Epidemiologic association between maternal smoking during pregnancy and intracranial hemorrhage in preterm infants.
The objective of this study was to evaluate the effect of maternal smoking during pregnancy on the risk of intracranial hemorrhage in preterm infants (born at 24 to 33 weeks of gestation). We conducted a case-control study of 96 preterm infants with intracranial hemorrhage and 96 gestational age-matched control subjects with negative cranial ultrasonographic findings. In conditional multiple logistic regression models, heavy maternal smoking ( > 10 cigarettes per day) during the latter half of pregnancy was associated with an increased risk of mild (grade I or II) intracranial hemorrhage (odds ratio = 5.96, 95% confidence interval 1.72 to 20.76; p = 0.005). After adjustment for the confounding effect of birth weight and respiratory distress syndrome, the risk of any intracranial hemorrhage (grade I to IV) was three times higher (adjusted odds ratio = 3.63, 95% confidence interval 1.37 to 9.63; p = 0.009) in infants of heavy smokers ( > 10 cigarettes per day) than in control subjects. The results of this study indicate that cigarette smoking during the latter half of pregnancy increases the risk of intracranial hemorrhage in preterm infants. The deleterious effect of smoking was greater for mild hemorrhages (grade I or II) and was confined to infants of heavy smokers.


Nerve growth factor increases sensitivity to bradykinin, mediated through B2 receptors, in capsaicin-sensitive small neurons cultured from rat dorsal root ganglia.
To examine the effects of nerve growth factor (NGF) on the response to bradykinin (BK) of primary afferent neurons, intracellular recordings were obtained from small (< 30 microm) and large (> or = 35 microm) neurons in rat dorsal root ganglia (DRG). The response to BK in the small neurons was tested in 23 freshly dissociated neurons (dissociated group), 37 neurons cultured in the absence of NGF (no-NGF group) and 117 neurons in the presence of NGF (NGF group). Application of BK (10(-7) or 10(-5) M) induced a depolarization in a small number of neurons in the freshly dissociated (13%) and the no-NGF (11%) groups. After cultivation with NGF, the percentage of neurons that were depolarized by BK significantly increased to 46% after 2 days of cultivation. In the NGF group, the percentage of neurons sensitive to BK was significantly greater among capsaicin (CAP)-sensitive than among CAP-insensitive neurons (48 vs 20%). This BK-induced depolarization was completely blocked by a B2 receptor antagonist, but not a B1 receptor antagonist. With large neurons, in contrast, NGF did not increase the percentage that were BK-sensitive (9% in the dissociated group vs 0% after being cultured 2 days with NGF). These results demonstrate that NGF increases sensitivity to BK, mediated through B2 receptors only, in capsaicin-sensitive small neurons cultured from rat DRGs.


Conformational analysis of endothelin-1: effects of solvation free energy.
In order to investigate conformational preferences of the 21-residue peptide hormone endothelin-1 (ET-1), an extensive conformational search was carried out in vacuo using a combination of high temperature molecular dynamics/annealing and a Monte Carlo/minimization search in torsion angle space. Fully minimized conformations from the search were grouped into families using a clustering technique based on rms fitting over the Cartesian coordinates of the atoms of the peptide backbone of the ring region. A wide range of local energy mining were identified even though two disulfide bridges (Cys1-Cys15 and Cys3-Cys11) constrain the structure of the peptide. Low energy conformers of ET-1 as a nonionized species in vacuo are stabilized by intramolecular interaction of the ring region (residues 1-15) with the tail (residues 16-21). Strained conformations for individual residues are observed. Conformational similarity to protein loops is established by matching to protein crystal structures. In order to assess the influence of aqueous environment on conformational preference, the electrostatic contribution to the solvation energy was calculated for ET-1 as a fully ionized species (Asp8, Lys9, Glu10, Asp18, N- and C-terminus) using a continuum electrostatics model (DelPhi) for each of the conformers generated in vacuo, and the total solvation free energy was estimated by adding a hydrophobic contribution proportional to solvent accessible surface area. Solvation dramatically alters the relative energetics of ET-1 conformers from that calculated in vacuo. Conformers of ET-1 favored by the electrostatic solvation energy in water include conformers with helical secondary structure in the region of residues 9-15. Perhaps of most importance, it was demonstrated that the contribution to solvation by an individual charge depends not only on its solvent accessibility but on the proximity of other charges, i.e., it is a cooperative effect. This was shown by the calculation of electrostatic solvation energy as a function of conformation with individual charges systematically turned "on" and "off". The cooperative effect of multiple charges on solvation demonstrated in this manner calls into question models that relate solvation energy simply to solvent accessibility by atom or residue alone.


A comparison between the use of a high-resolution CCD camera and 35 mm film for obtaining coloured micrographs.
In light microscopy, colour CCD cameras are now capable of generating image data sets that contain more information than can be captured with slow 35 mm colour reversal film. The resolution of colour CCD cameras with a high density of sensor elements (> or = 3300 x 2200 per channel of colour) is equivalent to that of slow 35 mm colour film over typical fields of view for objectives with a wide range of magnifications and numerical apertures. The contrast that can be achieved in images derived from the data sets obtained with colour CCD cameras far exceeds that found with film and can exceed that of human vision. Finally, the data sets collected with high-resolution colour CCD cameras are capable of being displayed at a wide range (four-fold) of different magnifications easily and interchangeably. Consequently, the combination of a data set that describes a relatively large field of view with one or two data sets that describe specific details taken with an eight-fold increase in magnification are all that is necessary to describe the salient features of the vast majority of stained specimens examined with transmitted light microscopy.


GAB2 rs2373115 variant contributes to Alzheimer's disease risk specifically in European population.
A genome-wide association study identified GAB2 rs2373115 to be associated with Alzheimer's disease (AD) risk in European population. However, inconsistent results are reported in East Asian population. Here, we performed an updated analysis using 65,704 samples including 20,982 AD cases and 44,722 controls. First, we investigated the GAB2 rs2373115 variant in Asian population using 3974 AD cases and 7568 controls. To further evaluate the effect of rs2373115 in different populations, we selected 17,008 AD cases and 37,154 controls in European population. We used three genetic models, and found no significant heterogeneity in Asian population. A fixed effect model analysis showed no significant association between rs2373115 and AD in Asian population. There was no significant heterogeneity in the pooled East Asian and European populations. The fixed effect model analysis again showed no significant association between rs2373115 and AD in these pooled populations. Taken together, these findings suggest that GAB2 rs2373115 may contribute to AD susceptibility only in European population but not in East Asian population.


Adding brain volume measures into response criteria in multiple sclerosis: the Río-4 score.
Brain volume changes (BVC) on therapy in MS are being considered as predictor for treatment response at an individual level. We ought to assess whether adding BVC as a factor to monitor interferon-beta response improves the predictive ability of the (no) evidence of disease activity (EDA-3) and Río score (RS-3) criteria for confirmed disability progression in a historical cohort. One hundred one patients from an observational cohort treated with interferon-beta were assessed for different cutoff points of BVC (ranged 0.2-1.2%), presence of active lesions (≥ 1 for EDA/≥ 3 for RS), relapses, and 6-month confirmed disability progression (CDP), measured by the Expanded Disability Status Scale, after 1 year. Sensitivity, specificity, and positive and negative predictive values for predicting confirmed disability progression at 4 years in original EDA (EDA-3) and RS (RS-3) as well as EDA and RS including BVC (EDA-4 and RS-4) were compared. Adding BVC to EDA slightly increased sensitivity, but not specificity or predictive values, nor the OR for predicting CDP; only EDA-3 showed a trend for predicting CDP (OR 3.701, p = 0.050). Adding BVC to RS-3 (defined as ≥ 2 criteria) helped to improve sensitivity and negative predictive value, and increased OR for predicting CDP using a cutoff of ≤ - 0.86% (RS-3 OR 23.528, p < 0.001; RS-4 for all cutoffs ranged from 15.06 to 32, p < 0.001). RS-4 showed areas under the curve larger than RS-3 for prediction of disability at 4 years. Addition of BVC to RS improves its prediction of response to interferon-beta.


Characteristics of a pyrimidine-specific 5'-nucleotidase in human erythrocytes.
A 5'-nucleotidase with unique specificity has been identified in the soluble fraction of normal human erythrocytes. It mediates the hydrolytic dephosphorylation of pyrimidine 5'-ribosemonophosphates but is catalytically ineffective with purine nucleotides or with the 2'-, 3'-, or cyclic isomers of pyrimidine nucleotides. Activities at 37 degrees in dialyzed hemolysates of nromal human erythrocytes averaged 7.3 and 6.2 mumol of Pi liberated per hour per g of hemoglobin for the substrates UMP and CMP, respectively. Activity with TMP as substrate was approximately one-half as much as with UMP or CMP. Apparent Michaelis constants were 0.33 mM UMP, 0.15 mM CMP, and 1.0 mM TMP. Magnesium was required for optimal activity, and this cation could not be replaced by Mn2+. Maximum activity was obtained between pH 7.0 and 7.5 with rapid decreases in more alkaline media and moderate decreases with acidification. The enzyme was quite sensitive to heat and was strongly inhibited by AMP, by some purine bases, and by both purine and pyrimidine nucleosides. Divalent cations of heavy metals were also strongly inhibitory, as were agents active against sulfhydryl groups. The presence of substrates and/or 2-mercaptoethanol provided considerable protection against some of these deleterious agents and conditions. Pyrimidine 5'-nucleotidase activity in hemolysates was clearly distinguishable from erythrocyte acid phosphatase and from leukocyte and serum alkaline phosphatases and nucleotidases.


Synthesis and biological evaluation of 5'-C-methyl nucleotide prodrugs for treating HCV infections.
Nucleotide prodrugs are of great clinical interest for treating a variety of viral infections due to their ability to target tissues selectively and to deliver relatively high concentrations of the active nucleotide metabolite intracellularly. However, their clinical successes have been limited, oftentimes due to unwanted in vivo metabolic processes that reduce the quantities of nucleoside triphosphate that reach the site of action. In an attempt to circumvent this, we designed novel nucleosides that incorporate a sterically bulky group at the 5'-carbon of the phosphoester prodrug, which we reasoned would reduce the amounts of non-productive PO bond cleavage back to the corresponding nucleoside by nucleotidases. Molecular docking studies with the NS5B HCV polymerase suggested that a nucleotide containing a 5'-methyl group could be accommodated. Therefore, we synthesized mono- and diphosphate prodrugs of 2',5'-C-dimethyluridine stereoselectively and evaluated their cytotoxicity and anti-HCV activity in the HCV replicon assay. All four prodrugs exhibited anti-HCV activity with IC50 values in the single digit micromolar concentrations, with the 5'(R)-C-methyl prodrug displaying superior potency relative to its 5'(S)-C-methyl counterpart. However, when compared to the unmethylated prodrug, the potency is poorer. The poorer potency of these prodrugs may be due to unfavorable steric interactions of the 5'-C-methyl group in the active sites of the kinases that catalyze the formation of active triphosphate metabolite.


Pancancer analysis of oncogenic BARX2 identifying its prognostic value and immunological function in liver hepatocellular carcinoma.
The transcription factor BarH-like homeobox 2 (BARX2), a member of the Bar-like homeobox gene family, is involved in cell proliferation, differentiation, immune responses and tumorigenesis. However, the potential role of BARX2 in the development of liver hepatocellular carcinoma (LIHC) remains unclear. Therefore, we aimed to study the biological role of BARX2 in hepatocellular carcinoma. Through the UALCAN, GTEx PORTAL, TIMER 2.0, LinkedOmics, SMART, MethSurv, Metascape, GSEA and STRING public databases, the BARX2 mRNA level, prognostic value, coexpressed genes, associated differentially expressed genes, DNA methylation and functional enrichment of LIHC patients were studied. The relationships between BARX2 expression and various clinical or genetic parameters of LIHC patients were determined using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and BEAT LIHC databases. In addition, the biological function of BARX2 in LIHC was studied in vitro. Through large-scale data mining, our study showed that BARX2 was differentially expressed between different normal and tumour tissues.BARX2 expression in LIHC tissues was significantly lower than that in corresponding controls, especially in patients with T2-4 stage disease. In patients with LIHC, overexpression of BARX2 was an independent poor prognostic factor associated with poor cytogenetic risk and gene mutations. Genomic hypermethylation of the BARX2 gene was associated with upregulated BARX2 expression and poor overall survival (OS) in LIHC. Functional enrichment analysis showed that BARX2 had an immunomodulatory role and was involved in the inflammatory response in LIHC occurrence. In conclusion, the oncogene BARX2 may serve as a new biomarker and prognostic factor for patients with LIHC. The immunomodulatory function of BARX2 deserves further validation in LIHC.


Spontaneous thrombosis of a residual arteriovenous malformation in eloquent cortex after surgery: case report.
The presence of a residual arteriovenous malformation (AVM) on postoperative angiograms is typically an indication for prompt return to the operating room to complete resection, because of the risk of early hemorrhage. This approach, however, may involve risks of neurological deficits when the residual AVM is in eloquent cortex. We present a case of complete thrombosis of a residual AVM after surgery. This residual AVM tissue was located in eloquent cortex. Complete spontaneous thrombosis of residual AVMs after surgery has only rarely been reported. This phenomenon raises questions regarding the most appropriate management for residual AVMs in eloquent cortex. The patient was a 43-year-old, right-handed, male patient with an AVM centered in the left precentral gyrus. The patient presented with medically intractable seizures and progressive right hemiparesis. After AVM resection, angiography revealed a residual AVM with early venous drainage. Angiography performed 1 week later demonstrated a persisting AVM nidus without early venous drainage. Angiography performed 3 months later demonstrated complete thrombosis of the residual AVM. The patient has been monitored for more than 1 year, without additional symptoms or therapy. We continue to advocate prompt return to the operating room when postoperative angiography reveals a residual AVM with persistent shunting. When the residual AVM is in eloquent cortex and is small, with a single draining vein, however, observation of the patient (with strict blood pressure control) and repeat angiography after 1 week represent an alternative strategy that is supported by this case report. As this case demonstrates, it is possible for small residual AVMs to thrombose. This may avert the need for reoperation for residual AVMs in eloquent cortex, with the potential for neurological deficits.


The discrete anatomical localization of vagal aortic afferents within a catecholamine-containing cell group in the nucleus solitarius.
The centripetal transport of horseradish peroxidase (HRP) was used to visualize the central projections of afferent fibers of the aortic arch nerve to the nucleus solitarius in pigeons. Our results indicate that aortic nerve afferents have a restricted distribution within one subdivision of the nucleus solitarius, designated the subnucleus sulcalis dorsalis. Histofluorescence studies revealed that the aortic nerve projection area is extremely rich in catecholamine-containing neurons.


Identification and characterization of syntenin binding protein in the black tiger shrimp Penaeus monodon.
Shrimp exhibit a diverse response to viral infection that is manifested in drastic up- and down-regulations of a variety of genes. In our previous work, we identified syntenin of the shrimp Penaeus monodon (Pm) as a dynamic responder to white spot syndrome virus (WSSV) infection, its message being greatly upregulated in the acute phase of the infection. In order to further explore the link between Pm-syntenin and viral infection, we performed a yeast two-hybrid screening of a P. monodon cDNA library, using Pm-syntenin as bait. One of the molecules that specifically interacted with Pm-syntenin was the receptor-binding domain of alpha-2-macroglobulin (alpha2M). A GST pull-down assay showed that GST-alpha2M, but not GST alone, was capable of co-precipitating syntenin. Another GST pull-down assay showed that GST-syntenin, but not GST alone, was capable of co-precipitating alpha2M. In addition, mutant analyses showed that the N-terminal 131 amino acids of syntenin were both necessary and sufficient to bind the C-terminus receptor-binding domain of alpha2M. Furthermore, WSSV-infected Pm showed a significant upregulation of the alpha2M message, suggesting that both syntenin and its protein partner alpha2M are upregulated in the acute phase of a WSSV infection. Taken together with a previous report showing the co-localization of alpha2M and syntenin in the exosome of a dendritic cell line, it is likely that syntenin, through its interaction with alpha2M, plays an important role in the immune defense mechanisms of viral infections of shrimps.


Temporary neurological dysfunction after surgery of the thoracic aorta: a predictor of poor outcome and impaired quality of life.
Transient neurological dysfunction (TND) consists of postoperative confusion, delirium and agitation. It is underestimated after surgery on the thoracic aorta and its influence on long-term quality of life (QoL) has not yet been studied. This study aimed to assess the influence of TND on short- and long-term outcome following surgery of the ascending aorta and proximal arch. Nine hundred and seven patients undergoing surgery of the ascending aorta and the proximal aortic arch at our institution were included. Two hundred and ninety patients (31.9%) underwent surgery because of acute aortic dissection type A (AADA) and 617 patients because of aortic aneurysm. In 547 patients (60.3%) the distal anastomosis was performed using deep hypothermic circulatory arrest (DHCA). TND was defined as a Glasgow coma scale (GCS) value <13. All surviving patients had a clinical follow up and QoL was assessed with an SF-36 questionnaire. Overall in-hospital mortality was 8.3%. TND occurred in 89 patients (9.8%). As compared to patients without TND, those who suffered from TND were older (66.4 vs 59.9 years, p<0.01) underwent more frequently emergent procedures (53% vs 32%, p<0.05) and surgery under DHCA (84.3% vs 57.7%, p<0.05). However, duration of DHCA and extent of surgery did not influence the incidence of TND. In-hospital mortality in the group of patients with TND compared to the group without TND was similar (12.0% vs 11.4%; p=ns). Patients with TND suffered more frequently from coronary artery disease (28% vs 20.8%, p=ns) and were more frequently admitted in a compromised haemodynamic condition (23.6% vs 9.9%, p<0.05). Postoperative course revealed more pulmonary complications such as prolonged mechanical ventilation. Additional to their transient neurological dysfunction, significantly more patients had strokes with permanent neurological loss of function (14.6% vs 4.8%, p<0.05) compared to the patients without TND. ICU and hospital stay were significantly prolonged in TND patients (18+/-13 days vs 12+/-7 days, p<0.05). Over a mean follow-up interval of 27+/-14 months, patients with TND showed a significantly impaired QoL. The neurological outcome following surgery of the ascending aorta and proximal aortic arch is of paramount importance. The impact of TND on short- and long-term outcome is underestimated and negatively affects the short- and long-term outcome.


[Effect of polymer complexons based on vinylpyrrolidone copolymers with vinyliminodiacetic acid and methacrtloylacetone on the antibiotic sensitivity of antibiotic-resistant bacterial strains].
Polymer complexons, such as copolymers of vinylpyrrolidone with vinyliminodiacetic acid and metacryloilacetone changed the permeability of the bacterial cell wall due to chelating of the metalic ions contained in the cell wall. An increase in the bacterial sensitivity to chloretracycline, methicillin, ampicillin and methicillin was observed in the presence of the above complexons.


Role for subgenomic mRNA in host translation inhibition during Sindbis virus infection of mammalian cells.
Sindbis virus subgenomic mRNA is efficiently translated in infected vertebrate cells whereas host translation is shut-off. Deletions in the 5'UTR of the subgenomic mRNA were made to investigate its role in viral gene expression. Deletion of nucleotides 1-10 and 11-20 caused a small plaque phenotype, reduced levels of subgenomic mRNA and structural proteins, and increased expression of nonstructural proteins. Whereas deletion 1-10 virus inhibited cellular protein synthesis, deletion 11-20 did so inefficiently. A large plaque revertant of deletion 11-20, possessing a duplication of the subgenomic promoter region, produced subgenomic mRNA at WT levels and restored inhibition of host protein synthesis. Further analysis of the mutant and revertant 5'UTR sequences showed the ability to shut-off host cell translation correlated with the efficiency of translation of subgenomic mRNA. We propose that the translational efficiency and quantity of the subgenomic mRNA play a role in inhibition of host cell translation.


[Prevalence of refractive errors in students in Northeastern Brazil].
To determine the prevalence of refractive errors in the public and private school system in the city of Natal, Northeastern Brazil. Refractometry was performed on both eyes of 1,024 randomly selected students, enrolled in the 2001 school year and the data were evaluated by the SPSS Data Editor 10.0. Ametropia was divided into: 1- from 0.1 to 0.99 diopter (D); 2- 1.0 to 2.99 D; 3- 3.00 to 5.99 D and 4- 6D or greater. Astigmatism was regrouped in: I- with-the-rule (axis from 0 to 30 and 150 to 180 degrees), II- against-the-rule (axis between 60 and 120 degrees) and III- oblique (axis between > 30 and < 60 and >120 and <150 degrees). The age groups were categorized as follows, in: 1- 5 to 10 years, 2- 11 to 15 years, 3- 16 to 20 years, 4- over 21 years. Among refractive errors, hyperopia was the most common with 71%, followed by astigmatism (34%) and myopia (13.3%). Of the students with myopia and hyperopia, 48.5% and 34.1% had astigmatism, respectively. With respect to diopters, 58.1% of myopic students were in group 1, and 39% distributed between groups 2 and 3. Hyperopia were mostly found in group 1 (61.7%) as well as astigmatism (70.6%). The association of the astigmatism axes of both eyes showed 92.5% with axis with-the-rule in both eyes, while the percentage for those with axis against-the-rule was 82.1% and even lower for the oblique axis (50%). The results found differed from those of most international studies, mainly from the Orient, which pointed to myopia as the most common refractive error, and corroborates the national ones, with the majority being hyperopia.


Plasma omega-3 polyunsaturated fatty acids and recurrence of endometrial cancer.
Omega-3 polyunsaturated fatty acids (PUFAs) were proposed to have potential effects against inflammation and cancer. However, results from epidemiology studies remain inconsistent. We aimed to explore the associations of plasma PUFAs with EC recurrence and all-cause mortality. Women diagnosed with endometrial cancer (EC) between 2008 and 2013 and underwent surgery at Fudan University Shanghai Cancer Center of China were recruited. Survival status was followed up through September 2017. EC recurrence and total cause deaths were identified through medical record and telephone interview. In total, 202 patients with enough plasma samples at time of surgery were included. There were 195 patients who provided baseline plasma and survival information included in the current study. Plasma omega-3 PUFAs were measured by GC-FID. Cox Proportional Hazard model adjusted for potential cofounders was used to estimate HRs and 95% CIs. Median follow-up time for patients was 58 months after surgery. A total of 13 recurrences and 11 all-cause deaths, of which, 2 deaths from EC, were identified. Level of plasma EPA was higher in recurrent patients than total patients (0.78% vs 0.51%, P = 0.015). Higher plasma eicosapentaenoic acid (EPA) level trended to have positive association with EC recurrence (P-trend = 0.04), although comparing to the lowest tertile, the highest tertile of EPA level was not significantly associated with increased risk of EC recurrence (HRT3vsT1 = 6.02; 95%CI = 0.7-52.06). The association between total omega-3 PUFA and EC recurrence tended to be stronger among patients with deeper myometrial invasion (OR = 3.41; 95%CI = 1.06-10.95; P-interaction = 0.04). Higher plasma EPA level was significantly associated with EC recurrence. Further studies are warranted to confirm these findings. ChiCTR1900025418; Retrospectively registered (26 August 2019); Chinses Clinical Trial Registry.


Isolation and characterization of a low-molecular weight seed protein from Ricinus communis.
A seed protein with an apparent molecular weight of 5000 has been isolated and purified from Ricinus communis. This protein has a very high content of glutamine and an unusual ultraviolet absorption spectrum. The amino-terminal sequence of 22 residues determined by automatic Edman degradation is: NH2-Pro-Ser-Gln-Gln-Gly-Cys-Cys-Gly-Gln-Ile-Gln-Glu-Gln-Gln-Asn-Leu-Arg-Gln-Cys-Gln-Glu-Tyr-.


An evaluation of the effects of mixed heavy metals on prediabetes and type 2 diabetes: epidemiological and toxicogenomic analysis.
The link between mixed heavy metals (mercury, lead, and cadmium), prediabetes, and type 2 diabetes mellitus (T2DM), especially molecular mechanisms, is poorly understood. Thus, we aimed to identify the association between mixed heavy metals and T2DM and its components using a data set from the Korean National Health and Nutrition Examination Survey. We further analyzed the main molecular mechanisms implicated in T2DM development induced by mixed heavy metals using in-silico analysis. Our findings observed that serum mercury was associated with prediabetes, elevated glucose, and ln2-transformed glucose when using different statistical methods. "AGE-RAGE signaling pathway in diabetic complications", "non-alcoholic fatty liver disease", "metabolic Syndrome X", and three miRNAs (hsa-miR-98-5p, hsa-let-7a-5p, and hsa-miR-34a-5p) were listed as the most important molecular mechanisms related to T2DM development caused by mixed heavy metals. These miRNA sponge structures were created and examined, and they may be beneficial in the treatment of T2DM. The predicted cutoff values for three heavy metal levels linked to T2DM and its components were specifically identified. Our results imply that chronic exposure to heavy metals, particularly mercury, may contribute to the development of T2DM. To understand the changes in the pathophysiology of T2DM brought on by a combination of heavy metals, more research is required.


Estrogen and skin: the effects of estrogen, menopause, and hormone replacement therapy on the skin.
Aging is associated with declining levels of several hormones, including estrogen. Although the effects of estrogen on the skin are still not fully understood, it is known that, in women, declining estrogen levels are associated with a variety of cutaneous changes, many of which can be reversed or improved by estrogen supplementation. Estrogens are C-18 steroids synthesized from cholesterol in the ovary premenopausally and in the peripheral tissue in postmenopausal women. Two estrogen receptors, alpha and beta, have been cloned and found in various tissue types. Studies of postmenopausal women indicate that estrogen deprivation is associated with dryness, atrophy, fine wrinkling, poor healing, and hot flashes. Epidermal thinning, declining dermal collagen content, diminished skin moisture, decreased laxity, and impaired wound healing have been reported in postmenopausal women. This article reviews the effects of declining estrogen levels on the skin and the effects of estrogen supplementation. At the conclusion of this learning activity, participants should be familiar with the pathways of estrogen synthesis, sites of estrogen receptors, age-dependent variations in serum estrogen concentration, the changes seen in postmenopausal skin, and the effects of estrogen supplementation.


Ureterocele associated with renal agenesia presented as a pelvic mass in an adult.
Adult ureteroceles are generally known as simple ureteroceles with minimal obstructive effects 1 that can usually be managed endoscopically. Such pathology presented with acute abdominal pain and fever in a 32-year-old man with left renal agenesia, a cranial blind left ureter and left obstructed ureterocele. The retained secretions were suppurative.


The safety of orthokeratology in myopic children and analysis of related factors.
To evaluate the safety of overnight orthokeratology (OK) wear and explore whether factors such as age, refraction and allergic conjunctivitis (AC) history were associated with corneal adverse events (AEs) incidence. Medical records of consecutive patients who started OK for myopia correction and continued for more than one year were retrospectively reviewed. Clinical data including sex, baseline age, spherical equivalent refraction (SER), and related medical histories were retrieved. A total of 489 eyes from 260 patients (age: 8-15 years; SER: -1.00 to -6.00 D) were included. Corneal adverse events were the primary outcome. The generalized estimating equations model was used to evaluate the effects of sex, age, SER, and allergic conjunctivitis history on corneal AE incidence over the one-year period. A total of 111 eyes (22.7%) had corneal AE during the one-year follow-up (corneal staining [n = 106], corneal infiltration [n = 5]) and the incidence of significant AE was 6.9%. The corneal AE incidence was associated with age (OR = 0.874, 95%CI = 0.781-0.978, p = 0.019); SER (OR=0.632, 95%CI=0.531-0.754, p < 0.001); and AC (OR=1.706, 95%CI=1.017-2.860, p = 0.043). High refraction was the key risk factor for significant AE (OR=0.542, 95%CI=0.401-0.732, p < 0.001). Orthokeratology is a safe option for children with myopia. Younger age, higher myopia, and AC were risk factors for corneal AE in OK wearers. Whereas, only higher myopia was a risk factor for significant AE.


Cephalic venous aneurysm in the wrist.
Venous aneurysms are benign vascular lesions usually located in the neck, lower extremity, and abdomen, but rarely in the upper extremity. There may be a mistake or delay in diagnosis because they are uncommon. We report a case of a healthy 54-year-old man who had a cephalic venous aneurysm in his wrist that grew slowly over 20 years. The diagnosis was made on MRI and confirmed with excisional surgery. Radiologists should consider venous aneurysms in the differential when evaluating soft tissue masses as they will often be the first to make the correct diagnosis.


Glial regulation of the cerebral microvasculature.
The brain is a heterogeneous organ with regionally varied and constantly changing energetic needs. Blood vessels in the brain are equipped with control mechanisms that match oxygen and glucose delivery through blood flow with the local metabolic demands that are imposed by neural activity. However, the cellular bases of this mechanism have remained elusive. A major advance has been the demonstration that astrocytes, cells with extensive contacts with both synapses and cerebral blood vessels, participate in the increases in flow evoked by synaptic activity. Their organization in nonoverlapping spatial domains indicates that they are uniquely positioned to shape the spatial distribution of the vascular responses that are evoked by neural activity. Astrocytic calcium is an important determinant of microvascular function and may regulate flow independently of synaptic activity. The involvement of astrocytes in neurovascular coupling has broad implications for the interpretation of functional imaging signals and for the understanding of brain diseases that are associated with neurovascular dysfunction.


Salvianolic Acid B-Loaded Chitosan/hydroxyapatite Scaffolds Promotes The Repair Of Segmental Bone Defect By Angiogenesis And Osteogenesis.
Salvianolic acid B has been proven as an effective drug to promote osteogenesis and angiogenesis which could be beneficial for bone repair. The objective of this study was to construct a salvianolic acid B-loaded chitosan/hydroxyapatite (Sal B-CS/HA) bone scaffold with controlled release and effective bioactivity. The characteristics, controlled release behavior and bioactivity of Sal B-CS/HA scaffold were evaluated in vitro. The bone repair effect was evaluated in the rabbit radius defect model. The results showed that chemical and physical characteristics of salvianolic acid B and chitosan/hydroxyapatite (CS/HA) material did not obviously change after the drug loading procedure; the drug release of salvianolic acid B was stable and continuous from the Sal B-CS/HA scaffold for 8 weeks in vitro; the biocompatibility of the Sal B-CS/HA was favorable by evaluation of cell morphology and proliferation; the osteogenic and angiogenic bioactivities of the Sal B-CS/HA scaffold were proved to be effective by in vivo and in vitro tests. Our results suggest that this salvianolic acid B-loaded bone scaffold has potential to be used for bone defect repair with both osteogenic and angiogenic bioactivities.


Geomagnetic/inertial navigation integrated matching navigation method.
The accuracy of an a priori geomagnetic reference map is a significant constraint on the geomagnetic matching navigation method. Especially when the aircraft enters an unknown environment, it is impossible to accomplish the navigation task using traditional geomagnetic navigation methods. Therefore, a geomagnetic/INS integrated matching navigation algorithm for long-scale navigation is proposed in this paper, which can perform navigation tasks regardless of whether there is an a priori geomagnetic map. This method combines a magnetogram-based matching navigation method with a geomagnetic bionic navigation method that does not require a geomagnetic map. The navigation trajectory is first analyzed in the area where the geomagnetic map is available, and the matching results are further corrected by filters for the inertial navigation system. Furthermore, when the aircraft flies through an unknown area without the a priori geomagnetic map, the nonmagnetic map navigation method is used to guide the aircraft to the destination. Finally, simulations are performed for the geomagnetic map distribution and noise effects that may occur during actual flight, and the obtained results show the effectiveness of the proposed algorithm in a complicated geomagnetic environment.


Improving the No-Show Rate of New Patients in Outpatient Psychiatric Practice: An Advance Practice Nurse-Initiated Telephone Engagement Protocol Quality Improvement Project.
The aim is to improve the uptake of psychiatric services for new patients being referred from primary care, counseling, and hospital discharge follow-up care. A convenience sample of 18 new patients participated in a provider-initiated telephone protocol to increase knowledge related to psychiatric treatment and remind patients of appointments the day before the initial visit. Fifteen patients attended the initial visit, resulting in a 26% reduction rate of no-show rates from 27% the previous year to 20% in a 3-month period. Introduction and reminder calls by psychiatric providers improve no-show rates.


Primary adenoid cystic carcinoma arising from an ectopic lacrimal gland involving both nasal orbits: a rare clinical entity.
Adenoid cystic carcinoma (ACC) is a slow-growing, locally invasive tumor of epithelial origin. The common sites of origin are the minor and major salivary glands and also the lacrimal glands. ACC accounts for 4.8% of primary orbital neoplasms and commonly arises superolaterally from the main lacrimal gland. Primary ACC of the orbit from an extra lacrimal region is quite rare. We present a case of ACC that occurred in ectopic lacrimal gland tissue involving the medial region of both orbits. A 74-year-old woman was admitted with a 4-week history of progressive painful proptosis in her left eye. Examination revealed a medium-size bilateral nasal canthal mass. Computed tomography (CT) scan revealed a nasal mass in both orbits with bone erosion. The patient underwent bilateral anterior orbitotomy and incisional biopsy was performed. Histopathology exam revealed an ACC with perineural and bone invasion. She refused orbital exenteration and radiation therapy was initiated.


Surgery of hemophiliacs--20 years' experience.
Seventy-seven hemophilic patients of type A or type B were subjected to a total of 108 major surgical procedures mainly in the field of general surgery, orthopedic surgery, or neurosurgery. The principles for the substitution therapy in the different types of procedures and different types of hemophilic diseases are described, as well as the indications for surgery and the surgical technique. The importance of prolonged substitution therapy postoperatively to avoid late hematoma, particularly in patients with severe hemophilia undergoing major surgery, is stressed. With this type of management there has been no increased intraoperative hemorrhage, and very few cases of late hematoma formation. By combining the substitution therapy with immunosuppression, it has been possible to operate also on patients with inhibitors against factor VIII or IX. The rate of complications, particularly the incidence of hepatitis, has been low with the type of substitution given in this series of patients. It is concluded that major surgery can be carried out even in severe hemophilia without significantly increased risk. The handling of the substitution therapy, and the surgical judgment and technique, offers however, special problems, necessitating centralization of elective cases.


High frequency oscillations in early cortical somatosensory evoked potentials.
To evaluate the characteristics of high frequency (HF) components of the early cortical somatosensory evoked potentials (SEPs). We recorded 8-channel SEPs from the frontal and left centro-parietal scalp after right median nerve stimulation with a wide band-pass (0.5-2000 Hz) and digitized at 40 kHz sampling rate in 12 healthy subjects. HF components were analyzed after digital band-pass filtering (300-1000 Hz). The power spectrum was obtained by a maximum entropy method. HF oscillations (maximum power at 600-800 Hz) consisting of 5 to 8 peaks were discriminated from the preceding P14 far-field in all cases and their phases were reversed between the frontal and contralateral parietal regions. In addition, in subjects with a high amplitude central P22 potential in original wide-band recordings, a single HF oscillation with a maximum at the central region was present. Furthermore, this component showed no phase reversal over the centro-parietal area. We therefore conclude that HF oscillations are superimposed not only on the tangential N20-P20 but on the radial P22 potential, and are generated from both tangential (area 3b) and radial (area 1) current sources.


Simultaneous presentation of IgA nephropathy and sarcoidosis.
Sarcoidosis and IgA nephropathy diagnosed simultaneously in a 23-year-old male patient is described. This association is most unusual. The possible inter-relationship between the two conditions is discussed.


Deep venous thrombosis in children with musculoskeletal infections: the clinical evidence.
Clinical manifestations of deep venous thrombosis (DVT) tend to overlap with those of deep-seated musculoskeletal infections (MSIs). Consequently, the incidence of DVT as a complication of MSI may be underestimated. The objective of this study was to evaluate the incidence, clinical features, and outcomes of MSI-related DVT in children. We systematically reviewed relevant studies retrieved from PubMed and Scopus databases. Overall, 93 children with MSIs who developed DVT were identified from 28 retrospective studies. The majority were boys. Osteomyelitis was the most frequent MSI (69/74, 93%). Staphylococcus aureus was the predominant pathogen (83/93, 89%); 61% of these isolates were methicillin-resistant S. aureus (MRSA). Pulmonary involvement, presumably due to septic emboli, was observed in 65% of the included children. Four children died due to multiple organ failure and two due to respiratory distress. In two of the three studies providing comparative data, MRSA infections were observed significantly more frequently in children who developed DVT compared to those who did not. Yet, the respective differences observed for methicillin-susceptible S. aureus (MSSA) infections were non-significant in these three studies. Despite the inclusion of many case reports and the retrospective design of the evaluated studies, our findings suggest that boys seem to be more frequently affected by MSIs complicated by DVT. Moreover, MRSA seems to be more frequently associated with DVT compared to MSSA. Pulmonary involvement appears to be a frequent complication. Prospective studies are needed in order to further clarify this issue.


Exercise testing in children with primary pulmonary hypertension.
Cardiopulmonary exercise testing is a useful noninvasive tool to assess physiological changes associated with exercise. Developing noninvasive methods to assess the severity of cardiopulmonary disorders, as well as the response to therapeutic interventions, is useful in conditions, such as primary pulmonary hypertension, in which invasive procedures carry significant risks. The 6-minute walk test is a simple measure of exercise endurance. Exercise studies that measure both hemodynamic and ventilatory responses provide additional information regarding the interaction of the circulatory and pulmonary systems. Subtle changes in exercise capacity may suggest deterioration prior to clinical manifestations. This may lead to an earlier reevaluation, including repeat cardiac catheterization, and subsequently changes in medical and/or surgical therapy.


Mitogen-activated protein kinase assays.
Polymorphonuclear neutrophils (PMN) play an essential role in host defense against bacteria and fungi through coordinated responses such as adhesion, migration, phagocytosis, secretion, and activation of the NADPH oxidase. The mitogen-activated protein kinases (MAPKs) and their activation kinase cascades, which transduce signals from the plasma membrane to the cytosol and nucleus, are an integral part of signaling pathways involved in many cellular responses. PMN express several members of the MAPK family that have been shown, mainly through the use of pharmacological inhibitors, to mediate the cellular activities triggered by a variety of extracellular agonists. Methods to determine MAPK activation have been greatly simplified with the availability of antibodies raised to active MAPKs. The recent development of novel inhibitors for the MAPK pathways may further our understanding of their role in neutrophil function.


Association of statin therapy with reduced coronary plaque rupture: an optical coherence tomography study.
Statin therapy induces plaque regression and may stabilize atheromatous plaques. Optical coherence tomography (OCT) is a high-resolution in-vivo imaging modality that allows characterization of atherosclerotic plaques. We aimed to demonstrate the potential utility of OCT in evaluating coronary plaques in patients with or without statin therapy. Patients undergoing cardiac catheterization were enrolled. We identified culprit lesions and performed intracoronary OCT imaging. Plaque lipid pool, fibrous cap thickness, and frequency of thin-cap fibroatheroma were evaluated using previously validated criteria. Macrophage density was determined from optical signals within fibrous caps. Presence of calcification, thrombosis, and rupture was assessed. Forty-eight patients were included (26 on statins, 22 without statins). Baseline characteristics were similar apart from lipid profile. Patients on statin therapy had lower total and low-density lipoprotein cholesterol concentrations (4.45+/-1.35 vs. 5.26+/-0.83 mmol/l, P=0.02; 2.23+/-0.78 vs. 3.26+/-0.62 mmol/l, P<0.001, respectively). Frequencies of lipid-rich plaque (69 vs. 82%), thin-cap fibroatheroma (31 vs. 50%), plaque calcification (15 vs. 5%) and thrombosis (15 vs. 32%), and fibrous cap macrophage density were comparable between statin and nonstatin groups (5.9 vs. 6.3%; all P=NS). Ruptured plaques were, however, significantly less frequent in patients on established statin therapy (8 vs. 36%; P=0.03) with a trend toward increased minimum fibrous cap thickness (78 vs. 49 microm; P=0.07). We demonstrated the use of OCT in plaque characterization and found that patients on prior statin therapy have reduced incidence of ruptured plaques and a trend toward thicker fibrous caps. This suggests that statins may stabilize coronary plaques.


Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity.
Nephrotoxicity severely limits the use of the anticancer drug cisplatin. Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress contribute to cisplatin-induced nephrotoxicity. We developed novel orally active epoxyeicosatrienoic acid (EET) analogs and investigated their prophylactic effect in cisplatin-induced nephrotoxicity in rats. Cisplatin-induced nephrotoxicity was manifested by increases in blood urea nitrogen, plasma creatinine, urinary N-acetyl-β-(d)-glucosaminidase activity, kidney injury molecule 1, and histopathology. EET analogs (10 mg/kg/d) attenuated cisplatin-induced nephrotoxicity by reducing these renal injury markers by 40-80% along with a 50-70% reduction in renal tubular cast formation. This attenuated renal injury is associated with reduced oxidative stress, inflammation, and ER stress evident from reduction in related biomarkers and in the renal expression of genes involved in these pathways. Moreover, we demonstrated that the attenuated nephrotoxicity correlated with decreased apoptosis that is associated with 50-90% reduction in Bcl-2 protein family mediated proapoptotic signaling, reduced renal caspase-12 expression, and a 50% reduction in renal caspase-3 activity. We further demonstrated in vitro that the protective activity of EET analogs does not compromise the anticancer effects of cisplatin. Collectively, our data provide evidence that EET analogs attenuate cisplatin-induced nephrotoxicity by reducing oxidative stress, inflammation, ER stress, and apoptosis without affecting the chemotherapeutic effects of cisplatin.


Clinical outcomes of transcatheter aortic valve implantation in failed bioprosthetic surgical valves vs. native aortic stenosis: insights from a meta-analysis.
There is no meta-analysis comparing clinical outcomes between valve-in-valve transcatheter aortic valve implantation for failed surgical bioprosthetic valves (ViV-TAVI) and native valve TAVI for aortic stenosis (NV-TAVI). We aimed to investigate clinical outcomes between ViV-TAVI and NV-TAVI using a meta-analysis. EMBASE and MEDLINE were searched through April 2020 to investigate the comparative outcomes between ViV-TAVI and NV-TAVI. The main outcomes were short-term (30-day/in-hospital) mortality, pacemaker implantation (PMI), life threatening and/or major bleeding, stroke, and coronary obstruction, and long-term (1-year) mortality and stroke. Our search identified 5 observational studies enrolling a total of 8428 patients (1442 patients with ViV-TAVI and 6986 with NV-TAVI). ViV-TAVI was associated with significantly lower rates of short-term mortality, PMI, and life threatening and/or major bleeding, compared with NV-TAVI (relative risk [RR] [95% CI] 0.54 [0.34-0.84], P = 0.007; 0.25 [0.19-0.35], P < 0.0001; 0.64 [0.46-0.89], P = 0.008, respectively). There were no significant differences in rates of short-term stroke and coronary obstruction between ViV-TAVI and NV-TAVI (RR [95% CI] 0.59 [0.35-1.01], P = 0.06; 1.86 [0.78-4.41], P = 0.16, respectively). ViV-TAVI was also associated with a significantly lower rate of 1-year mortality compared with NV-TAVI (RR [95% CI] 0.64 [0.51-0.81], P = 0.0002), whereas there was no significant difference in long-term stroke (RR [95% CI] 0.71 [0.45-1.12], P = 0.51). ViV-TAVI was associated with significantly lower rates of short-term mortality, PMI, and life threatening and/or major bleeding, and long-term mortality, without increased risks of stroke and coronary obstruction, compared with NV-TAVI.


Genetic analysis of HIV by in situ PCR-directed laser capture microscopy of infected cells.
Behind the exponential expansion of the acquired immunodeficiency syndrome (AIDS) epidemic, there is a continuous and progressive molecular evolution of human immunodeficiency virus (HIV)-1. In this regard, the molecular analysis of viral strains infecting several anatomic compartments in humans has become critical to understanding AIDS-related pathologies and to improving emerging therapeutic protocols. Laser capture microdissection provides outstanding results in the genetic analysis of HIV-1 variants detectable in AIDS patients. The ability of the instrument to microdissect infected cells from a heterogeneous tissue compartment allows the investigator to obtain critical information regarding the genetic nature of a specific viral strain. To perform laser capture microdissection with better accuracy, a priori detection techniques may provide useful information about HIV distribution in the tissue specimen. An in situ polymerase chain reaction (PCR) assay on a serial slide results in a detailed map of the viral infection specific for the case under analysis. The knowledge of HIV distribution in the tissue section is critical for improving the dissection of infected cells by laser capture microscopy. This chapter describes laser capture microdissection and in situ PCR and its role in the analysis of the genetic nature of HIV-1 variants and quasispecies.


Non-Contrast Cine Cardiac Magnetic Resonance Derived-Radiomics for the Prediction of Left Ventricular Adverse Remodeling in Patients With ST-Segment Elevation Myocardial Infarction.
To investigate the predictive value of radiomics features based on cardiac magnetic resonance (CMR) cine images for left ventricular adverse remodeling (LVAR) after acute ST-segment elevation myocardial infarction (STEMI). We conducted a retrospective, single-center, cohort study involving 244 patients (random-split into 170 and 74 for training and testing, respectively) having an acute STEMI (88.5% males, 57.0 ± 10.3 years of age) who underwent CMR examination at one week and six months after percutaneous coronary intervention. LVAR was defined as a 20% increase in left ventricular end-diastolic volume 6 months after acute STEMI. Radiomics features were extracted from the one-week CMR cine images using the least absolute shrinkage and selection operator regression (LASSO) analysis. The predictive performance of the selected features was evaluated using receiver operating characteristic curve analysis and the area under the curve (AUC). Nine radiomics features with non-zero coefficients were included in the LASSO regression of the radiomics score (RAD score). Infarct size (odds ratio [OR]: 1.04 (1.00-1.07); P = 0.031) and RAD score (OR: 3.43 (2.34-5.28); P < 0.001) were independent predictors of LVAR. The RAD score predicted LVAR, with an AUC (95% confidence interval [CI]) of 0.82 (0.75-0.89) in the training set and 0.75 (0.62-0.89) in the testing set. Combining the RAD score with infarct size yielded favorable performance in predicting LVAR, with an AUC of 0.84 (0.72-0.95). Moreover, the addition of the RAD score to the left ventricular ejection fraction (LVEF) significantly increased the AUC from 0.68 (0.52-0.84) to 0.82 (0.70-0.93) (P = 0.018), which was also comparable to the prediction provided by the combined microvascular obstruction, infarct size, and LVEF with an AUC of 0.79 (0.65-0.94) (P = 0.727). Radiomics analysis using non-contrast cine CMR can predict LVAR after STEMI independently and incrementally to LVEF and may provide an alternative to traditional CMR parameters.


The cytotoxin of Pseudomonas aeruginosa: cytotoxicity requires proteolytic activation.
The primary structure of a cytotoxin from Pseudomonas aeruginosa was determined by sequencing of the structural gene. The cytotoxin (31,700 Mr) lacks an N-terminal signal sequence for bacterial secretion but contains a pentapeptide consensus sequence commonly found in prokaryotic proteins which function in a TonB-dependent manner. The cytotoxin gene has a [G + C]-content of 53.8% which is considerably lower than generally observed for genes from Pseudomonas aeruginosa. The cytotoxin gene was exclusively detected in strain 158 but not in three other clinical isolates, as determined by Southern and Northern hybridization. The latter technique revealed that the toxin is translated from monocistronic mRNA. The promoter of the cytotoxin is inactive in Escherichia coli. Upon site-directed modification of the 5'-noncoding region by the polymerase chain reaction the gene was expressed under control of the trc-promoter. The gene product obtained in Escherichia coli was nontoxic. Toxicity was induced by subsequent treatment with trypsin. [35S]methionine-labeled cytotoxin with high specific radioactivity was obtained by in vitro transcription/translation. Like [125I] labeled material from Pseudomonas aeruginosa this polypeptide bound to membrane preparations from Ehrlich ascites cells, as evidenced by sedimentation through a sucrose gradient at neutral pH.


Potent and biostable inhibitors of the main protease of SARS-CoV-2.
Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection in vitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.


The impact of comorbid mental health symptoms and sex on sleep functioning in children with ADHD.
Children with attention-deficit/hyperactivity disorder (ADHD) display more sleep problems than their peers, but it remains unclear whether comorbid mental health symptoms [i.e., anxiety, depression, oppositional-defiant disorder (ODD)] are uniquely related to sleep functioning. It is also largely unknown whether boys and girls with ADHD differ in their sleep functioning. This study (1) examined whether boys or girls with ADHD differ in their sleep functioning, (2) evaluated comorbid symptoms as uniquely related to sleep functioning domains, and (3) explored whether sex moderated associations between comorbid symptoms and sleep. Participants were 181 children (ages 7-13; 69% male; 82% White) diagnosed with ADHD. Parents completed measures assessing their child's ADHD symptoms, comorbid symptoms, and sleep functioning. Girls had poorer sleep functioning than boys across most sleep functioning domains. Sixty percent of children met cutoff criteria for having sleep problems, though rates differed significantly between girls (75%) and boys (53%). No differences in rates of sleep problems were found between ADHD subtypes/presentations or between younger and older children. In path models including ADHD and comorbid symptom dimensions, anxiety symptoms were uniquely associated with increased bedtime resistance and sleep anxiety, ADHD hyperactive-impulsive symptoms were associated with more night wakings and more parasomnia behaviors, and ODD and depressive symptoms were associated with shorter sleep duration. Depression was also uniquely associated with increased daytime sleepiness and overall sleep problems. Sex did not moderate associations between comorbid symptoms and sleep problems. This study provides important preliminary evidence that girls with ADHD experience more sleep problems than boys with ADHD. Findings also demonstrate that the associations between comorbid symptoms and sleep functioning in children with ADHD vary based on both the specific symptoms and sleep domains examined.


Histological examination of the retinal ganglion layer in rabbits after experimental administration of the new immunosuppressive medicine--Cladribine.
The experiment was carried out on rabbit females of New Zealand breed weighing about 3 kg. Animals from the experimental group received Cladribine according to the schema of experimental treatment in the hairy cell leukemia and rabbits from the experimental group II--according to the schema of experimental treatment in multiple sclerosis. Specimens of retina were collected for histological examinations in the light microscope. It was revealed that administration of Cladribine in the dose corresponding to the therapeutic dose used in human for the treatment of the hairy cell leukemia and multiple sclerosis does not cause evident morphological changes in retinal ganglion cells on the level of light microscope.


Hydroxyapatite-alumina composites and bone-bonding.
Hydroxyapatite-alumina (HA/Al2O3) composites, with HA contents of 15, 25, 30 and 70, and pure HA as well as pure Al2O3, were densified at 1275 degrees C at a top pressure of 200 MPa for 2 h, using glass-encapsulated hot isostatic pressing. From the sintered ceramics, cylinders 2.8 x 6 mm2 were prepared by ultrasonic machining and implanted into the femoral cortical bones of 12 New Zealand White rabbits for 3 months. After killing the animals, the femur was dissected out and cut into three sections, each containing one cylinder. The specimens were mounted in a push-out device and force was applied along the long axis of the cylinder. The maximum force required to loosen the implant was recorded and the fracture surface of the bone implant was studied by scanning electron microscopy (SEM). The results indicate the important role of HA in new bone apposition to the implants, reflected by increasing bonding strength with increasing HA content in the composites. However, the relationship between HA content and the bonding strength was not linear. The composite with 70% HA and the pure HA ceramic had the same level of bonding strength and similar fracture interfaces in SEM, which supports the high bonding strength detected (about 15 MPa). Fractures occurred both in the bone and in the implant, indicating the stress transfer ability of the contact zone. This study presents qualitatively and quantitatively HA-dependent characteristics in bone-bonding. The mechanical strength of the composites was measured by a three-point bending test. The bending strength of the materials decreases with increasing HA content.


Necrotizing fasciitis with Clostridium perfringens after laparoscopic cholecystectomy.
Necrotizing fasciitis is a rapidly progressive infection of the fascia and subcutaneous tissues accompanied by a high mortality rate approaching 80% to 100%. Factors that predispose patients to this life-threatening complication include obesity, malnutrition, malignancy, chronic alcoholism, drug abuse, peripheral vascular disease, diabetes mellitus, and immunosuppressive therapy. The pathomechanisms for the development of this rare disease still remain unclear. We report a case of necrotizing fasciitis with Clostridium perfringens after laparoscopic cholecystectomy. The patient left the hospital 5 months after admission. Early recognition based on clinical signs (pain, asymmetric abdominal thickening, crepitus) and computed tomography scanning (gas dissection along fascial planes), in conjunction with prompt, aggressive surgical therapy and debridement of all devitalized tissue, high-dose antibiotic therapy, and therapy at the intensive care unit, appears to afford patients the best chance of survival.


Retrograde blood aspiration: a vital reaction.
Blood aspiration, which is based on an intact breathing activity, is one of the forensically most important vital reactions. On the example of 11 forensic cases it is shown that the aspiration of blood into the lung tissue is possible not only when the bleeding source is situated above the trachea or main bronchi, but also in a retrograde way, taking its origin from an injury of the peripheral lung tissue itself. Equally to 'classical' blood aspiration, the findings of retrograde blood aspiration are to be diagnosed by means of macroscopical and histological examination of the lung tissue. The lung tissue presents with roundish, reddish spots, which are situated close to, but separate from a lung contusion or other lung tissue injury, and microscopical examination reveals blood in the alveoli and the bronchioli. Retrograde blood aspiration may be a helpful vital sign in the forensic assessment of thorax trauma cases where no other vital reactions are present.


Early-stage Alzheimer disease: getting trial-ready.
Slowing the progression of Alzheimer disease (AD) might be the greatest unmet medical need of our time. Although one AD therapeutic has received a controversial accelerated approval from the FDA, more effective and accessible therapies are urgently needed. Consensus is growing that for meaningful disease modification in AD, therapeutic intervention must be initiated at very early (preclinical or prodromal) stages of the disease. Although the methods for such early-stage clinical trials have been developed, identification and recruitment of the required asymptomatic or minimally symptomatic study participants takes many years and requires substantial funds. As an example, in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Trial (the first phase III trial to be performed in preclinical AD), 3.5 years and more than 5,900 screens were required to recruit and randomize 1,169 participants. A new clinical trials infrastructure is required to increase the efficiency of recruitment and accelerate therapeutic progress. Collaborations in North America, Europe and Asia are now addressing this need by establishing trial-ready cohorts of individuals with preclinical and prodromal AD. These collaborations are employing innovative methods to engage the target population, assess risk of brain amyloid accumulation, select participants for biomarker studies and determine eligibility for trials. In the future, these programmes could provide effective tools for pursuing the primary prevention of AD. Here, we review the lessons learned from the AD trial-ready cohorts that have been established to date, with the aim of informing ongoing and future efforts towards efficient, cost-effective trial recruitment.


Stigmatization of men and women problem drinkers and their spouses. Differential perception and leveling of sex differences.
Ratings on semantic differential scales indicate strong stigmatization of alcoholic and drink men and women, weaker stigmatization of the spouses of alcoholics and a leveling of sex differences.


High-dose vaginal maintenance metronidazole for recurrent bacterial vaginosis: a pilot study.
The purpose of this study was to explore the benefit of high-dose intravaginal metronidazole as a maintenance therapy in reducing recurrence rates of bacterial vaginosis (BV). Eighteen women with a history of recurrent BV and symptomatic BV were treated with metronidazole 750 mg suppository intravaginally daily for 7 days. Those in remission by Amsel criteria received metronidazole 750 mg twice weekly for 3 months with further follow-up for 3 months. High-dose metronidazole intravaginally was associated with rare clinical recurrence during the period of use. After cessation of suppression therapy, recurrence was high.


Going outdoors daily predicts long-term functional and health benefits among ambulatory older people.
This article examines the association between frequency of going out of the house and health and functional status among older people. A randomly chosen cohort of ambulatory participants born in 1920 or 1921 from the Jerusalem Longitudinal Study underwent assessments for health, functional, and psychosocial variables at ages 70 and 77. Twelve-year mortality data were collected. Women went out daily less than did men. Participants going out daily at age 70 reported significantly fewer new complaints at age 77 of musculoskeletal pain, sleep problems, urinary incontinence, and decline in activities of daily living (ADLs). Logistic regression analysis indicated that not going out daily at age 70 was predictive of subsequent dependence in ADL, poor self-rated health, and urinary incontinence at age 77. Going out daily is beneficial among independent older people, correlating with reduced functional decline and improved health measures.


Potential Involvement of DNA Methylation in Hybrid Sterility in Hermaphroditic Argopecten Scallops.
DNA methylation is an important epigenetic modification factor in regulating fertility. Corresponding process remains poorly investigated in hermaphroditic scallops. The interspecific F1 hybrids between the hermaphroditic bay scallops (Argopecten irradians) and Peruvian scallops (Argopecten purpuratus) exhibited significant heterosis in yield, but sterility in hybrids obstructs the utilization of the genetic resources. However, the determination mechanism of hybrid sterility in the hermaphroditic Argopecten scallops is still unclear. In this study, the effect of DNA methylation in the hybrid sterility of hermaphroditic Argopecten scallops was explored. The results showed that the mean methylation level was higher in sterile hybrids than fertile hybrids, especially on chromosome 11 of the paternal parent. A total of 61,062 differentially methylated regions (DMRs) were identified, containing 3619 differentially methylated genes (DMGs) and 1165 differentially methylated promoters that are located in the DMRs of CG sequence context. The hyper-methylated genes were enriched into five KEGG pathways, including ubiquitin-mediated proteolysis, ECM-receptor interaction, non-homologous end-joining, notch signaling, and the mismatch repair pathways. The DMGs might induce hybrid sterility by inhibition of oogenesis and egg maturation, induction of apoptosis, increased ROS, and insufficient ATP supply. Our results would enrich the determination mechanism of hybrid sterility and provide new insights into the utilization of the genetic resources of the interspecific hybrids.


Structural changes in dendritic loci and protective effect of neurotrophic factors from the cerebral cortex of animals with favorable outcome of experimental hemorrhagic stroke.
Structural changes in the sensorimotor cortex of the cerebral hemispheres were studied in rats with experimental hemorrhagic stroke in the internal capsule. Changes in the shape and decrease in the density distribution of spines on apical dendrites of layer V pyramidal neurons of the sensorimotor cortex were revealed. Some fractions isolated from the complex of neurotrophic factors of the cerebral cortex of animals with a favorable outcome of hemorrhagic stroke were shown to affect the distal and proximal dendritic loci. As differentiated from the "nonactive" fraction, the "active" fraction improved the behavior of rats surviving hemorrhagic stroke. The density distribution of spines (particularly in the distal region of apical dendrites of pyramidal neurons in layer V of the cerebral cortex) was stabilized after treatment with the "active" fraction. The "nonactive" fraction had a selective effect on the proximal loci.


Distinct migratory pattern of naive and effector T cells through the blood-CSF barrier following Echovirus 30 infection.
Echovirus 30 (E-30) is one of the most frequently isolated pathogens in aseptic meningitis worldwide. To gain access to the central nervous system (CNS), E-30 and immune cells have to cross one of the two main barriers of the CNS, the epithelial blood-cerebrospinal fluid barrier (BCSFB) or the endothelial blood-brain barrier (BBB). In an in vitro model of the BCSFB, it has been shown that E-30 can infect human immortalized brain choroid plexus papilloma (HIBCPP) cells. In this study we investigated the migration of different T cell subpopulations, naive and effector T cells, through HIBCPP cells during E-30 infection. Effects of E-30 infection and the migration process were evaluated via immunofluorescence and flow cytometry analysis, as well as transepithelial resistance and dextran flux measurement. Th1 effector cells and enterovirus-specific effector T cells migrated through HIBCPP cells more efficiently than naive CD4+ T cells following E-30 infection of HIBCPP cells. Among the different naive T cell populations, CD8+ T cells crossed the E-30-infected HIBCPP cell layer in a significantly higher number than CD4+ T cells. A large amount of effector T cells also remained attached to the basolateral side of the HIBCPP cells compared with naive T cells. Analysis of HIBCPP barrier function showed significant alteration after E-30 infection and trans- as well as paracellular migration of T cells independent of the respective subpopulation. Morphologic analysis of migrating T cells revealed that a polarized phenotype was induced by the chemokine CXCL12, but reversed to a round phenotype after E-30 infection. Further characterization of migrating Th1 effector cells revealed a downregulation of surface adhesion proteins such as LFA-1 PSGL-1, CD44, and CD49d. Taken together these results suggest that naive CD8+ and Th1 effector cells are highly efficient to migrate through the BCSFB in an inflammatory environment. The T cell phenotype is modified during the migration process through HIBCPP cells.


Environmental impacts of cage culture in Lake Victoria: the case of Shirati Bay-Sota, Tanzania.
The experimental cage culture was conducted at Shirati bay, Lake Victoria from February to August 2013, to investigate the impacts of the small scale cage culture on the environment. Three locations along the cages, at the intermediate and one in the offshore (control) were sampled for water quality parameters, phytoplankton and macro invertebrates. A notable increase in nutrient concentration was observed after the set of cages among the stations. However DO, pH, and water transparency showed no major changes and was within the recommended ranges. Cyanophytes an indicator of inorganic pollution dominated before and after the set of cages, an increase in phytoplankton numerical abundance was observed after stocking of fish in cages. In addition there was an increase in the invertebrate community especially bivalves and gastropods. In conclusion we found no consistent environmental change caused by cage culture, and therefore it can be allowed in Lake Victoria, Tanzania part, with close monitoring of its impacts.


Intrinsic uncoupling in the ATP synthase of Escherichia coli.
The ATP hydrolysis activity and proton pumping of the ATP synthase of Escherichia coli in isolated native membranes have been measured and compared as a function of ADP and Pi concentration. The ATP hydrolysis activity was inhibited by Pi with an half-maximal effect at 140 microM, which increased progressively up in the millimolar range when the ADP concentration was progressively decreased by increasing amounts of an ADP trap. In addition, the relative extent of this inhibition decreased with decreasing ADP. The half-maximal inhibition by ADP was found in the submicromolar range, and the extent of inhibition was enhanced by the presence of Pi. The parallel measurement of ATP hydrolysis activity and proton pumping indicated that, while the rate of ATP hydrolysis was decreased as a function of either ligand, the rate of proton pumping increased. The latter showed a biphasic response to the concentration of Pi, in which an inhibition followed the initial stimulation. Similarly as previously found for the ATP synthase from Rhodobacter caspulatus [P. Turina, D. Giovannini, F. Gubellini, B.A. Melandri, Physiological ligands ADP and Pi modulate the degree of intrinsic coupling in the ATP synthase of the photosynthetic bacterium Rhodobacter capsulatus, Biochemistry 43 (2004) 11126-11134], these data indicate that the E. coli ATP synthase can operate at different degrees of energetic coupling between hydrolysis and proton transport, which are modulated by ADP and Pi.


Idiopathic, sustained, inappropriate secretion of ADH with associated hypertension and thirst.
A 15 year old girl presented with excessive thirst and hypertension (170/110 mm Hg). Biochemical investigations revealed serum sodium 118 meq/liter, serum osmolality 238 mosmol/liter, urine sodium 90 meq/liter, urine osmolality 700 mosmol/liter, persistenly elevated serum antidiuretic hormone (ADH) levels (5.8 to 11.9 pg/ml) and no obvious cause for the hypertension. The hypertension is, at least in part, volume-related, diminishing with fluid restriction. Features of gross water intoxication (e.g., confusion, coma) have not occurred. The etiology of the inappropriate secretion of ADH is not obvious but is not thought to be due to "resetting of osmoreceptors" as evidenced by failure to maximally dilute urine following a water load test and persistently elevated serum ADH levels. A similar patient described by Epstein and associates in 1962 is presently well with persistent features of inappropriate secretion of ADH.


Pristimerin exerts antitumor activity against MDA-MB-231 triple-negative breast cancer cells by reversing of epithelial-mesenchymal transition via downregulation of integrin β3.
Pristimerin, a natural flavonoid compound, has potential anti-tumor activities. These activities have been illustrated in various cancer cell lines, including MDA-MB-231 cells. MDA-MB-231 cells are a representative mesenchymal subtype of triple negative breast cancer (MES-TNBC) cell line. Currently, the main treatment for patients with advanced MES-TNBC is cytotoxic chemotherapy. We tried to examine the role and effect of pristimerin on epithelial-mesenchymal transition (EMT) in MDA-MB-231 cells. The effects of pristimerin on the proliferation of MDA-MB-231 cells were investigated by cloning formation growth assay. In vitro transwell and adhesion assays were performed for cell invasion and adhesion. The expression levels of EMT markers in E-cadherin and N-cadherin were examined by western blotting. We also established overexpressed- and silenced-integrin β3 cell lines to evaluate the role of integrin β3 in mediating the EMT reversion events in MDA-MB-231 cells. Pristimerin inhibited cell proliferation, and its inhibitory effect was dose-dependent. We demonstrated that pristimerin reserved EMT by upregulating E-cadherin and downregulating N-cadherin expression. Meanwhile, we revealed that pristimerin inhibited mRNA and protein expression of integrin β3, which is a key heterodimeric transmembrane receptor associated with EMT. These inhibitory effects and reversion of EMT were enhanced when integrin β3 was knockdown in MDA-MB-231 cells, while the overexpression of integrin β3 attenuated these effects. In vivo studies using xenograft mouse model demonstrated that pristimerin inhibited tumor growth. Our findings provide important insights into the effects of pristimerin on inhibiting cancer progression and EMT reversion by suppression of integrin β3.


B-cell depleters attenuate the humoral response to SARS-CoV-2 vaccines in multiple sclerosis patients: A case-control study.
B-cell depleting agents are FDA approved for the treatment of RRMS (ocrelizumab (OCR) and ofatumumab (OFA)) and PPMS (OCR). In the case of OCR, prior studies have raised concerns about patients' ability to form antibodies in response to various antigens, especially SARS-CoV-2. In addition, emerging data have shown an attenuated humoral response to vaccines against SARS-CoV-2. The objective of this study is to determine whether b-cell depleters or sphingosine 1-phosphate (S1P) modulators attenuate the antibody response to various SARS-CoV-2 vaccines in patients with MS as compared with other MS disease modifying therapies (DMTs). This is a case-control study looking at the odds of developing antibodies to three SARS-CoV-2 vaccines (Pfizer-BioNTech, Moderna, and Johnson & Johnson) in patients treated with b-cell depleters or S1P modulators versus other disease modifying therapies. Patients were recruited at the Comprehensive MS Center at Methodist Hospitals. Patients who did not have a prior COVID-19 infection and received one of the three vaccines were tested for antibodies against the SARS-CoV-2 spike protein (Labcorp, semi-quantitative total antibody) at least two weeks following the final dose of the vaccine. Groups (B-cell, S1P modulators, other DMT, and no DMT) were compared on antibody level. The main outcome was whether or not a humoral response was detected by antibody testing. Dichotomous antibody response was tested using logistic regression models, and the quantitative response was tested using ANCOVA adjusted for covariates (age, sex, race, MS type, disease duration, vaccine, and lymphocyte count). P-values <0.05 were considered significant. Sixty-seven patients were enrolled in the study, with 17 on OCR, 3 on OFA, 12 on S1P modulators, 29 on other DMT, and 6 not currently on any DMT. Patients who received OCR or OFA had decreased odds of forming antibodies (OR 0.031, p < 0.001, 95% CI (0.003-0.268)). Patients who received S1P modulators did not have decreased odds of forming antibodies (OR 0.413, p = 0.413, 95% CI (0.28-21.7). However, when analyzing the antibody response as a continuous variable, patients on S1P modulators showed lower absolute levels of antibodies (p = 0.024). Patients who received B-cell depleters within the prior 6 months of SARS-CoV-2 vaccination had decreased odds of developing antibodies compared with other DMTs. In line with other similar research, this suggests that b-cell depleters attenuate the antibody response to SARS-CoV-2 vaccines. Although S1P modulators had an attenuation of the absolute antibody level, the odds of being negative did not differ from those on other DMTs.


Determination of puerarin in pharmaceutical and biological samples by capillary zone electrophoresis with UV detection.
A rapid and efficient capillary zone electrophoresis (CZE) method with ultraviolet detection has been successfully developed for the determination of puerarin in Xinkeshu capsules and biological samples. The optimal CZE conditions were determined to be 70 mM H(3)BO(3)-Na(2)B(4)O(7), pH 9.2, injection time 5s, applied voltage 25 kV, working temperature 25°C and detection wavelength 254 nm. Under these conditions, a linear range from 17.3 to 138 μg/mL with the correlation coefficient of 0.9998 and limit of detection of 34.6 ng/mL (S/N=3) for puerarin were obtained. The relative standard deviation of the migration time and peak area of puerarin were 0.23-0.91, 0.43-1.62, 0.10-0.64 and 0.64-1.32% for intra-day and inter-day analyses, respectively. Satisfactory results were obtained for recovery and repeatability. The proposed method was successfully applied to analyze the puerarin content in Xinkeshu capsules and some biological samples with good results. It is suitable for applications in pharmaceutical industries for quality control and in clinical laboratories for therapeutic drug monitoring purposes.


Usefulness of SynCAM3 and cyclin D1 immunohistochemistry in distinguishing superficial CD34-positive fibroblastic tumor from its histological mimics.
Superficial CD34-positive fibroblastic tumor (SCPFT) is a fibroblastic/myofibroblastic soft tissue tumor of rarely metastasizing intermediate malignancy. Some recent studies have described a relationship between SCPFT and PRDM10-rearranged soft tissue tumor (PRT) based on SynCAM3 and PRDM10 expression on immunohistochemistry. We performed CD34, cytokeratin AE1/AE3, SynCAM3, and PRDM10 immunohistochemistry in SCPFT and its histological mimics, including myxoinflammatory fibroblastic sarcoma (MIFS), superficially localized myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma. We also examined cyclin D1 expression because it is expressed in MIFS and MFS. We conducted fluorescence in situ hybridization (FISH) of PRDM10 rearrangement in SCPFT cases. On immunohistochemistry, only SCPFT showed strong and diffuse SynCAM3 expression. SCPFT also exhibited strong nuclear and weak cytoplasmic cyclin D1 expression, which was similar to that observed in MIFS. Two of five SCPFT cases exhibited nuclear PRDM10 expression. FISH revealed PRDM10 split signals in 44% and 24% of tumor cells in two SCPFT cases showing nuclear PRDM10 expression on immunohistochemistry, respectively. A minority of non-SCPFT cases showed focal SynCAM3 expression, but a combination of SynCAM3 and cyclin D1 in addition to CD34 and cytokeratin AE1/AE3 may be useful for the differential diagnosis of SCPFT and its histological mimics.


[Diplopia, enophthalmos and motility disorders in isolated orbital floor fractures].
In cases of pure blow-out fracture with unequivocal clinical symptoms (limitation of movement of the globe, dislocation and/or enophthalmos) and confirmed X-ray findings, early surgery is the treatment of choice. In cases where the clinical findings are less pronounced, a "wait-and-see" policy, keeping the patient under observation, seems appropriate for the sake of avoiding surgical trauma. Coronal computerized tomography offers advantages in cases where the diagnosis is questionable.


Beneficiation and recovery of indium from liquid-crystal-display glass by hydrometallurgy.
Considering indium scarcity, the end-of-life (EOL) LCD, which accounts for up to 90% of market share can be a feasible secondary resource upon successful recycling. In the preferred hydrometallurgical process of such critical metals, leaching is the essential primary and essential phase has been investigated. In this process, LCD was mechanically separated along with other parts from EOL TVs through a smartly engineered process developed at our institute, Institute for Advanced Engineering (IAE), the Republic of Korea. After removing plastics and metals from the LCD, it was mechanically shredded for size reduction. The mechanically shredded LCD waste was leached with HCl for recovery of indium. Possible leaching parameters such as; effect of acid concentration, pulp density, temperature and effect of oxidant H2O2 concentration were investigated to identify the best conditions for indium extraction. Indium (76.16×10-3g/L) and tin (10.24×10-3g/L) leaching was achieved at their optimum condition, i.e. lixiviant of 5M HCl, a pulp density of 500g/L, temperature 75°C, agitation speed of 400rpm and time for 120min. At optimum condition the glass, plastic and the valuable metal indium have completely been separated. From indium enriched leach liquor, indium can be purified and recovered through hydrometallurgy.


Unexpected high robustness of electrochemical cross-coupling for a broad range of current density.
Electro-organic synthesis is a powerful technique for the sustainable preparation of compounds. However, many electrosynthetic reactions require complex equipment, are limited to a very narrow current density range, or have very long reaction times; some also involve nonselective transformations and bad scalability. The robust and selective synthesis of nonsymmetric biphenols and partially protected derivatives is established by anodic C-C cross-coupling. The setup is simple, involving constant current conditions and undivided cells. Its key is a unique electrolyte system based on fluorous alcohols and mixtures, particularly 1,1,1,3,3,3-hexafluoroisopropanol. This allows variations of the current density of more than two orders of magnitude without decreasing selectivity or product yield. This exceptional effect is unknown for electro-organic synthesis of products that have similar oxidation potentials as the starting materials. It potentially paves the way for industrial electrolyzers with variable current consumption, which could enable the flexible use of energy surplus in the electricity supply.


Opportunities and limits of wastewater-based epidemiology for tracking global health and attainment of UN sustainable development goals.
Wastewater-based epidemiology (WBE) emerged as a powerful, actionable health management tool during the COVID-19 pandemic. Hypothesizing future uses, we explored its potential for real-time, tracking of progress in attaining United Nations Sustainable Development Goals (SDGs) globally as a non-expensive method using existing infrastructure. We inventoried (i) literature-documented sewerage infrastructure, (ii) demographics of populations served, and (iii) WBE markers informative of 9 SDGs. Among the 17 different sustainable development goals listed by the UN 2030 agenda, more than half of these may be monitored by using WBE monitoring at centralized treatment infrastructure as tabulated in this study. Driven mainly by COVID-19, WBE currently is practiced in at least 55 countries, reaching about 300 million people. Expansion of WBE to 109,000 + treatment plants inventoried in 129 countries would increase global coverage 9-fold to 34.7% or 2.7 billion, leaving out 5 billion people not served by centralized sewerage systems. Associations between population demographics and present-day infrastructure are explored, and geospatial regions particularly vulnerable to infectious disease outbreaks are identified. The results suggest that difference in the differential outcomes in well-being is an outcome of the sanitation infrastructure inequalities and lack of sanitation infrastructure creates doubly disadvantaged populations at risk of poor hygiene and cut off from the early-warning benefits of conventional WBE. This is the first study to explore the feasibility and potential barriers to the use of WBE for tracking the attainment of SDGs globally with at least 9 out of 17 SDGs.


Sensitivity to functors in Japanese aphasics.
Forty-two aphasic patients (11 amnesic, 11 Wernicke's, and 20 Broca's) and 10 controls were tested for sensitivity to functors in affirmative declarative sentences with sentence- verification tasks. The stimuli were constructed according to the following factors: Reversibility of Subject and Object, Voice, Word Order and Truth. The task required the subject to decide if a sentence presented auditorily was true or false with respect to a picture. The results indicated that functors differed among themselves in their understandability depending on sentence types in which they were embedded, and that there were no qualitative differences in sensitivity to functors among different clinical types of aphasia.


Acute migraine headache: possible sensitization of neurons in the spinal trigeminal nucleus?
To investigate trigeminal sensory processing in patients with migraine using a novel "nociception-specific" blink reflex. Seventeen patients with unilateral migraine headache were studied within 6 hours of onset. Blink reflexes were elicited with a standard stimulating electrode (standard blink reflex) and concentric stimulating electrode (nociception-specific blink reflex) during the acute migraine attack, after treatment with IV lysine acetylsalicylate (1,000 mg) or oral zolmitriptan (5 mg) and interictally. After standard stimulation, no differences were detected for the R1 and R2 onset latencies and areas under the curve (AUC) between the different time points and the headache and nonheadache side. Nociception-specific stimulation revealed a shortening of R2 onset latencies (44.3 +/- 5.4 ms for headache side vs 48.9 +/- 5.8 ms for nonheadache side) during the acute migraine attack compared with the headache-free interval (49.8 +/- 5.3 vs 49.8 +/- 4.5 ms). The AUC of the R2 increased on the headache side by 680% and on the nonheadache side by 230% compared with the headache-free interval. Drug treatment parallel to pain relief increased the onset latencies (zolmitriptan: 48.0 +/- 8.2 ms for headache side vs 52.3 +/- 7.6 ms for nonheadache side; lysine acetylsalicylate: 48.0 +/- 5.0 ms for headache side vs 51.2 +/- 5.6 ms for nonheadache side) and reduced the AUC of R2 (zolmitriptan by 45% and lysine acetylsalicylate by 48%). The data suggest temporary sensitization of central trigeminal neurons during acute migraine attacks.


Vergence eye movements impairments in schizophrenia and bipolar disorder.
One of the most evaluated eye tracking tasks in schizophrenia (SZ) and bipolar disorder (BD) are smooth pursuit eye movements. They rely on the maintenance of slowly moving object on the fovea. While most of the studies evaluated tracking of a target that moves in the fronto-parallel plane, only two assessed vergence eye movements (VEM), which relies on the pursuit of object that moves in depth. The aim of our study was to compare VEM performance in SZ and BD. We evaluated 28 SZ patients, 32 BD patients and 25 healthy controls (HC). Participants underwent thorough optometric examination before eye tracking task. VEM were measured with the use of infrared eye tracker and dedicated vergence stimuli generator. SZ patients showed higher mean break and recovery points of fusion and shorter correct tracking time than HC. BD individuals revealed tracking accuracy deficits and higher number of saccades than HC. Compared to BD, SZ patients showed decrease of maximal convergence and divergence. Moreover, they presented tracking accuracy deficits of non-dominant eye: altered eyes positioning error during convergence and divergence gain. Exploratory analysis revealed significant gender differences between groups in terms of binocular VEM parameters. In this study we have recognized pattern of eye movement disturbances differentiating abovementioned groups. SZ patients showed decreased vergence tracking range with shorter tracking time and impaired accuracy of non-dominant eye, while BD patients showed higher number of saccades with decreased tracking accuracy. Neuroimaging studies are necessary to identify neuronal underpinnings of VEM impairments in SZ and BD.


Isolation and characterization of anti-inflammatory and anti-proliferative compound, for B-cell Non-Hodgkin lymphoma, from Nyctanthes arbor-tristis Linn.
Nyctanthes arbor-tristis Linn. is native to Indo-Pak sub-continent and has high medicinal values in Ayureda. This plant has been used traditionally for the treatment of sciatica, rheumatism, chronic fever, diabetes, snakebite, dysentery, cachexia and cancer. Studies have shown many pharmacological properties such as anti-cancer efficacy against Dalton's ascetic lymphoma, cytotoxicity against T-cell leukemia, anti-inflammatory, anti-diabetic and anti-oxidant effects. Aim of the study was to explore the anti-inflammatory and anti-proliferative potential of N. arbor-tristis. Ethanol extract of fresh and uncrushed aerial parts of N. arbor-tristis was used in the present study. A new compound nyctanthesin A was isolated following a bioactivity-guided fractionation and chromatographic separations. Its chemical structure was elucidated through spectral studies including 1D, 2D-NMR experiments and HREIMS. The intracellular reactive oxygen species (ROS) and nitric oxide (NO) generation from phagocytes were detected by chemiluminescence technique and Griess method, respectively. TNF-α and TGF-β production was quantified by ELISA. Anti-lymphoma and cytotoxic activities were assessed by alamar blue and MTT assays, respectively. The transcription and protein expression level of Bcl-2, COX-2, p38 MAPK, PDL-1, NF-κB, c-Myc and PNF-κB was performed by qRT-PCR and protein blot assays, respectively. Petroleum ether insoluble fraction of the ethanol extract of fresh and uncrushed aerial parts of N. arbor-tristis revealed anti-inflammatory potential by inhibiting ROS. A previously undescribed compound nyctanthesin A was isolated from this fraction and characterized by UV, IR, NMR and HREIMS. It showed significant anti-inflammatory property by inhibiting ROS, NO and TNF-α production. The strong anti-proliferative effects on B- cell lymphoma cells, DOHH2 and Raji, revealed its anti-lymphoma potential along with non-toxic profile against BJ and NIH-3T3 fibroblast cells of normal origin. The qRT-PCR results showed marked inhibition of Bcl-2, COX-2, p38 MAPK, PDL-1, c-Myc, NF-κB, and PNF-κB at transcription level in DOHH2 cells with comparatively lesser but significant effects in Raji cells, where the expression of Bcl-2 gene was not affected. The protein expression of PNF-κB in DOHH2 cells was inhibited by 66% (P < 0.05) and COX-2 in both cell lines was inhibited by 50% (P < 0.05) at 60 μg/mL. A moderate non-significant inhibition of TGF-β (∼20%) was observed in both cell lines at 100 μg/mL CONCLUSIONS: Scientific evidences reported here validate the anti-inflammatory and anti-cancer potential of the plant.


Synthesis and anti-angiogenic activity of 6-(1,2,4-thiadiazol-5-yl)-3-amino pyridazine derivatives.
General screening for inhibitors of microvessel growth in vitro in the rat aortic ring assay led to the discovery of a novel series of thiadiazole pyridazine compounds with potential anti-angiogenic activity. Chemical optimization produced orally active compounds with potent in vitro and in vivo anti-angiogenesis and anti-tumor activities.


Improved co-production of S-adenosylmethionine and glutathione using citrate as an auxiliary energy substrate.
The effects of sodium citrate on the fermentative co-production of S-adenosylmethionine (SAM) and glutathione (GSH) using Candida utilis CCTCC M 209298 were investigated. Sodium citrate was beneficial for the biosynthesis of SAM and GSH and in turn improved intracellular SAM and GSH contents. Adding 2 g/L of sodium citrate at 15 h was the most efficient approach for achieving elevated co-production of SAM and GSH. Using this sodium citrate addition mode, co-production of SAM and GSH reached 663.9 mg/L, which was increased by 27.5% compared to the control. Based on analysis of the kinetic parameters, evaluation of the energy metabolism and assay of key enzymes, sodium citrate was verified to act as an auxiliary energy substrate for the overproduction of SAM and GSH.


Increased importance of the documented development stage in process validation.
Current trends in pharmaceutical quality assurance moved when the Federal Drug Administration (FDA) of the USA published its new guideline on process validation in 2011. This guidance introduced the lifecycle approach of process validation. In this short communication some typical changes from the point of view of practice of API production are addressed in the light of inspection experiences. Some details are compared with the European regulations.


Current and emerging treatment strategies for hair loss in women of color.
Hair loss is common in women of color, and is associated with significant psychosocial complaints. Early clinical recognition and prompt initiation of intervention with medical treatment is critical to halt the disease process. In this article, we review the clinical presentations of nonscarring and scarring alopecias in women of color, use of dermoscopy for early recognition of the disease process, and medical, procedural, and surgical interventions. In conditions that result in scarring alopecia, such as late-stage traction, frontal fibrosing, or central centrifugal cicatricial alopecia, patients may benefit from procedural interventions, such as hair transplantation, platelet rich plasma injections, low-level laser therapy, or scalp therapy.