An update on the pharmacotherapeutic interventions for smoking cessation.
Cigarette smoking can damage every organ in the body and is the leading known preventable cause of death globally. It is estimated that 70% of patients want to quit, and about 50% report a quit attempt in the past year, yet only 4-7% are successful. These low quit rates represent the importance of appropriate treatment for smoking cessation through behavioral and pharmacotherapeutic means. Pharmacotherapy approximately doubles patients' chances of quitting, and the first-line approved pharmacotherapetuic options include nicotine gum, lozenge, patch, nasal spray, and inhaler, sustained-release bupropion, and varenicline. Second-line therapies include nortriptyline and clonidine. Recent evidence suggests a potential role for cytisine and naltrexone. Healthcare providers play an important role in helping patients quit smoking; therefore, a clear understanding of appropriate dosing, regimen, technique, disadvantages, advantages, warnings/precautions, and contraindications for available pharmacotherapeutic options is essential. To improve chances of success, providers should consider patient preferences and prior experiences with quitting, provide medication-specific counseling for the selected therapy, and encourage adherence with the behavioral and pharmacotherapeutic treatment regimen.


[Lumbar disk hernia in children. Apropos of 12 cases].
Lumbar disc herniation in young adolescent is uncommon. Twelve patients of 13 to 16 years old (4 boys and 8 girls) are reported. Traumatic history is encountered only in 1/3 of cases and any spinal abnormality is noted in this series. The rapidity in clinical course is the main difference compared with the lumbosciatalgia of the adult. The mean interval of time between the beginning of clinical signs and surgery is 5 months and a half. A positive straight leg raising test is always present as well as antalgic pseudo-scoliosis. The radiculalgia without lumbalgia is the essential sign in on fourth of cases. The myelography and C.T. scan revealed lumbar disc herniation 5 times in L4-L5 intervertebral space and 7 times in L5-S1 space. The intervertebral disc is reached by unilateral interlaminal approach. The complete removal of the disc is always difficult as the disc is not dehydrated at this age. The radiculalgia disappears immediately in the postoperative period as well as the lumbalgia. The back pain persist some months following the surgery. Up the date any response is noted but the authors think that some prudence is necessary in the evaluation of the results especially because of the incomplete removal of disc in young patients. The authors think also that well hydrated and simply protruded disc of young adolescent may constitute an excellent indication for chemonucleolysis.


William Orange CB, MD, FRCP, LSA: A Broadmoor pioneer.
William Orange was the second Medical Superintendent of Broadmoor and in the 23 years he spent there created a management style that was greatly admired. Among his patients were the painter Richard Dadd, the Surgeon of Crowthorne and the Brighton poisoner. As advisor to the Home Office he also made a significant contribution to the interface between medicine and the law.


Sodium, potassium food intake and global cardiovascular risks in Togo.
To assess urinary sodium/potassium intake and identify its links with global cardiovascular risk (GCVR) according to the WHOPEN approach to WHO/ISH (International High Blood Pressure Society). It was a cross-sectional and analytical study that took place from July 6, 2020, to September 17, 2021, in Togo, in the Aneho, Notse and Dapaong localities. It focused on 400 adults selected by sampling. The analysis of two urine samples was done. Cardiovascular risk scores were determined from specific graphs that take into account age, gender, systolic blood pressure, diabetes status, and smoking behavior. Among the 400 respondents, 49% lived in rural areas. The average age was 41 (30; 51) years. The average sodium and potassium intakes were respectively 3.2 g (1.04-5.99) or 7.95 g of salt and 1.4 g (1.89-5.62) per day. The risk of excessive sodium intake was 2.39 times higher in urban areas than in rural ones (P=0.049). Residing in rural areas was associated with high potassium intakes compared to urban ones [OR=3,2 IC (1.89-5.62)]. Thirteen percent (13%) of respondents were likely to develop at least a deadly or non-deadly cardiovascular disease in the next 10 years 'time, of whom 5% present a high risk. Excessive sodium intake increases by 2.10 times the risk of a deadly cardiovascular disease occurrence. Sodium intakes are high while potassium intakes are low with a subsequent GCVR in the three cities. Sodium intakes were associated with GCVR. It is necessary to take steps to reduce excessive sodium intake and improve potassium intake.


Depleting Mycobacterium tuberculosis of the transcription termination factor Rho causes pervasive transcription and rapid death.
Rifampicin, which inhibits bacterial RNA polymerase, provides one of the most effective treatments for tuberculosis. Inhibition of the transcription termination factor Rho is used to treat some bacterial infections, but its importance varies across bacteria. Here we show that Rho of Mycobacterium tuberculosis functions to both define the 3' ends of mRNAs and silence substantial fragments of the genome. Brief inactivation of Rho affects over 500 transcripts enriched for genes of foreign DNA elements and bacterial virulence factors. Prolonged inactivation of Rho causes extensive pervasive transcription, a genome-wide increase in antisense transcripts, and a rapid loss of viability of replicating and non-replicating M. tuberculosis in vitro and during acute and chronic infection in mice. Collectively, these data suggest that inhibition of Rho may provide an alternative strategy to treat tuberculosis with an efficacy similar to inhibition of RNA polymerase.


Circulating Tumor Cells Accurately Predicting Progressive Disease After Treatment in a Patient with Non-small Cell Lung Cancer Showing Response on Scans.
Lung cancer is the leading cause of cancer-related deaths worldwide. Most patients present with advanced inoperable disease. Traditionally, responses to treatments are evaluated using different imaging modalities, which can sometimes be confusing. This is particularly more relevant in stage 3 disease where, after radiation therapy, persistent tumors on scans can represent active disease or scar tissue. We have been evaluating role of circulating tumor cells (CTCs) in that setting. Here we present the case of a 68-year-old male with stage 3 disease whose primary tumor responded to chemoradiotherapy on imaging, but whose CTC count was higher than the pre-treatment value. The patient later developed liver metastases. In this case, the CTC count more accurately predicted the patient's prognosis and highlights the need for exploration of the CTC count as a tool supplemental to imaging modalities.


Disease severity indexes and treatment evaluation criteria in vitiligo.
There is a current lack of consensus regarding methods of assessment of vitiligo. Recently, the Vitiligo Area Scoring Index (VASI) and the Vitiligo European Task Force (VETF) were proposed to offer more accurate measures of disease severity indexes and treatment evaluation criteria. It would make sense to combine the VASI with the VETF system. We proposed an original scale for treatment evaluation criteria in vitiligo based on VASI. We plan to add the digital image analysis system, health-related quality of life questionnaire, affected skin location, and skin color in the original scale.


Experimental scoliosis in an immature goat model: a method that creates idiopathic-type deformity with minimal violation of the spinal elements along the curve.
Experimental scoliosis was created in an immature goat model. To create a progressive, structural, idiopathic-type, lordoscoliotic curve convex to the right in the thoracic spine of the immature goat while maintaining the anterior and posterior elements of the spine along the maximal curve in a pristine state. Progressive scoliotic curves in a small animal model have been created using a posterior asymmetric tether. However, attempts in larger animal models have had less success and typically required violation of the spinal elements. Scoliosis was created in 40 Spanish Cross X female goats (age 1-2 months, weight 8-12 kg) using a left posterior asymmetric tether from T5 to L1. Convex rib resection and concave rib tethering from T8 to T13 were performed before compression across the rigid construct. Goats were followed over a 6- to 15-week period with serial radiographs to document progression of the deformity. Of the 40 goats that underwent posterior assymetric tethering with rib procedures, 7 (18%) encountered substantial complications (five deaths and two neurologic injuries). Of the 33 available for analysis, 27 goats (82%) developed progressive, structural, idiopathic-type, lordoscoliotic curves in convex to the right in the thoracic spine. All curves demonstrated characteristic radiographic features of idiopathic scoliosis including significant displacement of the apical vertebra from the midline, wedging of both the vertebral bodies and discs, rotation, and decreased flexibility. Initial scoliosis after posterior asymmetric tethering measured 42 degrees on average (range 33-50 degrees ) and progressed to 60 degrees on average (range 44-73 degrees ) over 6 to 15 weeks. The average progression of +18 degrees (range 6-37 degrees ) was statistically significant (P < 0.001). This study establishes an experimental model for scoliosis that creates progressive, structural, idiopathic-type, lordoscoliotic curves convex to the right in the thoracic spine of the immature goat with high statistical significance (P < 0.001). In addition, this method of experimental scoliosis creation avoids violation of the spinal elements throughout the maximal portion of the curve providing an ideal opportunity subsequent study of the deformity.


A spectrum of B-cell differentiation defects.
The nonparallel relationships between development of classes of B lymphocytes and of serum immunoglobulins during ontogeny and in some patients imply: 1) that B-cell differentiation is discontinuous and 2) that class-specific-controls for terminal B-lymphocyte differentiation exist. Three separate defects in B-cell differentiation in vivo have been identified using pokeweed mitogen stimulation of lymphocytes. B lymphocytes may fail to develop, may develop but lack the capacity to differentiate further, or may be normal in both respects. The latter result suggests involvement of other cell types in antibody deficiency.


Tool Condition Monitoring and Remaining Useful Life Prognostic Based on a Wireless Sensor in Dry Milling Operations.
Tool breakage causes losses of surface polishing and dimensional accuracy for machined part, or possible damage to a workpiece or machine. Tool Condition Monitoring (TCM) is considerably vital in the manufacturing industry. In this paper, an indirect TCM approach is introduced with a wireless triaxial accelerometer. The vibrations in the three vertical directions (x, y and z) are acquired during milling operations, and the raw signals are de-noised by wavelet analysis. These features of de-noised signals are extracted in the time, frequency and time-frequency domains. The key features are selected based on Pearson's Correlation Coefficient (PCC). The Neuro-Fuzzy Network (NFN) is adopted to predict the tool wear and Remaining Useful Life (RUL). In comparison with Back Propagation Neural Network (BPNN) and Radial Basis Function Network (RBFN), the results show that the NFN has the best performance in the prediction of tool wear and RUL.


Draft Genome Sequence of Acinetobacter sp. Strain VT-511 Isolated from the Stomach of a Patient with Gastric Cancer.
We report the draft genome sequence of Acinetobacter sp. strain VT-511, which was obtained from the stomach of a patient with gastric cancer. The genome of Acinetobacter sp. VT-511 is composed of approximately 3,416,321 bp and includes 3,214 predicted protein-coding genes.


The Effect of a Feeding Schedule Change and the Provision of Forage Material on Hair Eating in a Group of Captive Baboons (Papio hamadryas sp.).
Hair eating in nonhuman primates is thought to result from a frustrated appetitive drive produced by an inappropriate diet. To investigate whether hair eating could be reduced through changes in diet, a 2-part study was conducted with a group of baboons (Papio hamadryas sp.). The 1st part involved changing to a twice-daily feeding routine, thus providing prolonged access to an appropriate food source. The 2nd part involved scattering a grain mix to encourage more foraging while maintaining a once-daily feeding routine. Changing the feeding routine unexpectedly resulted in a significant increase in hair manipulation and ingestion. Providing additional grain did not significantly decrease hair manipulation and ingestion, but several individuals did show a reduction in these behaviors. Prolonged access to biscuits and the provision of a grain mix may have failed to satisfy the urge to forage because little effort was needed for their collection prior to consumption. Although the current study failed to significantly decrease hair eating, it provides valuable insight into further avenues of research on the behavior.


Your fate is in your hands? Handedness, digit ratio (2D:4D), and selection to a national talent development system.
Over the past decade a small evidence base has highlighted the potential importance of seemingly innocuous variables related to one's hands, such as hand dominance and the relative length of the second and fourth digits (2D:4D ratio), to success in sport. This study compared 2D:4D digit ratio and handedness among handball players selected to advance in a national talent development system with those not selected. Participants included 480 youth handball players (240 females and 240 males) being considered as part of the talent selection programme for the German Youth National team. Hand dominance and digit ratio were compared to age-matched control data using standard t-tests. There was a greater proportion of left-handers compared to the normal population in males but not in females. There was also a lower digit ratio in both females and males. However, there were no differences between those selected for the next stage of talent development and those not selected on either handedness or digit ratio. These results add support for general effects for both digit ratio and handedness in elite handball; however, these factors seem inadequate to explain talent selection decisions at this level.


Cigarette smoke induced oxidative insult in local population of Pokhara.
To assess the effect of cigarette smoking on lipid peroxidation induced oxidative stress, antioxidants, uric acid and blood sugar in normal subjects. The study included 61 normal subjects with regular smoking habit and 57 never-smokers normal subjects matched in respect to socio-economic status, age and BMI. Information regarding smoking habit and other personal details were collected by oral questionnaire. Total antioxidant activity (TAA), reduced glutathione (GSH), alpha-tocopherol (alpha-T), ascorbic acid (AA), uric acid (UA), plasma and urinary thiobarbituric acid reactive substances (TBARS), fasting blood sugar (FBS) and urinary creatinine (Cr) were estimated by standard procedures in both the groups. Ferric Reducing Antioxidant Power (FRAP) procedure is used to estimate TAA which measures total dietary antioxidants. Statistical analysis was done with SPSS version 10. The mean pack years smoked by smokers was 14.4 +/- 15.8. The plasma TBARS level in smokers and never-smokers was 2.6 +/- 0.8 and 2.5 +/- 0.6 micromol/L respectively. The respective figure for urinary TBARS level was 4.6 +/- 2.7 and 3.7 +/- 1.4 micromol/gmCr. Smokers did not show any significant difference from never-smokers with respect to GSH, alpha-T, AA, plasma TBARS and FBS. However, the smokers had significantly lower levels of TAA (p<0.05) and raised level of urinary TBARS (p<0.05) and uric acid (p<0.01) as compared to never-smokers. Our study suggests that smoking induces mild lipid peroxidation but the body is able to compensate for it by removing its adducts. Importantly it also indicates enhanced oxidation of purines which are essential components of both DNA and RNA. Dietary antioxidants are consumed to scavenge free radicals (FR) and other reactive species (RS) in smoke. Female smokers are more prone to oxidative insult than male smokers. In summary RS present in smoke induce mild lipid peroxidation but are not the major contributors of redox imbalance in smoke induced toxicity in the selected subjects.


Method for estimating the decomposition of hexadecane in the marine environment.
A method, based on quantitating 14CO2 produced from [14C]hexadecane, has been developed for estimating the rate of hexadecane decomposition in seawater of Tokyo Bay during the summer stagnation period. The rate of hexadecane decomposition was from 0.1 to 1.3 mug/h per liter of seawater at the surface layer in the polluted gyre of the inner part of Tokyo Bay during the summer of 1974. A similar horizontal distribution pattern was seen for the density of hexadecane-decomposing bacteria.


Translational Repression in Malaria Sporozoites.
Malaria is a mosquito-borne infectious disease of humans and other animals. It is caused by the parasitic protozoan, Plasmodium. Sporozoites, the infectious form of malaria parasites, are quiescent when they remain in the salivary glands of the Anopheles mosquito until transmission into a mammalian host. Metamorphosis of the dormant sporozoite to its active form in the liver stage requires transcriptional and translational regulations. Here, we summarize recent advances in the translational repression of gene expression in the malaria sporozoite. In sporozoites, many mRNAs that are required for liver stage development are translationally repressed. Phosphorylation of eukaryotic Initiation Factor 2α (eIF2α) leads to a global translational repression in sporozoites. The eIF2α kinase, known as Upregulated in Infectious Sporozoite 1 (UIS1), is dominant in the sporozoite. The eIF2α phosphatase, UIS2, is translationally repressed by the Pumilio protein Puf2. This translational repression is alleviated when sporozoites are delivered into the mammalian host.


Impact of Isotonic Beverage on the Hydration Status of Healthy Chinese Adults in Air-Conditioned Environment.
People living in tropical climates spend much of their time in confined air-conditioned spaces, performing normal daily activities. This study investigated the effect of distilled water (W) or isotonic beverage (IB) on the hydration status in subjects living under these conditions. In a randomized crossover design, forty-nine healthy male subjects either consumed beverage or IB over a period of 8 h (8 h) in a controlled air-conditioned environment. Blood, urine, and saliva samples were collected at baseline and after 8 h. Hydration status was assessed by body mass, urine output, blood and plasma volume, fluid retention, osmolality, electrolyte concentration and salivary flow rate. In the IB group, urine output (1862 ± 86 mL vs. 2104 ± 98 mL) was significantly lower and more fluids were retained (17% ± 3% vs. 7% ± 3%) as compared to W (p < 0.05) after 8 h. IB also resulted in body mass gain (0.14 ± 0.06 kg), while W led to body mass loss (-0.04 ± 0.05 kg) (p = 0.01). A significantly smaller drop in blood volume and lower free water clearance was observed in IB (-1.18% ± 0.43%; 0.55 ± 0.26 mL/min) compared to W (-2.11% ± 0.41%; 1.35 ± 0.24 mL/min) (p < 0.05). IB increased salivary flow rate (0.54 ± 0.05 g/min 0.62 ± 0.04 g/min). In indoor environments, performing routine activities and even without excessive sweating, isotonic beverages may be more effective at retaining fluids and maintaining hydration status by up to 10% compared to distilled water.


A whole-field polariscope using a liquid crystal polarization rotator.
A novel polariscope using a liquid crystal (LC) polarization rotator is proposed for full-field subfringe photoelastic stress analysis. The system uses a light-emitting diode-based modified Senarmont polariscope with an added liquid crystal polarization rotator to generate phase shifts by applying suitable voltages to the LC element. Four phase shift polariscope images are captured and analyzed to get the stress distribution. A comparative study with the gray-field polariscope method which uses a rotating analyzer shows good agreement.


Euglycaemic ketoacidosis in a non-diabetic primigravida following an appendicectomy.
Pregnancy creates significant alterations in energy metabolism which itself is a physiological adaptation to provide continuous flow of energy metabolites to the foetus. The state of insulin resistance created by hormonal changes in pregnancy enables free flow of glucose to the foetus and allows its absorption through facilitated diffusion. As glucose is preferentially available for the foetus, maternal fasting glucose level would be less than that of a non-pregnant state and in contrast plasma ketones and free fatty acids levels are elevated, resulting in a state of accelerated starvation. These metabolic alterations place a pregnant woman at a higher risk of developing euglycaemic ketoacidosis when allowed to fast for prolonged periods due to medical, surgical and psychological reasons. We report a rare case of euglycaemic ketoacidosis causing severe increased anion gap metabolic acidosis in a non-diabetic mother following surgery for appendicitis at a gestation of 27 weeks.


Deciphering Metabolic Currencies That Support Marine Microbial Networks.
Microbes are omnipresent in the biosphere and perform biological and chemical processes critical to ecosystem function, nutrient cycling, and global climate regulation. In the ocean, microbes constitute more than two-thirds of biomass with abundances reaching over one million microbial cells per milliliter of seawater. Our understanding of the marine microbial world has rapidly expanded with use of innovative molecular and chemical 'omics tools to uncover previously hidden taxonomic diversity, spatiotemporal distributions, and novel metabolic functions. Recognition that specific microbial taxa cooccur in consistent patterns in the ocean has implicated microbe-microbe interactions as important, but poorly constrained, regulators of microbial activity. Here, I examine cooperative interactions among marine plankton, with a focus on the metabolic "currencies" that establish microbial partnerships in the surface-ocean trade economy. I discuss current and future directions to study microbial metabolic interactions in order to strengthen our understanding of ecosystem interdependencies and their impact on ocean biogeochemistry.


Endocrinology and the brain: corticotropin-releasing hormone signaling.
Corticotropin-releasing hormone (CRH) is a key player of basal and stress-activated responses in the hypothalamic-pituitary-adrenal axis (HPA) and in extrahypothalamic circuits, where it functions as a neuromodulator to orchestrate humoral and behavioral adaptive responses to stress. This review describes molecular components and cellular mechanisms involved in CRH signaling downstream of its G protein-coupled receptors (GPCRs) CRHR1 and CRHR2 and summarizes recent findings that challenge the classical view of GPCR signaling and impact on our understanding of CRHRs function. Special emphasis is placed on recent studies of CRH signaling that revealed new mechanistic aspects of cAMP generation and ERK1/2 activation in physiologically relevant contexts of the neurohormone action. In addition, we present an overview of the pathophysiological role of the CRH system, which highlights the need for a precise definition of CRHRs signaling at molecular level to identify novel targets for pharmacological intervention in neuroendocrine tissues and specific brain areas involved in CRH-related disorders.


[Acute urinary complications after prostate iodine-125 brachytherapy: evaluation and risk factors].
Evaluation of acute urinary toxicity following prostate Iodine-125 brachytherapy and determination of risk factors. Between September 2000 and July 2001, 50 men were entered into the study. A clinical follow-up accompanied by an objective measurement of urinary morbidity, including uroflowmetry and post-void residue, enabled the evaluation of acute toxicity before and then at one, three and six months of the implantation. Predictors were also searched for. 38 (76%) patients developed urinary disorders but those remained minor or moderate. The IPSS, as well as uroflowmetry deteriorated significantly at the first and third month post-implant, before improving during the sixth month. Besides, the variations of the post-void residue were less significant. Concerning the factors of risk, an initial IPSS superior to eight and a prior alpha-blocker treatment were the preoperative identified risk factors. Regarding dosimetric parameters, preoperative U30 and postoperative D90, D95, V100, V150 and V200 were identified. Though remaining minor or moderate, the great frequency of acute urinary toxicity following prostate brachytherapy requires frank and open dialogue with the patient in conjunction with an evaluation of the urinary status before implantation Patients with higher initial IPSS or having required a prior alpha-blocker treatment are more exposed to these disorders and their correlated postoperative dosimetric factors.


Performance analysis in saber.
Fencing is a sport practiced by both men and women, which uses 3 weapons: foil, épée, and saber. In general, there are few scientific studies available in international literature; they are limited to the performance analysis of fencing bouts, yet there is nothing about saber. There are 2 kinds of competitions in the World Cup for both men and women: the "FIE GP" and "A." The aim of this study was to carry out a saber performance analysis to gain useful indicators for the definition of a performance model. In addition, it is expected to verify if it could be influenced by the type of competition and if there are differences between men and women. Sixty bouts: 33 FIE GP and 27 "A" competitions (35 men's and 25 women's saber bouts) were analyzed. The results indicated that most actions are offensive (55% for men and 49% for women); the central area of the piste is mostly used (72% for men and 67% for women); the effective fighting time is 13.6% for men and 17.1% for women, and the ratio between the action and break times is 1:6.5 for men and 1:5.1 for women. A lunge is carried out every 23.9 seconds by men and every 20 seconds by women, and a direction change is carried out every 65.3 seconds by men and every 59.7 seconds by women. The data confirm the differences between the saber and the other 2 weapons. There is no significant difference between the data of the 2 different kinds of competitions.


[Screening for prostate cancer: present status and future perspectives].
In Japan, about three fourth municiparities and 90% human dry dock (a thorough medical checkup) institutions provide a prostate specific antigen (PSA) testing as a screening tool for early detection of prostate cancer. However, the exposure of screening for prostate cancer is very low compared to developed Western countries. The merits of introducing PSA-based screening could be cause-specific mortality reduction and prevention of developing metastatic disease, which was recently confirmed by prospective randomized controlled trials. On the other hand, some men participating in the screening program may be of drawbacks in terms of overdetection and overtreatment. Therefore, providing a fact sheet on screening for prostate cancer and also providing an optimal screening system including more accurate cancer detection, minimally invasive treatment and active surveillance strategy, which can reduce overdetection, overtreatment, and loss of QOL due to treatment, would be very important. The merits of PSA screening will increase and the drawbacks will decrease in the future due to progress in the diagnostic modalities and treatment strategies. At present, a baseline consensus is to conduct PSA-based screening according to well-balanced guidelines published by the Japanese Urological Association.


Tsc2 expression increases the susceptibility of renal tumor cells to apoptosis.
Although the precise role for the tuberous sclerosis complex-2 tumor suppressor gene (Tsc2) in tumor suppression is not clear, many studies have implicated Tsc2 in the regulation of cell differentiation, cell cycle control, GTPase activity, transcription, polycystin-1 localization, and translation initiation. We propose that Tsc2 also increases susceptibility to apoptosis, and that this functional role may contribute to the tumor suppressor activity of Tsc2. We previously characterized the apoptotic response of a Tsc2-null renal tumor cell line (ERC-18) to the tumor promoter okadaic acid (OKA). In the present study, we expressed Tsc2 in ERC-18 cells and compared the effect of Tsc2 expression on apoptotic induction. Tsc2 expression increased the susceptibility of ERC-18 cells to apoptosis induced by OKA and the phosphatidylinositol-3' kinase inhibitor, LY294002. In addition, Tsc2 expression abrogated OKA-induced cell detachment of ERC-18 cells. These results indicate that the OKA-induced, caspase-independent detachment previously observed in ERC-18 cells is Tsc2-dependent, and may support an additional role for the Tsc2 in regulating cell adhesion.


Urine neutrophil gelatinase-associated lipocalin: a diagnostic and prognostic marker for acute kidney injury (AKI) in hospitalized cirrhotic patients with AKI-prone conditions.
Acute kidney injury (AKI) is known to increase mortality in hospitalized cirrhotic patients; therefore early identification is utmost significance. There are only a few studies evaluating the cut-off level of urine neutrophil gelatinase-associated lipocalin (uNGAL) for diagnosing AKI and its prognostic value in cirrhotic patients. We aimed to determine the accuracy of uNGAL as a biomarker for early identification of AKI and to determine the cut-off level of uNGAL for diagnosing AKI in hospitalized cirrhotic patients; and (2) to explore the association of 30-day liver-related mortality with uNGAL level. We prospectively enrolled cirrhotic patients admitted at the King Chulalongkorn Memorial Hospital during May 1, 2011 to Dec 31, 2013. UNGAL levels were measured within 24 h after admission. Clinical and laboratory data were obtained. Patients were followed up to 30 days. Of 137 cirrhotic hospitalized patients, 121 cirrhotic patients (88.3 %) with AKI-prone conditions were included with mean age of 57.3 ± 14.7 years. Thirty-five patients (29 %) developed AKI within 72 h of admission. The causes of AKI were prerenal azotemia (68.6 %), acute tubular necrosis (25.7 %), hepatorenal syndrome (5.7 %), respectively. The mean uNGAL level was significantly higher in the patients who developed AKI compared with those who did not (290.6 ± 356.3 vs. 54.4 ± 73.7 ng/mL; P = 0.0001). The AUC of uNGAL for diagnosing AKI was 0.83 (95 % [CI]: 0.76-0.91) with the optimal cut-off level of 56 ng/mL, providing 77.1 % sensitivity and 73.3 % specificity. Fourteen percent of subjects died during the 30-day follow-up period. The mean uNGAL levels were significantly higher in the mortality group. The AUC of uNGAL in predicting mortality was 0.75 (95 % [CI]: 0.66-0.85), with a best cut-off level of 72 ng/mL providing 70.6 % sensitivity and 69.2 % specificity. However, in multivariate logistic regression analysis, uNGAL is not an independent factor for 30-day liver-related mortality prediction. uNGAL is a valid marker for the early detection of AKI in hospitalized cirrhotic patients with AKI-prone conditions; however, its level could not independently predict 30-day liver-related mortality.


Inhibitory effects of crude drug components on the proliferation of cultured human mesangial cells.
The effects of a component of an Oriental medicine and green tea plants utilized for the traditional beverage on the proliferation of mesangial cells were determined in terms of the 3H-thymidine uptake. When magnesium lithospermate B was added to the medium of the mesangial cell culture, it suppressed the proliferation of mesangial cells at a concentration of 50 micrograms/ml. The 3H-thymidine uptake began to display an inhibitory action from the 6.25 micrograms/ml (-)-epicatechin 3-O-gallate, (-)-epigallocatechin 3-O-gallate or green tea tannin mixture, showing a more conspicuous inhibition at 50 micrograms/ml that did the magnesium lithospermate B at the corresponding concentration. In particular, (-)-epigallocatechin 3-O-gallate, the predominant component of the green tea tannin mixture, exerted an inhibitory effect at a relatively low concentration.


A rare case of mucopolysaccharidosis: Hunter syndrome.
We report a rare case of Hunter syndrome-mucopolysaccharidosis type II (MPS II) with atypical presentation of mild mental retardation, acrocephalic head without corneal clouding, and multiple skin eruptions along with oral, dental, and radiographic findings. It is a rare syndrome with a very low prevalence of 1:100,000 births and as such the clinician should be aware of this syndrome.


Automated determination of protein-nitrogen in cereals and grains.
This paper presents the design, performance, and operational characteristics of a new direct reading instrument for determining nitrogen in cereal and grain. Precision, accuracy, range, speed, ease of operation, sensitivity, sample size, and flexibility of the instrument are presented. Results on various cereals and grains are presented and compared with those obtained by the Kjeldahl technique. The apparatus is the result of research for a rapid method for determining nitrogen in organic material. The instrument uses a combination of a unique high temperature sample oxidation, a sampling valve for separating combustion products, and thermal conductivity detection for the liberated nitrogen in a helium carrier gas.


Diselenium-linked dimeric prodrug nanomedicine breaking the intracellular redox balance for triple-negative breast cancer targeted therapy.
Triple-negative breast cancer (TNBC) has been regarded as the strongest malignancy in cases of breast cancer with a poor prognosis. The development of effective treatment strategies for TNBC has always been an urgent and unmet need. The intracellular redox balance is essential for maintaining TNBC cell malignancy. Disrupting intracellular redox balance by enlarging reactive oxygen species (ROS) generation and facilitating glutathione (GSH) depletion to amplify intracellular oxidative stress may be an alternative strategy to eliminate TNBC cells. However, inducing ROS generation and GSH depletion concurrently may be challenging. Herein, a diselenium linked-dimeric prodrug nanomedicine FA-SeSe-NPs was developed to break the intracellular redox homeostasis for TNBC targeted therapy. The dimeric prodrug was synthesized by conjugating two cucurbitacin B (CuB) molecules via one diselenium bond, which was subsequently assembled with FA-PEG-DSPE to form the final nanomedicine FA-SeSe-NPs. Using the active targeting potential of folic acid (FA), FA-SeSe-NPs could accumulate in tumor tissue with elevated levels and then be specifically internalized by cancer cells. In the high ROS and GSH conditions of TNBC cells, the diselenium bond can specifically respond to ROS to produce selenium free radicals to increase ROS and react with GSH to generate S-Se bond to deplete GSH. The released CuB further induced ROS production in TNBC cells. The diselenium bond and CuB functioned synergistically to amplify oxidative stress to kill the TNBC cells. Here, we provide a promising strategy to disrupt the intracellular redox balance of cancer cells for effective TNBC therapy.


Synthesis of Amorphous InSb Nanowires and a Study of the Effects of Laser Radiation and Thermal Annealing on Nanowire Crystallinity.
Although various synthesis and characterization strategies have been employed for the synthesis of crystalline nanowires, there is very little work done on development of low-dimensional amorphous semiconductors. This paper presents a simple strategy to grow amorphous InSb (a-InSb) nanowires (NWs) in a chemical vapor deposition (CVD) system. The NWs were grown on Si substrate coated with indium film and the lack of crystallinity in the as-grown stoichiometric NWs was ascertained by Raman spectroscopy and electron transport measurements. A model proposed to explain the amorphous NW growth mechanism takes into account the fact that NW growth was carried out at the high temperature ramp-up rate of 75 ∘C/min. This high rate is believed to affect the growth kinematics and determine the arrangement of atoms in the growing NW. Raman spectrum of the as-grown sample shows a broad peak around 155 cm-1, indicative of the presence of high density of homopolar Sb-Sb bonds in the amorphous matrix. It was also found that high intensity laser light induces localized crystallization of the NW, most likely due to radiation-stimulated diffusion of defects in a-InSb. The nonlinear trend of the current-voltage characteristics for individually contacted a-InSb NWs was analyzed to prove that the non-linearity is not induced by Schottky contacts. At high bias fields, space charge limited conduction was the proposed electron transport mechanism. Post-growth annealing of the as-grown a-InSb NWs was found to be very effective in causing the NWs to undergo a phase transition from amorphous to crystalline.


Quantum-Dot-Induced Modification of Surface Functionalization for Active Applications of Whispering Gallery Mode Resonators.
Quantum dots can modify the properties of the whispering gallery mode resonators (WGMRs) used in various potential applications. A deposition of a suitable nanomaterial for the surface functionalization of WGMRs allows for the achievement of high quality (Q) factors. Here, we show that the WGMR surface can be functionalized using quantum dots. We demonstrate that WGMRs covered with thin layers of HgS and PbS quantum dots are suitable for third-harmonic generation due to the high Q factor of the developed microresonators, thus significantly lowering the pumping power required for nonlinear optical interactions.


Common infectious morbidity and white blood cell count in middle childhood predict behavior problems in adolescence.
We examined the associations of middle childhood infectious morbidity and inflammatory biomarkers with adolescent internalizing and externalizing behavior problems. We recruited 1018 Colombian schoolchildren aged 5-12 years into a cohort. We quantified white blood cell (WBC) counts and C-reactive protein at enrollment and prospectively recorded incidence of gastrointestinal, respiratory, and fever-associated morbidity during the first follow-up year. After a median 6 years, we assessed adolescent internalizing and externalizing behavior problems using child behavior checklist (CBCL) and youth self-report (YSR) questionnaires. Behavior problem scores were compared over biomarker and morbidity categories using mean differences and 95% confidence intervals (CI) from multivariable linear regression. Compared with children without symptoms, CBCL internalizing problem scores were an adjusted 2.5 (95% CI: 0.1, 4.9; p = .04) and 3.1 (95% CI: 1.1, 5.2; p = .003) units higher among children with moderate diarrhea with vomiting and high cough with fever rates, respectively. High cough with fever and high fever rates were associated with increased CBCL somatic complaints and anxious/depressed scores, respectively. WBC >10,000/mm3 was associated with both internalizing problem and YSR withdrawn/depressed scores. There were no associations with externalizing behavior problems. Whether or not decreasing the burden of common infections results in improved neurobehavioral outcomes warrants further investigation.


Recognition of adverse drug events in older hospitalized medical patients.
To assess medical teams' ability to recognize adverse drug events (ADEs) in older inpatients. The study cohort comprised 250 patients aged 65 years or older consecutively admitted to Internal Medicine wards of three hospitals in the Netherlands between April and November 2007. An independent expert team identified ADEs present upon admission or occurring during hospitalization by a structured retrospective patient chart review. For all ADEs identified, the expert team assessed causality, severity, preventability, and recognition by medical teams. The medical teams did not recognize 19.9 % of all ADEs present upon admission {60.4 ADEs [95 % confidence interval (CI) 51.5-70.8] per 100 hospitalizations} and 20.3 % of all ADEs occurring during the hospital stay [47.2 ADEs (95 % CI 39.4-56.5) per 100 hospitalizations]. Unrecognized ADEs were significantly more often ADEs with possible causality (p=0.014, df=1), ADEs caused by medication errors (p<0.001, df=1), and ADEs not manifesting as new symptoms (p<0.001, df=1). The medical teams did not recognize 23.2 % of mild to moderately severe ADEs and 16.5 % of severe, life-threatening, or fatal ADEs. The recognition of ADEs varied with event type. The recognition of ADEs by medical teams was substantial for those ADEs with evident causality and with clinically apparent and severe consequences. ADEs mimicking underlying pathologies with a lower severity went unrecognized much more often, as did those resulting only in abnormal laboratory values. Tools to improve the recognition of ADEs by medical teams should, therefore, focus on those ADEs that are more challenging to detect.


Weakly guiding graded-index ring-core fiber supporting 16-channel long distance mode division multiplexing systems based on OAM modes with low MIMO-DSP complexity.
We propose a weakly guiding graded-index ring-core fiber (RCF) with trench-assisted structure. The simulation analysis indicates that such a special fiber design is able to support 8 orbital angular momentum (OAM) mode groups (MGs) with low inter-group crosstalk (< -25 dB/km) and low intra-group differential mode delay (DMD) (< 125 ps/km) for higher order OAM MGs with topological charge |l| = 4, 5, 6, 7. The designed RCF also shows favorable tolerance characteristics to ellipticity and bending. Moreover, stable and distinguished broadband performance of proposed RCF is verified over the whole C band ranging from 1530 nm to 1565 nm. This kind of fiber design could be employed in small-scale multiple-input multiple-output digital signal processing (MIMO-DSP) intra-group modes multiplexing transmission combined with MIMO-free inter-group mode multiplexing transmission. The simulated results of the designed RCF show its great potential of the 16-channel long-distance mode division multiplexing (MDM) transmission with low MIMO-DSP complexity.


Spontaneous rupture of liver plasmacytoma mimicking hepatocellular carcinoma.
Extramedullary plasmacytoma of the liver is rare. Here, we report a case presenting with rupture of extramedullary plasmacytoma of the liver. She had a past history of multiple myeloma with IgA lambda type. Her serum was positive for hepatitis C virus infection and exhibited elevated levels of serum protein induced by vitamin K absence or antagonist-II. She was initially diagnosed as rupture of hepatocellular carcinoma (HCC) and then treated with transarterial chemoembolization (TACE) since bloody ascites and formation of hematoma were seen around hyper-vascular liver tumors on computed tomography. However, the clinical course of this case after TACE was atypical for HCC rupture, as shown by the development of a huge intra-abdominal abscess extending from the liver tumor. Immuno-histochemical analysis of the tumor biopsy specimen revealed massive infiltration of plasma cells expressing IgA and lambda chain. To our knowledge, this is the first case of rupture of extramedullary liver plasmacytoma.


Pan-Cancer Analysis of Genomic Sequencing Among the Elderly.
We hypothesized that elderly patients might have age-specific genetic abnormalities yet be underrepresented in currently available sequencing repositories, which could limit the effect of sequencing efforts for this population. Leveraging The Cancer Genome Atlas (TCGA) data portal, 9 tumor types were analyzed. The frequency distribution of cancer by age was determined and compared with Surveillance, Epidemiology, and End Results data. Using the estimated median somatic mutational frequency of each tumor type, the samples needed beyond TCGA to detect a 10% mutational frequency were calculated. Microarray data from a separate prospective cohort were obtained from primary prostatectomy samples to determine whether elderly-specific transcriptomic alterations could be identified. Of the 5236 TCGA samples, 73% were from patients aged <70 years. Comparing the distribution of TCGA samples by age to the Surveillance, Epidemiology, and End Results data, patients <70 years were well represented across most tumor types, but patients aged 80 to 99 years were underrepresented in all cancers (median TCGA underrepresentation of 167%). All cancers (except for colorectal) contained enough samples to detect a 10% mutational frequency in patients aged <60 years. In contrast, no cancer type had enough samples for which a 10% mutational frequency could be detected in patients aged ≥80 years. To further interrogate whether elderly patients with cancer were likely to harbor age-specific molecular abnormalities, we accessed transcriptomic data from a separate, larger database of >2000 prostate cancer samples. That analysis revealed significant differences in the expression of 10 genes in patients aged ≥70 years compared with those <70 years, of which 7 are involved in androgen signaling and/or DNA repair. Elderly patients have been underrepresented in genomic sequencing studies. Our data suggest the presence of elderly-specific molecular alterations. Further dedicated efforts to understand the biology of cancer among the elderly will be important moving forward.


Interaction of Dark Excited States. Comparison of Computational Approaches.
A systematic theoretical study of the electronic interaction of dark excited states in a model system, formaldehyde dimer is reported. Using the fragment transition density scheme, we estimate the excitonic interaction in different configurations of the dimer. The excited state properties of the system are computed with several quantum mechanical methods. We show that the orbital interaction of the monomers rather than Coulomb interaction of their transition quadrupoles gives the major contribution to the coupling at intermolecular distances shorter than 5 Å. It is found that the exitonic interaction alters drastically by conformational changes. Benchmark couplings computed with EOM CCSD, MS-CASPT2, CASSCF, TD DFT, CIS, and INDO/S and different basis sets are provided. The evaluation of the calculations shows that the TD cam-B3LYP scheme performs best, giving good estimates for all considered structures. In contrast, the TD B3LYP scheme leads to drastically overestimated values. The data obtained using the Tamm-Dancoff approximation are similar to the TD DFT results. CASSCF and CIS calculations underestimate the coupling, indicating that dynamic electron correlation may have a large effect on the short-range coupling. The INDO/S method fails to describe the excited state interaction both at short and long distances.


Talbot effect in waveforms containing subwavelength multilobe superoscillations.
The self-imaging of periodic light patterns, also known as the Talbot effect, is usually limited to periods that are larger than the wavelength. Here we present, theoretically and experimentally, a method to overcome this limitation by using superoscillating light patterns. The input intensity distribution is a periodic band-limited function with relatively large periods, but it contains regions of multilobe periodic oscillations with periods that are smaller than half of the wavelength. We observe the revival of the input pattern, including the subwavelength superoscillating regions, at large distances of more than 40 times the optical wavelength. Moreover, at fractional Talbot distances, we observe even faster local oscillations, with periods of approximately one-third of the optical wavelength.


On the taxonomy of the genus Thysanoptyx Hampson, 1894, with description of two new species from Indochina (Lepidoptera, Erebidae, Arctiinae).
The taxonomic structure of the genus Thysanoptyx Hampson, 1894 is discussed, and the genus is subdivided into five species-groups. Two new species, T. indosinica Volynkin Dubatolov, sp. nov. from Thailand, Cambodia and Vietnam, and T. mirifica Volynkin Dubatolov, sp. nov. from Vietnam are described. Adults, male and female genitalia of the new species and their congeners are illustrated. The checklist of the genus Thysanoptyx is presented.


A model of COVID-19 pandemic with vaccines and mutant viruses.
This paper proposes a compartment model (SVEIHRM model) based on a system of ordinary differential equations to simulate the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Emergence of mutant viruses gave rise to multiple peaks in the number of confirmed cases. Vaccine developers and WHO suggest individuals to receive multiple vaccinations (the primary and the secondary vaccinations and booster shots) to mitigate transmission of COVID-19. Taking this into account, we include compartments for multiple vaccinations and mutant viruses of COVID-19 in the model. In particular, our model considers breakthrough infection according to the antibody formation rate following multiple vaccinations. We obtain the effective reproduction numbers of the original virus, the Delta, and the Omicron variants by fitting this model to data in Korea. Additionally, we provide various simulations adjusting the daily vaccination rate and the timing of vaccination to investigate the effects of these two vaccine-related measures on the number of infected individuals. We also show that starting vaccinations early is the key to reduce the number of infected individuals. Delaying the start date requires increasing substantially the rate of vaccination to achieve similar target results. In the sensitivity analysis on the vaccination rate of Korean data, it is shown that a 10% increase (decrease) in vaccination rates can reduce (increase) the number of confirmed cases by 35.22% (82.82%), respectively.


Monitoring of patients with head injuries.
A practical protocol for evaluating and monitoring head injured patients has been presented. It has been stressed that monitoring is an ongoing process which begins with the initial evaluation and continues throughout the patient's hospital stay. The level of monitoring and thus the parameters to be monitored are determined on an individualized basis according to the patient's clinical status and his level of stupor and coma. It has been suggested that for mild head injuries, adequate monitoring includes periodic evaluation of the neurological status and vital signs; but the more severely injured patients require extensive and frequent monitoring of a large number of clinical and physiological parameters. Among the many parameters, the continuous monitoring of ICP and the respiratory system are perhaps the most useful indicators of the patient's condition. Several methods for continuous ICP monitoring which are readily adaptable to most neurosurgical practices have been discussed. These include the intraventricular catheter, subarachnoid screw, and the closed Rickham reservoir connected to a ventricular catheter. In our institution, the Rickham reservoir has been used to monitor ICP and at the time of this report, satisfactory ICP recordings have been obtained in 27 of 30 head injury patients. Although this method requires a small surgical procedure, we believe that the decreased incidence of infection, the rapid access to ventricular fluid, and its potential for long term monitoring justify its use. Suggestions for monitoring other physiological parameters have also been presented. Particular emphasis has been placed on the management of infants and children with head injuries. The clinical entity of chronic subdural hematoma in infants and children has been used to illustrate the value of ICP monitoring as a guide to further treatment. Finally, we have briefly discussed the place of computers in day to day patient care, research, and monitoring.


The eradication of a large scabies outbreak using community-wide health education.
The successful experience in eradicating a large outbreak of scabies in an underdeveloped Arabic village community in Western Galilee of about 3,000 people is reviewed. In this village the number of cases of scabies increased over a five-year period to a maximum of 22 per cent of the entire village population, representing 66 per cent of all the families. A seven-person health team with a strong background in health education was entrusted with the task of eradicating scabies in the community. A plan, conceived and carried out by the team, consisted of four phases: data gathering, information giving, treatment, and evaluation and summary. The goal of eradicating scabies in this community was achieved. The strategy of the campaign emphasized the following points: the entire community was the target group and was involved maximally throughout the campaign; the professional responsibility was concentrated in the hands of the team.


Genipin crosslinked chitosan/PEO nanofibrous scaffolds exhibiting an improved microenvironment for the regeneration of articular cartilage.
Towards optimizing the growth of extracellular matrix to produce repair cartilage for healing articular cartilage (AC) defects in joints, scaffold-based tissue engineering approaches have recently become a focus of clinical research. Scaffold-based approaches by electrospinning aim to support the differentiation of chondrocytes by providing an ultrastructure similar to the fibrillar meshwork in native cartilage. In a first step, we demonstrate how the blending of chitosan with poly(ethylene oxide) (PEO) allows concentrated chitosan solution to become electrospinnable. The chitosan-based scaffolds share the chemical structure and characteristics of glycosaminoglycans, which are important structural components of the cartilage extracellular matrix. Electrospinning produced nanofibrils of ∼100 nm thickness that are closely mimicking the size of collagen fibrils in human AC. The polymer scaffolds were stabilized in physiological conditions and their stiffness was tuned by introducing the biocompatible natural crosslinker genipin. We produced scaffolds that were crosslinked with 1.0% genipin to obtain values of stiffness that were in between the stiffness of the superficial zone human AC of 600 ± 150 kPa and deep zone AC of 1854 ± 483 kPa, whereas the stiffness of 1.5% genipin crosslinked scaffold was similar to the stiffness of deep zone AC. The scaffolds were degradable, which was indicated by changes in the fibril structure and a decrease in the scaffold stiffness after seven months. Histological and immunohistochemical analysis after three weeks of culture with human articular chondrocytes (HACs) showed a cell viability of over 90% on the scaffolds and new extracellular matrix deposited on the scaffolds.


Acute nutmeg poisoning.
We present a case of acute nutmeg poisoning in a 16-year-old youth who had ingested the substance for recreational purposes. He developed a number of neurological symptoms and signs along with non-specific electrocardiographic changes and anti-cholinergic-type symptoms. We describe the pharmacology of nutmeg and its constituents, discuss its metabolism, and make recommendations about the management of nutmeg poisoning. Emergency staff should be aware of the effects of nutmeg, which may present in marijuana users who seek alternative substances.


RNase H2 degrades toxic RNA:DNA hybrids behind stalled forks to promote replication restart.
R-loops represent a major source of replication stress, but the mechanism by which these structures impede fork progression remains unclear. To address this question, we monitored fork progression, arrest, and restart in Saccharomyces cerevisiae cells lacking RNase H1 and H2, two enzymes responsible for degrading RNA:DNA hybrids. We found that while RNase H-deficient cells could replicate their chromosomes normally under unchallenged growth conditions, their replication was impaired when exposed to hydroxyurea (HU) or methyl methanesulfonate (MMS). Treated cells exhibited increased levels of RNA:DNA hybrids at stalled forks and were unable to generate RPA-coated single-stranded (ssDNA), an important postreplicative intermediate in resuming replication. Similar impairments in nascent DNA resection and ssDNA formation at HU-arrested forks were observed in human cells lacking RNase H2. However, fork resection was fully restored by addition of triptolide, an inhibitor of transcription that induces RNA polymerase degradation. Taken together, these data indicate that RNA:DNA hybrids not only act as barriers to replication forks, but also interfere with postreplicative fork repair mechanisms if not promptly degraded by RNase H.


Roles of stiffness and excluded volume in DNA denaturation.
The nature and the universal properties of DNA thermal denaturation are investigated by Monte Carlo simulations. For suitable lattice models we determine the exponent c describing the decay of the probability distribution of denaturated loops of length l, P approximately l(-c). If excluded volume effects are fully taken into account, c = 2.10(4) is consistent with a first order transition. The stiffness of the double stranded chain has the effect of sharpening the transition, if it is continuous, but not of changing its order and the value of the exponent c, which is also robust with respect to inclusion of specific base-pair sequence heterogeneities.


Cell-size maintenance: universal strategy revealed.
How cells maintain a stable size has fascinated scientists since the beginning of modern biology, but has remained largely mysterious. Recently, however, the ability to analyze single bacteria in real time has provided new, important quantitative insights into this long-standing question in cell biology.


Acute heart failure: a novel approach to its pathogenesis and treatment.
Acute heart failure (HF) is one of the most common syndromes in emergency medicine, however, its exact pathogenesis has remained largely unknown. Based on clinical and hemodynamic data we have sub-divided acute HF into four syndromes: cardiogenic shock, pulmonary edema, hypertensive crisis and exacerbated HF. Cardiogenic shock is caused by a severe reduction in cardiac power which is not met by an adequate increase in peripheral vascular resistance leading to significant decrease in blood pressure and end organ perfusion. Hence the treatment of cardiogenic shock should be directed at improving cardiac performance (by optimizing filling pressure, intra-aortic balloon pump and immediate revascularization) and administration of peripheral vasoconstrictors. The other acute HF syndromes (pulmonary edema, HTN crisis and exacerbated HF) are caused by a combination of progressive excessive vasoconstriction superimposed on reduced left ventricular functional reserve. The impaired cardiac power and extreme vasoconstriction induce a vicious cycle of afterload mismatch resulting in a dramatic reduction of CO and elevated left ventricular end diastolic pressure, which is transferred backwards to the pulmonary capillaries yielding pulmonary edema. Therefore, the immediate treatment of these acute HF syndromes should be based on the administration of strong, fast-acting intravenous vasodilators such as nitrates or nitroprusside. After initial stabilization, therapy should be directed at reducing recurrent episodes of acute HF, by prevention of repeated episodes of excessive vasoconstriction along with efforts to optimize cardiac function.


Anatomical study of the ankle with view to the anterior arthroscopic portals.
This article evaluates the risk of interference with the neurovascular structures in the four anterior ankle arthroscopic portals, described on each side of the extensor tendons: anteromedial, medial midline, anterocentral and anterolateral. Complications after ankle arthroscopies have been described in up to 17%, most being neurovascular. To quantify the neurovascular risks we dissected 68 cadaveric feet and evaluated the correlations between tendons, vessels and nerves. The mean distance between tibialis anterior and extensor hallucis longus and between extensor hallucis longus and extensor digitorum longus is 4 mm, but in 10-20% these tendons are in apposition or are overlapped. The tibialis anterior vascular bundle was absent in 11.8%, was located between the tibialis anterior and the extensor hallucis longus in 3% and between the extensor hallucis longus and the extensor digitorum longus in 64.7%. A peroneal vascular bundle or branches of the tibialis anterior vascular bundle were located lateral to the extensor digitorum longus/peroneus tertius tendon in 88.2%. Transverse vascular branches were identified in 41.2% over the medial side of the joint line and in 52.9% over the lateral side. The deep peroneal nerve was located between the extensor hallucis longus and the extensor digitorum longus tendons in 58.8%. The superficial peroneal nerve had branches located between the tibialis anterior and the extensor hallucis longus tendons in 2.9%, between the extensor hallucis longus and the extensor digitorum longus tendons in 23.5% and lateral to the extensor digitorum longus/peroneus tertius tendon in 32.4%. These results show that the anteromedial and medial midline portals are the safest. The anterolateral portal should be noted not only for the risks to the superficial peroneal nerve, but also to the peroneal vessels.


[Effect of erythromycin on apoptosis of epithelial cell in nasal polyps].
To study the effect of erythromycin on apoptosis and expression of Bax and Bcl-2 of epithelial cell in nasal polyps. Epithelial cells from thirty nasal polyps and fifteen inferior turbinates were cultured in Dulbecco Eagle and Ham F12 (1:1) and divided into two groups (one group were treated with Erythromycin). Apoptosis was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling and expression of Bcl-2 and Bax detected by immunohistochemistry at 1, 3, 5 days after culture. The apoptosis indexes (AI) of epithelial cell in nasal polyps after cultured for 1, 3, 5 days with erythromycin were (33.23 +/- 6.50)%, (38.21 +/- 7.22)% and (52.63 +/- 7.86)% respectively. The AI of epithelial cell in inferior turbinates were (31.02 +/- 5.60)%, (32.13 +/- 7.15)% and (39.64 +/- 7.48)% respectively. There was significant difference between two groups at 5 day after culture (P < 0.05). Expression of Bax and Bcl-2 of epithelial cell was significantly higher in nasal polyps than that in inferior turbinates (P < 0.01). Expression of Bax of epithelial cell cultured with erythromycin was significantly higher than that in the controls (P < 0.05). Apoptosis was clearly promoted after 5 day culture with Erythromycin (P < 0.05). Erythromycin promoted expression of Bax and apoptosis of epithelial cell in nasal polyps.


Comprehensive Survey of Domiciliary Triatomine Species Capable of Transmitting Chagas Disease in Southern Ecuador.
Chagas disease is endemic to the southern Andean region of Ecuador, an area with one of the highest poverty rates in the country. However, few studies have looked into the epidemiology, vectors and transmission risks in this region. In this study we describe the triatomine household infestation in Loja province, determine the rate of Trypanosoma cruzi infection in triatomines and study the risk factors associated with infestation. An entomological survey found four triatomine species (Rhodnius ecuadoriensis, Triatoma carrioni, Panstrongylus chinai, and P. rufotuberculatus) infesting domiciles in 68% of the 92 rural communities examined. Nine percent of domiciles were infested, and nymphs were observed in 80% of the infested domiciles. Triatomines were found in all ecological regions below 2,200 masl. We found R. ecuadoriensis (275 to 1948 masl) and T. carrioni (831 to 2242 masl) mostly in bedrooms within the domicile, and they were abundant in chicken coops near the domicile. Established colonies of P. chinai (175 to 2003 masl) and P. rufotuberculatus (404 to 1613 masl) also were found in the domicile. Triatomine infestation was associated with surrogate poverty indicators, such as poor sanitary infrastructure (lack of latrine/toilet [w = 0.95], sewage to environment [w = 1.0]). Vegetation type was a determinant of infestation [w = 1.0] and vector control program insecticide spraying was a protective factor [w = 1.0]. Of the 754 triatomines analyzed, 11% were infected with Trypanosoma cruzi and 2% were infected with T. rangeli. To date, only limited vector control efforts have been implemented. Together with recent reports of widespread sylvatic triatomine infestation and frequent post-intervention reinfestation, these results show that an estimated 100,000 people living in rural areas of southern Ecuador are at high risk for T. cruzi infection. Therefore, there is a need for a systematic, sustained, and monitored vector control intervention that is coupled with improvement of socio-economic conditions.


Life cycles and host-parasite relationships of Microsporidia in culicine mosquitoes.
Heterosporous (polymorphic) microsporidia in mosquitoes are characterized by intricate life cycles involving multiple spore types responsible for horizontal (per os) and vertical (transovarial) transmission. They affect two generations of the mosquito and some involve an obligate intermediate host. Heterosporous microsporidia are generally very host and tissue specific with complex developmental sequences comprised of unique stages and events. Full details on the intricate relationships between heterosporous microsporidia and their mosquito hosts have only recently been elucidated. Edhazardia aedis (Kudo, 1930) and Culicospora magna (Kudo, 1920) have developmental sequences in larvae that involve gametogony followed by plasmogamy and nuclear association to form diplokarya. These diplokaryotic stages then undergo karyogamy and form binucleate spores responsible for transovarial transmission. In the filial generation, haplosis occurs as a result of nuclear dissociation to produce uninucleate spores infectious to larval mosquitoes. Amblyospora californica (Kellen et Lipa, 1960) has similar sequences except that haplosis is by meiosis to produce spores infectious for a copepod intermediate host. A third spore type is formed in the intermediate host responsible for infection in a new generation of the mosquito host.


Non-current diagnostic software in Hamilton Medical's Hamilton-C2 ventilators may, in rare cases, cause the ventilator to stop delivering breaths.
While investigating a problem report involving a Hamilton Medical Hamilton-C2 ventilator, ECRI Institute learned that the diagnostic component of software versions prior to 2.0.7 could, in rare cases, cause the ventilator to enter a fail-safe condition and terminate the delivery of breaths to the patient even though the unit may be capable of safely continuing ventilation. Hamilton has incorporated changes in the software (beginning with version 2.0.7) to reduce the possibility of this behavior occurring. Facilities using Hamilton-C2 ventilators equipped with software version 2.0.6 or earlier should contact their local Hamilton Medical representative to arrange for their units to be updated to the current software version.


ESCRT-I mediates FLS2 endosomal sorting and plant immunity.
The plant immune receptor FLAGELLIN SENSING 2 (FLS2) is present at the plasma membrane and is internalized following activation of its ligand flagellin (flg22). We show that ENDOSOMAL SORTING COMPLEX REQUIRED FOR TRANSPORT (ESCRT)-I subunits play roles in FLS2 endocytosis in Arabidopsis. VPS37-1 co-localizes with FLS2 at endosomes and immunoprecipitates with the receptor upon flg22 elicitation. Vps37-1 mutants are reduced in flg22-induced FLS2 endosomes but not in endosomes labeled by Rab5 GTPases suggesting a defect in FLS2 trafficking rather than formation of endosomes. FLS2 localizes to the lumen of multivesicular bodies, but this is altered in vps37-1 mutants indicating compromised endosomal sorting of FLS2 by ESCRT-I loss-of-function. VPS37-1 and VPS28-2 are critical for immunity against bacterial infection through a role in stomatal closure. Our findings identify that VPS37-1, and likewise VPS28-2, regulate late FLS2 endosomal sorting and reveals that ESCRT-I is critical for flg22-activated stomatal defenses involved in plant immunity.


Effect of school water fluoridation on dental caries: results in Seagrove, NC, after eight years.
In 1968 at Seagrove, NC, fluoride was added to the water supply of a rural school (grades 1 through 12) at a level of 6.3 ppm, seven times the optimum level recommended for community water fluoridation in the area. Findings after eight years showed that children in grades 1 through 8 had approximately 40% fewer DMF surfaces than did their counterparts on the baseline. A comparison of these findings with those of another school fluoridation study, in which a level of 4.5 times the optimum concentration had been tested, showed only a slight advantage to the children at Seagrove. However, the full potential of school water fluoridation at seven times the optimum level cannot be determined until children in all grades will have been exposed since entering the first grade.


Aripiprazole Facilitates Extinction of Conditioned Fear in Adolescent Rats.
Anxiety disorders are the most common type of mental disorder during adolescence, which is at least partly due to the resistance to extinction exhibited at this age. The dopaminergic system is known to be dysregulated during adolescence; therefore, we aimed to facilitate extinction in adolescent rats using the dopamine receptor 2 partial agonist aripiprazole (Abilify™), and examine the behavioral and neural outcomes. Adolescent rats were conditioned to fear a tone. The next day, rats received extinction 30 min after a systemic injection of either 5 mg/kg aripiprazole or vehicle, and then were tested the following day. For the immunohistochemistry experiment, naïve and "no extinction" conditions were added and rats were perfused either on the extinction day or test day. To assess the activation of neurons receiving dopaminergic input, c-Fos, and dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) labeled neurons were quantified in the amygdala and the medial prefrontal cortex (mPFC). Systemic treatment with aripiprazole at the time of extinction significantly reduced freezing at test the next day. This effect was not observed in rats that were fear conditioned but did not receive any extinction. Aripiprazole's facilitation of extinction was accompanied by increased activation of neurons in the mPFC. Taken together, aripiprazole represents a novel pharmacological adjunct to exposure therapy worthy of further examination. The effect of aripiprazole is related to enhanced activation of mPFC neurons receiving dopaminergic innervation.


The LOSS OF APOMEIOSIS (LOA) locus in Hieracium praealtum can function independently of the associated large-scale repetitive chromosomal structure.
Apomixis or asexual seed formation in Hieracium praealtum (Asteraceae) is controlled by two independent dominant loci. One of these, the LOSS OF APOMEIOSIS (LOA) locus, controls apomixis initiation, mitotic embryo sac formation (apospory) and suppression of the sexual pathway. The LOA locus is found near the end of a hemizygous chromosome surrounded by extensive repeats extending along the chromosome arm. Similar apomixis-carrying chromosome structures have been found in some apomictic grasses, suggesting that the extensive repetitive sequences may be functionally relevant to apomixis. Fluorescence in situ hybridization (FISH) was used to examine chromosomes of apomeiosis deletion mutants and rare recombinants in the critical LOA region arising from a cross between sexual Hieracium pilosella and apomictic H. praealtum. The combined analyses of aposporous and nonaposporous recombinant progeny and chromosomal karyotypes were used to determine that the functional LOA locus can be genetically separated from the very extensive repeat regions found on the LOA-carrying chromosome. The large-scale repetitive sequences associated with the LOA locus in H. praealtum are not essential for apospory or suppression of sexual megasporogenesis (female meiosis).


Localization of QTLs for seed color using recombinant inbred lines of Brassica napus in different environments.
Yellow seed is one of the most important traits of Brassica napus L. Efficient selection of the yellow-seed trait is one of the most important objectives in oilseed rape breeding. Two recombinant inbred line (RIL) populations (RIL-1 and RIL-2) were analyzed for 2 years at 2 locations. Four hundred and twenty SSR, RAPD, and SRAP marker loci covering 1744 cM were mapped in 26 linkage groups of RIL-1, while 265 loci covering 1135 cM were mapped in 20 linkage groups of RIL-2. A total of 19 QTLs were detected in the 2 populations. A major QTL was detected adjacent to the same marker (EM11ME20/200) in both maps in both years. This major QTL could explain 53.71%, 39.34%, 42.42%, 30.18%, 24.86%, and 15.08% of phenotypic variation in 6 combinations (location x year x population). BLASTn analysis of the sequences of the markers flanking the major QTL revealed that the homologous region corresponding to this major QTL was anchored between genes At5g44440 and At5g49640 of Arabidopsis thaliana chromosome 5 (At C5). Based on comparative genomic analysis, the bifunctional gene TT10 is nearest to the homologue of EM11ME20/200 on At C5 and can be considered an important candidate gene for the major QTL identified here. Besides providing an effective strategy for marker-assisted selection of the yellow-seed trait in B. napus, our results also provide important clues for cloning of the candidate gene corresponding to this major QTL.


[Using MSR model to analyze the impact of gene-gene interaction with related to the genetic polymorphism of metabolism enzymes on the risk of breast cancer].
To identify the interactions of susceptive genes with related to the genetic polymorphism of metabolism enzymes (CYP1A1, GSTT1 and GSTM1) and their impacts on the risk of breast cancer; and to test the feasibility of using Multifactor Dimensionality Reduction (MDR) model in analyzing gene-gene interactions. A paired case-control study, matched by age and menstruate state, was conducted. From December 2003 to September 2004, 78 pairs of people with and without breast cancers were investigated. The variant genotypes of CYP1A1 Msp I and GSTT1/M1 were identified by PCR-RFLP and multiplex PCR assays. The gene-gene interactions were analyzed with the MDR model. Based on the result of the MDR model, a conditional logistic regression model was constructed as the final cause-effect interpretative model. The interaction between CYP1A1 Msp I variant genotype (vv) and GSTT1 null genotype gave the best MDR model with statistical significance (Sign Test, P = 0.05). The model Testing Balance Accuracy was 0. 5920. The Cross-Validation consistency was 10/10. The final conditional logistic regression based on the MDR model showed that passive smoking, abortion and gene-gene interaction were risks of breast cancers, with an OR (95% confidence interval) of 12.234 (1.7459-85.7279), 4.554 (1.3250-15.6507) and 9.597 (1.5783-58.3599), respectively. The MDR model may be an effective method for estimating risks of breast cancers due to gene-gene and gene-environment interactions. The gene-gene interaction with related to the genetic polymorphism of metabolism enzymes (CYP1A1 and GSTT1) may increase the risk of breast cancer by disturbing the metabolism of estrogen.


"I do not care for a lunatic's role": modes of regulation and resistance inside the Colquitz Mental Home, British Columbia, 1919-33.
This article chronicles the experiences of 100 male patients who were confined at the Provincial Mental Home, Colquitz, Vancouver Island between 1919 and 1933. Through an analysis of clinical records and other sources,I reconstruct the organizational and human environment that prevailed at Colquitz during the tenure of its first lay supervisor, Granby Farrant; I chart the diverse modes of discipline through which officials sought to maintain the institutional regimen; and I document the efforts undertaken by patients to resist authority, transcend their surroundings, and seek redemption and hope both inside and beyond the Colquitz wall.


Regional variations in semen quality of community-dwelling young men from Flanders are not paralleled by hormonal indices of testicular function.
Epidemiological studies of sperm quality are hampered by problems such as low participation rates and poor comparability of results due to methodological differences in semen analysis. More objective sperm quality-related serum markers would facilitate worldwide comparisons of male reproductive status. Our objectives were to investigate to what extent a set of hormonal indices of testicular function, previously established in a clinical setting, could predict regional variations in seminal parameters in men from the general population. We recruited 101 men aged 20-40 years from two regions in Flanders, and assessed their sperm parameters and levels of serum reproductive hormones. In one region compared to another, the participants had lower sperm counts (by 34%; P=.06), lower total sperm counts (by 41%; P=.02) and poorer sperm morphology (by 32%; P<.001), which were paralleled by significantly lower levels of free testosterone (by 11%; P=.03), while for total testosterone (T) and follicle-stimulating hormone (FSH), the differences were not significant (both P=.09) at 10% and 17%, respectively. There were no differences in inhibin B and the T to luteinizing hormone (LH) ratio, which are markers of testicular function. Receiver operating characteristic curve analysis revealed that T:LH, inhibin B, and the inhibin B/FSH ratio had significant discriminatory power between men with sperm concentrations below or above 13.5x10(6)/mL. Regional variations in the semen quality of community-dwelling individuals are not necessarily reflected in altered hormonal indices of testicular function and thus, these markers, validated in clinical settings, are not valid substitutes for the traditional semen quality assessment used in epidemiological population studies.


[The menopausal hormone therapy in 2016].
The menopausal hormone therapy (MHT) is the first line treatment for climacteric symptoms related to estrogen deficiency. A personalized evaluation of the benefit-risk ratio should precede a MHT prescription, and take into consideration cardiovascular, thromboembolic, oncological and osteoporosis risks. MHT should be prescribed at the lowest effective dose and for the shortest duration, respecting the window of opportunity in the 10 years following menopause or before the age of 60 years. The choice of the MHT type depends on the patient's profile, her medical history and personal preferences, with the aim of improving quality of life from a physical, psychological and sexual point of view.


Surface-decorated nanoliposomal leonurine targets activated fibroblast-like synoviocytes for efficient rheumatoid arthritis therapy.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes progressive joint destruction, leading to impaired life quality, disability, and even premature mortality. However, current medications suffer from limited clinical outcomes and severe side effects due to low bioavailability and non-specific distribution after administration. Herein, a targeting nanosystem (HAP-Lipo@Leo) was constructed for efficient RA treatment, which can precisely deliver a natural anti-arthritic drug leonurine (Leo) to the inflamed joint by HAP-1 peptide-mediated recognition of activated fibroblast-like synoviocytes (FLS). More specifically, HAP-Lipo@Leo was prepared by a combination of thin film hydration and high-pressure microfluidization and surface-decorated with HAP-1 peptide and PEG before encapsulating Leo by the ammonium sulfate gradient method. The as-obtained HAP-Lipo@Leo can be selectively internalized by activated FLS and impairs the lamellipodia formation and overexpression of inflammatory cytokines, both of which play detrimental roles in joint damage. Furthermore, HAP-Lipo@Leo demonstrated arthritic joint-specific distribution, significant inhibition of synovial inflammation, and reversal of cartilage and bone destruction in adjuvant-induced arthritis rats as evidenced by comprehensive investigations including ELISA tests, histopathology examinations, and micro-CT analysis. In addition, HAP-Lipo@Leo exhibited good biocompatibility and safety both in vitro and in vivo. Taken together, HAP-Lipo@Leo holds great potential for clinical RA management by integrating activated FLS targeting, long circulation, multifaceted therapeutic effects, and excellent biocompatibility.


Chemomodulatory influence of Ferula asafoetida on mammary epithelial differentiation, hepatic drug metabolizing enzymes, antioxidant profiles and N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats.
The present study was conducted to ascertain the modulatory influences of Ferula asafoetida L. (asafoetida, flavoring agent) on the mammary epithelial tissue differentiation, hepatic drug metabolizing enzymes, antioxidant profiles and N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis in Sprague-Dawley rats. Feeding with two doses of asafoetida (1.25 and 2.5% w/w in diet) showed a remarkable increase in the development and differentiation of ducts/ductules (p < 0.01-0.005), lobules (p < 0.005) and a decrease in terminal end buds (p < 0.05-0.005) as compared to both normal and MNU-treated control animals. To assess the biochemical parameters, effect of asafoetida on drug-metabolizing enzymes was evaluated in the liver of rats. Asafoetida treatment significantly reduced (p < 0.05) the levels of cytochrome P450 and b5. There was an enhancement in the activities of glutathione S-transferase (p < 0.05-0.005), DT-diaphorase (p < 0.05-0.01), superoxide dismutase (p < 0.01-0.005) and catalase (p < 0.05-0.005) and in the level of reduced glutathione (p < 0.05-0.005), followed by asafoetida treatment. Also, asafoetida significantly restored the level of antioxidant system, depleted by MNU-treatment. The strengthening of antioxidant system by the lower and higher doses of asafoetida in the presence and absence of MNU was further substantiated by a significant inhibition (p < 0.005) in lipid peroxidation as measured by thiobarbituric acid-reactive substances (TBARS) in the liver of rat. Further, in long-term animal studies, where MNU was used to induce mammary carcinogenesis, asafoetida treatment resulted in a significant reduction in the multiplicity (p < 0.001) and size of palpable mammary tumors (p < 0.005-0.001) and a delay in mean latency period of tumor appearance (p < 0.005). Together, these findings indicate the chemopreventive potential of asafoetida against MNU-induced mammary carcinogenesis. Thus, asafoetida needs further investigation with regard to identification and characterization of its active principle(s) and mechanism of action, for this compound to be developed as a potential chemopreventive agent for human cancers.


Characterization of a glucoamylase G2 from Aspergillus niger.
Peptide fragments were generated by enzymic or chemical degradation of the small form, G2, and the large form, G1, of Aspergillus niger glucoamylase (EC 184.108.40.206). The G2 form was either identical to residues Ala1-Pro512 or to Ala1-Ala514 of the G1 polypeptide chain containing 616 amino acid residues. Structural analysis of the O-linked carbohydrates from the 70-amino-acid-residues long extensively glycosylated segment of G2 revealed no significant differences in the contents of single mannose and oligosaccharide units in comparison to the corresponding region of G1. The results suggest that the present G2 form has been generated by limited proteolysis of the larger G1. In contradistinction to this, a recently reported splicing out of an intervening sequence from G1 mRNA leads to a smaller mRNA coding for a G2 protein product with a different COOH-terminal sequence than the G2 form described in the present work [Boel et al. (1984) EMBO J. 3, 1097-1102].


[Heavy metals accumulation in river sediments of Chongming Island, Shanghai City, and its environmental risk].
Heavy metals accumulation in river sediments can reflect the environmental quality of river waters. It's of practical significance to study the accumulation level of heavy metals in river sediments and its environmental risk. In this paper, the heavy metals accumulation in river sediments of three typical towns of Chongming Island was studied, and the results showed that the average accumulation of Zn, Cr, Cu, Pb and Cd in Chengqiao Town, Baozhen Town and Chenjia Town was 103.1, 79.2, 39.0, 29.7 and 0.300 mg x kg(-1), 99.0, 104.0, 50.5, 32.7 and 0.308 mg x kg(-1), and 86.7, 79.5, 32.2, 30.5 and 0.274 mg x kg(-1), respectively. In South Chongming, the average accumulation of Zn, Cr, Cu, Pb and Cd was 94.72, 81.35, 38.52, 30.78 and 0.297 mg x kg(-1), respectively. The environmental risk assessment by using geoaccumulation index (I(geo)) indicated that these three towns had a low-medium rank environmental risk of heavy metals accumulation in river sediments, and the probability of achieving medium rank risk was in the order of Chengqiao > Baozhen > Chenjia.


Frodo proteins: modulators of Wnt signaling in vertebrate development.
The Frodo/dapper (Frd) proteins are recently discovered signaling adaptors, which functionally and physically interact with Wnt and Nodal signaling pathways during vertebrate development. The Frd1 and Frd2 genes are expressed in dynamic patterns in early embryos, frequently in cells undergoing epithelial-mesenchymal transition. The Frd proteins function in multiple developmental processes, including mesoderm and neural tissue specification, early morphogenetic cell movements, and organogenesis. Loss-of-function studies using morpholino antisense oligonucleotides demonstrate that the Frd proteins regulate Wnt signal transduction in a context-dependent manner and may be involved in Nodal signaling. The identification of Frd-associated factors and cellular targets of the Frd proteins should shed light on the molecular mechanisms underlying Frd functions in embryonic development and in cancer.


Selection of Phage Display Peptides Targeting Human Pluripotent Stem Cell-Derived Progenitor Cell Lines.
The ability of human pluripotent stem cells (hPS) to both self-renew and differentiate into virtually any cell type makes them a promising source of cells for cell-based regenerative therapies. However, stem cell identity, purity, and scalability remain formidable challenges that need to be overcome for translation of pluripotent stem cell research into clinical applications. Directed differentiation from hPS cells is inefficient and residual contamination with pluripotent cells that have the potential to form tumors remains problematic. The derivation of scalable (self-renewing) embryonic progenitor stem cell lines offers a solution because they are well defined and clonally pure. Clonally pure progenitor stem cell lines also provide a means for identifying cell surface targeting reagents that are useful for identification, tracking, and repeated derivation of the corresponding progenitor stem cell types from additional hPS cell sources. Such stem cell targeting reagents can then be applied to the manufacture of genetically diverse banks of human embryonic progenitor cell lines for drug screening, disease modeling, and cell therapy. Here we present methods to identify human embryonic progenitor stem cell targeting peptides by selection of phage display libraries on clonal embryonic progenitor cell lines and demonstrate their use for targeting quantum dots (Qdots) for stem cell labeling.


Adjuvant chemotherapy in rectal cancer: defining subgroups who may benefit after neoadjuvant chemoradiation and resection: a pooled analysis of 3,313 patients.
Recent literature suggests that the benefit of adjuvant chemotherapy (aCT) for rectal cancer patients might depend on the response to neoadjuvant chemoradiation (CRT). Aim was to evaluate whether the effect of aCT in rectal cancer is modified by response to CRT and to identify which patients benefit from aCT after CRT, by means of a pooled analysis of individual patient data from 13 datasets. Patients were categorized into three groups: pCR (ypT0N0), ypT1-2 tumour and ypT3-4 tumour. Hazard ratios (HR) for the effect of aCT were derived from multivariable Cox regression analyses. Primary outcome measure was recurrence-free survival (RFS). One thousand seven hundred and twenty three (1723) (52%) of 3,313 included patients received aCT. Eight hundred and ninety eight (898) patients had a pCR, 966 had a ypT1-2 tumour and 1,302 had a ypT3-4 tumour. For 122 patients response, category was missing and 25 patients had ypT0N+. Median follow-up for all patients was 51 (0-219) months. HR for RFS with 95% CI for patients treated with aCT were 1.25(0.68-2.29), 0.58(0.37-0.89) and 0.83(0.66-1.10) for patients with pCR, ypT1-2 and ypT3-4 tumours, respectively. The effect of aCT in rectal cancer patients treated with CRT differs between subgroups. Patients with a pCR after CRT may not benefit from aCT, whereas patients with residual tumour had superior outcomes when aCT was administered. The test for interaction did not reach statistical significance, but the results support further investigation of a more individualized approach to administer aCT after CRT and surgery based on pathologic staging.


Cerebellar Purkinje cell loss in aging Hu-Bcl-2 transgenic mice.
The number of cerebellar Purkinje cells is increased by over 40% in young transgenic mice that overexpress a human Bcl-2 transgene (Hu-Bcl-2). To determine whether the Bcl-2-mediated rescue of Purkinje cells persists through life, the numbers of Purkinje cells were estimated in 6-, 12-, 18-, and 24-month-old Hu-Bcl-2 transgenic mice and age-matched controls. In addition, the expression of four markers for Purkinje cell differentiation, calbindin (CaBP), the 67-kDa isoform of glutamic acid decarboxylase (GAD67), gamma-aminobutyric acid transaminase (GABA-T), and the NMDA-R1 receptor subtype (NMDA-NR1) was analyzed in 6-month-old Hu-Bcl-2 transgenics and controls to determine whether overexpression of Bcl-2 and rescue from naturally occurring cell death affects the normal differentiation of Purkinje cells. The estimates of Purkinje cell numbers showed that the number of Purkinje cells in the Hu-Bcl-2 transgenics declines after 6 months to approach wild-type values by 18 months. Although the exogenous human BCL-2 is still expressed in Purkinje cells at 24 months, the expression levels of human BCL-2 appear to decline significantly after 6 months, suggesting that survival of the supernumary Purkinje cells depends on the sustained overexpression of Bcl-2. All the Purkinje cells in the Hu-Bcl-2 transgenic mice appeared to express normal levels of the differentiation markers analyzed so there was no evidence for a class of Purkinje cells that do not differentiate normally when rescued from naturally occurring cell death.


Synthesis and biological evaluation of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamides as pyruvate dehydrogenase kinase 1 (PDK1) inhibitors to reduce the growth of cancer cells.
Most cancer cells exhibit a high rate of glycolysis and reduced capacity in mitochondrial oxidative phosphorylation. The expression of pyruvate dehydrogenase kinases (PDKs) was found to be increased in many cancer cells. Inhibition of PDKs increases the oxidative phosphorylation of glucose, which may disrupt the balance between the demand and supply of oxygen in cancer cell, thus leading to cell death. Several reports suggested that compounds containing (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide group could inhibit PDKs in pyruvate dehydrogenase primary enzymatic assay. However, none of them were capable of reducing the growth of cancer cells. Herein, we report the synthesis and biological evaluation of some novel PDK1 inhibitors containing the (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide warhead. Excitingly, these novel PDK1 inhibitors exhibited good potency to reduce the growth of cancer cells. We have demonstrated that these compounds could physically associate with PDK1 and activate pyruvate dehydrogenase in low micromolar levels.


Genome-Wide Identification and Functional Characterization of FAR1-RELATED SEQUENCE (FRS) Family Members in Potato (Solanum tuberosum).
FAR1-RELATED SEQUENCE (FRS) transcription factors are generated by transposases and play vital roles in plant growth and development, light signaling transduction, phytohormone response, and stress resistance. FRSs have been described in various plant species. However, FRS family members and their functions remain poorly understood in vegetative crops such as potato (Solanum tuberosum, St). In the present study, 20 putative StFRS proteins were identified in potato via genome-wide analysis. They were non-randomly localized to eight chromosomes and phylogenetic analysis classified them into six subgroups along with FRS proteins from Arabidopsis and tomato. Conserved protein motif, protein domain, and gene structure analyses supported the evolutionary relationships among the FRS proteins. Analysis of the cis-acting elements in the promoters and the expression profiles of StFRSs in various plant tissues and under different stress treatments revealed the spatiotemporal expression patterns and the potential roles of StFRSs in phytohormonal and stress responses. StFRSs were differentially expressed in the cultivar "Xisen 6", which is exposed to a variety of stresses. Hence, these genes may be critical in regulating abiotic stress. Elucidating the StFRS functions will lay theoretical and empirical foundations for the molecular breeding of potato varieties with high light use efficiency and stress resistance.


Assessment of Influential Variables in the Pricing of Locally Manufactured Pharmaceuticals: Current Challenging Situation in Iran.
The lack of transparency and predictability seems to remain one of the major complaints in the pharmaceutical pricing procedure in Iran, but there is not enough official evidence to support it. The main objective of this study was to identify influential variables officially or unofficially influencing the pharmaceuticals pricing in Iran and also clarifying the degree of importance of each variable from the viewpoints of two groups: the pricing Commission members (owners of pricing procedure) and other stakeholders in the pharmaceutical sector. Semi-structured interviews with experts were performed to extract the influential variables. A Likert scale questionnaire was designed based on extracted variables and used in above-mentioned two groups of experts. The validity and reliability of the questionnaire were assessed before use. About 68 influential variables were extracted which classified into eight categories or domains. Less than 50% of extracted influential variables on pharmaceutical pricing have been mentioned in Iran pricing regulations. There were statistically significant differences between the two group's viewpoints in terms of importance and effect of some variables on pricing procedure. Conflict of interest, lack of transparency and a sound framework were found as the main problems in Iran pharmaceutical pricing procedure and may lead to "case-by-case" decision making. As such, the output of the pricing commission is not transparent and predictable for its beneficiaries.


Fractional anisotropy of the fornix and hippocampal atrophy in Alzheimer's disease.
Decrease in the directionality of water diffusion measured with fractional anisotropy (FA) on diffusion tensor imaging has been linked to loss of myelin and axons in the white matter. Fornix FA is consistently decreased in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Furthermore, decreased fornix FA is one of the earliest MRI abnormalities observed in cognitively normal individuals who are at an increased risk for AD, such as in pre-symptomatic carriers of familial AD mutations and in pre-clinical AD. Reductions of FA at these early stages, which predicted the decline in memory function. Fornix carries the efferent projections from the CA1 and CA3 pyramidal neurons of the hippocampus and subiculum, connecting these structures to the septal nuclei, anterior thalamic nucleus, mammillary bodies, and medial hypothalamus. Fornix also carries the afferent cholinergic and GABAergic projections from the medial septal nuclei and the adjacent diagonal band back to the medial temporal lobe, interconnecting the core limbic structures. Because fornix carries the axons projecting from the hippocampus, integrity of the fornix is in-part linked to the integrity of the hippocampus. In keeping with that, fornix FA is reduced in subjects with hippocampal atrophy, correlating with memory function. The literature on FA reductions in the fornix in the clinical spectrum of AD from pre-symptomatic carriers of familial AD mutations to pre-clinical AD, MCI, and dementia stages is reviewed.