p-Coumarate:CoA ligase as a key gene in the yield of catechins in tea [Camellia sinensis (L.) O. Kuntze].
Tea is an important crop known for its beverage and antioxidant polyphenols -- catechins and its derivatives. Catechins are synthesized through flavonoid (FL) pathway and stored in the vacuole. A metabolic flux for the operation of FL pathway is maintained through the supply of 4-coumaroyl-CoA of phenylpropanoid pathway. 4-Coumaroyl-CoA is synthesized through the catalytic activity of p-coumarate:CoA ligase (4CL) using 4-coumaric acid and acetyl-CoA as the substrates. The present manuscript reports the full-length cDNA cloning of 4CL from tea (Cs4CL accession number DQ194356) and its association with catechin yield. Cs4CL comprised of 2,165 bp with an open reading frame (ORF) of 1,764 nt, starting from 118 to 1,882 encoding 588 amino acids. Altering catechin content through a variety of environmental conditions such as drought stress (DS), abscisic acid (ABA) and gibberellic acid (GA(3)) treatments, and wounding established a strong positive correlation coefficient between catechins content and the expression of Cs4Cl. In addition, tea clones with high levels of catechins had higher expression of Cs4Cl whereas tea clones with lower catechins exhibited lower expression of this gene. Exposure of tea shoots to 50-100 microM catechins led to down-regulation of the expression of Cs4CL suggesting product-mediated feedback regulation and an important role for the phenylpropanoid pathway in determining catechin yield in tea.


Magnetic investigations of human mesencephalic neuromelanin.
Pigmentation of neurons in substantia nigra is due to neuromelanin, a pigment that stores large amounts of iron. Human mesencephalic neuromelanin has been investigated by means of magnetic susceptibility measurements as a function of temperature. Magnetic measurements provide a physico-chemical characterization of the iron cluster buried in the organic melanin matrix and support the view that iron is not simply chelated, but rather is organized in a three-dimensional network. The paramagnetism of isolated iron ions is observed, in agreement with electron paramagnetic resonance spectroscopy. Furthermore, antiferromagnetic grains with a large size distribution function are present. These grains contain N spins coupled antiferromagnetically; however, N(1/2) spins are decoupled from the grain bulk and parallelly aligned. The latter subgrains are superparamagnetic with a blocking temperature ranging between 5 K and room temperature. This behavior has not been observed in synthetic melanin, where the paramagnetic contribution is strongly enhanced. Preliminary results on pigment isolated from patients affected by Parkinson's disease, a neurodegenerative pathology involving primarily pigmented neurons in substantia nigra pars compacta, show a lower total magnetization compared to control neuromelanin. The temperature behavior of zero field cooling and field cooling magnetizations is similar for both. The significant depletion of iron content in Parkinson's disease neuromelanin could indicate a progressive Fe migration from its storage environment to the cytosol.


Isolation, sequence analysis, and intron-exon arrangement of the gene encoding bovine rhodopsin.
We have isolated cDNA clones generated from the mRNA encoding the opsin apoprotein of bovine rhodopsin and used these cDNAs to isolate genomic DNA clones containing the complete opsin gene. Nucleotide sequence analysis of the cloned DNAs has yielded a complete amino acid sequence for bovine rhodopsin and provided an intron-exon map of its gene. The mRNA homologous sequences in the 6.4 kb gene consist of a 96 bp 5' untranslated region, a 1044 bp coding region, and a surprisingly long approximately 1400 bp 3' untranslated region, and are divided into five exons by four introns that interrupt the coding region. Secondary structure analysis predicts that the bovine rhodopsin chain, like that of bacteriorhodopsin, contains seven transmembrane segments. Interestingly, three of the four introns are immediately distal to the codons for three of these segments, and one of these introns marks the boundary between the C-terminal domain and a transmembrane domain.


Health management of horses under high challenge from trypanosomes: a case study from Serengeti, Tanzania.
Horses kept for recreational riding purposes by a wildlife tourism company in a heavily tsetse fly-infested region of north-western Tanzania were systematically monitored to investigate the occurrence, presentation and management of tsetse-transmitted trypanosomosis. During a 23-month period, 18 clinical cases were diagnosed (Trypanosoma brucei or Trypanosoma congolense were identified) and treated and trypanosomes were implicated of involvement in four deaths. Pyrexia consistently aided early detection (17 cases). Ataxia, weight loss and anaemia were seen in chronic cases and conferred a poor prognosis. Delaying treatment by more than 2 days from the onset of clinical signs led to prolonged disease course and more severe anaemia. Early detection, prompt treatment, thorough post-treatment health monitoring and rigorous prophylactic measures helped keep clinical cases to manageable levels, but re-infection remained a constant, insidious threat.


Validation of the 24-h perceived exertion recall survey in women in rural Tigray, Ethiopia.
Physical activity affects nutritional status and health. Currently, there are few validated survey tools for estimating physical activity in rural areas of low-income countries, including Ethiopia, which limits the ability of researchers to assess how physical activity affects nutritional status. This study used accelerometry to validate 2 in-person questionnaires, the global physical activity questionnaire (GPAQ) and the 24-h perceived exertion recall survey (PERS). This study recruited 180 women aged between 18 and 45 y living in rural Tigray, Ethiopia. Participants had previously participated in an impact evaluation of a public work safety net. They wore an accelerometer for 8 d and responded to perceived exertion questionnaires twice. Data were collected on 89 women during the short rainy period and 91 women during the main rainy season. A survey method was considered valid if the proportion of time spent in moderate or vigorous physical activity (MVPA) levels had a Pearson's correlation coefficient of >0.40 to the proportion of time spent in MVPA recorded by accelerometry. The GPAQ had high reliability, but the overall validity was poorer than accelerometry. The proportion of time spent in MVPA according to the accelerometer was associated with discordance between GPAQ and accelerometry. MVPA levels, as measured by the 24-h PERS, had a fair agreement with accelerometry. The agreement increased to moderate/acceptable when adjusted for season and BMI. The 24-h PERS is a valid tool for estimating the physical activity of women living in rural highland Ethiopia. It can be used in future research to understand the physical activity demands of living in rural highland Ethiopia, enabling more targeted programs to address undernutrition.


The Vanishing Coin Illusion: When sound congruence affects visual representation of motion.
In the "classic" vanishing ball illusion (VBI), a magician pretends to throw a ball and the audience sees it go up and then disappear. To gain a better understanding of the mechanisms involved, we conducted two experiments to analyze the permeability of this type of illusion to auditory information. A modified version of the VBI (i.e., the Vanishing Coin Illusion [VCI]), was presented, and this was either accompanied by a sound or was not. The results show that the presence of a sound adds to the success of the illusion (Experiment 1), especially when this sound is congruent with the illusion (Experiment 2). Based on these results, we discuss the mechanisms at work in this illusion.


Neuroradiology including magnetic resonance.
The radiological assessment of drug resistant temporal lobe epilepsy has changed dramatically over the last few years. New CT scan techniques and the increasing application of MRI have meant that ever more subtle lesions can now be regularly identified. The major challenge now lies in the accurate identification of atrophic lesions such as Ammon's horn sclerosis.


Association of dietary n - 3 polyunsaturated fatty acids with breast cancer risk: Serial mediating roles of erythrocyte n - 3 polyunsaturated fatty acids.
Dietary n - 3 polyunsaturated fatty acids (PUFAs) were found to be inversely associated with breast cancer risk; however, the underlying pathways between them remain uncertain. We aimed to explore serial mediatory roles of erythrocyte n - 3 PUFAs in association between dietary n - 3 PUFAs and breast cancer risk. Using a case-control study, 850 cases and 861 controls completed structured questionnaires with dietary information. Erythrocyte n - 3 PUFAs were measured by gas chromatography. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multiple unconditional logistic regression models to examine association between dietary n - 3 PUFAs and breast cancer risk. Mediation analyses with bootstrapping were conducted to investigate indirect effects. Higher intake of dietary ALA, long-chain n - 3 PUFAs and total n - 3 PUFAs was associated with lower risk of breast cancer. The adjusted OR tertile 3 v.1 (95% CI) was 0.70 (0.55, 0.90) for ALA, 0.76 (0.60, 0.97) for long-chain n - 3 PUFAs and 0.74 (0.58, 0.94) for total n - 3 PUFAs, respectively. Mediation analysis showed that erythrocyte long-chain n - 3 PUFAs served as sequential mediators in the relationship between dietary long-chain or total n - 3 PUFAs and breast cancer risk. In particular, erythrocyte long-chain n - 3 PUFAs completely mediated the association between dietary long-chain n - 3 PUFAs and breast cancer risk [indirect effect (95% CI) = -0.982 (-1.529, -0.508)]. The relationship between dietary total n - 3 PUFAs and breast cancer risk was partly mediated by erythrocyte long-chain n - 3 PUFAs [indirect effect (95% CI) = -0.107 (-0.216, -0.014)], accounting for 19.31%. However, the serial mediation model in dietary ALA and risk of breast cancer was not statistically significant [indirect effect (95% CI) = -0.042 (-0.144, 0.049)]. This study highlights the complexity and inaccuracy in using a simple analysis of individual dietary n - 3 PUFAs to examine their associations with breast cancer risk without considering the variety of metabolic processes. Interventions aimed at increasing erythrocyte long-chain n - 3 PUFAs may represent a promising strategy for breast cancer prevention.


Operation for hypertrophic subaortic stenosis in the aged.
To determine if operative palliation of idiopathic hypertrophic subaortic stenosis (IHSS) is worthwhile in the elderly, hemodynamic, cardiac conduction, symptomatological, functional, and survival data were examined in 52 patients (39 women) 65 years old and older (mean age, 69 years; range, 65 to 81 years) who had a left ventricular myotomy and myectomy (LVMM) (Morrow procedure) alone or with concomitant operations. Seventy-four percent of all operative survivors underwent catheterization an average of 6 months postoperatively. The mean follow-up was 54 months (range, 5 to 120 months). The population was divided for analyses into those with coronary artery disease (CAD) (N = 11,21%) and those without (N = 41). The peak resting left ventricular outflow tract gradient was reduced from 65 +/- 16 mm Hg to 3 +/- 1 mm Hg (p less than 0.01) in the group with CAD and from 95 +/- 13 mm Hg to 17 +/- 9 mm Hg (p less than 0.001) in the group without CAD. Significant reductions in peak gradients in response to provocation also occurred in both groups. New conduction abnormalities occurred in 72% of survivors, 85% of whom showed improvement in regard to symptoms. The overall average New York Heart Association Functional Class was 3.2 +/- 0.1 preoperatively and at latest follow-up, 1.9 +/- 0.1 (p less than 0.001). The hospital mortality for LVMM alone in the absence of CAD was 8% with a 5-year actuarial survival of 75 +/- 8%. LVMM in the presence of CAD resulted in an operative mortality of 27% (N = 3); all deaths were related to an acquired ventricular septal defect.(ABSTRACT TRUNCATED AT 250 WORDS)


A comparison of currently used serum lipase and amylase procedures in the serial detection of enzyme elevations in acute pancreatitis.
Twenty-eight patients having acute pancreatitis were followed during convalescence with serum amylase and lipase determinations. Starch and p-nitrophenyl-oligosaccharide substrates were used for amylase. Dimercaptotributyrate and triolein were employed for lipase. The extreme sensitivity of the lipase procedure using the tributyrate detected a persistent elevation of lipase when other parameters of measurement had returned to normal.


Effects of ambient temperature and precipitation on the risk of dengue fever: A systematic review and updated meta-analysis.
We systematically reviewed the published studies on the relationship between dengue fever and meteorological factors and applied a meta-analysis to explore the effects of ambient temperature and precipitation on dengue fever. We completed the literature search by the end of September 1st, 2019 using databases including Science Direct, PubMed, Web of Science, and Google Scholar. We extracted relative risks (RRs) in selected studies and converted all effect estimates to the RRs per 1 °C increase in temperature and 10 mm increase in precipitation, and combined all standardized RRs together using random-effect meta-analysis. Our results show that dengue fever was significantly associated with both temperature and precipitation. Our subgroup analyses suggested that the effect of temperature on dengue fever was most pronounced in high-income subtropical areas. The pooled RR of dengue fever associated with the maximum temperature was much lower than the overall effect. Temperature and precipitation are important risk factors for dengue fever. Future studies should focus on factors that can distort the effects of temperature and precipitation.


Neurogenic bladder treatment by doubling the recommended antimuscarinic dosage.
The dosage of the antimuscarinic drugs: Tolterodine ER or Trospium was increased to a higher-than-recommended dosage in patients where the manufacturer's recommended dosage had failed. All patients were suffering from neurogenic detrusor overactivity incontinence. Tolerability and success were evaluated in the present study. Twenty-one patients with neurogenic detrusor overactivity were evaluated: 17 with spinal cord injury, 3 with multiple sclerosis, and 1 with a meningomyelocele. All patients catheterized themselves or were catheterized. If neurogenic detrusor overactivity continued and the medication was well tolerated, the dosage was doubled to either 8 mg of Tolterodine ER [2 x 4 mg (n = 11)] or 90 mg of Trospium [3 x 30 mg (n = 10)]. The follow-up was monitored by a bladder diary and urodynamic evaluation. Sixteen patients significantly decreased their incontinence episodes from 8-12 episodes before to 0-2 episodes during the doubled treatment. The reflex volume increased from 202 +/- 68 to 332 +/- 50 ml (P < 0.001). Cystometric capacity enlarged from 290 +/- 56 to 453 +/- 63 ml (P < 0.001). One patient had to stop the medication because of intolerable side effects and five patients did not experience satisfactory benefit. The increased dosage of Tolterodine or Trospium is an effective treatment in patients with neurogenic bladder.


The impact of hepatocyte nuclear factor-1α on liver malignancies and cell stemness with metabolic consequences.
Hepatocyte nuclear factor-1 alpha (HNF-1α) is a transcription factor expressed predominantly in the liver among other organs. Structurally, it contains POU-homeodomain that binds to DNA and form proteins that help in maintaining cellular homeostasis, controlling metabolism, and differentiating cell lineages. Scientific research over the period of three decades has reported it as an important player in various liver malignancies such as hepatocellular cancers (HCCs), hepatocellular adenoma (HA), and a more specific HNF-1α-inactivated human hepatocellular adenoma (H-HCAs). Abundant clinical and rodent data have noted the downregulation of HNF-1α in parallel with liver malignancies. It is also interesting to notice that the co-occurrence of mutated HNF-1α expression and hepatic carcinomas transpires typically along with metabolic repercussion. Moreover, scientific data implies that HNF-1α exerts its effects on cell stemness and hence can indirectly impact liver malignancies and metabolic functioning. The effects of HNF-1α on cell stemness present a future opportunity to explore a possible and potential breakthrough. Although the mechanism through which inactivated HNF-1α leads to hepatic malignancies remain largely obscure, several key signal molecules or pathways, including TNF-α, SHP-1, CDH17, SIRT, and MIA-2, have been reported to take part in the regulations of HNF-1α. It can be concluded from the present scientific data that HNF-1α has a great potential to serve as a target for liver malignancies and cell stemness.


Expression of neuritin during liver maturation and regeneration.
Cell surface molecules are not only important for cell-cell interactions but also useful for a marker to define cell types and differentiation stages. Unlike hematopoietic system in which numerous such antigens have been identified, only a few cell surface molecules have been used to define differentiation stage of hepatocytes. In order to identify such cell surface molecules, we performed DNA microarray analysis using mRNA from fetal hepatocytes in E12.5 and E17.5 mice and cDNAs encoding a membrane protein were selected. Northern blot analysis was employed to confirm the genes upregulated during maturation of fetal hepatocytes and neuritin, a GPI-anchored protein, was found as a membrane protein expressed in hepatocytes, but not in nonparenchymal cells. Its expression increased along with liver development and the maximum expression was achieved from the neonatal to adult stage. The neuritin protein was localized in sinusoidal lumen of hepatocytes in adult liver. Partial hepatectomy transiently downregulated the expression of neuritin. The expression of neuritin mRNA in C/EBPalpha deficient liver was reduced to about 50% of that of wild type mice. Thus, neuritin expression is well correlated to the maturation of hepatocytes and can be a useful tool to define the differentiation stage of hepatocytes.


Diagnostic accuracy of a combination of salivary hemoglobin levels, self-report questionnaires, and age in periodontitis screening.
This study evaluated the predictive performance of a combination of self-report questionnaires, salivary hemoglobin levels, and age as a non-invasive screening method for periodontitis. The periodontitis status of 202 adults was examined using salivary hemoglobin levels, responses to 10 questions on a self-report questionnaire, and the Community Periodontal Index (CPI). The ability of those two variables and the combination thereof with age to predict the presence of CPI scores of 3-4 and 4 was assessed using logistic regression and receiver operating characteristic (ROC) curve analysis. CPI scores of 3-4 and 4 were present among 79.7% and 46.5% of the sample, respectively. The area under the ROC curves (AUROCs) of salivary hemoglobin levels for predicting prevalence of CPI scores of 3-4 and 4 were 0.63 and 0.67, respectively (with sensitivity values of 71% and 60% and specificity values of 56% and 72%, respectively). Two distinct sets of five questions were associated with CPI scores of 3-4 and 4, with AUROCs of 0.73 and 0.71, sensitivity values of 76% and 66%, and specificity values of 63% and 69%. The combined model incorporating both variables and age showed the best predictive performance, with AUROCs of 0.78 and 0.76, sensitivity values of 71% and 65%, and specificity values of 68% and 77% for CPI scores of 3-4 and 4, respectively. The combination of salivary hemoglobin levels and self-report questionnaires was shown to be a valuable screening method for detecting periodontitis.


Enhancement of lipopolysaccharide-stimulated cyclooxygenase-2 mRNA expression and prostaglandin E2 production in gingival fibroblasts from individuals with Down syndrome.
It is well known that Down syndrome (DS) is a premature ageing syndrome. Periodontal disease in individuals with DS develops rapidly and extensively in a relatively younger age bracket compared with that in healthy controls. The mechanisms involved in the periodontal inflammatory processes in DS patients are not fully understood. In the present study, the non-inflamed gingival fibroblasts isolated from seven patients with DS (DGF) and seven healthy controls (NDGF) were stimulated with lipopolysaccharide (LPS) derived from Actinobacillus actinomycetemcomitans (A. a.). We measured the level of prostaglandin E2 (PGE2) production by DGF and NDGF by radioimmunoassay, and also measured the mRNA expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) by using the real-time PCR method. We found the higher levels of LPS-stimulated COX-2 mRNA expression and PGE2 production in DGF when compared with those in NDGF. This study may indicate that overexpression of LPS-stimulated COX-2 induced a greater ability of DGF to produce PGE2, and that these phenomena may be responsible for the severer periodontal disease in DS patients.


SAKE: a new quantification tool for positron emission tomography studies.
In dynamic positron emission tomography (PET) studies, spectral analysis (SA) refers to a data-driven quantification method, based on a single-input single-output model for which the transfer function is described by a sum of exponential terms. SA allows to quantify numerosities, amplitudes and eigenvalues of the transfer function allowing, in this way, to separate kinetic components of the tissue tracer activity with minimal model assumptions. The SA model can be solved with a linear estimator alone or with numerical filters, resulting in different types of SA approaches. Once estimated the number, amplitudes and eigenvalues of the transfer function, one can distinguish the presence in the system of irreversible and/or reversible components as well as derive parameters of physiological significance. These characteristics make it an appealing alternative method to compartmental models which are widely used for the quantitative analysis of dynamic studies acquired with PET. However, despite its applicability to a large number of PET tracers, its implementation is not straightforward and its utilization in the nuclear medicine community has been limited especially by the lack of an user-friendly software application. In this paper we proposed SAKE, a computer program for the quantitative analysis of PET data through the main SA methods. SAKE offers a unified pipeline of analysis usable also by people with limited computer knowledge but with high interest in SA.


Neurocognitive functioning in patients recently diagnosed with bipolar disorder.
Cognitive dysfunction in bipolar disorder (BD) is well established in the literature; however, there are few studies of neurocognition in patients early in the course of the illness. In this study we compare neurocognitive function in a cohort of first-contact mania patients with a healthy control group matched for age, gender, and education. Patients with a first manic episode (FM) (n = 34) or previous untreated manic episodes (PM) (n = 21) were neuropsychologically tested following their first treated manic episode. A total of 110 matched healthy control comparison subjects were also tested. The following cognitive domains were evaluated: verbal and visual learning and memory, attention, processing speed, executive functioning, and IQ. Results were corrected for speed of processing differences and were compared with previously reported results for multiple-episode BD patients. BD patients early in their disease course showed impairments in psychomotor speed, attention, learning and memory, executive functioning, and IQ. When controlling for speed of processing, measures of visuoconstructive reasoning and motor dexterity remained statistically significant. Eighteen percent of FM and 16% of PM patients were found to have clinically significant neurocognitive impairment. No significant relationship between clinical symptoms and neurocognition was found. The first-contact mania patients studied were found to have smaller neurocognitive deficits compared to multiple-episode patients in previous studies. Neurocognitive dysfunction is present in early BD and is clinically significant for a proportion of patients. Our findings also suggest that neurocognitive dysfunction may increase with illness progression.


In vivo determination of the kinetic parameters of glucose transport in the human brain using 11C-methyl-D-glucose (CMG) and dynamic positron emission tomography (dPET).
A method was developed to measure simultaneously the rate constants for glucose influx and glucose efflux, and the Michaelis-Menten constant (KM) and maximal velocity (Vmax) for glucose transport across the blood-brain barrier (BBB) in any selected brain area. Moreover, on the basis of a mathematical model, the local perfusion rate (LPR) and local unidirectional glucose transport rate (LUGTR) are calculated in terms of parameters of the time-activity curves registered over different brain regions; 11C-methyl-D-glucose (CMG) is used as an indicator. The transaxial distribution of activity in the organism is registered using dynamic positron-emission tomography (dPET). The method was used in 4 normal subjects and 50 patients with ischemic brain disease. In normals, the rate constant for CMG efflux was found to be 0.25 +/- 0.04 min-1 in the cortex and 0.12 +/- 0.02 min-1 in white matter. In the cortex, the KM was found to be 6.42 mumol/g and the Vmax was 2.46 mumol/g per minute. The LUGTR ranged from 0.43 to 0.6 mumol/g per minute in the cortex, and from 0.09 to 0.12 mumol/g per minute in white matter. The LPR was calculated to be 0.80-0.98 ml/g per minute for the cortex and 0.2-0.4 ml/g per minute for white matter. In patients with stroke, the ischemic defects appeared to be larger in CMG scans than in computed x-ray tomography (CT) scans. Prolonged reversible ischemic neurological deficit was associated with a significant fall in the LUGTR but no change in the LPR in the corresponding cerebral cortex. Normal LUGTR and significantly decreased LPR were registered in a patient with progressive occlusion of the middle cerebral artery. In a patient with transient ischemic attacks, a slightly reduced LPR and a disproportionally reduced LUGTR were observed before operation. After extra- and intracranial bypass surgery, the LPR became normal, whereas the LUGTR increased but did not achieve normal values.


Sonoporation as a cellular stress: induction of morphological repression and developmental delays.
For sonoporation to be established as a drug/gene delivery paradigm, it is essential to account for the biological impact of this membrane permeation strategy on living cells. Here we provide new insight into the cellular impact of sonoporation by demonstrating in vitro that this way of permeating the plasma membrane may inadvertently induce repressive cellular features even while enhancing exogenous molecule uptake. Both suspension-type (HL-60) and monolayer (ZR-75-30) cells were considered in this investigation, and they were routinely exposed to 1-MHz pulsed ultrasound (pulse length, 100 cycles; pulse repetition frequency, 1 kHz; exposure period, 60 s) with calibrated field profile (spatial-averaged peak negative pressure, 0.45 MPa) and in the presence of microbubbles (cell:bubble ratio, 10:1). The post-exposure morphology of sonoporated cells (identified as those with calcein internalization) was examined using confocal microscopy, and their cell cycle progression kinetics were analyzed using flow cytometry. Results show that for both cell types investigated, sonoporated cells exhibited membrane shrinkage and intra-cellular lipid accumulation over a 2-h period. Also, as compared with normal cells, the deoxyribonucleic acid synthesis duration of sonoporated cells was significantly lengthened, indicative of a delay in cell cycle progression. These features are known to be characteristics of a cellular stress response, suggesting that sonoporation indeed constitutes as a stress to living cells. This issue may need to be addressed in optimizing sonoporation for drug/gene delivery purposes. On the other hand, it raises opportunities for developing other therapeutic applications via sonoporation.


[THE MOSQUITOES (DIPTERA, CULICIDAE) OF THE KIROV REGION].
It analyzed the data of mosquitoes caching on the Kirov region area. The habitat distribution and species diversity are analyzes. The checklist includes 25 species.


Synthesis and SAR of potent and orally bioavailable tert-butylpyrrolidine archetype derived melanocortin subtype-4 receptor modulators.
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed.


Protein dependent fate of hepatic cells under nicotine induced stress and curcumin ameliorated condition.
Nicotine is mainly metabolized in liver. Its abuse elicits acute phase response by activating macrophages to produce pro-inflammatory cytokines, which play critical role in apoptosis or cell proliferation. The protective pharmacological mechanism of curcumin against nicotine-induced toxicity on protein malnourished liver is still remaining unclear. This study investigated the ameliorative mechanism of curcumin against nicotine-induced toxicity and also fate of liver particularly under protein restricted condition. Female Albino-rats maintained under normal/protein-restricted diets, were subcutaneously injected with nicotine tartrate (2.5 mg/kg body weight/day) and orally supplemented with curcumin (80 mg/kg body weight/day) for 21 days. The animals were then sacrificed to dissect out liver and proceed with further experiments. Interactions of nicotine with DNA both in vivo and in vitro were observed by thermal denaturation and DNA laddering assays. Effects of nicotine on hepatic cells were monitored by differential staining, comet assay, cytokine profiling, mRNA and protein expression. Nicotine caused more intense DNA damage, promoted hepatic cell death through up-regulating pro-apoptotic proteins and signaling molecules in protein malnourished individuals. Through up-regulation of anti-apoptotic proteins and proliferation promoting molecules, nicotine dysregulated homeostasis in normal protein condition. Curcumin significantly ameliorated the nicotine-induced toxicity in both conditions and regulated the imbalance between cell survival and death induced by nicotine. The protein content present in the nicotine induced hepatic cell decides either cell-survival pathway or cytotoxic pathway.


The effect of serum on the crystallization of calcium oxalate in whole human urine: inhibition disguised as apparent promotion.
The effect of serum on calcium oxalate crystallization was studied in whole human urine. At concentrations between 0.005% to 0.10% (v/v), serum had no effect on the metastable limit of urine as detected by the Coulter Counter. However, serum caused a marked increase in the number and volume of calcium oxalate crystals deposited in response to an oxalate load. That this increase in volume reflected true deposition of calcium oxalate was confirmed by determining calcium concentration and by including control urines containing added serum but no exogenous oxalate. Analysis of particle size distributions showed that the crystals deposited in the presence of serum were smaller than those occurring in the control. Since serum did not affect the limit of metastability, the enhancement of crystal volume is unlikely to be a result of heterogeneous nucleation. We hypothesize that the apparent promotion effect of serum is due to its inhibition of crystal aggregation which increases the crystal surface area available for calcium oxalate deposition.


2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry.
2-Aminothiophenes are important five-membered heterocyclic building blocks in organic synthesis, and the chemistry of these small molecules is still developing based on the discovery of cyclization by Gewald. Another attractive feature of 2-aminothiophene scaffolds is their ability to act as synthons for the synthesis of biological active thiophene-containing heterocycles, conjugates and hybrids. Currently, the biological actions of 2-aminothiophenes or their 2-N-substituted analogues are still being investigated because of their various mechanisms of action (e.g., pharmacophore and pharmacokinetic properties). Likewise, the 2-aminothiophene family is used as diverse promising selective inhibitors, receptors, and modulators in medicinal chemistry, and these compounds even exhibit effective pharmacological properties in the various clinical phases of appropriate diseases. In this review, major biological and pharmacological reports on 2-aminothiophenes and related compounds have been highlighted; most perspective drug-candidate hits were selected for discussion and described, along with additional synthetic pathways. In addition, we focused on the literature dedicated to 2-aminothiophenes and 2-N-substituted derivatives, which have been published from 2010 to 2017.


Factor XIII levels in relation to gynaecological operations.
In 25 patients with vaginal hysterectomies and 14 with abdominal hysterectomies, Factor XIII activity in the antiseruminhibition test of Bohn and Haupt was measured in the first 7 postoperative days. Both groups showed a statistically significant reduction in activity (40--50%) which started at 2 h after operation and lasted until the 3rd postoperative day. The route of operation did not significantly affect the results and neither did the phase of the cycle nor the age of the patient.


Divulging the anti-acetylcholinesterase activity of Colletotrichum lentis strain KU1 extract as sustainable AChE active site inhibitors.
Alzheimer's disease (AD), also called senile dementia is a neurodegenerative disease seen commonly in the elderly and is characterised by the formation of β-amyloid plaques and neurofibrillary tangles (NFT). Though a complete understanding of the disease is lacking, recent studies showed the role of the enzyme acetylcholinesterase (AChE) in pathogenesis. Finding new lead compounds from natural sources has always been a quest for researchers. Endophytic fungi are a set of microbes that reside within plants without causing any harm. This study focuses on screening endophytes for the production of active acetylcholinesterase inhibitors. Five endophytic fungi were isolated from Catharanthus roseus and screened for AChE inhibitory activity. Three isolates were found to inhibit AChE inhibitory activity and were distinguished based on molecular and microscopic methods. The mycelial extract was taken for the bioassay-guided column chromatography and TLC was performed on the active fraction. The GC-MS and NMR analysis identified the active compounds in the extract as 9-hexadecen-1-ol and erucamide. Molecular docking studies revealed that the compounds are thermodynamically feasible and have significant glide scores. Computational studies revealed that the hydroxyl group of 9-hexadecen-1-ol forms a hydrogen bond with Ser 293 in the active site of AChE, whereas the active site interactions were predominantly hydrophobic in the case of erucamide and are reflected in AChE inhibition assays.


Painful bone metastasis: efficacy of radiotherapy assessed by the patients: a randomized trial comparing 4 Gy X 6 versus 10 Gy X 2.
Fifty-seven patients with painful bone metastases were randomized to receive 4 Gy in 6 fractions over 3 weeks with 2 fractions per week or 10 Gy in 2 fractions with an interval of one week. Pain intensity was assessed by scoring the consumption of analgesics combined with patient self-evaluation on a visual analogue scale. Treatment results were identical in the two treatment groups, with satisfactory pain control in about 48% of the patients. In other studies with physician evaluation of pain control, better results have invariably been reported, suggesting some degree of observer bias. A review of the literature as well as the results of this study indicates that within wide ranges no optimal radiation schedule or dose exist for reducing pain in bone metastases. Therefore short courses of treatment using moderate doses should be preferred for the convenience of the patients.


Frogs at the summits: phylogeny of the Andean frogs of the genus Telmatobius (Anura, Telmatobiidae) based on phenotypic characters.
A phylogenetic hypothesis for the frogs of the genus Telmatobius that includes a comprehensive sample of the morphological and geographical variation is lacking. Obtaining such a hypothesis constitutes the main focus of this contribution. A phylogenetic matrix was generated based on 97 phenotypic characters and 56 terminals. A parsimony analysis of this matrix was performed with TNT. Telmatobius is found to be monophyletic and well supported by 11 synapomorphies. Although the consensus tree shows several polytomies, four main groups have been recovered. The well-supported T. verrucosus Group includes forest and sub-paramo species from Bolivia and Peru, and is the sister group of the remaining species. The T. bolivianus Group includes forest and inter-Andean valley species from Argentina and Bolivia but it is poorly supported. Two supported high-altitude groups have been recovered, the T. macrostomus Group from the Central Andes of Peru, and the T. marmoratus Group from the Altiplano-Puna Plateau of Argentina, Bolivia, Peru and Chile and its adjacent Pacific and Northern slopes. The synapomorphies proposed for Telmatobius are discussed as well as the evolution of some of these synapomorphies and other characters within the genus.


Completely ossified thoracic intradural meningioma in an elderly patient: A case report and literature review.
Spinal meningioma is the second most common spinal neoplasm that commonly occurs in middle-aged women. As a rare histological variation of meningioma, completely ossified meningioma (OSM) and its standard surgical strategies have been reported. However, the surgical outcomes of elderly OSM cases (age >70) are less investigated. Herein, we intend to present an elderly OSM case and review the elderly OSM cases in published literatures. An 85-year-old female presented with 10-year history of back pain and developed radiating pain on her left lower extremity within the last 2 weeks. A magnetic resonance imaging scan revealed an intradural tumor at the T11 level. A computed tomography scan demonstrated that the mass was completely ossified and had distinct borders (D-F). In a dynamic contrast-enhanced magnetic resonance imaging scan, the mass presented as a lateral intradural extramedullary tumor with abundant blood supply (). The patient underwent en bloc intradural tumorectomy via posterior approach. After surgery, the patient's pain was relieved. However, the patient spent another 3 weeks in hospital due to a series of post-surgery complications, including hypostatic pneumonia, pulmonary heart failure, hydrothorax in both thoracic cavities, hypoproteinemia, and deep venous thrombosis on both of her legs. The complications recovered after 3-weeks treatment. In 1-year follow up, no additional symptom was found and the patient was recurrence free. Our report indicated that the surgical outcome can be satisfying in elderly OSM patients, while the post-operative complications frequently occur due to the poor physical condition of elderly patients. As a result, treatment of peri-operative complications of elderly OSM patients also deserves greater attention along with surgical resection.


Stalking in Adolescence: A Case Report.
Stalking has overlaps with criminal justice system and mental health services. Research has, so far, identified stalking to be a predominantly adult male phenomenon. We present the case of a 15-year-old girl who was referred for stalking her learning mentor. The relevant literature is discussed and areas for further research are highlighted.


Biodegradable microspheres II: Immune response to a heterologous and an autologous protein entrapped in polyacryl starch microparticles.
Human serum albumin (HSA) and mouse serum albumin were entrapped in biodegradable microparticles of polyacrylstarch. When HSA entrapped in microparticles was injected i.v. in Balb/c mice a dose-dependent immune response was elicited. No detectable response was obtained when mouse serum albumin entrapped in microparticles was given to the mice. Neither was any response detected when free HSA or free HSA in combination with empty microparticles were injected, as measured by indirect plaque-forming cells in the spleen and serum antibody titers. The immune response to entrapped HSA had a long duration and was mainly T-cell-dependent as athymic nude mice (Nu/Nu) only generated a weak immune response upon injection of the particle entrapped antigen.


Computerized prescriber order entry and opiate prescription in ambulatory care visits.
To assess the impact of computerized prescriber order entry (CPOE) on opioid-prescribing practices. This study analyzed 233,390 office-based medical visits in the 2011-2015 National Ambulatory Medical Care Survey. We used survey-adjusted logistic regression analysis comparing prescription of opiate medications by physicians with and without CPOE. Results were adjusted by covariates describing patient demographics, insurance status, and geography; clinical factors including noncancer pain, cancer, and other chronic medical problems; and physician specialty category and solo practitioner status. Opiates were prescribed in 10.4% of patient visits to physicians with access to CPOE in the sample, compared with 7.5% of visits to physicians without access to CPOE. The adjusted odds of opiate prescription were 1.35 times greater in visits to physicians who had access to CPOE (P = 0.001; 95% CI 1.14-1.58). Among patients visits citing pain (n = 52,978), the adjusted odds of opioid prescription were significantly greater when physicians had access to CPOE (odds ratio 1.28, 95% CI 1.02-1.61; P = 0.035). These findings support efforts to review and redesign embedded CPOE tools to improve guideline adherence and reduce problematic opiate prescription.


A cross-platform survey of CT image quality and dose from routine abdomen protocols and a method to systematically standardize image quality.
Through this investigation we developed a methodology to evaluate and standardize CT image quality from routine abdomen protocols across different manufacturers and models. The influence of manufacturer-specific automated exposure control systems on image quality was directly assessed to standardize performance across a range of patient sizes. We evaluated 16 CT scanners across our health system, including Siemens, GE, and Toshiba models. Using each practice's routine abdomen protocol, we measured spatial resolution, image noise, and scanner radiation output (CTDIvol). Axial and in-plane spatial resolutions were assessed through slice sensitivity profile (SSP) and modulation transfer function (MTF) measurements, respectively. Image noise and CTDIvol values were obtained for three different phantom sizes. SSP measurements demonstrated a bimodal distribution in slice widths: an average of 6.2 ± 0.2 mm using GE's 'Plus' mode reconstruction setting and 5.0 ± 0.1 mm for all other scanners. MTF curves were similar for all scanners. Average spatial frequencies at 50%, 10%, and 2% MTF values were 3.24 ± 0.37, 6.20 ± 0.34, and 7.84 ± 0.70 lp cm(-1), respectively. For all phantom sizes, image noise and CTDIvol varied considerably: 6.5-13.3 HU (noise) and 4.8-13.3 mGy (CTDIvol) for the smallest phantom; 9.1-18.4 HU and 9.3-28.8 mGy for the medium phantom; and 7.8-23.4 HU and 16.0-48.1 mGy for the largest phantom. Using these measurements and benchmark SSP, MTF, and image noise targets, CT image quality can be standardized across a range of patient sizes.


IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep Apnea.
This study examined insulin-like growth factor-1 (IGF-1) production and its association with the metabolic syndrome (MS) in men with obstructive sleep apnea (OSA). In total, 47 overweight and obese men who had been referred for suspected OSA underwent polysomnography and were classified based on the apnea-hypopnea index (AHI) into three groups: no OSA, < 5 events/h (n = 11); mild OSA, ≥ 5 to < 15 events/h (n = 8); and moderate-severe OSA, ≥ 15 events/h (n = 28). The assessment of the somatotropic axis function included IGF-1 measurement. MS was diagnosed according to the National Cholesterol Education Program guidelines. IGF-1 level in the moderate-severe OSA group was lower than in the no-OSA group (156.8 ± 54.3 μg/L versus 225.5 ± 80.5 μg/L; p = 0.013). IGF-1 level was negatively correlated with body mass index, waist circumference (WC), AHI, and sleep duration with oxygen (O2) saturation < 90% and positively correlated with the average and minimum O2 saturation (p = 0.027). In a multivariable linear regression, considering WC and minimum O2 saturation as independent variables, only the minimum O2 saturation was a predictor of low IGF-1 levels. The proportions of patients with MS were different between the three groups (18.2% in no OSA; 25% in mild OSA, and 57.1% in moderate-severe OSA; p = 0.047). Furthermore, in the lowest tertile of IGF-1 value, 66.7% of patients were affected by MS (p = 0.049). Hemoglobin (Hb)A1c correlated negatively with the minimum O2 saturation and IGF-1 levels. However, in multivariable linear regression only IGF-1 levels were a predictor of HbA1c levels. The occurrence of OSA is associated with a reduction in IGF-1 levels. IGF-1 alterations in OSA also seem to be associated with a higher prevalence of MS.


Effect of blending ratio of wheat, orange fleshed sweet potato (Ipomoea batatas L.) powder and haricot bean ( Phaseolus vulgarisL.) flour on proximate composition, physical properties and sensory acceptability of biscuits.
Background Protein-energy deficiency (PEM) is still a major health issue in developing countries, and it is the leading cause of disease and death in children under the age of 5 years. Methods 100:0:0; 90:5:5; 80:10:10; 70:15:15; 60:20:20; and 50:25:25 per cent wheat:haricot bean: orange-fleshed sweet potato (OFSP) flours were used to make composite cookies. Standard methods were used to evaluate the proximate structure, physical properties, and sensory assessment. A one-way analysis of variance (ANOVA) model was used to statistically evaluate the data using the statistical analysis system (SAS) software package, version 9.0 standard methods. Results The results showed that partially replacing wheat with haricot bean and OFSP increased the proximate composition significantly. When wheat was replaced with haricot bean and OFSP, the physical characteristics of the biscuits did not vary significantly from those of biscuits made entirely of wheat flour. Sensory acceptability (appearance, color, flavor, taste, and overall acceptability) was higher in the composite biscuits with up to 40% wheat substitution than in the 100% wheat flour biscuits. Conclusions Based on the findings of this report, using OFSP and a haricot bean to wheat flour blend in biscuit formulation appears to be promising in terms of nutritional quality, acceptability, and cost. It is proposed that these products be marketed to vitamin A deficiency (VAD) customers as a newly established product to help mitigate food insecurity.


Different neuronal populations of the rat median preoptic nucleus express c-fos during sleep and in response to hypertonic saline or angiotensin-II.
The median preoptic nucleus (MnPN) of the hypothalamus contains sleep-active neurones, and sleep-related Fos-immunoreactivity (IR) in this nucleus is primarily expressed in GABAergic cells. The MnPN also contains cells responsive to hypertonic saline and to angiotensin-II (Ang-II). To clarify functional relationships between MnPN neurones involved in the regulation of sleep and body fluid homeostasis, we examined c-fos expression in the MnPN after administration of hypertonic saline and Ang-II in both spontaneously sleeping and sleep-deprived rats. Systemic administration of hypertonic saline and intracerebroventricular (i.c.v.) injection of Ang-II increased Fos-IR in both spontaneously sleeping and sleep-deprived rats, compared to control animals. To determine if the population of MnPN neurones activated in response to osmotic and hormonal stimuli is similar to or different from neurones activated during sleep, we quantified Fos-IR in MnPN GABAergic neurones in spontaneously sleeping hypertonic saline- and Ang-II-treated rats versus respective control rats. Fos-IR evoked by these treatments occurred primarily (80-85%) in non-GABAergic neurones. Findings of the present study provide evidence that separate populations of MnPN neurones are involved in the regulation of sleep and body fluid homeostasis.


Ozone: a natural bioactive molecule with antioxidant property as potential new strategy in aging and in neurodegenerative disorders.
Systems medicine is founded on a mechanism-based approach and identifies in this way specific therapeutic targets. This approach has been applied for the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Nrf2 plays a central role in different pathologies including neurodegenerative disorders (NDs), which are characterized by common pathogenetic features. We here present wide scientific background indicating how a natural bioactive molecule with antioxidant/anti-apoptotic and pro-autophagy properties such as the ozone (O3) can represent a potential new strategy to delay neurodegeneration. Our hypothesis is based on different evidence demonstrating the interaction between O3 and Nrf2 system. Through a meta-analytic approach, we found a significant modulation of O3 on endogenous antioxidant-Nrf2 (p < 0.00001, Odd Ratio (OR) = 1.71 95%CI:1.17-2.25) and vitagene-Nrf2 systems (p < 0.00001, OR = 1.80 95%CI:1.05-2.55). O3 activates also immune, anti-inflammatory signalling, proteasome, releases growth factors, improves blood circulation, and has antimicrobial activity, with potential effects on gut microbiota. Thus, we provide a consistent rationale to implement future clinical studies to apply the oxygen-ozone (O2-O3) therapy in an early phase of aging decline, when it is still possible to intervene before to potentially develop a more severe neurodegenerative pathology. We suggest that O3 along with other antioxidants (polyphenols, mushrooms) implicated in the same Nrf2-mechanisms, can show neurogenic potential, providing evidence as new preventive strategies in aging and in NDs.


Determination of the O-serovars of Pseudomonas aeruginosa by slide coagglutination.
Determination of the somatic (O-) antigens of Pseudomonas aeruginosa by conventional slide agglutination is frequently complicated by the barely discernible, slow reaction of native cells. For diagnostic purposes a more practical procedure, a coagglutination test, has been developed in which protein A bearing Staphylococcus aureus (ATCC 12598) cells are added to the agglutination process occurring between specific anti-O serum and native Pseudomonas aeruginosa. Compared to the conventional method, slide O-coagglutination yields larger agglutinates in a shorter mean reaction time, i.e. one minute vs four minutes. Moreover, strains not reacting in the O-agglutination method or reacting only with polyvalent anti-O serum can be grouped by O-coagglutination, and cross reactions between reference strains of different O-groups do not occur. This method facilitates O-grouping of Pseudomonas aeruginosa in epidemiological investigations.


Catalytic decomposition of gaseous 1,2-dichlorobenzene over CuOx/TiO₂ and CuOx/TiO₂-CNTs catalysts: Mechanism and PCDD/Fs formation.
Gaseous 1,2-dichlorobenzene (1,2-DCBz) was catalytically decomposed in a fixed-bed catalytic reactor using composite copper-based titanium oxide (CuOx/TiO2) catalysts with different copper ratios. Carbon nanotubes (CNTs) were introduced to produce novel CuOx/TiO2-CNTs catalysts by the sol-gel method. The catalytic performances of CuOx/TiO2 and CuOx/TiO2-CNTs on 1,2-DCBz oxidative destruction under different temperatures (150-350 °C) were experimentally examined and the correlation between catalyst structure and catalytic activity was characterized and the role of oxygen in catalytic reaction was discussed. Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) generation during 1,2-DCBz catalytic oxidation by CuOx/TiO2-CNTs composite catalyst was also examined. Results indicate that the 1,2-DCBz destruction/removal efficiencies of CuOx (4 wt%)/TiO2 catalyst at 150 °C and 350 °C with a GHSV of 3400 h(-1) are 59% and 94% respectively and low-temperature (150 °C) catalytic activity of CuOx/TiO2 on 1,2-DCBz oxidation can be improved from 59 to 77% when CNTs are introduced. Furthermore, oxygen either in catalyst or from reaction atmosphere is indispensible in reaction. The former is offered to activate and oxidize the 1,2-DCBz adsorbed on catalyst, thus can be generally consumed during reaction and the oxygen content in catalyst is observed lost from 39.9 to 35.0 wt% after reacting under inert atmosphere; the latter may replenish the vacancy in catalyst created by the consumed oxygen thus extends the catalyst life and raises the destruction/removal efficiency. The introduction of CNTs also increases the Cu(2+)/Cu(+) ratio, chemisorbed oxygen concentration and surface lattice oxygen binding energy which are closely related with catalytic activity. PCDD/Fs is confirmed to be formed when 1,2-DCBz catalytically oxidized by CuOx/TiO2-CNTs composite catalyst with sufficient oxygen (21%), proper temperature (350 °C) and high concentration of 1,2-DCBz feed (120 ppm).


Controlling type 2 diabetes mellitus with herbal medicines: A triple-blind randomized clinical trial of efficacy and safety.
The use of alternative medicines is common in patients with diabetes mellitus. The primary aim of the present study was to determine the effects of cinnamon and Caucasian whortleberry (Vaccinium arctostaphylos L.) on blood glucose control, lipid profile and body mass index (BMI) in patients with type 2 diabetes (T2DM). In all, 105 T2DM patients were recruited to the present randomized triple-blinded clinical trial. Patients were randomly divided into three groups and administered either placebo, cinnamon or whortleberry supplements (1 g/day) for 90 days. Fasting blood glucose (FBG), serum insulin, lipid profiles, and HbA1c were measured before and after the study. There were no significant differences in baseline characteristics among the three groups. After treatment, FBG, 2-h blood postprandial glucose and homeostasis model assessment of insulin resistance (HOMA-IR) scores were significantly reduced in patients in the whortleberry group, but not in the placebo group. After treatment, there was a significant difference in BMI between the cinnamon and control groups (P = 0.02). There were no significant differences in any variables between the cinnamon and whortleberry groups (P>0.05 for all). In addition, there was a significant decrease in all indices of glucose control in all the cinnamon and whortleberry groups (P < 0.05). There were no significant differences in blood glucose levels, insulin sensitivity or lipid profile among the three groups. However, the use of cinnamon and whortleberry in addition to conventional medical treatment is recommended to adjust weight and blood glucose levels in patients with T2DM, respectively.


A case of discordant histology and expression of programmed death ligand 1 between primary tumor and brain metastases in adenosquamous carcinoma of the lung.
A patient presented with vomiting and gait disturbance. Investigation revealed a single cerebellar tumor and another tumor in the upper lobe of the left lung. Based on the severe vomiting and gait disturbance, we removed the cerebellar tumor first, achieving resolution of symptoms. The cerebellar tumor was pathologically diagnosed as metastatic lung adenocarcinoma. No other metastases were identified, including in the mediastinal lymph nodes. We therefore resected the primary lung tumor. On final pathological analysis, the tumor in the upper lobe of the left lung was diagnosed as adenosquamous carcinoma with no lymph node metastasis. PD-L1 expression was low in the primary lung adenosquamous carcinoma and high in the cerebellar metastasis. Furthermore, both tumors were KRASG12C -positive. Tumor PD-L1 expression is considered important for immune escape. In this case, adenocarcinoma cells in the primary adenosquamous carcinoma may have migrated to form a cerebellar metastasis. In advanced lung cancer, tumor growth may be observed in some lesions even when many other lesions are controlled by chemo- or immunotherapy. Biopsy to confirm histology and PD-L1 expression is worth considering, depending on the location of the metastases and the invasiveness of the biopsy procedure.


Heterogeneous Pseudo-Supervised Learning for Few-shot Person Re-Identification.
How to obtain good retrieval performance in the case of few-shot labeled samples is the current research focus of Person Re-Identification. To facilitate formal analysis, we formally put forward the concept of Pseudo-Supervised Learning (PSL) to represent a series of research works based on label generation under few-shot condition. Through extensive investigations, we find that the main problem that needs to be solved of PSL is how we can improve the quality of pseudo-label. To solve this problem, in this work, we proposed a simple yet effective Heterogeneous Pseudo-Supervised Learning (H-PSL) framework based on classical PSL to implement asynchronous match, which boosts the feature expression and then a better label prediction in the following. Specifically, a novel isomer is constructed as the feature extractor and is trained with a much larger amount of pseudo-supervised data, i.e., samples with pseudo-labels. In this way, the isomer obtains advanced feature expression. We then deliberately implement a cross-level asynchronous match mechanism between model and pseudo-supervised data. As a result, the quality of pseudo-label is greatly improved and the feature expression performance also be optimized accordingly. In addition, to make better use of pseudo-supervised data, we also designed a knowledge fusion strategy to integrate the pseudo labels and their confidence which are easily obtained by the base model and isomer. Encouragingly, knowledge fusion strategy further removes the noise-labeled samples from candidate data. We conduct experiments on four popular datasets to fully verify the universality of the proposed method. The experimental results show that the proposed method improves the performance of all compared baseline works.


[Retro-odontoid pseudotumor in diffuse idiopathic skeletal hyperostosis].
Retro-odontoid pseudotumors are lesions caused by inflammatory granulation or reactive soft tissue hypertrophy from chronic atlantoaxial subluxation. However, one-third of the cases reported in the medical literature did not show atlantoaxial instability clearly. The authors present the case of a 76-year-old man previously diagnosed with diffuse idiopathic skeletal hyperostosis who presented with severe progressive myelopathy. A magnetic resonance imaging of his cervical spine revealed a retro-odontoid predural mass, which caused a severe compression of the cervical spinal cord. The patient underwent a posterior laminectomy of the atlas and an occipitocervical fusion. After surgery, the pseudotumor was considerably smaller and the neurological symptoms improved.


Neopetrosiamides, peptides from the marine sponge Neopetrosia sp. that inhibit amoeboid invasion by human tumor cells.
[structure: see text] Neopetrosiamdes A (1) and B (2), two diastereomeric tricyclic peptides that inhibit amoeboid invasion of human tumor cells, have been isolated from the marine sponge Neopetrosia sp. collected in Papua New Guinea. The structures of the neopetrosiamides were elucidated by analysis of MS and NMR data and confirmed by chemical degradation.


Effects of a dolphin interaction program on children with autism spectrum disorders: an exploratory research.
Interaction programs involving dolphins and patients with various pathologies or developmental disorders (e.g., cerebral palsy, intellectual impairment, autism, atopic dermatitis, post-traumatic stress disorder, depression) have stimulated interest in their beneficial effects and therapeutic potential. However, the true effects observed in different clinical and psycho-educational setups are still controversial. An evaluation protocol consisting of the Childhood Autism Rating Scale (CARS), Psychoeducational Profile-Revised (PEP-R), Autism Treatment Evaluation Checklist (ATEC), Theory of Mind Tasks (ToM Tasks) and a custom-made Interaction Evaluation Grid (IEG) to evaluate behavioural complexity during in-pool interactions was applied to 10 children diagnosed with Autism Spectrum Disorders. The ATEC, ToM Tasks and CARS results show no benefits of the dolphin interaction program. Interestingly, the PEP-R suggests some statistically significant effects on 'Overall development score', as well as on their 'Fine motor development', 'Cognitive performance' and 'Cognitive verbal development'. Also, a significant evolution in behavioural complexity was shown by the IEG. This study does not support significant developmental progress resulting from the dolphin interaction program.


Retraction: Effect of exercise at light loads with manipulative resistance on infraspinatus, trapezius (upper fiber) and deltoid (middle fiber) muscle activities in shoulder joint elevation.
[This retracts the article on p. 627 in vol. 27.].


"They're hoping we can stop it": Student leadership in sexual violence intervention and response at West Point.
This study identified risks and opportunities in peer leadership approaches to sexual violence intervention and response. Constructivist grounded theory was used to analyze semistructured interviews with 24 cadets, including a bystander intervention scenario. With regard to bystander intervention, cadets adhered to gendered assumptions that blocked action, drew upon community values to plan intervention, and thus prepared in ways that reinforced gender biases. With regard to incident response, cadets struggled with cynicism regarding their role in addressing sexual assault, but wanted incidents to be reported despite victim blaming and lack of supports, and responded from their feelings instead of skillfully acting on their values. This study explicates opportunities for leveraging community values in service of intervention and response while illustrating risks of rape myths and gender biases. Addressing inaccurate assumptions and reinforcing positive values could better prepare cadets and other undergraduate students for leadership.


Synergistic enhancement of cancer therapy using a combination of heat shock protein targeted HPMA copolymer-drug conjugates and gold nanorod induced hyperthermia.
In the field of nanomedicine, selective delivery to cancer cells is a common goal, where active targeting strategies are often employed to increase tumor accumulation. In this study, tumor hyperthermia was utilized as a means to increase the active delivery of heat shock protein (HSP) targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates. Following hyperthermia, induced expression of cell surface heat shock protein (HSP) glucose regulated protein 78 kDa (GRP78) was utilized for targeted drug therapy. Conjugates bearing the anticancer agents aminohexylgeldanamycin (AHGDM), docetaxel (DOC), or cisplatin and the GRP78 targeting peptide WDLAWMFRLPVG were synthesized and characterized. Binding to cell surface expressed heat shock protein GRP78 on the surface of human prostate cancer DU145 cells was evaluated. HSP targeted AHGDM and DOC conjugates demonstrated active binding comparable to native targeting peptide. They were then assessed in vitro for the ability to synergistically induce cytotoxicity in combination with moderate hyperthermia (43 °C, 30 min). HSP targeted DOC conjugates exhibited high potency against DU145 cells with an IC₅₀ of 2.4 nM. HSP targeted AHGDM and DOC conjugates demonstrated synergistic effects in combination with hyperthermia with combination index values of 0.65 and 0.45 respectively. Based on these results, HSP targeted DOC conjugates were selected for in vivo evaluation. In DU145 tumor bearing mice, a single treatment of tumor hyperthermia, induced via gold nanorod mediated plasmonic photothermal therapy, and intravenous administration of HSP targeted HPMA copolymer-docetaxel at 10mg/kg resulted in maintained tumor regression for a period of 30 days. These results demonstrate the potential for tumor hyperthermia to increase the delivery of HSP targeted macromolecular chemotherapeutics.


Subcellular distribution, a factor in risk evaluation of pentachlorophenol.
Pentachlorophenol (PCP) is a potent uncoupler of mitochondrial phosphorylation in vitro and also interferes with microsomal detoxication functions in vitro. This favours flavin mediated oxygenation compared with flavin cytochrome P-450 dependent reactions. Gas chromatographic analysis of subcellular fractions, obtained by zonal centrifugation showed markedly lower PCP concentration in mitochondria and a high accumulation in microsomes compared with cytosol. This increases the likelihood that PCP in vivo causes a malfunction in microsomal detoxication.


"Oh, by the way ...": the closing moments of the medical visit.
To define and describe the communication between physicians and patients in the closing phase of the medical visit. To identify types of communication throughout the visit that are associated with the introduction of a new problem during the closing moments of the visit or with longer closures. Audiotaping of office visits. Tapes were analyzed using a modified Roter Interactional Analysis System (RIAS). The coders' definition of closure was compared with the opinion of communication experts. Outpatient offices of practicing physicians. Eighty-eight patients visiting 20 primary care physicians participated. Physicians were selected by a letter from the Oregon Board of Medical Examiners. The mean number of years from graduation was 16 (range 3-47). One physician per site participated. Frequencies of physician and patient communication behaviors and global affect scores were calculated and correlations were drawn using t-test and chi-square analyses. The physicians initiated the closing in 86% of the visits. The physicians clarified the plan of care in 75% of the visits and asked whether the patients had more questions in 25% of the cases. The patients introduced new problems not previously discussed in 21% of the closures. New problems in closure were associated with less information exchanged previously by physicians and patients about therapy (t = -3.28, p = 0.002; t = -2.26, p = 0.03), fewer orientation statements by physicians (t = 1.86, p = 0.001), and higher patient affect scores (t = 0.252, p = 0.016). Long closures (> 2 minutes) correlated with physicians' asking open-ended questions (0.2438; p = 0.019), laughing (0.3002; p = 0.005), showing responsiveness to patients (0.3996; p < 0.001), being self-disclosing (0.3948; p < 0.001), and engaging in psychosocial discussion with patients (0.2410; p = 0.020). This study is the first description of how physicians and patients communicate during the closing of office visits. Notably, the patients raised new problems at the end of the visit in 21% of the cases. The findings suggest ways physicians might improve communication in the closing phase of the medical interview. Orienting patients in the flow of the visit, assessing patient beliefs, checking for understanding, and addressing emotions and psychosocial issues early on may decrease the number of new problems in the final moments of the visit.


FTY720 promotes pulmonary fibrosis when administered during the remodelling phase following a bleomycin-induced lung injury.
Fibrosis complicates numerous pathologies including interstitial lung diseases. Sphingosine analogs such as FTY720 can alleviate lung injury-induced fibrosis in murine models. Contradictorily, FTY720 also promotes in vitro processes normally leading to fibrosis and high doses in vivo foster lung fibrosis by enhancing vascular leakage into the lung. The goal of this study was to determine the effect of low doses of FTY720 on lung fibrosis triggered by an acute injury in mice. We first defined the time-boundaries delimiting the inflammatory and remodelling phases of an injury elicited by bleomycin based on neutrophil counts, total lung capacity and lung stiffness. Thereafter, FTY720 (0.1 mg/kg) was delivered during either the inflammatory or the remodelling phases of bleomycin-induced injury. While FTY720 decreased fibrosis by 60% and lung stiffness by 28% when administered during the inflammatory phase, it increased fibrosis (2.1-fold) and lung stiffness (1.7-fold) when administered during the remodelling phase. FTY720-induced worsening of fibrosis was associated with an increased expression of connective tissue growth factor, but not with vascular leakage into the lung. Thus, the timing of FTY720 delivery following a bleomycin-induced lung injury determines pro-vs anti-fibrotic outcomes.


Temporal resolution of dichoptic and second-order motion mechanisms.
We addressed the question of whether low-level motion analysers can integrate signals binocularly. We compared the temporal sensitivity in motion discrimination tasks using monocular and dichoptic first-order motion and monocular and dichoptic second-order motion. Three human observers were required to discriminate the direction of motion of either sinusoidal gratings (1 c/deg), used as a stimulus for first-order motion analysers, or the envelopes of contrast-modulated stationary sinusoidal gratings (carrier frequency 5 c/deg, carrier contrast 0.1, modulation frequency 1 c/deg), used as a stimulus for second-order motion analysers. Contrast sensitivity was measured as a function of temporal frequency. The moving grating or envelope was generated by summing two non-moving sinusoidally flickering gratings or envelopes in spatiotemporal quadrature. These were either combined monocularly or presented dichoptically. Sensitivity to the moving envelope was highest at a temporal frequency between 0.5 and 2 Hz, depending on the observer, and declined rapidly at high temporal frequencies. None of the observers was able to discriminate the direction of motion of envelopes moving faster than 4 Hz. Dichoptic and monocular presentation produced very similar results. Sensitivity to a monocularly presented moving grating was fairly uniform between 1 and 8 Hz, and declined slightly at 16 Hz. In one of three observers sensitivity to the dichoptically presented grating was very close to that of the monocularly presented grating at all temporal frequencies tested (from 1 to 16 Hz). All observers could discriminate the direction of motion of the dichoptically presented grating at 8 Hz, but two of the three were unable to discriminate its direction of motion at 16 Hz. These results indicate that second-order motion analysers have very poor temporal resolution and that dichoptic motion analysers have very good resolution. We suggest that this implies that there are low-level motion analysers that are capable of integrating information binocularly.


Total serum IgE levels in a large cohort of patients with severe or difficult-to-treat asthma.
Limited data are available on levels of IgE in large cohorts of patients with severe or difficult-to-treat asthma. To examine IgE levels and disease in patients from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. From January 2001 to October 2001, 4,923 patients were screened for inclusion in the study. Of these, 4,756 patients 6 years or older with severe or difficult-to-treat asthma were enrolled and completed a baseline study visit. Total serum IgE levels were measured at the baseline visit and are summarized by geometric means. The mean total IgE level of the population is 106.6 IU/mL (95% confidence interval, 101.5-112.0 IU/mL). Children (6-12 years old) and adolescents (13-17 years old) have higher mean IgE levels than adults (> or =18 years old) (P < .001). Males have a higher mean IgE level than females (P < .001). IgE levels are higher among nonwhite patients than white patients (P < .001). Current smokers have higher IgE levels than past smokers or never smokers (P < .001). Among children, patients with severe asthma have a higher mean IgE level (280.2 IU/mL) than patients with moderate (145.8 IU/mL) or mild (137.8 IU/mL) asthma (P < .001). Among adults, patients with childhood-onset asthma have higher IgE levels (124.3 IU/mL [n = 1,348]) than patients with adult-onset asthma (65.7 IU/mL [n = 1,956]) (P < .001). In patients with severe or difficult-to-treat asthma from the TENOR study, higher total IgE levels were observed in males, children, smokers, nonwhite racial/ethnic groups, and adults with childhood-onset disease. In addition, IgE levels are associated with asthma severity among younger patients.


Studies on the mechanism of Mycobacterium smegmatis L-lactate oxidase. 5-Deazaflavin mononucleotide as a coenzyme analogue.
Apo-lactic oxidase from Mycobacterium smegmatis reconstituted with the deazaisoalloxazine analogue of FMN, 5-deazaFMN, undergoes reduction by L-lactate but not catalytic reoxidation by O2. The rate of deazaFMN-holo-enzyme reduction by substrate is 1.1 min-1. With L-[alpha-3-H]-lactate, direct tritium transfer to enzyme-bound deazaFMN occurs during reduction. No evidence for a stable covalent lactate-deazaFMN adduct has been obtained. The deaza-FMNH2-enzyme is reoxidized extremely slowly by O2, consistent with the sluggish nonenzymatic reaction of deaza-FMNH2 with oxygen. On the other hand, addition of pyruvate to the deazaFMNH2-enzyme causes rapid reoxidation, a process not detected in the absence of enzyme.


Xenon preconditioning reduces brain damage from neonatal asphyxia in rats.
Xenon attenuates on-going neuronal injury in both in vitro and in vivo models of hypoxic-ischaemic injury when administered during and after the insult. In the present study, we sought to investigate whether the neuroprotective efficacy of xenon can be observed when administered before an insult, referred to as 'preconditioning'. In a neuronal-glial cell coculture, preexposure to xenon for 2 h caused a concentration-dependent reduction of lactate dehydrogenase release from cells deprived of oxygen and glucose 24 h later; xenon's preconditioning effect was abolished by cycloheximide, a protein synthesis inhibitor. Preconditioning with xenon decreased propidium iodide staining in a hippocampal slice culture model subjected to oxygen and glucose deprivation. In an in vivo model of neonatal asphyxia involving hypoxic-ischaemic injury to 7-day-old rats, preconditioning with xenon reduced infarction size when assessed 7 days after injury. Furthermore, a sustained improvement in neurologic function was also evident 30 days after injury. Phosphorylated cAMP (cyclic adenosine 3',5'-monophosphate)-response element binding protein (pCREB) was increased by xenon exposure. Also, the prosurvival proteins Bcl-2 and brain-derived neurotrophic factor were upregulated by xenon treatment. These studies provide evidence for xenon's preconditioning effect, which might be caused by a pCREB-regulated synthesis of proteins that promote survival against neuronal injury.


Plastic in the air?! - Spider webs as spatial and temporal mirror for microplastics including tire wear particles in urban air.
Studies concerning quantities of microplastics (MP) including tire wear particles (TWP) contamination in air samples are scarce. Spider webs have been suggested as a cheap and easily accessible biomonitor particularly for inorganic contaminates. Here, we emphasize the potential of spider webs to gain insights in the spatial and temporal trends of MP in urban air. The samples, collected in a mid-sized German city, were processed with Fentons reagent and measured using pyrolysis-gas chromatography-mass spectrometry for specific, polymer related indicator compounds. All samples contained TWP and other MP. The latter are detected and quantified as pyrolysis products of a polymer backbone. The results were expressed as clusters (prefix "C"). Determined polymer contaminations ranged from 11.4 μg/mg to 108 μg/mg spider web sample. The dominant polymer was C-PET (Ø 36.0% of total MP) derived most likely from textile fibers. Additionally, there was evidence for traffic-related contaminations. In particular car tire tread (Ø 40.8% of total MP) and ⁎C-PVC (Ø 12.0% of total MP) were found, with the latter presumably originating from paint used for road markings. Truck tire tread, C-PE, C-PP, C-PS, C-PMMA, and C-PC were also frequently found, but in much lower abundance (Ø <6.4% of total MP). Differences in contamination levels could be plausibly related to the sampling locations.


Primary care services in the English NHS: are they a thorn in the side of integrated care systems? A qualitative analysis.
As integrated care systems are embedded across England there are regions where the integration process has been evaluated and continues to evolve. Evaluation of these integrated systems contributes to our understanding of the challenges and facilitators to this ongoing process. This can support integrated care systems nationwide as they continue to develop. We describe how two integrated care partnerships in different localities, at differing stages of integration with contrasting approaches experienced challenges specifically when integrating with primary care services. The aim of this analysis was to focus on primary care services and how their existing structures impacted on the development of integrated care systems. We carried out an exploratory approach to re-analysing our previously conducted 51 interviews as part of our prior evaluations of integrated health and care services which included primary care services. The interview data were thematically analysed, focussing on the role and engagement of primary care services with the integrated care systems in these two localities. Four key themes from the data are discussed: (i) Workforce engagement (engagement with integration), (ii) Organisational communication (information sharing), (iii) Financial issues, (iv) Managerial information systems (data sharing, IT systems and quality improvement data). We report on the challenges of ensuring the workforce feel engaged and informed. Communication is a factor in workforce relationships and trust which impacts on the success of integrated working. Financial issues highlight the conflict between budget decisions made by the integrated care systems when primary care services are set up as individual businesses. The incompatibility of information technology systems hinders integration of care systems with primary care. Integrated care systems are national policy. Their alignment with primary care services, long considered to be the cornerstone of the NHS, is more crucial than ever. The two localities we evaluated as integration developed both described different challenges and facilitators between primary care and integrated care systems. Differences between the two localities allow us to explore where progress has been made and why.


Extreme snowfall and residential care: A case report of a 2-year-old girl with heart failure.
In residential care, the daily use of social networking services with patients (and patients' families) helps prepare for a potential disaster. This enables health workers to continue providing essential care even during disasters, while saving human and medical resources for those who need them the most.


Anti-Mullerian hormone in premenopausal women and after spontaneous or surgically induced menopause.
The objectives of this study were: (1) to determine anti-Mullerian hormone (AMH) levels in menopausal women, and (2) to confirm the source of AMH in cycling women and its disappearance after the removal of the source. An observational and prospective study was conducted. A total of 47 women were recruited for the study. The study population consisted of the following groups of patients: (A) women of late reproductive age (n = 24; mean age +/- SD, 44 +/- 2.8 years); (B) menopausal women (n =14; mean age, 56 +/- 4 years); and (C) regularly cycling women undergoing surgical menopause (n = 9; mean age, 43 +/- 4 years). Blood samples were obtained from all patients. In patients undergoing surgery, blood samples were obtained before and after surgery. AMH was undetectable in 13 of 14 postmenopausal women, whereas it was undetectable in only two of 24 women of late reproductive age. A significant negative correlation has been found between AMH and age or follicle-stimulating hormone (FSH) in women of late reproductive age. In women who were candidates for oophorectomy, samples were obtained 3-5 days after surgery. AMH was undetectable after the surgery in all women. We found that AMH levels decreased in women in the late reproductive period and that menopause and ovariectomy in regularly cycling women are associated to undetectable AMH in serum. These observations confirm that the ovary could be the only source of AMH in women and that it is a novel marker for ovarian aging.


Conformational dynamics of single protein molecules studied by direct mechanical manipulation.
Advances in single-molecule manipulation techniques have recently enabled researchers to study a growing array of biological processes in unprecedented detail. Individual molecules can now be manipulated with subnanometer precision along a simple and well-defined reaction coordinate, the molecular end-to-end distance, and their conformational changes can be monitored in real time with ever-improving time resolution. The behavior of biomolecules under tension continues to unravel at an accelerated pace and often in combination with computational studies that reveal the atomistic details of the process under investigation. In this chapter, we explain the basic principles of force spectroscopy techniques, with a focus on optical tweezers, and describe some of the theoretical models used to analyze and interpret single-molecule manipulation data. We then highlight some recent and exciting results that have emerged from this research field on protein folding and protein-ligand interactions.


Staphylococcus epidermidis as a cause of postoperative wound infection after cardiac surgery: assessment of pathogenicity by a wound-scoring method.
Wound infection after clean surgery prolongs hospital stay but the organism most commonly isolated from wound discharge, Staphylococcus epidermidis, is often dismissed as a contaminant or commensal. The wounds of 517 patients were assessed, after cardiac surgery, by a wound-scoring method ('ASEPSIS') and a close comparison was made of the appearance and clinical outcome of 89 wounds, from which bacteria were isolated. There was no significant difference in the scores of 49 wounds, where S. epidermidis was the sole isolate (9.5 per cent of all wounds, 95 per cent CI 6.9-12.0 per cent), and 13 wounds infected with Staphylococcus aureus (2.5 per cent, 95 per cent CI 1.2-3.9 per cent). Repeat cultures were obtained from 21 of the 49 wounds and, in 16 of these, the second isolate showed the same biochemical reactions and antibiotic resistance pattern as the first. Infection of sternal wounds is commoner with coagulase-negative staphylococci than with S. aureus and, clinically, is just as severe.


On the Biopsychosocial Costs of Alienated Labor.
Data from the national, longitudinal Mid-Life in the US (MIDUS) study were used to examine work alienation and its relationship to biological health as well as psychological and social functioning. The alienation measure focuses on the autonomy and creativity the work provides. We hypothesized that alienated work would have negative associations with each of the three domains: in biology, higher 'allostatic load' (biological dysregulation); in psychology, poorer cognitive performance; and socially, negative impacts on family life. The outcomes are generally as predicted, though there are notable differences for men and women.


Use of electroconvulsive therapy for individuals receiving inpatient psychiatric care on a nationwide scale in France: Variations linked to health care supply.
A comprehensive understanding of variations in the use of electroconvulsive therapy (ECT) among health care providers in charge of ECT referrals is lacking. Our objectives were to document ECT use and its variations on a nationwide scale in France and to identify the factors that were significantly associated with these variations. Administrative health claims data on hospitalization were used to perform a descriptive analysis of ECT use for adult patients receiving inpatient psychiatric care in mainland France in 2019 and its variations across hospitals in charge of ECT referrals. Based on a conceptual framework drawn from the literature on medical practice variations, a multilevel logistic regression was then conducted to identify patients, hospitals and contextual characteristics that were significantly associated with ECT treatment using non-ECT-treated patients receiving inpatient psychiatric care as the reference population. Patients receiving ECT (n = 3288) were older, more frequently female and had more severe diagnoses than other patients seen in inpatient care (n = 295,678). Significant variations were observed in the rate of ECT use across hospitals (n = 468), with a coefficient of variation largely above one. In the multivariable analysis, ECT treatment was associated with patient characteristics (which accounted for 6% of the variations) but also with characteristics of the hospitals and their environments (44% of the variations), including the type of hospital and its distance to the closest facility providing ECT. Variations in ECT use were strongly linked to health care supply characteristics, which raises questions about access to quality mental health care.


BACE1 gene variants do not influence BACE1 activity, levels of APP or Aβ isoforms in CSF in Alzheimer's disease.
The BACE1 gene encodes the beta-site APP-cleaving enzyme 1 and has been associated with Alzheimer's disease (AD). BACE1 is the most important β-secretase responsible for the generation of Alzheimer-associated amyloid β-proteins (Aβ) and may play a role in the amyloidogenic process in AD. We hypothesized that BACE1 gene variants might influence BACE1 activity or other markers for APP metabolism in the cerebrospinal fluid (CSF) and thereby contribute to the development of AD. We genotyped a Swedish sample of 269 AD patients for the rs638405 single nucleotide polymorphism (SNP) in the BACE1 gene and correlated genotype data to a broad range of amyloid-related biomarkers in CSF, including BACE1 activity, levels of Aβ40, Aβ42, α- and β-cleaved soluble APP (α-sAPP and β-sAPP), as well as markers for Alzheimer-type axonal degeneration, i.e., total-tau and phospho-tau181. Gene variants of BACE1 were neither associated with amyloid-related biomarkers, nor with markers for axonal degeneration in AD.


Reactive formation of hyaluronic acid in the rabbit corneal alkali burn.
The presence and distribution of reactively formed hyaluronic acid (HA) was assessed in the rabbit cornea following a penetrating alkali burn. The injury was inflicted by applying a round, 5.5 mm, filter paper soaked in 1 N NaOH centrally on the cornea for 60 seconds. Biochemical analysis revealed a significant increase of HA two weeks after injury, a peak concentration after 1 month, and a decrease again at three months. Histochemical analysis revealed the presence of hyaluronic acid in the healing epithelium, in the repopulating keratocytes/fibroblasts, and in the cells forming the retrocorneal membrane. Extensive amounts filled lacunae in the stroma as well as the spaces between collagen lamellae. A slow restoration of normal appearing corneal stroma took place at the periphery. Significant staining for HA in lacunae was present centrally in the wound after three months.


The hexosamine pathway and coat complex II promote malignant adaptation to nutrient scarcity.
The glucose-requiring hexosamine biosynthetic pathway (HBP), which produces UDP-N-acetylglucosamine for glycosylation reactions, promotes lung adenocarcinoma (LUAD) progression. However, lung tumor cells often reside in low-nutrient microenvironments, and whether the HBP is involved in the adaptation of LUAD to nutrient stress is unknown. Here, we show that the HBP and the coat complex II (COPII) play a key role in cell survival during glucose shortage. HBP up-regulation withstood low glucose-induced production of proteins bearing truncated N-glycans, in the endoplasmic reticulum. This function for the HBP, alongside COPII up-regulation, rescued cell surface expression of a subset of glycoproteins. Those included the epidermal growth factor receptor (EGFR), allowing an EGFR-dependent cell survival under low glucose in anchorage-independent growth. Accordingly, high expression of the HBP rate-limiting enzyme GFAT1 was associated with wild-type EGFR activation in LUAD patient samples. Notably, HBP and COPII up-regulation distinguished LUAD from the lung squamous-cell carcinoma subtype, thus uncovering adaptive mechanisms of LUAD to their harsh microenvironment.


Characterization of the bacterial archaeal diversity in hydrocarbon-contaminated soil.
A polyphasic approach combining culture-based methods with molecular methods is useful to expand knowledge on microbial diversity in contaminated soil. Microbial diversity was examined in soil samples from a former industrial site in the European Alps (mainly used for aluminum production and heavily contaminated with petroleum hydrocarbons) by culture-dependent and culture-independent methods. The physiologically active eubacterial community, as revealed by fluorescence-in-situ-hybridization (FISH), accounted for 6.7% of the total (DAPI-stained) bacterial community. 4.4% and 2.0% of the DAPI-stained cells could be attributed to culturable, heterotrophic bacteria able to grow at 20°C and 10°C, respectively. The majority of culturable bacterial isolates (34/48) belonged to the Proteobacteria (with a predominance of Alphaproteobacteria and Gammaproteobacteria), while the remaining isolates were affiliated with the Actinobacteria, Cytophaga-Flavobacterium-Bacteroides and Firmicutes. A high fraction of the culturable, heterotrophic bacterial population was able to utilize hydrocarbons. Actinobacteria were the most versatile and efficient degraders of diesel oil, n-alkanes, phenol and PAHs. The bacterial 16S rRNA gene clone library contained 390 clones that grouped into 68 phylotypes related to the Proteobacteria, Bacteroidetes, Actinobacteria and Spirochaetes. The archaeal 16S rRNA gene library contained 202 clones and 15 phylotypes belonging to the phylum Euryarchaeota; sequences were closely related to those of methanogenic archaea of the orders Methanomicrobiales, Methanosarcinales, Methanobacteriales and Thermoplasmatales. A number of bacterial and archaeal phylotypes in the clone libraries shared high similarities with strains previously described to be involved in hydrocarbon biodegradation. Knowledge of the bacterial and archaeal diversity in the studied soil is important in order to get a better insight into the microbial structure of contaminated environments and to better exploit the bioremediation potential by identifying potential hydrocarbon degraders and consequently developing appropriate bioremediation strategies.


MiR-150-5p Overexpression in Triple-Negative Breast Cancer Contributes to the In Vitro Aggressiveness of This Breast Cancer Subtype.
MiR-150-5p is frequently deregulated in cancer, with expression and mode of action varying according to the tumor type. Here, we investigated the expression levels and role of miR-150-5p in the aggressive breast cancer subtype triple-negative breast cancer (TNBC). MiR-150-5p expression levels were analyzed in tissue samples from 113 patients with invasive breast cancer (56 TNBC and 57 non-TNBC) and 41 adjacent non-tumor tissues (ANT). Overexpression of miR-150-5p was observed in tumor tissues compared with ANT tissues and in TNBC compared with non-TNBC tissues. MiR-150-5p expression levels were significantly associated with high tumor grades and the Caucasian ethnicity. Interestingly, high miR-150-5p levels were associated with prolonged overall survival. Manipulation of miR-150-5p expression in TNBC cells modulated cell proliferation, clonogenicity, migration, and drug resistance. Manipulation of miR-150-5p expression also resulted in altered expression of its mRNA targets, including epithelial-to-mesenchymal transition markers, MYB, and members of the SRC pathway. These findings suggest that miR-150-5p is overexpressed in TNBC and contributes to the aggressiveness of TNBC cells in vitro.


Rosiglitazone attenuates inflammation and CA3 neuronal loss following traumatic brain injury in rats.
Rosiglitazone, a potent peroxisome proliferator-activated receptor (PPAR)-γ agonist, has been shown to confer neuroprotective effects in stroke and spinal cord injury, but its role in the traumatic brain injury (TBI) is still controversial. Using a controlled cortical impact model in rats, the current study was designed to determine the effects of rosiglitazone treatment (6 mg/kg at 5 min, 6 h and 24 h post injury) upon inflammation and histological outcome at 21 d after TBI. In addition, the effects of rosiglitazone upon inflammatory cytokine transcription, vestibulomotor behavior and spatial memory function were determined at earlier time points (24 h, 1-5 d, 14-20 d post injury, respectively). Compared with the vehicle-treated group, rosiglitazone treatment suppressed production of TNFα at 24 h after TBI, attenuated activation of microglia/macrophages and increased survival of CA3 neurons but had no effect on lesion volume at 21 d after TBI. Rosiglitazone-treated animals had improved performance on beam balance testing, but there was no difference in spatial memory function as determined by Morris water maze. In summary, this study indicates that rosiglitazone treatment in the first 24 h after TBI has limited anti-inflammatory and neuroprotective effects in rat traumatic injury. Further study using an alternative dosage paradigm and more sensitive behavioral testing may be warranted.


Region-specific alterations of adenosine receptors expression level in kidney of diabetic rat.
Pathological alterations of renal function in insulin-dependent diabetes have been attributed to numerous factors, including adenosine. This study examined the expression levels of adenosine receptors (ARs) in the kidney of the streptozotocin-induced diabetic rat. In the diabetic kidney A1-AR mRNA levels increased 1.7- and 2.8-fold in cortex and medulla, respectively. This was accompanied by increased A1-AR protein levels in membranes of kidney cortex (1.5-fold) and medulla (threefold). A1-AR immunoreactivity increased strongly along medullar tubules especially in the collecting duct. The levels of A2a-AR mRNA increased twofold in diabetic kidney cortex but remained unchanged in medulla; however, A2a-AR protein levels increased more than threefold in cortex. Immunohistochemistry showed increased A2a-AR immunoreactivity in luminal membranes of cortical collecting ducts and in epithelial cells of preglomerular vessels. There were no significant changes in A2b-AR expression in diabetic kidney except in medullar membranes, where the receptor protein content decreased by 60%. A3-AR mRNA levels in diabetic kidney remained unchanged, but membrane-associated A3-AR protein levels increased by 70% in diabetic kidney cortex and decreased by 80% in medulla. These changes in ARs genes expression, receptor protein content, and cellular and tissue distribution, correspond to abnormalities characteristic of the diabetic kidney, suggesting involvement in pathogenesis of diabetic nephropathy.


Development and validation of a stability indicating isocratic HPLC method for gemcitabine with application to drug release from poly lactic-co-glycolic acid nanoparticles and enzymatic degradation studies.
Previously reported HPLC methods for gemcitabine determination are time-consuming with complicated mobile phases and gradient elution. Thus, a sensitive and stability-indicating isocratic HPLC method, which provides simple, fast and precise measurements, was developed. This method was applied to study the digestive enzymatic degradation of gemcitabine, for the first time, and the protection afforded following incorporation into poly lactic-co-glycolic acid (PLGA) nanoparticles. An analytical HPLC method was developed with an optimized combination of operating conditions. Forced degradation and application of the method to in-vitro drug release studies were conducted. Finally, gemcitabine-loaded nanoparticles were exposed to the digestive enzymes pepsin, trypsin and α-chymotrypsin, and the resulting degradation evaluated. The analytical method was linear between 1 and 100 μg/ml, with excellent accuracy of 99.91-101.77% and precision of 1.71 or lower, with a 0.014 μg/ml limit of detection (LOD) and a 0.043 μg/ml limit of quantification (LOQ). Following exposure of gemcitabine to stressors, the drug was relatively stable in strong acid (1 N HCl), base (1 N NaOH) and as an aqueous solution exposed to light over 7 days, with less than 10% degradation. However, gemcitabine was more susceptible to degradation at 70°C and oxidative conditions (3% v/v H2 O2 ) with greater than 10% degradation noted after 7 days. In-vitro drug release studies demonstrated a sustained drug release profile from PLGA nanoparticles, which also improved the resistance of gemcitabine to enzymatic degradation. These results demonstrate the utility and effectiveness of this simple isocratic HPLC method in evaluating the overall performance of a gemcitabine-loaded formulation.