of Nephro-Urological Care in Children with Myelomeningocele?
Myelomeningocele (MMC) results from a failure of normal neural tube fusion in early fetal development. Retrospective, observational study of medical data of 54 children treated in Pediatric Nephrology and Urology Clinics for five years was performed. The following data were analyzed: serum creatinine, eGFR, urine analysis, renal scintigraphy (RS), renal ultrasound, and urodynamics. Mean age of studied population: 12.3 years, median of eGFR at the beginning and at the end of survey was 110.25 and 116.5 mL/min/1.73 m² accordingly. Median of frequency of urinary tract infections (fUTI): 1.2 episodes/year. In 24 children: low-pressure, in 30 children: high-pressure bladder was noted. Vesicouretral reflux (VUR) was noted in 23 children (42.6%). fUTI were more common in high-grade VUR group. High-grade VURs were more common in group of patients with severe renal damage. At the end of the survey 11.1% children were qualified to higher stages of chronic kidney disease. Renal parenchyma damage progression in RS was noted in 22.2% children. Positive VUR history, febrile recurrent UTIs, bladder wall trabeculation, and older age of the patients constitute risk factors of abnormal renal scans. More than 2.0 febrile, symptomatic UTIs annually increase by 5.6-fold the risk of severe renal parenchyma damage after five years.


Hypothalamic inflammation and gliosis in obesity.
Hypothalamic inflammation and gliosis are recently discovered mechanisms that may contribute to obesity pathogenesis. Current research in this area suggests that investigation of these central nervous system responses may provide opportunities to develop new weight loss treatments. In rodents, hypothalamic inflammation and gliosis occur rapidly with high-fat diet consumption prior to significant weight gain. In addition, sensitivity or resistance to diet-induced obesity in rodents generally correlates with the presence or absence of hypothalamic inflammation and reactive gliosis (brain response to injury). Moreover, functional interventions that increase or decrease inflammation in neurons and glia correspondingly alter diet-associated weight gain. However, some conflicting data have recently emerged that question the contribution of hypothalamic inflammation to obesity pathogenesis. Nevertheless, several studies have detected gliosis and disrupted connectivity in obese humans, highlighting the potential translational importance of this mechanism. There is growing evidence that obesity is associated with brain inflammation in humans, particularly in the hypothalamus where its presence may disrupt body weight control and glucose homeostasis. More work is needed to determine whether this response is common in human obesity and to what extent it can be manipulated for therapeutic benefit.


High-dose cytarabine and mitoxantrone as salvage therapy for refractory non-Hodgkin's lymphoma.
High-dose cytarabine (ara-C) alone or in combination with mitoxantrone each has shown to be active in therapeutic trials of refractory non-Hodgkin's lymphoma (NHL). In this study, we administered these two drugs to 14 patients with advanced and refractory NHL. Ara-C was administered at a dosage of 3 gm/sqm for 2-hour intravenous infusion every 12 hours from day 1 to day 4 (8 doses), and mitoxantrone was given at a dosage of 6 mg/sqm/day for 1-hour intravenous infusion from day 1 to day 5. The clinical efficacy and toxicity were assessed by WH0 criteria. Four patients (28%) attained complete remission (CR) and 2 had partial remission (PR). Of the 4 CR patients, the remission lasted 5 months in one patient and 4 months in another. The remaining 2 patients had CR of only 1.3 months. Myelosup-pression with subsequent infection was the major toxicity of this regimen. Severe neutropenia (<1,000/uL) lasted for an average of 20 days, and thrombocytopenia (<50,000/uL) 24 days. Nonmyeloid toxicities included 100% alopecia, 93% stomatitis, 43% hepatotoxicity, 36% dermatitis, 28% CNS toxicity and 7% chemical conjunctivitis. A proportion of refractory NHL patients will respond to high-dose ara-C + mitoxantrone, despite that severe myelosuppression is frequently encountered.


Detection and quantification of carotid artery stenosis: efficacy of various Doppler velocity parameters.
The purpose of this study was to evaluate and compare the accuracies of the different Doppler velocity parameters used to grade stenoses of the carotid artery. Seven velocity parameters determined with Doppler spectra were compared with angiographic findings in 138 carotid bifurcations: the peak systolic and peak end-diastolic velocities in the internal and common carotid arteries, the ratios of peak systolic and peak end-diastolic velocities between the internal and common carotid arteries, and the ratio of peak systolic velocity in the internal carotid artery to peak end-diastolic velocity in the common carotid artery. A receiver-operating-characteristic (ROC) analysis was performed, with and without correction for the bias introduced by preferentially selecting patients for angiography, if the Doppler results indicated a lesion. Multiple regression analysis was performed to predict the percent stenosis and to predict the probability of a 70% or greater stenosis. Of the Doppler parameters, the peak systolic velocity in the internal carotid artery and its ratio to the peak end-diastolic velocity in the common carotid artery were the most accurate and had equivalent test performance (ROC area = 0.94; after correction for verification bias, ROC area = 0.78). In multiple regression analysis, the peak systolic velocity in the internal carotid artery was the most significant parameter, although its ratio to the peak end-diastolic velocity in the common carotid artery had incremental value in detecting a 70% or greater stenosis, and the peak systolic velocity in the common carotid artery provided additional information for quantifying the stenosis. The peak systolic velocity in the internal carotid artery is the best single velocity parameter for quantifying a stenosis and for detecting a 70% or greater stenosis.


Diastolic time in diabetes. Impairment of diastolic time during dynamic exercise in type 2 diabetes with retinopathy.
To evaluate the effect of microangiopathic complications and autonomic dysfunction on diastolic time (DT) during dynamic exercise, 19 patients with type 2 diabetes and ten normal subjects were studied using ear densitography. All subjects had neither an ischemic electrocardiographic response nor chest pain during maximal treadmill exercise. The DT and heart rate (HR) had an inverse nonlinear relation, and electromechanical systole (QS2) and HR had an inverse linear relation during exercise. When the exercise DT-HR and QS2-HR relations were compared, a significant lengthening of QS2, with a consequent shortening of DT, was observed in diabetic patients with retinopathy, compared to patients without retinopathy and normal subjects (p less than 0.005), while no significant differences were found between diabetic patients without retinopathy and normal subjects; however, there were no significant differences in the exercise DT-HR and QS2-HR relations among diabetic patients with and without autonomic dysfunction and normal subjects. A more prominent abbreviation in the diastolic perfusion time observed in patients with retinopathy would be meaningful because microangiopathy might already have limited subendocardial blood flow. Thus, patients with type 2 diabetes who have retinopathy have a potential risk of aggravation of left ventricular function through the deterioration of myocardial blood flow.


[Intracorneal ring segments for the correction of myopia--suggestions to ensure a high standard of quality].
The implantation of intracorneal ring segments (ICR-S) is the first reversible refractive surgical technique for the correction of low myopia. It is an effective and safe technique with a low rate of complications. Despite numerous publications it is a relatively new technique and its long-term tolerance cannot yet be assessed. Hence, it is recommendable to examine operated patients according to a standardised protocol for a longer period of time postoperatively. In this paper we present appropriate documentation forms. Based on experience gained in more than 100 ring implantations and a follow-up of three years, suggestions for follow-up dates and methods were developed. Follow-up dates are recommended before surgery, on the day of surgery, on the 1 st postoperative day, after the first postoperative week and the first, third, sixth and twelfth postoperative months and thereafter annually. The examination methods are listed in nine different documentation forms adapted to each follow-up date. In the Ophthalmological Department of the Clinic of Neubrandenburg, Germany, anonymous data are recorded by electronic data processing continuously and analyzed every three months. This guarantees to continually ensure the standard of quality. Other centres implanting intracorneal ring segments are welcome to make use of this system. The documentation forms are a suggestion for standardisation of the follow-up after implantation of intracorneal ring segments. The adaptation of the forms to the further development is necessary and planned. It allows a comparison and early feedback on own results and is a contribution to long-term observation and to ensure a high standard of quality in a patient-oriented standard of care.


Gender Differences in Adherence and Response to Antiretroviral Treatment in the Stratall Trial in Rural District Hospitals in Cameroon.
Evidence of gender differences in antiretroviral treatment (ART) outcomes in sub-Saharan Africa is conflicting. Our objective was to assess gender differences in (1) adherence to ART and (2) virologic failure, immune reconstitution, mortality, and disease progression adjusting for adherence. Cohort study among 459 ART-naive patients followed up 24 months after initiation in 2006-2010 in 9 rural district hospitals. Adherence to ART was assessed using (1) a validated tool based on multiple patient self-reports and (2) antiretroviral plasma concentrations. The associations between gender and the outcomes were assessed using multivariate mixed models or accelerated time failure models. One hundred thirty-five patients (29.4%) were men. At baseline, men were older, had higher body mass index and hemoglobin level, and received more frequently efavirenz than women. Gender was not associated with self-reported adherence (P = 0.872, 0.169, and 0.867 for moderate adherence, low adherence, and treatment interruption, respectively) or with antiretroviral plasma concentrations (P = 0.549 for nevirapine/efavirenz). In contrast, male gender was associated with virologic failure [odds ratio: 2.18, 95% confidence interval (CI): 1.31 to 3.62, P = 0.003], lower immunologic reconstitution (coefficient: -58.7 at month 24, 95% CI: -100.8 to -16.6, P = 0.006), and faster progression to death (time ratio: 0.30, 95% CI: 0.12 to 0.78, P = 0.014) and/or to World Health Organization stage 4 event (time ratio: 0.27, 95% CI: 0.09 to 0.79, P = 0.017). Our study provides important evidence that African men are more vulnerable to ART failure than women and that the male vulnerability extends beyond adherence issues. Additional studies are needed to determine the causes for this vulnerability to optimize HIV care. However, personalized adherence support remains crucial.


Halted Lymphocyte Egress via Efferent Lymph Contributes to Lymph Node Hypertrophy During Hypercholesterolemia.
Dyslipidemia is a central component of atherosclerosis and metabolic syndrome linked to chronic inflammation and immune dysfunction. Previously, we showed that hypercholesterolemic apolipoprotein E knock out (apoE-/-) mice exhibit systemic effects including skin inflammation and hypertrophic lymph nodes (LNs). However, the mechanisms accounting for LN hypertrophy in these mice remain unknown. Here, we show that hypercholesterolemia led to the accumulation of lymphocytes in LNs. We excluded that the increased number of lymphocytes in expanded LNs resulted from increased lymphocyte proliferation or entry into those LNs. Instead, we demonstrated that the egress of lymphocytes from the enlarged LN of apoE-/- mice was markedly decreased. Impairment in efferent lymphatic emigration of lymphocytes from LNs resulted from an aberrant expansion of cortical and medullary sinuses that became hyperplastic. Moreover, CCL21 was more abundant on these enlarged sinuses whereas lymph levels of sphingosine 1 phosphate (S1P) were decreased in apoE-/- mice. Normal LN size, lymphatic density and S1P levels were restored by reversing hypercholesterolemia. Thus, systemic changes in cholesterol can sequester lymphocytes in tissue draining LNs through the extensive remodeling of lymphatic sinuses and alteration of the balance between retention/egress signals leading to LN hypertrophy which subsequently may contribute to poor immunity. This study further illustrates the role of lymphatic vessels in immunity through the regulation of immune cell trafficking.


Evaluation of antioxidant enzymes activity and malondialdehyde levels in patients with chronic periodontitis and diabetes mellitus.
The aim of this study is to investigate the impact of diabetes, a known risk factor for periodontitis, on activities of antioxidant enzymes superoxide dismutase (SOD), glutathione reductase (GR), and catalase (CAT) as well as levels of free radical damage marker malondialdehyde (MDA) in blood and saliva of individuals with chronic periodontitis (CP). Sixty patients with CP (30 patients with type 2 diabetes mellitus [DMCP] and 30 systemically healthy patients [CP]) and 60 periodontally healthy individuals (30 patients with type 2 diabetes mellitus and 30 systemically healthy patients [PH]) were included in this study. After clinical measurements, blood and saliva samples were collected. SOD, GR, and CAT activities in red blood cell lysate and saliva and MDA levels in plasma and saliva samples were spectrophotometrically assayed. An analysis of variance test followed by a post hoc test was used to compare the intragroup and intergroup variances among the study groups. MDA levels in both the periodontitis groups were higher than in the periodontally healthy groups, but the difference between the CP and DMCP groups did not reach statistical significance (P >0.05). There was a highly significant difference between the CP and PH groups for all the enzymes studied except for SOD in blood. Only salivary SOD and GR activities were significantly different in the CP and DMCP groups. This study favors the role of oxidative stress in both diabetes and periodontitis. It shows that the compensatory mechanism of the body is partially collapsed because of excessive production of free radicals during periodontitis and is not able to cope with increased free radical generation attributable to diabetes, thereby worsening the situation.


Heat shock protein 60 in rostral ventrolateral medulla reduces cardiovascular fatality during endotoxaemia in the rat.
The rostral ventrolateral medulla (RVLM) is the origin of a 'life-and-death' signal that reflects central cardiovascular regulatory failure during brain stem death. Using an experimental endotoxaemia model, we evaluated the hypothesis that the 60 kDa heat shock protein 60 (HSP60) reduces cardiovascular fatality during brain stem death via an anti-apoptotic action in the RVLM. In Sprague-Dawley rats maintained under propofol anaesthesia, proteomic or Western blot analysis revealed a progressive augmentation of HSP60 expression in the RVLM after intravenous administration of Escherichia coli lipopolysaccharide (30 mg kg(-1)). Pretreatment with a microinjection of actinomycin D or cycloheximide into bilateral RVLM significantly blunted this HSP60 increase, whereas real-time PCR showed progressive augmentation of hsp60 mRNA. Intriguingly, superimposed on the augmented expression was a progressive decline in mitochondrial, or elevation in cytosolic, HSP60 in ventrolateral medulla. Loss-of-function manipulations in the RVLM using anti-HSP60 antiserum or antisense hsp60 oligonucleotide exacerbated mortality by potentiating the cardiovascular depression during experimental endotoxaemia, alongside intensified nucleosomal DNA fragmentation, elevated cytoplasmic histone-associated DNA fragments or augmented cytochromec-caspase-3 cascade of apoptotic signalling in the RVLM. Immunoprecipitation coupled with immunoblot analysis further revealed a progressive increase in the complex formed between HSP60 and mitochondrial or cytosolic Bax or mitochondrial Bcl-2 during endotoxaemia, alongside a dissociation of the cytosolic HSP60-Bcl-2 complex. We conclude that HSP60 redistributed from mitochondrion to cytosol in the RVLM confers neuroprotection against fatal cardiovascular depression during endotoxaemia via reduced activation of the cytochrome c-caspase-3 cascade of apoptotic signalling through enhanced interactions with mitochondrial or cytosolic Bax or Bcl-2.


Pharmacokinetics and retinal toxicity of intravitreal liposome-encapsulated 5-fluorouridine.
Fluoropyrimidines may be effective in preventing proliferative vitreoretinopathy after repair of complicated retinal detachments. Liposome encapsulation of these antiproliferative drugs may extend the intravitreal half-life and increase their efficacy. The current study evaluated the pharmacokinetic behavior of intravitreally injected 5-fluorouridine (5-FUR), free and encapsulated in liposomes, either conventionally or coated with collagen into 25 New Zealand rabbits. Additionally, we investigated the retinal toxicity of intravitreal injections of 100, 250 and 500 microg as well as 1 mg 5-FUR as free drug or encapsulated in liposomes in the rabbit eye. The half-life of free 5-FUR after liposome injection into the vitreous cavity was 18.17+/-2.43 h, considerably longer than the half-life of free 5-FUR (0.82 h). Electrophysiologic tests did not show any changes in latency and a-wave amplitude and minimal changes in the b-wave amplitude. Histopathologic studies revealed integrity of the inner limiting membrane, and mild vacuolization in the outer retina. Encapsulation of 5-FUR within liposomes markedly increases its intravitreal half-life. Our study suggests that liposome-encapsulated 5-FUR is not toxic to the retina even at doses of 1 mg.


Golfing skill level postural control differences: a brief report.
Golfers have better balance than their age-matched counterparts; however, it is uncertain if this persists during the swing as a function of skill level. The purpose of the study was to investigate dynamic postural control (center of mass (COM) motion) measured during different phases of the swing in golfers of varying proficiency. Eighteen healthy golfers were grouped by handicap: novice (no handicap, n = 7), intermediate (handicap 15-19, n = 7), and advanced (handicap 9-14, n = 4). Indoor testing was performed hitting 3 tee shots using a common driver. A five-camera (60 Hz) motion analysis system (9 markers) was used to extract kinematics data. There were no significant group differences in gender, age, or BMI. Advanced players had lower COM displacement with respect to address at the time of maximum arm speed (p = 0. 001) compared to intermediate (57%, p = 0.014) and novice (73%, p = 0.023). These changes persisted after COM distance and time normalization. Advanced golfers had improved COM linearity during the downswing (p < 0.001) compared to intermediate (30%, p = 0.029) and novice (51%, p < 0.001). Advanced players had decreased COM displacement at the time of maximum arm speed and a more linear COM path during the early downswing. Further study should focus on these changes during ball launch conditions. Key pointsStudies suggest that static and dynamic balance is important in golf. However, none have investigated dynamic postural control during the golf swing in golfers of varying proficiency.Our findings suggest advanced players demonstrated improved postural control at the point of maximum arm speed when compared to less skilled players. Furthermore, center of mass acceleration in advanced players is closer to impact than less-skilled players.We observed an increased center of mass linearity of trajectory during the early downswing for advanced players over novice players. We theorized this strategy may help advanced golfers to improve the economy of COM motion during golf swing and improve the performance of the shot.


Cerebellar haemorrhage as a cause of neurogenic pulmonary edema - case report.
The neurogenic pulmonary edema is a rare clinical situation caused by an imbalance characterized by an excessive sympathetic outflow. It is observed mostly in young patients, is associated with brain or spinal cord haemorrhage, trauma, tumours or infections and is usually fatal. A case of neurogenic pulmonary edema in a 27-year-old woman is presented, caused by a cerebellar haemorrhage due to a vermian and paravermian arteriovenous malformation rupture. The vermian and hemispheric haemorrhage injuring the sub-lobule IX-b of the uvula induced a disruption of both carotid baroreceptor and chemoreceptor reflexes control mechanisms. Medical treatment with controlled ventilation, PEEP, diuretics and morphine reverted the pulmonary edema. After surgical treatment of the haemorrhage and cerebellar AVM the patient recovered to an almost normal social and professional life. The cerebellar lesion induced a temporary vermian sub lobule IX-b dysfunction that was responsible for the sympathetic storm that evoked the neurogenic pulmonary edema.


Acclimation of Photosynthetic Light Reactions during Induction of Inorganic Carbon Accumulation in the Green Alga Chlamydomonas reinhardtii.
Cells of the unicellular green algae Chlamydomonas reinhardtii were grown in high dissolved inorganic carbon (DIC) concentrations (supplied with 50 milliliters per liter CO(2)[g]) and transferred to low DIC concentrations (supplied with </= 100 microliters per liter CO(2)[g]). Immediately after transfer from high to low DIC the emission of photosystem II related chlorophyll a fluorescence was substantially quenched. It is hypothesized that the suddenly induced inorganic carbon limitation of photosynthesis resulted in a phosphorylation of LHCII, leading to the subsequent state 1 to state 2 transition. After 2 hours of low-DIC acclimation, 77 K fluorescence measurements revealed an increase in the fluorescence emitted from photosystem I, due to direct excitation, suggesting a change in photosystem II/photosystem I stoichiometry or an increased light harvesting capacity of photosystem I. After 5 to 6 hours of acclimation a considerable increase in spillover from photosystem II to photosystem I was observed. These adjustments of the photosynthetic light reactions reached steady-state after about 12 hours of low DIC treatment. The quencher of fluorescence could be removed by 5 minutes of dark treatment followed by 5 minutes of weak light treatment, of any of four different light qualities. It is hypothesized that this restoration of fluorescence was due to a state 2 to state 1 transition in low-DIC acclimated cells. A decreased ratio of violaxanthin to zeaxanthin was also observed in 12 hour low DIC treated cells, compared with high DIC grown cells. This ratio was not coupled to the level of fluorescence quenching. The role of different processes during the induction of a DIC accumulating mechanism is discussed.


Mitochondrial dynamics and segregation during the asymmetric division of Arabidopsis zygotes.
The zygote is the first cell of a multicellular organism. In most angiosperms, the zygote divides asymmetrically to produce an embryo-precursor apical cell and a supporting basal cell. Zygotic division should properly segregate symbiotic organelles, because they cannot be synthesized de novo. In this study, we revealed the real-time dynamics of the principle source of ATP biogenesis, mitochondria, in Arabidopsis thaliana zygotes using live-cell observations and image quantifications. In the zygote, the mitochondria formed the extended structure associated with the longitudinal array of actin filaments (F-actins) and were polarly distributed along the apical-basal axis. The mitochondria were then temporally fragmented during zygotic division, and the resulting apical cells inherited mitochondria at higher concentration compared to the basal cells. Further observation of postembryonic organs showed that these mitochondrial behaviours are characteristic of the zygote. Overall, our results showed that the zygote has spatiotemporal regulation that unequally distributes the mitochondria.


Effects of Thiamin Restriction on Exercise-Associated Glycogen Metabolism and AMPK Activation Level in Skeletal Muscle.
This study aimed to investigate the direct influence of a decrease in the cellular thiamin level, before the onset of anorexia (one of the symptoms of thiamin deficiency) on glycogen metabolism and the AMP-activated protein kinase (AMPK) activation levels in skeletal muscle at rest and in response to exercise. Male Wistar rats were classified as the control diet (CON) group or the thiamin-deficient diet (TD) group and consumed the assigned diets for 1 week. Skeletal muscles were taken from the rats at rest, those that underwent low-intensity swimming (LIS), or high-intensity intermittent swimming (HIS) conducted immediately before dissection. There were no significant differences in food intake, locomotive activity, or body weight between groups, but thiamin pyrophosphate in the skeletal muscles of the TD group was significantly lower than that of the CON group. Muscle glycogen and lactate levels in the blood and muscle were equivalent between groups at rest and in response to exercise. The mitochondrial content was equal between groups, and AMPK in the skeletal muscles of TD rats was normally activated by LIS and HIS. In conclusion, with a lowered cellular thiamin level, the exercise-associated glycogen metabolism and AMPK activation level in skeletal muscle were normally regulated.


Semi-mechanistic partial buffer approach to modeling pH, the buffer properties, and the distribution of ionic species in complex solutions.
In many biological science and food processing applications, it is very important to control or modify pH. However, the complex, unknown composition of biological media and foods often limits the utility of purely theoretical approaches to modeling pH and calculating the distributions of ionizable species. This paper provides general formulas and efficient algorithms for predicting the pH, titration, ionic species concentrations, buffer capacity, and ionic strength of buffer solutions containing both defined and undefined components. A flexible, semi-mechanistic, partial buffering (SMPB) approach is presented that uses local polynomial regression to model the buffering influence of complex or undefined components in a solution, while identified components of known concentration are modeled using expressions based on extensions of the standard acid-base theory. The SMPB method is implemented in a freeware package, (pH)Tools, for use with Matlab. We validated the predictive accuracy of these methods by using strong acid titrations of cucumber slurries to predict the amount of a weak acid required to adjust pH to selected target values.


Lessons learned from first case of Cesarean delivery in a COVID-19 positive parturient in Greek region.
We report the successful anesthetic management of a 24-year-old patient, with an active COVID-19 viral infection, scheduled for elective Cesarean section at 40th week of pregnancy. This was the first case in Greek region, and we report and discuss the difficulties and safety issues regarding a COVID-19 positive patient during an elective cesarean delivery. Regional anesthesia with full protective equipment for health personnel involved, along with careful planning and adherence to guidelines achieved safe completion of the operation.


Comparison of high-resolution and dynamic reaction cell ICP-MS capabilities for forensic analysis of iron in glass.
Forensic laboratories routinely conduct analysis of glass fragments to determine whether or not there is an association between a fragment(s) recovered from a crime scene or from a suspect to a particular source of origin. The physical and optical (refractive index) properties of the fragments are compared and, if a "match" between two or more fragments is found, further elemental analysis can be performed to enhance the strength of the association. A range of spectroscopic techniques has been used for elemental analysis of this kind of evidence, including inductively coupled plasma mass spectrometry (ICP-MS). Because of its excellent sensitivity, precision, and accuracy, several studies have found that ICP-MS methods (dissolution and laser-ablation) provide the best discrimination between glass fragments originating from different sources. Nevertheless, standard unit-resolution ICP-MS instruments suffer from polyatomic interferences including (40)Ar(16)O(+), (40)Ar(16)O(1)H(+), and refractory oxide (40)Ca(16)O(+) that compromise measurements of trace levels of Fe(56+) and Fe(57+), for example. This is a drawback in the analysis of glass fragments because iron has been previously identified as a good discriminating element. Currently, several techniques are available that enable reduction of such interferences. However, there are no data comparing detection limits of iron in glass using those techniques. The aim of this study was to compare, the analytical performance of high-resolution sector field inductively coupled plasma mass spectrometry (HR-SF-ICP-MS) and quadrupole ICP-MS equipped with a dynamic reaction cell (DRC-ICP-MS), for the detection of iron in glass, in terms of accuracy, precision, and method detection limits (MDLs). Analyses were conducted using conventional acid-digestion and laser-ablation methods. For laser-ablation analyses, carrier gases were compared to assess the effect on detection limits in the detection of iron isotopes. Iron polyatomic interferences were reduced or resolved by using a dynamic reaction cell and high-resolution ICP-MS. MDLs as low as 0.03 microg g(-1) and 0.14 microg g(-1) were achieved in laser-ablation and solution-based analyses, respectively. Use of helium as carrier gas improved detection limits for both iron isotopes in medium-resolution HR-SF-ICP-MS and in DRC-ICP-MS.


Ovarian feedback, mechanism of action and possible clinical implications.
The secretion of gonadotrophins from the pituitary in women is under ovarian control via negative and positive feedback mechanisms. Steroidal and non-steroidal substances mediate the ovarian effects on the hypothalamic-pituitary system. During the follicular phase of the cycle, estradiol (E(2)) plays a key role, while circulating progesterone (at low concentrations) and inhibin B contribute to the control of LH and FSH secretion respectively. During the luteal phase, both E(2) and progesterone regulate secretion of the two gonadotrophins, while inhibin A plays a role in FSH secretion. The intercycle rise of FSH is related to changes in the levels of the steroidal and non-steroidal substances during the luteal-follicular transition. In terms of the positive feedback mechanism, E(2) is the main component sensitizing the pituitary to GnRH. Activity of a non-steroidal ovarian substance, named gonadotrophin surge-attenuating factor (GnSAF), has been detected after ovarian stimulation. It is hypothesized that GnSAF, by antagonizing the sensitizing effect of E(2) on the pituitary, regulates the amplitude of the endogenous LH surge at midcycle. Disturbances in the feedback mechanisms can occur in various abnormal conditions or after treatment with pharmaceutical compounds that interfere with the production or the action of endogenous hormones.


Haploidy, diploidy and evolution of antifungal drug resistance in Saccharomyces cerevisiae.
We tested the hypothesis that the time course of the evolution of antifungal drug resistance depends on the ploidy of the fungus. The experiments were designed to measure the initial response to the selection imposed by the antifungal drug fluconazole up to and including the fixation of the first resistance mutation in populations of Saccharomyces cerevisiae. Under conditions of low drug concentration, mutations in the genes PDR1 and PDR3, which regulate the ABC transporters implicated in resistance to fluconazole, are favored. In this environment, diploid populations of defined size consistently became fixed for a resistance mutation sooner than haploid populations. Experiments manipulating population sizes showed that this advantage of diploids was due to increased mutation availability relative to that of haploids; in effect, diploids have twice the number of mutational targets as haploids and hence have a reduced waiting time for mutations to occur. Under conditions of high drug concentration, recessive mutations in ERG3, which result in resistance through altered sterol synthesis, are favored. In this environment, haploids consistently achieved resistance much sooner than diploids. When 29 haploid and 29 diploid populations were evolved for 100 generations in low drug concentration, the mutations fixed in diploid populations were all dominant, while the mutations fixed in haploid populations were either recessive (16 populations) or dominant (13 populations). Further, the spectrum of the 53 nonsynonymous mutations identified at the sequence level was different between haploids and diploids. These results fit existing theory on the relative abilities of haploids and diploids to adapt and suggest that the ploidy of the fungal pathogen has a strong impact on the evolution of fluconazole resistance.


A second UDP-glucose pyrophosphorylase is required for differentiation and development in Dictyostelium discoideum.
Uridine diphosphoglucose pyrophosphorylase (UDPGP) is a developmentally regulated enzyme in Dictyostelium discoideum, which is involved in trehalose, cellulose, and glycogen synthesis. Two independent UDPGP proteins are believed to be responsible for this activity. To determine the relative contributions of each protein, the genes encoding them were disrupted individually. Cells lacking the udpgp1 gene exhibit normal growth and development and make normal levels of cellulose. In agreement with these phenotypes, udpgp1(-) cells still have UDPGP activity, although at a reduced level. This supports the importance of the second UDPGP gene. This newly identified gene, ugpB, encodes an active UDPGP as determined by complementation in Escherichia coli. When this gene is disrupted, cells undergo aberrant differentiation and development ending with small, gnarled fruiting bodies. These cells also have decreased spore viability and decreased levels of glycogen, whose production requires UDPGP activity. These phenotypes suggest that UgpB constitutes the major UDPGP activity produced during development. Sequence analysis of the two UDPGP genes shows that UgpB has higher homology to other eukaryotic UDPGPs than does UDPGP1. This includes the presence of 5 conserved lysine residues. Udpgp1 only has 1 of these lysines.


Association between Dietary Magnesium Intake and Glycemic Markers in Ghanaian Women of Reproductive Age: A Pilot Cross-Sectional Study.
Low magnesium intake has been shown to be associated with an increased risk of type 2 diabetes mellitus (T2DM) in several studies conducted in high-income countries. However, very few studies have been performed in Africa, where many countries have a growing rate of T2DM. We conducted a pilot cross-sectional study among 63 women in Ghana to investigate the association between magnesium intake and glycemic markers. We assessed dietary magnesium using a food frequency questionnaire and glycemic markers using fasting blood glucose and glycated hemoglobin A1c (HbA1c). Our findings showed that the mean magnesium intake was 200 ± 116 mg/day. The prevalence of T2DM was 5% by measuring fasting blood glucose and 8% by measuring HbA1c. Unadjusted linear regression models revealed that higher magnesium intake significantly predicted higher fasting blood glucose levels (β = 0.31; 95% CI: 0.07, 0.55; p = 0.01) and HbA1c levels (β = 0.26; 95% CI: 0.01, 0.51; p = 0.04). In adjusted analyses, magnesium intake was no longer significantly associated with either fasting blood glucose levels (β = 0.22; 95% CI: -0.03, 0.46; p = 0.08) or HbA1c levels (β = 0.15; 95% CI: -0.08, 0.39; p = 0.20). In conclusion, our study did not show a significant association between magnesium intake and glycemic markers in women of reproductive age in Ghana. The results of this study need to be further substantiated because this was the first study to examine magnesium intake and glycemic markers in this population in Africa.


Effects of Polyamines on Chlorophyll and Protein Content, Photochemical Activity, and Chloroplast Ultrastructure of Barley Leaf Discs during Senescence.
The polyamines putrescine, spermidine, and spermine prevent the loss of chlorophyll normally associated with senescence of excised leaf tissue maintained in darkness on water (control). Retention of chlorophyll in barley leaf discs was in the range of 90% 4 days after excision and placement on effective polyamine solutions. In contrast, the loss of soluble protein was hastened with 0.5 millimolar spermidine and spermine treatments but it was retarded by 0.5 millimolar putrescine.Photosystem I and II activities of chloroplasts from polyamine-treated leaf discs declined more rapidly as compared to the control. Chloroplast ultrastructural changes resulting from the polyamine treatments included the apparent destruction of the envelope, preservation of thylakoid membrane structure, and reduced accumulation of osmiophilic bodies. The influence of polyamines on senescence-related processes may be due to their cationic nature.


A liquid chromatography-tandem mass spectrometry assay for the determination of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, in human plasma and urine and its application to a single-dose pharmacokinetic study in healthy Chinese volunteers.
Nemonoxacin (TG-873870) is a novel C-8-methoxy nonfluorinated quinolone with higher activity than ciprofloxacin, levofloxacin and moxifloxacin against Gram-positive pathogens including methicillin-susceptible or methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae with various resistant phenotypes. A rapid, sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated to determine the concentration of nemonoxacin in human plasma and urine. Protein precipitation and liquid-liquid extraction were employed for plasma and urine sample preparations, respectively, and extract was then injected into the system. Separation was performed on a C(18) reversed-phase column using acetonitrile-0.1% formic acid as a mobile phase. Both analyte and internal standard (gatifloxacin) were determined using electrospray ionization and the MS data acquisition via the selected reaction monitoring in positive-ion mode. The lower limit of quantification was 5 ng/mL and the calibration curves were linear in the concentration range of 5-1000 ng/mL. The accuracy, precision, selectivity, linearity, recovery, matrix effect and stability were validated for TG-873870 in human plasma and urine. The method was successfully applied to a pharmacokinetic study enrolling 12 healthy Chinese volunteers administered nemonoxacin malate capsules.


What Brings You Here? Exploring Why Young Adults Seek Help for Social Anxiety.
Social anxiety disorder typically manifests in young adulthood, but there is an absence of qualitative research on the actual experiences of young adults suffering with this disorder. The aim of the present study was to investigate the lived experiences of 29 Norwegian university students who were seeking professional help for symptoms of social anxiety. We conducted in-depth interviews prior to a clinical trial. The interviews were transcribed and analyzed using a team-based thematic analysis method based on a hermeneutic-phenomenological epistemology. We identified five themes: (a) from being shy to interpreting anxiety as a mental health problem, (b) experiencing emotions as threatening and uncontrollable, (c) encountering loneliness as relationships fall away, (d) hiding the vulnerable self from others, and (e) deciding to face social fears in the future. We relate our findings to existing theory and research, discuss our process of reflexivity, highlight study limitations, and suggest implications for future research.


Bag3 promotes resistance to apoptosis through Bcl-2 family members in non-small cell lung cancer.
In non-small cell lung cancer (NSCLC) certain molecular characteristics, which are related to molecular alterations have been investigated. These are responsible for both the initiation and maintenance of the malignancy in lung cancer. The aim of this study was to evaluate the influence of Bag3 (Bcl-2 associated athanogene 3) in the regulation of apoptosis on NSCLC. Bag3 and Hsp70 expression were examined by immunohistochemistry to confirm their potential roles in the prevalence of NSCLC. We also established human normal bronchial epithelial cells and HOP-62 cell line as the model to analyze cell apoptosis and the expression of Hsp70, Bcl-XL and Bcl-2, which were affected by Bag3. In this study, we found that Bag3 and Hsp70 are highly expressed in few tissues and cell lines of NSCLC. Bag3 inhibits apoptosis in human normal bronchial epithelial cell lines and sustain the survival of NSCLC cells. Bag3, Hsp70, Bcl-XL and Bcl-2 are up-regulated in NSCLC cell lines. At the same time, the silencing of Bag3 results in diminishing protein levels of Bcl-XL and Bcl-2. The results of immunoprecipitation identified that Bag3 could interact with Hsp70, Bcl-XL and Bcl-2 NSCLC cells directly or indirectly. We conclude that NSCLC cells were protected from apoptosis through increasing Bag3 expression and consequently promoted the expression of Bcl-XL and Bcl-2.


Repair Effects of Bone Marrow Mesenchymal Stem Cells on Demyelination of Trigeminal Ganglion in Rats with Trigeminal Neuralgia.
The current study investigated the effects of bone marrow mesenchymal stem cells (BMSCs) on pain behavior in rats with trigeminal neuralgia induced by infraorbital nerve chronic constriction injury (ION-CCI), and the repair effects of BMSCs on pathological changes in trigeminal ganglion demyelination. BMSCs or phosphate-buffered saline (PBS) alone were injected around trigeminal ganglion in ION-CCI rats via a rat brain stereotaxic apparatus. Mechanical pain threshold (von Frey test) and face grooming behavior were measured in each group. Recovery of demyelination of trigeminal ganglion was observed via electron microscopy 2 weeks later, and BMSC differentiation was observed via immunofluorescence. Rats in the BMSC group exhibited significant improvements in mechanical pain threshold and face grooming behavior compared with the PBS group. BMSCs could repair demyelinating changes in trigeminal ganglion in ION-CCI rats. Only cells expressing GFAP, S-100, and p75 were observed via immunofluorescence, and no PKH67-labeled BMSCs were observed in the trigeminal ganglion. No BMSC differentiation was observed in the trigeminal ganglion. Injection of BMSCs around the trigeminal ganglion could relieve trigeminal neuralgia effectively and repair trigeminal ganglion demyelination. No differentiation of BMSCs injected around the trigeminal ganglion into Schwann cells was observed. The mechanism of trigeminal neuralgia demyelination repair requires further investigation.


Binol quinone methides as bisalkylating and DNA cross-linking agents.
The photogeneration and detection of new binol quinone methides undergoing mono- and bisalkylation of free nucleophiles was investigated by product distribution analysis and laser flash photolysis in water solution using binol quaternary ammonium derivatives 2 and 12 as photoactivated precursors. The alkylation processes of N and S nucleophiles are strongly competitive with the hydration reaction. DNA cross-linking potency of the water-soluble binol quaternary ammonium salt 2 was investigated as a pH function and compared to that of other quaternary ammonium salts capable of benzo-QM (QM = quinone methide) photogeneration by gel electrophoresis. DFT calculations in the gas phase and in water bulk on the binol and benzo quaternary ammonium salts 2 and 4 evidence structural and electrostatic features of the binol derivative which might offer a rationalization of its promising high photo-cross-linking efficiency.


Gemcitabine in breast cancer: future directions.
Gemcitabine is an active drug in advanced breast cancer both as a single agent and in combination with other chemotherapeutic agents. Its unique mechanisms of action, which involve masked DNA chain termination and several self-potentiating effects on DNA and RNA synthesis enzymes, result in broad and potent activity across many cancer types. Preclinical models have suggested positive interactions with other agents such as trastuzumab, and early-phase clinical trials are exploring potential synergistic activity with another DNA-synthesis targeting drug, the multitargeted antifolate, pemetrexed (Alimta). Many small trials have confirmed the efficacy and tolerability of gemcitabine alone or in combinations with other drugs as summarized in this supplement. Furthermore, neoadjuvant clinical models have shown promising pathologic complete response rates, an endpoint that correlates with prolonged survival. These results taken together have now set the stage for more definitive phase III trials of gemcitabine combinations compared to standard combinations that will directly assess the independent contribution of gemcitabine. In the metastatic setting, survival benefits (if any) are likely to be limited, but the potential to achieve this with preservation of quality of life is good. Synergistic combinations with biological therapies or novel chemotherapeutic agents need to be further explored, and ultimately, randomized trials will be needed to define optimal regimens. The largest clinical benefits might be derived from the proper deployment of gemcitabine combinations with taxanes and/or anthracyclines in the adjuvant setting. Highly active and well-tolerated therapies, especially those that are justified based on preclinical and neoadjuvant models, represent our best hope for successors to current adjuvant regimens. Such trials are now either in the planning stages or already under way.


Bispecific monoclonal antibody-mediated targeting of an indium-111-labeled DTPA dimer to primary colorectal tumors: pharmacokinetics, biodistribution, scintigraphy and immune response.
Eleven patients with primary colorectal carcinoma tumors (4 +/- 2 cm) were given intravenous injections of 1-10 mg of an anti-CEA, anti-In-DTPA bispecific Fab'-Fab monoclonal antibody, and 2-8 days later, were injected with 1.2-4.2 nmol of an 111In-labeled DTPA dimer (6 mCi). The bispecific antibody exhibited good stability and F(ab)'2-like pharmacokinetics. After injection, the 111In-DTPA dimer distributed in a large volume (88 ml/kg-180 ml/kg) and cleared through the kidneys (mean residence time in the whole body: 9 hr-16 hr). Uptake of 111In by the tumor using this two-step technique (1.8%-17.5% injected dose ID/kg, measured from surgical samples 48 hr after hapten injection) was not found significantly lower than that achieved with our reference 111In-labeled anti-CEA F(ab)'2 1 to 4 days after injection in six patients with similar clinical status (5.5%-30.2% ID/kg). In addition, tumor-to-blood and tumor-to-liver uptake ratios were significantly improved (blood 7.8 versus 4.2, liver 2.8 versus 0.8). As a result, low background images allowed detection of 12 of 13 lesions, 4 hr and 24 hr after hapten injection. However, 7 of 11 patients developed HAMA.


Functional Loss and Mortality in Randomized Clinical Trials for Amyotrophic Lateral Sclerosis: To Combine, or Not to Combine-That is the Estimand.
Amyotrophic lateral sclerosis is a rapidly progressive disease leading to death in, on average, 3-5 years after first symptom onset. Consequently, there are frequently a non-negligible number of patients who die during the course of a clinical trial. This introduces bias in end points such as daily functioning, muscle strength, and quality of life. In this paper, we outline how the choice of strategy to handle death affects the interpretation of the trial results. We provide a general overview of the considerations, positioned in the estimand framework, and discuss the possibility that not every strategy provides a clinically relevant answer in each setting. The relevance of a strategy changes as a function of the intended trial duration, hypothesized treatment effect, and population included. It is important to consider this trade-off at the design stage of a clinical trial, as this will clarify the exact research question that is being answered, and better guide the planning, design, and analysis of the study.


Different effect of hyperglycemia on stroke outcome in non-diabetic and diabetic patients--a cohort study.
Relationship between hyperglycemia and stroke outcome is unclear, partly due to the small sample size in most studies, and partly due to lack of consensus concerning the cutoff level for hyperglycemia. In a cohort study, we investigated whether on-admission hyperglycemia is an independent predictor for 30-day case fatality by analyzing data of 2496 consecutive computed tomography (CT) verified acute ischemic stroke patients (2077 non-diabetic and 419 diabetic) included in the prospective, hospital-based Debrecen Stroke Database. Instead of using an arbitrary cutoff level for hyperglycemia, quartiles of on-admission glucose level were used for Kaplan-Meier survival curves and Cox proportional hazard modeling. The four quartiles of serum glucose level were in the range as follows: <5.2 mmol/l, 5.201-6.1 mmol/l, 6.101-7.5 mmol/l, and >7.501 mmol/l (n = 664, 618, 597, and 617, respectively). Among all 2496 participants, the adjusted hazard ratios for death increased with each quartile of admission glucose 1.96 [95% confidence interval (CI): 1.07-3.60; P = 0.03], 1.56 (95% CI: 0.83-2.94; P = 0.17), and 3.04 (95% CI: 1.70-5.44; P < 0.0001) for the second, third, and fourth quartiles, respectively). Upon stratification with respect to diabetes, we found similarly high risk for poor outcome among non-diabetic patients, while the risk was considerably lower among diabetic patients. These data suggest that even mild elevation of on-admission glucose levels is an independent predictor of 30-day case fatality. So, we propose that the ideal target blood glucose level is lower for non-diabetic than diabetic patients.


Chemical composition and antimycobacterial activity of the essential oil from Anemia tomentosa var. anthriscifolia.
The essential oil from Anemia tomentosa var. anthriscifolia showed in vitro activity against Mycobacterium tuberculosis (MIC 100 microg/ml) and therefore was characterized by gas chromatography (GC) and by gas chromatography coupled with mass spectrometry (GC-MS). The major constituents of this essential oil were triquinane sesquiterpenes: silphiperfol-6-ene (14.7%), (-)-epi-presilphiperfolan-1-ol (30.6%), presilphiperfol-7-ene (3.9%), cameroonan-7 alpha-ol (4.4%), prenopsan-8-ol (1.9%) and presilphiperfolan-8-ol (8.3%), suggesting the existence of different chemotypes for this species. The essential oil was fractionated by column chromatography and its major constituent and fractions were assayed against Mycobacterium tuberculosis and M. smegmatis. (-)-epi-Presilphiperfolan-1-ol exhibited an MIC of 120 microg/ml against M. tuberculosis H37Rv.


Contextualized Contribution of Kindness to Favorable Goal- and Circumstantial-Driven Neuropsychological Regulation.
Kindness involves care and non-judgmental understanding toward someone. As a prosocial inclination, kindness would increase the possibility of favorable interaction with the environment, with a successful adjustment of one's response in novel or challenging circumstances, taking into account rules or goals. This adjustment ability is commonly referred to as executive functions, dependent on the prefrontal and parietal functioning, still under development during late adolescence. This study aimed to investigate if kindness would relate with the executive functions. If so, it would correlate more with measures of self-regulation, mainly dependent on the medial prefrontal corticosubcortical circuits. Also, among self-regulating processes, kindness would be more associated with autonomic responses-choices guided by one's understanding/intention - than with adaptive responses-changes on one's choices triggered by unfavorable circumstances. A sample of 46 (31 female; 18 to 21 years-old) healthy college students from the University of the State of Rio de Janeiro attended a clinical interview and a comprehensive neuropsychological assessment. Kindness was measured by the Compassion Scale subscore. Generalized non-linear models for each neuropsychological variable were executed on R, followed by an estimation of weighted parameters for each factor. Significant models which included kindness (weighted parameter Pc > 74) and all of their psychosocial or sociodemographic factors on their maximum expression (Pc > 74) were identified. In a contextualized joint influence with other psychosocial and sociodemographic factors, kindness fits equally goal- and circumstantial- self-regulation, as well as integrative organization of information. Kindness is a principle that optimizes a refreshing and prosocial interaction with the environment. As it anticipates sharing and cooperation behaviors, it might have a primordial function on individual and social development.


One hundred years of virology: a chief's perspective.
The ubiquitous nature of viruses has had its impact throughout the living world. Virus disease can be found in higher animals, birds, plants, arthropods, protozoa and bacteria. Viruses are no modern phenomenon, although it is only in the last 50 or so years that a fuller knowledge of their biological, chemical and physical properties has emerged. This short account recalls the development of human virology in particular, from the first discovery of a 'filterable virus' in 1892 to the spectacular technological breakthroughs during the 1950's and 1960's, leading to the molecular virology of today. This account was written to accompany an exhibition of artefacts displayed during the IBMS Congress in Birmingham in September 2001.


Community-wide reduction in prevalence and intensity of intestinal helminths as a collateral benefit of lymphatic filariasis elimination programs.
Annual mass treatment with antifilarial drugs is the cornerstone of the global program to eliminate lymphatic filariasis (LF). Although the primary goal of the program is to interrupt transmission of LF, additional public health benefits also are expected because of the known anthelminthic properties of these drugs. Since rapid re-infection with intestinal helminths occurs following treatment, annual de-worming may not be sufficient to produce a lasting reduction in the prevalence and intensity of these infections. We conducted stool examinations in four sentinel communities before and approximately nine months after each of two rounds of mass drug administration (MDA) with diethylcarbamazine and albendazole in the context of an LF elimination program in Leogane, Haiti. At baseline, overall Ascaris, Trichuris, and hookworm infection prevalences were 20.9%, 34.0%, and 11.2%, respectively (n = 2,716 stools). Nine months after the second MDA, Ascaris, Trichuris and hookworm prevalences had decreased significantly, to 14.1%, 14.6%, and 2.0%, respectively (n = 814 stools). Infection intensity decreased significantly for all three parasites as well. These results demonstrate that substantial reductions in intestinal helminth infections are associated with mass treatment of filariasis in Haiti and are consistent with the conclusion that high levels of coverage for the LF program can decrease transmission of geohelminths.


Epidemiology, complications and management of diabetes in Ethiopia: a systematic review.
Non-communicable diseases are becoming major problems of public health importance in most developing countries as a result of the effects of globalization and epidemiologic transition; however, there is little evidence regarding diabetes and other non-communicable diseases in these countries. The aim of this study was to conduct a systematic review of the literature on the magnitude of diabetes, the relationship between malnutrition and diabetes, diabetic complications, and the management of diabetes in Ethiopia. Relevant studies and other evidence were identified by searches in the Embase from 1970 to December 2011 and by reviewing the reference lists from retrieved articles. Relevant articles from non-indexed local journals were also included. Data were extracted and summarized using the major themes of the systematic review. Although the prevalence of diabetes in Ethiopia is estimated to be 2% nationally, evidence suggests that it prevalence could be >5% in those older than 40 years of age in some settings. Studies in the 1980s and 1990s have reported conflicting evidence regarding malnutrition-related diabetes; however, more recent studies are reconfirming a strong association between malnutrition and diabetes. There is remarkable prevalence of both acute and chronic complications in diabetic cases in Ethiopia. In addition to this, more than one-third, but only less than half, of diabetic patients in Ethiopia receive standard diabetes care. The results of this study indicate that, in response to the emergence of diabetes and other non-communicable diseases, effective and efficient prevention and control strategies should be designed and implemented in Ethiopia.


Enhanced specificity of bacterial spore identification by oxidation and mass spectrometry.
Addition of an oxidizing agent (e.g., hydrogen peroxide) to intact spores selectively and completely oxidizes Met-containing biomarker proteins by formation of Met sulfoxides. This reaction increases the masses of the biomarker proteins observed in matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) of Bacillus spores by Deltam = (16 x n) Da, where n is the number of Met residues in the sequence of each individual protein. The procedure is very rapid, and can be performed in situ (i.e., on the MALDI target). It confirms the identity of individual biomarkers by comparing the number of Met amino acids from the experimentally determined mass shifts with predictions for n from the tentative amino acid sequence for each protein. In turn, accurate determination of n for several biomarkers allows rapid validation of the initial spore identification by MALDI-MS.


Wegener's granulomatosis of the breast.
A 60-year-old woman presented with a painless self-detected breast lump. After wide local excision, the histology of this radiologically suspicious lump turned out to be an inflammatory lesion with granulomatous foci, suggesting a diagnosis of granulomatous mastitis. Prior to the excision biopsy, this woman had suffered from and been treated for anterior uveitis, secretory otitis media, and proximal myopathy. Four weeks later, a skin biopsy of a rapidly developing widespread petechial rash, mainly affecting the lower limbs, confirmed the diagnosis as Wegener's granulomatosis. Treatment with intravenous steroids and later cyclophosphamide produced rapid remission.


Physician approach to the recognition and initial management of hypertension. Results of a statewide survey of Maryland physicians.
A representative sample of Maryland physicians in three practice settings (family/general, internal medicine, and specialty practice) participated in a survey designed to identify their attitudes toward patients with high blood pressure. Respondents recommended initial laboratory investigations more frequently and treatment at lower levels of blood pressure than was the case in a national physician survey performed in 1977. Family/general practitioners were the most cautious in respect to recommending antihypertensive drug therapy. They expressed greater enthusiasm, however, for nonpharmacologic treatment of hypertension and other cardiovascular risk factors. Physicians in each of the three practice settings expressed strong support for the use of diuretics as initial drug therapy in patients with mild hypertension. Impediments to long-term care were overwhelmingly believed to be patient- rather than physician-related.


Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity.
Obesity is associated with low-grade chronic inflammation, which contributes to cellular dysfunction promoting metabolic disease. Obesity during pregnancy leads to a proinflammatory milieu in the placenta; however, the underlying causes for obesity-induced placental inflammation remain unclear. Here, we examine the mechanisms by which saturated fatty acids and inflammatory cytokines induce inflammation in placental trophoblasts. We conducted global transcriptomic profiling in BeWo cells following palmitate and/or TNFα treatment and gene/protein expression analyses of MAPK pathways and characterized downstream transcription factors directly regulating inflammatory cytokines. Microarray analysis revealed increased expression of genes regulating inflammation, stress response, and immediate early response in cytotrophoblasts in response to palmitic acid (PA), TNFα, or a combination of both (PA + TNFα). Both gene ontology and gene set enrichment analysis revealed MAPK and EGR-1 signaling to be upregulated in BeWo cells, which was confirmed via immunoblotting. Importantly, activation of JNK signaling was necessary for increased proinflammatory cytokine (IL-6, TNFα, and IL-8) and EGR1 mRNA. Consistent with the requirement of JNK signaling, ChIP analysis confirmed the recruitment of c-Jun and other MAPK-responsive immediate early factors on the EGR1 promoter. Moreover, recruitment of EGR-1 on cytokine promoters (IL-6, TNFα, and IL-8) and an impaired proinflammatory response following knockdown of EGR-1 suggested it as a central component of the mechanism facilitating inflammatory gene expression. Finally, akin to in vitro findings, term placenta from obese women also had both increased JNK and p38 signaling and greater EGR-1 protein relative to lean women. Our results demonstrate that lipotoxic insults induce inflammation in placental cells via activation of JNK/EGR-1 signaling.


Plasmoblastic lymphoma as cause of perianal fistula: a case report and literature review.
We report the case of a 33-year-old HIV-infected man who presented with a recurrent, nonhealing perianal fistula. After multiple benign biopsies, the diagnosis of plasmablastic lymphoma (PBL) eventually was made. The patient underwent chemotherapy and radiation with a complete response. Perianal fistulas are frequent in HIV-positive patients, but PBL as a cause is extremely rare. This often delays the diagnosis and treatment of this highly aggressive disease. We review the literature and discuss the pitfalls in the diagnosis and management of the disease.


Transcriptome analysis of human autosomal trisomy.
We present transcriptome analyses of primary cultures of human fetal cells from pregnancies affected with trisomy 21 (t21) and trisomy 13 (t13). Pooled mRNA samples from t21 and t13 cases were used for comparative hybridizations to cDNA arrays with pooled mRNA from normal cells. When the array cDNAs were grouped by chromosomal location the relevant trisomic chromosome could be clearly identified as showing the most significant misregulation. The average level of transcription on the trisomic chromosome was increased only approximately 1.1-fold compared to normal cells on array analysis. Since the karyotype could be accurately predicted by the transcriptome this could provide a novel method of detecting aneusomy of unknown position. Subsequent analysis of individuals cases demonstrated that variation in transcriptional profiles between samples within each class made transcriptional karyotyping difficult without pooling or the use of arrays with a higher proportion of all human cDNAs. Interestingly, consistent differences in the relative expression levels between chromosomes were detected suggesting that genomic control mechanisms may act over larger distances than previously thought. Most (>95%) >+/-2 SD misregulated genes did not map to the trisomic chromosome and significant misregulation was more common in t13 than t21. These data support a model of a subtle primary upregulation of genes on the trisomic chromosome resulting in a secondary, generalized and more extreme transcriptional misregulation. It seems likely that the degree of this misregulation determines the severity of the phenotype in most aneuploidy.


Gentamicin Released from Porous Scaffolds Fabricated by Stereolithography.
Porous oligolactide-hydroxyapatite composite scaffolds were obtained by stereolithographic fabrication. Gentamicin was then coated on the scaffolds afterwards, to achieve antimicrobial delivery ability to treat bone infection. The scaffolds examined by stereomicroscope, SEM, and μCT-scan showed a well-ordered pore structure with uniform pore distribution and pore interconnectivity. The physical and mechanical properties of the scaffolds were investigated. It was shown that not only porosity but also scaffold structure played a critical role in governing the strength of scaffolds. A good scaffold design could create proper orientation of pores in a way to strengthen the scaffold structure. The drug delivery profile of the porous scaffolds was also analyzed using microbiological assay. The release rates of gentamicin from the scaffolds showed prolonged drug release at the levels higher than the minimum inhibitory concentrations for S. aureus and E. coli over a 2-week period. It indicated a potential of the scaffolds to serve as local antibiotic delivery to prevent bacterial infection.


Mechanisms underpinning interventions to reduce sexual violence in armed conflict: A realist-informed systematic review.
Sexual violence is recognised as a widespread consequence of armed conflict and other humanitarian crises. The limited evidence in literature on interventions in this field suggests a need for alternatives to traditional review methods, particularly given the challenges of undertaking research in conflict and crisis settings. This study employed a realist review of the literature on interventions with the aim of identifying the mechanisms at work across the range of types of intervention. The realist approach is an exploratory and theory-driven review method. It is well suited to complex interventions as it takes into account contextual factors to identify mechanisms that contribute to outcomes. The limited data available indicate that there are few deterrents to sexual violence in crises. Four main mechanisms appear to contribute to effective interventions: increasing the risk to offenders of being detected; building community engagement; ensuring community members are aware of available help for and responses to sexual violence; and safe and anonymous systems for reporting and seeking help. These mechanisms appeared to contribute to outcomes in multiple-component interventions, as well as those relating to gathering firewood, codes of conduct for personnel and legal interventions. Drawing on pre-existing capacity or culture in communities is an additional mechanism which should be explored. Though increasing the risk to offenders of being detected was assumed to be a central mechanism in deterring sexual violence, the evidence suggests that this mechanism operated only in interventions focused on gathering firewood and providing alternative fuels. The other three mechanisms appeared important to the likelihood of an intervention being successful, particularly when operating simultaneously. In a field where robust outcome research remains likely to be limited, realist methods provide opportunities to understand existing evidence. Our analysis identifies the important potential of building in mechanisms involving community engagement, awareness of responses and safe reporting provisions into the range of types of intervention for sexual violence in crises.


Glycogen phosphorylase as a molecular target for type 2 diabetes therapy.
The regulation of the hepatic glucose output through glycogenolysis is an important target for type 2 diabetes therapy. Glycogenolysis is catalyzed in liver, muscle and brain by tissue specific isoforms of glycogen phosphorylase (GP). Because of its central role in glycogen metabolism, GP has been exploited as a model for structure-assisted design of potent inhibitors, which may be relevant to the control of blood glucose concentrations in type 2 diabetes. Several regulatory binding sites have been identified in GP, such as the catalytic, the allosteric, and the inhibitor binding sites. Protein crystallography has contributed significant structural information on the specificity and interactions that distinguish the binding sites, and also revealed a new unexpected binding site (new allosteric site). In this review, the kinetic, crystallographic binding, and physiological studies of a number of compounds, inhibitors of GP, are described, and the essential inhibitory and binding properties of specific compounds are analyzed in an effort to provide rationalizations for the affinities of these compounds and to exploit the molecular interactions that might give rise to a better inhibitor. These studies have given new insights into fundamental structural aspects of the enzyme enhancing our understanding of how the enzyme recognizes and specifically binds ligands, that could be of potential therapeutic value in the treatment of type 2 diabetes.


Cytokinins of the Developing Mango Fruit : Isolation, Identification, and Changes in Levels during Maturation.
The cytokinin activity has been isolated and identified from extracts of immature mango (Mangifera indica L.) seeds. The structures of zeatin, zeatin riboside, and N(6)-(Delta(2)-isopentenyl)adenine riboside were confirmed on the basis of their chromatographic behavior and mass spectra of trimethylsilyl derivatives. Both trans and cis isomers of zeatin and zeatin riboside were also identified by the retention times of high performance liquid chromatography. In addition, an unidentified compound appeared to be a cytokinin glucoside.The concentration of cytokinins in the panicle and pulp of mango reached a maximum 5 to 10 days after full bloom and decreased rapidly thereafter. The cytokinin level in the seed remained high until the 28th day after full bloom. The quantity of cytokinins in pulp per fruit increased from the 10th day after full bloom, the maximum being attained around the 50th day after full bloom. Similarly, the amount of cytokinins per seed increased from the 10th day after full bloom, reaching a peak on the 40th day and decreasing gradually thereafter.A high percentage of fruit set in mango was persistently maintained by supplying 6-benzylaminopurine (1.5 x 10(3) micromolar) onto the panicle at the anthesis stage and by supplying gibberellic acid (7.2 x 10(2) micromolar) and naphthalene acetamide (3.1 x 10 micromolar) at the young fruit stage.


Validation of the AQT color-form additive model for screening and monitoring pharmacological treatment of ADHD.
This retrospective study used a quick test of cognitive speed (AQT) processing-speed and efficiency measures for evaluating sensitivity and monitoring effects during pharmacological treatment of adults with ADHD. Color (C), form (F), and color-form (CF) combination naming were administered to 69 adults during outpatient evaluation, and pre- and posttreatment results were compared for 64 adults. At intake without medication, naming times (s) were significantly longer and overhead, CF - (C + F), larger than after stabilization of ADHD symptoms. Means for single-dimension naming were in the normal range, and for CF and overhead, means were in the atypical ranges. After treatment, CF and overhead improved to within normal ranges. On average, dual-dimension processing speed increased by 31% and efficiency by 73%. Sensitivity at intake was 91%, using fail-criteria for CF and/or overhead. Results support previous estimates of sensitivity and ability to monitor pharmacological-treatment effects in ADHD.


[Transnasal endoscopic sinus surgery for diseases in the ethmoid-sphenoid area].
To explore the proprieties of diseases in the ethmoid-sphenoid area and improve the effects of treatment and diagnose of these kinds of diseases. 51 cases of diseases in the ethmoid-sphenoid areas,who had undergone transnasal endoscopic sinus surgery, were investigated. Among them, 41 cases of diseases in the ethmoid-sphenoid area involved at the same time were undergone surgery by ethmoid approach, 10 cases with isolated sphenoid diseases were done via nasal cavity. Forty-eight cases did not develop serious complications after surgical treatments, and 3 cases recurrence during the follow-up. Diseases in the ethmoid-sphenoid area readily ignored because there are few specific early-stage symptoms. Computer-tomographer scan is helpful to the diagnose and introductive to the procedure of surgery. Transnasal endoscopic sinus surgery can make patients suffer less, and leaves no scar in the face.


Risk Factors of Stunting and Wasting among Children Aged 6-59 Months in Household Food Insecurity of Jima Geneti District, Western Oromia, Ethiopia: An Observational Study.
Undernutrition is the most difficult and widespread public health concern in low-income nations including Ethiopia. Therefore, this study aimed to investigate the associated risk factors of stunting and wasting among children aged 6-59 months in Jima Geneti district, Western Oromia, Ethiopia. A community-based cross-sectional study was conducted on 500 children from December 1 to 28, 2020. A multiple-stage sampling method was performed to select children from each kebele. Anthropometric measurements were taken, and the nutritional status was generated using WHO Anthro v. 3.2.1. Data analysis was performed using the SPSS version 20.0. Bivariate and multivariate logistic regression analyses were carried out to identify the associated risk factors of stunting and wasting among children in the study area. Statistical significance was set at p < 0.05. The study results showed that the prevalence of stunting and wasting among children was 27% and 11.8%, respectively. The findings of this study also revealed that the prevalence of household food insecurity and poor dietary diets was 19.6% and 52.2%, respectively. Low wealth status (AOR = 2.5; 95% CI: 1.1, 5.55) and poor dietary diets (AOR = 4.7; 95% CI: 2.5, 8.83) were associated risk factors for stunting. However, child meal frequency (AOR = 3.9; 95% CI: 1.23, 12.6), and children who did feed leftover food (AOR = 2.75; 95% CI: 1.02, 7.44) were associated risk factors for wasting. Poor dietary diets (AOR = 2.65; 95% CI: 1.06, 6.66) were also associated risk factors for wasting. The findings of this study concluded that the prevalence of stunting and wasting was high in the study area. Therefore, addressing family-level risk factors which are major drivers of children's nutritional status is crucial to ensure the nutritional status of children.


Stepwise modification of a modular enhancer underlies adaptation in a Drosophila population.
The evolution of cis regulatory elements (enhancers) of developmentally regulated genes plays a large role in the evolution of animal morphology. However, the mutational path of enhancer evolution--the number, origin, effect, and order of mutations that alter enhancer function--has not been elucidated. Here, we localized a suite of substitutions in a modular enhancer of the ebony locus responsible for adaptive melanism in a Ugandan Drosophila population. We show that at least five mutations with varied effects arose recently from a combination of standing variation and new mutations and combined to create an allele of large phenotypic effect. We underscore how enhancers are distinct macromolecular entities, subject to fundamentally different, and generally more relaxed, functional constraints relative to protein sequences.


Valproate in adolescents with photosensitive epilepsy with generalized tonic-clonic seizures only.
To assess the effects of valproate (VPA) on seizure response/control and photosensitivity (PS) in adolescents suffering from photosensitive epilepsy with generalized tonic-clonic seizures only (EGTCS). We prospectively evaluated 55 adolescents with newly diagnosed EGTCS and PS at presentation, who received VPA monotherapy. Two phases of the study were defined and analysed separately. In the phase I, the electroclinical data of patients were compared over three time points: T1 (at 6 months of treatment); T2 (at 12 months of treatment); and T3 (at 36 months of treatment). In the phase II, only patients who stopped VPA were evaluated over a period of 12 months. At both T2 and T3 there was a significant great percentage of seizure-free patients compared with that at T1 (78.2% vs 69.1%, p < 0.01; and 85.5% vs 69.1%, p < 0.001) and a similar trend was also noted according to PS-free patients (70.9% vs 52.7%, p < 0.01; 80.0% vs 52.7% p < 0.001). At the end of the phase II, 46.5% and 32.6% out of 43 patients who stopped VPA had seizure relapses and reappearance of PS, respectively. In particular, 78.6% of the 14 patients with PS reappearance presented the same type of EEG response showed at study entry. VPA monotherapy is very effective for both seizure outcome control and PS reduction in adolescents with EGTCS. Treatment discontinuation induces relapse of seizures and PS in a certain number of patients. PS reappearance presented the same type of EEG response showed before VPA treatment.


The workshop as an effective method of dissemination: the importance of the needs of the individual.
The workshop is one of a number of strategies that can be used to disseminate information. This study set out to evaluate the effectiveness of the workshop as a method of disseminating information which had as its aim the introduction of new practices. A series of workshops, attended by G and H grade nurses, were carried out in a large teaching Hospital in England. The information which was disseminated concerned recruitment and retention activities for nurses which had been proposed in recent government documents, in particular in the Strategy for Nursing in England 'Making a Difference' by the UK Department of Health. Two sample groups of 25 nurses (workshop attendees and non-attendees) were interviewed. The interviews took place shortly after the workshops and were repeated 7 months later. The first set of interviews explored the nurses' intention to implement changes in their clinical areas and the second set of interviews identified actual change. The findings from the study suggests that the workshops were an effective means of producing changes in practice. However, the interviews also identified the value of personal engagement, especially in relation to meeting individual human needs, which were facilitated through the workshop. These emotions appeared to have an influence on the success of the nurses in implementing change and it is proposed that these outcomes should be considered when determining the benefits of a dissemination strategy.


Inflammatory bowel disease and pregnancy: report of two cases treated with infliximab and a review of the literature.
Inflammatory bowel disease is relatively frequent in women of childbearing age. Disease management requires greater attention during this clinical condition because of potential risk of maternal-fetal complications. Infliximab has been shown to be safe during pregnancy and lactation, but reports in the literature are scarce. We report two cases of refractory Crohn's disease treated with infliximab with good results, in women. Both patients became pregnant during maintenance regimen and treatment was continued. The literature regarding pregnant patients with inflammatory bowel disease was reviewed.


Recovery of pituitary-gonadal function in male rats after long-term suppression induced by a single injection of microcapsules of LH-RH antagonist cetrorelix (SB-75).
The clinical utility of luteinizing hormone-releasing hormone (LH-RH) analogs can be greatly enhanced by a sustained delivery system, which could maintain elevated peptide levels in the blood for prolonged periods of time, up to several weeks. Recently, we developed long-acting microcapsules and microgranules of the LH-RH antagonist SB-75. In this study, we examined the suppressive effects of a single injection of microcapsules of antagonist SB-75 on gonadotropin and testosterone secretion, as well as on fertility, in male rats and the reversibility of those effects. Serum SB-75 levels were measured by RIA. A dose of 20 mg of microcapsules/rat containing 3.58 mg of antagonist in poly(D,L-lactide-co-glycolide), administered intramuscularly produced SB-75 levels higher than 20 ng/ml for approximately 24 days, and a significant elevation was maintained until day 90. Serum testosterone was decreased to castration values for 164 days and LH levels were suppressed below the detection limit of the RIA for a period of 102 days. Serum FSH was suppressed by more than 90%, as compared to control animals, for a period of 58 days and remained significantly decreased until day 164 after the injection. This treatment also caused a significant decrease in the weights of the testes, seminal vesicles, and ventral prostate 30 days after peptide administration. The histology of the testes from the treated rats showed that spermatogenesis was totally depressed. No mature elongated or round spermatids were found in the seminiferous tubules, spermatocytes being the most advanced germ cell form in 99.5% of the testicular tubules.(ABSTRACT TRUNCATED AT 250 WORDS)


Chagas disease: progress and new perspectives.
Chagas disease, also known as American trypanosomiasis, is caused by infection with the protozoan parasite Trypanosoma cruzi. The Pan American Health Organization (PAHO) estimates that currently 7.7 million of people have Trypanosoma cruzi infection in the 21 endemic countries from the southern and southwestern United States to central Argentina and Chile. The only approved therapeutics for the treatment of Chagas disease are two nitroheterocyclic compounds as a nitrofuran (nifurtimox; Lampit) and a nitroimidazole (benznidazole; Rochagan). However, the anti-Trypanosoma cruzi activities of these compounds were discovered empirically over three decades ago. The treatment of Chagas disease with nifurtimox or benznidazole is unsatisfactory because of their limited efficacy in the prevalent chronic stage of the disease and their toxic side effects. In this context, this article will review the current knowledge of the different aspects involved in this illness, such as Trypanosoma cruzi transmission, physiology and biochemistry of the etiological agent, epidemiological aspects and current treatments for American trypanosomiasis. An important section of this review will focus on the different strategies in drug discovery for Chagas disease, including methodology, in vitro screening studies against whole parasites, novel rationally developed approaches on the basis of the increasing knowledge of the biochemistry of Trypanosoma cruzi and the recent progress in the understanding and validation of several targets for the therapy of Chagas's disease. A summary of the most relevant drug targets such as sterol biosynthesis pathway, cysteine protease pathway, pyrophosphate metabolism and purine salvage pathway will be reviewed. Moreover, recent studies regarding other strategies currently under development including thiol-dependent redox metabolism, lysophospholipid analogues and DNA binders will also be discussed.


Comparison of pulmonary function in immigrant vs US-born Asian Indians.
This study investigated whether there is a difference in pulmonary function between healthy adult US-born Asian Indians and immigrant Asian Indians attributable to country of birth, environmental, and socioeconomic factors. FEV(1), FVC, and forced mid-expiratory flow between 25% and 75% of vital capacity (FEF(25-75)) were measured in India-born and US-born subjects residing in the Chicago metropolitan area. Hollingshead Index of Social Position was used to evaluate socioeconomic factors. There were 262 India-born (61.8% male), and 200 US-born (50% male) subjects who were healthy lifelong nonsmokers; their age range was 16 to 36 years. US-born Asian Indian men and women were taller and had higher pulmonary function values for height and age compared with immigrant Asian Indian men and women. The differences were most pronounced in women: about 7% for FVC, 9% for FEV(1), and 17% for FEF(25-75). Immigrant and US-born subjects did not differ in socioeconomic position. We conclude that US-born Asian Indian men and women have higher pulmonary function values for age and height compared with immigrant Asian Indian men and women. This probably reflects the effect of differing environmental conditions, which cause year-of-birth trends in lung volumes.