Cyclosporine A sensitizes human non-small cell lung cancer cells to gefitinib through inhibition of STAT3.
The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have dramatically prolonged the overall survival of non-small cell lung cancer (NSCLC) patients with EGFR-activating mutation, but the presence of primary or acquired resistance eventually leads to therapeutic failure. Thus, how to improve the efficacy and reverse the resistance to EGFR-TKIs remains a significant challenge. In this study, we found that CsA significantly augmented the anti-cancer effect of gefitinib in EGFR-TKI-sensitive and -resistant NSCLC cells. Mechanistically, CsA promoted gefitinib-induced apoptosis through inhibition of the STAT3 pathway. Similar with the function of CsA, siRNAs against STAT3 also enhanced gefitinib-induced apoptosis in multiple lung cancer cells. Xenograft studies further demonstrated that CsA promoted the anti-cancer activity of gefitinib on lung cancer cells through inhibition of STAT3. Moreover, NSCLC patients with high levels of phosphorylated STAT3 (Y705) showed a significantly poorer therapeutic response to EGFR-TKIs. This study provides preclinical evidence that the combination of CsA or a STAT3 inhibitor with EGFR-TKIs is a promising approach to improve the efficacy of EGFR-TKIs for the treatment of patients with advanced NSCLC.


The effect of inhibitors of protein synthesis on the reexpression of surface immunoglobulin following antigenic modulation.
P3, a cell line derived from the plasmacytoma MOPC-21 secretes IgG1 (K) and is sensitive to complement (C')-mediated lysis by antibody directed against gamma1 or K. Sensitivity is attributed to the presence of immunoglobulin molecules on the surface membrane, designed Ig-mem. This sensitivity is abolished by antigenic modulation of Ig-mem. Modulated cells, when incubated in the absence of antibody, recover sensitivity to lysis in 4 hr. By measuring the rate of recovery, it has been possible to study the effects of various drugs on the reexpression of Ig-mem. Treatment of modulated cells with cycloheximide (Cx), pactamycin Pc), anisomycin (An), homoharringtonine (Ha) or sparsomycin (Sm), each a specific inhibitor of a different step in protein synthesis, produces a significant reduction in the rate of recovery. Paradoxically, puromycin (Pm), also a specific inhibitor of protein synthesis, does not reduce the rate of recovery. Studies were performed using Pm together with each of the other drugs to gain an understanding of the relationship between protein synthesis and recovery from modulation. Based upon these studies, we conclude that continued operation of the initiation cycle of protein synthesis is required for reexpression of Ig-mem in the absence of de novo protein formation.


[Cu(dipicolinoylamide)(NO3)(H2O)] as anti-COVID-19 and antibacterial drug candidate: Design, synthesis, crystal structure, DFT and molecular docking.
For first time the new N-picolinoypicolinlamide was obtained as in situ ligand during the reaction of 2,4,6-ris(2-pyridyl)-,3,5-triazine with aqueous solution of CuNO3·3H2O and formed the corresponding complex [Cu(dipicolinoylamide)(NO3)(H2O)]. The crystal structure of the obtained complex was determined by x-ray structure. The complex crystallizes in space group P21/n, a = 10.2782(9) Å, b = 7.5173(6) Å, c = 17.738(2) Å, α = 90.00°, β = 91.368(1)°, γ = 90.00°, V = 1370.1(2) Å3, Z = 4. The copper center has a distorted octahedral geometry. DFT calculations show good agreement between theoretical and X-ray data. The Molecular docking studies were executed to consider the nature of binding and binding affinity of the synthesized compounds with the receptor of COVID-19 main protease viral protein (PDB ID: 6lu7), the receptor of gram -ve bacteria (Escherichia coli, PDB ID: 1fj4) and the receptor of gram +ve bacteria (Staphylococcus aureus, PDB ID: 3q8u and Proteus PDB ID: 5i39) and with human DNA. Finally, in silico ADMET predictions was also examined.


Assessment of fetal thymus size in pregnant women with rheumatic diseases: A case-control study.
To investigate the fetal thymic-thoracic ratio (TT-ratio) in pregnancies diagnosed with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Thirty-two pregnant women with rheumatic disease and 96 low-risk pregnant women between 20 and 37 weeks were included in the study. Three control patients were randomly selected for each study patient. TT-ratio was calculated by measuring the anterior-posterior diameter of the thymus and the intrathoracic mediastinal diameter. Data were compared between the study group, including RA and AS, and the control group. Thirty-two pregnant women with arthritis, 19 diagnosed with RA and 13 with AS, were evaluated. The mean value of the study group TT-ratio was 0.33; control group, 0.36; a statistically significant difference was found (p < 0.001). Perinatal outcomes were not different when compared with control patients. There was a negative correlation between disease duration, maternal C-reactive protein, erythrocyte sedimentation rate, and TT-ratio. This is the first study to prospectively evaluate the fetal TT-ratio in patients with RA and AS. Systemic inflammation appears to affect fetal thymus size. Appropriate management of maternal rheumatic diseases is essential for developing the thymus, a vital immune system component.


Behavioral analysis and nursing interventions for reducing disruptive behaviors of patients with dementia.
In this study, two cases were used to examine the potential of behavioral analysis as an intervention to decrease disruptive behaviors of institutionalized individuals with dementia. Behavioral modeling was used to teach the principles of behavioral analysis. The nurses observed a behavior change plan implemented by the investigator, revised the plan based on behavioral analysis techniques, and subsequently implemented the revised behavioral strategies. The patients' disruptive behaviors decreased markedly when the behavioral intervention was implemented. Patients resumed disruptive behaviors when care was provided without the behavioral plan. The findings suggest the need to address interventions in nursing research, education, and practice that use behavioral analysis to reduce disruptive behaviors in individuals with dementia.


The immune system's involvement in obesity-driven type 2 diabetes.
Type 2 diabetes is now a worldwide epidemic, strongly correlated with an elevated incidence of obesity. Obesity-associated adipose tissue inflammation is a major cause of the decreased insulin sensitivity seen in type 2 diabetes. Recent studies have shed light on the cross-talk between the immune system and organismal metabolism. This review discusses the connection between inflammation in adipose tissue and systemic insulin resistance, focusing on the roles of innate and adaptive immune cell subsets in the pathogenesis of this metabolic disease.


Measuring levels of biogenic amines and their metabolites in rat brain tissue using high-performance liquid chromatography with photodiode array detection.
We developed a method to detect biogenic amines and their metabolites in rat brain tissue using simultaneous high-performance liquid chromatography and a photodiode array detection. Measurements were made using a Hypersil Gold C-18 column (250 × 2.1 mm, 5 µm). The mobile phase was 5 mM perchloric acid containing 5 % acetonitrile. The correlation coefficient was 0.9995-0.9999. LODs (S/N = 3) and LOQs (S/N = 10) were as follows: dopamine 0.4 and 1.3 pg, 3, 4-dihydroxyphenylacetic acid 8.4 and 28.0 pg, serotonin 0.4 and 1.3 pg, 5-hydroxyindolacetic acid 3.4 and 11.3 pg, and homovanillic acid 8.4 and 28.0 pg. This method does not require derivatization steps, and is more sensitive than the widely used HPLC-UV method.


Homozygous mutations in PJVK and MYO15A genes associated with non-syndromic hearing loss in Moroccan families.
Autosomal recessive non-syndromic hearing loss is a heterogeneous disorder and the most prevalent human genetic sensorineural defect. In this study, we investigated the geneticcause of sensorineural hearing loss in Moroccan patients and presented the importance of whole exome sequencing (WES) to identify candidate genes in two Moroccan families with profound deafness. After excluding mutations previously reported in Moroccan deaf patients, whole exome sequencing was performed and Sanger sequencing was used to validate mutations in these genes. Our results disclosed the c.113_114insT (p.Lys41GlufsX8) and c.406C > T (p.Arg130X) homozygous mutations in PJVK and a homozygous c.5203C > T (p.Arg1735Trp) mutation in MYO15A, both genes responsible for non-syndromic recessive hearing loss DFNB59 and DFNB3, respectively. We identified in Moroccan deaf patients two mutations in PJVK and one mutation in MYO15A described for the first time in association with non-syndromic recessive hearing loss. These results emphasize that whole exome sequencing is a powerful diagnostic strategy to identify pathogenic mutations in heterogeneous disorders with many various causative genes.


Radical Cystectomy Versus Chemoradiation for Muscle-invasive Bladder Cancer: Impact of Treatment Facility and Sociodemographics.
The present study sought to compare the differences in practice patterns, as well as clinical outcomes for patients with muscle-invasive bladder cancer undergoing treatment with either radical cystectomy (RC) or concurrent chemoradiaiton (CRT). The National Cancer Data Base (NCDB) was queried for patients diagnosed with T2/T3/T4aN0M0 bladder cancer, between 2004-2013, that received definitive treatment with either RC or CRT. 16,960 patients met the inclusion criteria; 1,450 (8.5%) underwent CRT, while 15,510 (91.5%) were treated with RC. Patients undergoing CRT were older, more likely to be female, African American, received treatment at an academic facility, and lived <20 miles of the treatment facility. CRT was associated with worse median OS (32.8 months vs. 36.1 months; p=0.0004). Older patients are more likely to undergo bladder preservation therapy, while those living farther away from treatment facilities are less likely to under CRT.


Carboxyhaemoglobin and methaemoglobin findings in burnt bodies.
The often observed absence of carboxyhaemoglobin in burnt (charred) bodies is re-discussed in the light of two new cases in which the inhalation of very hot gases obviously led to reflex breathing and circulation arrest. (Macro and microscopic evaluations of the upper respiratory tract can give significant information as to whether a person was still alive at the time of the fire outbreak.) In the cadaver blood of people who survived a given period after a fire, high methaemoglobin values (up to 37%) were found. This was caused by the inhalation of nitrogen oxides that were produced by burning plastic.


Grouping of coefficients for the calculation of inter-molecular similarity and dissimilarity using 2D fragment bit-strings.
This paper compares 22 different similarity coefficients when they are used for searching databases of 2D fragment bit-strings. Experiments with the National Cancer Institute s AIDS and IDAlert databases show that the coefficients fall into several well-marked clusters, in which the members of a cluster will produce comparable rankings of a set of molecules. These clusters provide a basis for selecting combinations of coefficients for use in data fusion experiments. The results of these experiments provide a simple way of increasing the effectiveness of fragment-based similarity searching systems.


Cardiac phosphorylase kinase. Deactivation by selective dephosphorylation of alpha' and beta subunits.
We have documented previously that although the phosphorylation of the beta subunit of cardiac phosphorylase kinase plays a major role in activation of the enzyme, enzyme activity is also modulated by either cAMP-dependent or cAMP-independent phosphorylation of the alpha' subunit (Sul, H. S., Cooper R. H., Whitehouse S., and Walsh D. A. (1982) J. Biol. Chem. 257, 3484-3490). This paper reports that deactivation of 32P-labeled cardiac phosphorylase kinase by protein phosphatase occurs concomitantly with the dephosphorylation of either the alpha' or beta subunits. However, enzyme activation attributable to alpha' subunit phosphorylation is still apparent after dephosphorylation of the beta subunit and, similarly, that caused by beta subunit phosphorylation is maintained after alpha' subunit dephosphorylation. These data support out previously stated conclusion that both alpha' and beta subunit phosphorylation regulates the activity of cardiac phosphorylase kinase.


HIV serostatus and factors related to physical and mental well-being in Latina family AIDS caregivers.
In a survey of 154 Latina AIDS caregivers living in Los Angeles, we examined differences in the stress process for those who were HIV seropositive, seronegative, and those with an unknown serostatus. Most caregivers were monolingual, poor, suffered from chronic physical illness unrelated to HIV, and received few services. All three subsamples reached clinical cut-off levels for depression on the brief symptom inventory. In the sample as a whole and in all three groups we examined differences in primary and secondary stressors as predictors of mental and physical well-being; differences in background factors as they relate to mental and physical well-being; and differences in predictive value of various factors that may attenuate the relationship between stress and mental and physical well-being. Models predicting both mental and physical well-being differ across subsamples divided on the basis of serostatus. Based on these findings, we discuss implications for service provision designed to target these underserved Latina AIDS caregivers.


Characteristics of respiratory distress syndrome in infants of different gestational ages.
The purpose of this study was to compare the risk factors, clinical characteristics, and complications of respiratory distress syndrome (RDS) in infants delivered very preterm, late preterm, and term in order to help optimize the management of RDS in neonates. A retrospective study was conducted on neonates admitted to the NICU between January 2006 and December 2010. The enrolled infants with RDS were categorized as very preterm (<32(0/7) weeks gestation), moderately preterm (32(0/7)-33(6/7) weeks), late preterm (34(0/7)-36(6/7) weeks), and term (37(0/7)-42(0/7) weeks). The rates, potential risk factors, clinical characteristics, and complications of RDS of these four groups were comparatively analyzed. There was an increasing trend in incidence of RDS among the NICU admissions annually. Caesarean section without labor was significantly associated with RDS in term and late preterm infants (P < 0.001). Rates of requirements for ventilator and pulmonary surfactant were similar in very preterm and term infants but significantly lower in late preterm infants (P < 0.001). The oxygenation index value was not substantially lower in late preterm and term infants compared to very preterm infants, and the arterial oxygenation efficiency was improved slowly (P < 0.001). Incidence of pneumonia and occurrence of pneumothorax were significantly higher in term infants (P < 0.001). Term infants with RDS showed an association of RDS with caesarean section without labor and lung infection. These infants also showed slower improvement of oxygenation after surfactant administration and mechanical ventilation, and they experienced a high rate of pneumothorax complication, which was also noticed in late preterm neonates.


The Potential Therapeutic Capacity of Inhibiting the Brain Renin-Angiotensin System in the Treatment of Co-Morbid Conditions in Epilepsy.
Epilepsy is one of the most prevalent neurological diseases and although numerous novel anticonvulsants have been approved, the proportion of patients who are refractory to medical treatment of seizures and have progressive co-morbidities such as cognitive impairment and depression remains at about 20-30%. In the last decade, extensive research has identified a therapeutic capacity of the components of the brain renin-angiotensin system (RAS) in seizure- and epilepsy-related phenomena. Alleviating the activity of RAS in the central nervous system is considered to be a potential adjuvant strategy for the treatment of numerous detrimental consequences of epileptogenesis. One of the main advantages of RAS is associated with its modulatory influence on different neurotransmitter systems, thereby exerting a fine-tuning control mechanism for brain excitability. The most recent scientific findings regarding the involvement of the components of brain RAS show that angiotensin II (Ang II), angiotensin-converting enzyme (ACE), Ang II type 1 (AT1) and type 2 (AT2) receptors are involved in the control of epilepsy and its accompanying complications, and therefore they are currently of therapeutic interest in the treatment of this disease. However, data on the role of different components of brain RAS on co-morbid conditions in epilepsy, including hypertension, are insufficient. Experimental and clinical findings related to the involvement of Ang II, ACE, AT1, and AT2 receptors in the control of epilepsy and accompanying complications may point to new therapeutic opportunities and adjuvants for the treatment of common co-morbid conditions of epilepsy.


Biological effects and mechanisms of fisetin in cancer: a promising anti-cancer agent.
Fisetin, a natural flavonoid, possesses numerous biological activities that have been extensively studied in various diseases. When it comes to cancer, fisetin exhibits a range of biological effects, such as suppressing cell growth, triggering programmed cell death, reducing the formation of new blood vessels, protecting against oxidative stress, and inhibiting cell migration. Moreover, fisetin has the ability to enhance the effectiveness of chemotherapy. The anticancer properties of fisetin can be attributed to a diverse array of molecules and signaling pathways, including vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), PI3K/Akt/mTOR, and Nrf2/HO-1. Consequently, fisetin holds promise as a therapeutic agent for anticancer treatment. In this review, we place emphasis on the biological functions and various molecular targets of fisetin in anticancer therapy.


Gait regularity assessed by wearable sensors: Comparison between accelerometer and gyroscope data for different sensor locations and walking speeds in healthy subjects.
Inertial measurement units (IMU), including accelerometers and gyroscopes, can support the assessment of gait regularity, relevant for an effective walking. Gait regularity is typically quantified by an autocorrelation analysis of trunk/pelvis accelerations. A methodological upgrade fosters a multi-sensor approach including upper and lower limbs. Very few studies dealt with gait regularity using gyroscope data and no comparison between the two inertial sensors has been published. Therefore, this study compares gait regularity assessment by autocorrelation analyses performed on accelerometer and gyroscope data simultaneously acquired. Twenty-five adult healthy subjects walked steady-state on treadmill at three speeds (3.6, 5.0, 6.4 km/h), with rest between. Four IMUs were firmly attached on the trunk, pelvis, wrist and ankle. The autocorrelation method was applied to time-windows of the signal vector magnitude and resulted, on average for each trial, in its regularity index (RI) and periodicity index (PI), i.e. the stride time. Results showed that both sensors identified the same PI (Spearman correlation coefficient = 0.999), and evidenced that, for matched sensor locations and gait speeds, the accelerometer-based RI was larger/equal to the gyroscope-based RI on 86.3% of all conditions (overall median of gyroscope-to-accelerometer RI ratio was 91.1%). The two sensors gave always statistically different RI, with the exception of the ankle at the lowest speed and wrist at higher speeds. Such results help remove potential confounders from analyses performed with different sensors and support the use of accelerometers for gait regularity assessment, not excluding that gyroscopes may be more suitable for other human movements.


Safety, tolerability, and seizure control during long-term treatment with adjunctive brivaracetam for partial-onset seizures.
To report pooled safety/tolerability and seizure outcome data from adults with uncontrolled partial-onset (focal) seizures (POS) receiving adjunctive brivaracetam (BRV) during phase IIb/III and long-term follow-up (LTFU) studies. Seizure outcome data were pooled from phase IIb (NCT00175929 and NCT00175825), III/IIIb (NCT00490035, NCT00464269, NCT00504881, and NCT01261325) and associated LTFU studies (NCT00175916, NCT00150800, and NCT01339559). Safety/tolerability data were pooled from these studies plus NCT01405508, NCT01653262, and NCT01728077 (LTFU). Patients received placebo (during core studies) or BRV 5-200 mg/day. Safety/tolerability and seizure outcomes (BRV modal doses 50-200 mg/day) were assessed until January 17, 2014. Of 2,186 patients (97.3% with POS and 2.7% with other seizure types) who received BRV 50-200 mg/day, 2,051 (93.8%) completed core studies and continued in LTFU studies. Total BRV exposure: 5,339.4 patient-years (≥8.0 years in 41 patients); 6-, 12-, 24-, and 60-month retention: 91.0%, 79.8%, 68.1%, and 54.4%, respectively. Safety/tolerability data pooled from 2,186 patients: ≥1 treatment-emergent adverse event (TEAE) reported by 1,848 (84.5%) patients; 1,184 (54.2%) reported ≥1 TEAE considered treatment-related. Most frequent TEAEs (≥10%): headache (20.9%), dizziness (17.5%), somnolence (15.2%), nasopharyngitis (13.2%), fatigue (11.3%), and convulsion (10.6%). Serious TEAEs (SAEs) and treatment-related SAEs: 401 (18.3%) and 95 (4.3%) patients, respectively. Of 28 (1.3%) deaths, four (14.3%) were considered possibly treatment related by the investigator. Pooled seizure outcome data (1,836 patients): median POS frequency/28 days at baseline was 8.9; on treatment, median percentage reduction from baseline in POS/28 days was 48.8%, and ≥50% responder rate was 48.7%. Complete seizure freedom: 4.9%, 4.2%, 3.0%, and 3.3% for ≥6, 12, 24, and 60 months, respectively. Improvements were seen in health-related quality of life (HRQoL) from baseline, assessed by Quality of Life in Epilepsy Inventory-31. Adjunctive BRV treatment in adults with POS was effective and generally well tolerated when administered long-term (≥8.0 years). Retention was high and HRQoL improvements were observed.


Nitric oxide production in PCD: possible evidence for differential nitric oxide synthase function.
Primary cilliary dyskinesia (PCD) is characterized by decreased levels of fractional exhaled nitric oxide (FeNO), thought to reflect low activity of airway inducible nitric oxide synthase (iNOS) levels. Alveolar NO (Calv) concentration and bronchial NO (JNO) flux can be calculated from FeNO measured at multiple exhalation flow rates. We hypothesised that whereas bronchial NO would be reduced in PCD due to reduced iNOS function, alveolar NO would reflect endothelial NOS (eNOS) function and be normal. We recorded the medical history; measured FeNO at multiple flow rates (50, 100, 200, 260 ml/sec); and performed spirometry in 24 children (aged 8-16 years). FeNO50 of the PCD children was significantly lower than normal mean (+/-SD) 8.1 +/- 1.3 ppb versus 12.5 +/- 1.6 ppb, P = 0.033. The mean +/- SD values of PCD (n = 24) and normal (n = 20) subjects were respectively: JNO: 383.5 +/- 307.9 versus 650.1 +/- 489 pl/s, P = 0.033, Calv: 1.60 +/- 0.78 versus 1.60 +/- 0.75 ppb, P = NS. We show that Calv is normal in PCD, demonstrating that there is no generalized disorder of NO handling in this condition. This differs from a previous report. Furthermore, we speculate that these data may provide supportive evidence that variable flow NO measurements can assess the relative activity of iNOS and eNOS.


Diphasic electrodermal response, heart rate and moods.
The simultaneous recording of spontaneous EDA (mono and diphasic SPR), HR and mood self-rating (Q-sort of adjectives), on 35 normal subjects, for 5 consecutive weeks has shown that: (1) The emission of diphasic SPR is significantly related to an increase in monophasic EDA (in frequency and in amplitude) and to a lesser degree with HR acceleration; (2) Such a physiological pattern is significantly associated with depressive mood, though independent from anxious mood. These results confirm the importance of morphological aspects of SPR in assessing normal mood states.


Sample Preparation and Imaging Conditions Affect mEos3.2 Photophysics in Fission Yeast Cells.
Photoconvertible fluorescent proteins (PCFPs) are widely used in super-resolution microscopy and studies of cellular dynamics. However, our understanding of their photophysics is still limited, hampering their quantitative application. For example, we do not know the optimal sample preparation methods or imaging conditions to count protein molecules fused to PCFPs by single-molecule localization microscopy in live and fixed cells. We also do not know how the behavior of PCFPs in live cells compares with fixed cells. Therefore, we investigated how formaldehyde fixation influences the photophysical properties of the popular green-to-red PCFP mEos3.2 in fission yeast cells under a wide range of imaging conditions. We estimated photophysical parameters by fitting a three-state model of photoconversion and photobleaching to the time course of fluorescence signal per yeast cell expressing mEos3.2. We discovered that formaldehyde fixation makes the fluorescence signal, photoconversion rate, and photobleaching rate of mEos3.2 sensitive to the buffer conditions likely by permeabilizing the yeast cell membrane. Under some imaging conditions, the time-integrated mEos3.2 signal per yeast cell is similar in live cells and fixed cells imaged in buffer at pH 8.5 with 1 mM DTT, indicating that light chemical fixation does not destroy mEos3.2 molecules. We also discovered that 405-nm irradiation drove some red-state mEos3.2 molecules to enter an intermediate dark state, which can be converted back to the red fluorescent state by 561-nm illumination. Our findings provide a guide to quantitatively compare conditions for imaging mEos3.2-tagged molecules in yeast cells. Our imaging assay and mathematical model are easy to implement and provide a simple quantitative approach to measure the time-integrated signal and the photoconversion and photobleaching rates of fluorescent proteins in cells.


Transesophageal ecocardiography: the correct intraoperative way to detect the source of peripheral embolism in an emergency.
Arterial thromboembolism in patients with an unknown source of embolization is associated with significant morbidity and mortality. Once the acute process has been treated, a search of the offending embolic source must be conducted to prevent additional episodes. The most common sources of peripheral embolism include intracardiac thrombi (>85%), thrombus within arterial aneurysm, thrombus overlying complex atherosclerotic plaques, and paradoxical embolization from deep venous thrombus. A strong association has been shown between protruding, noncalcified plaques>4 cm in the aorta detected by transesophageal echocardiography and the risk of embolism. Moreover, as many as 25-50% of protruding plaques may have superimposed mobile thrombi ranging from one to several centimeters, and this imparts a high embolic risk. The formation of thrombi in morphologically normal aorta is a rare event. We report a case of peripheral embolization in a young man caused by a thrombus in the descending aorta detected by transesophageal echocardiography.


Osteoporotic stress fractures in anorexia nervosa: etiology, diagnosis, and review of four cases.
Anorexia nervosa (AN) is a chronic eating disorder characterized by self-imposed semi-starvation that affects 1% of adolescent females. AN predisposes to osteoporosis through hypothalamic dysfunction, which may lead to elevated cortisol as well as diminished estrogen and progesterone. The osteoporosis associated with AN affects both trabecular and cortical bone and increases the risk of osseous fracture. Fractures in this population may go unrecognized, because planar X-rays may be nondiagnostic for 6 weeks or more. Four women with AN ranging in ages from 22 to 34 with skeletal pain and nondiagnostic roentgenographs are described. Stress fractures in these patients were subsequently identified by bone scan. Although moderate exercise in patients with AN-associated osteoporosis may be beneficial, strenuous exercise can be detrimental, with its potential risk of stress fractures and exacerbation of the underlying neurohormonal abnormalities. This risk for fracture may persist well after improvement in the patient's AN.


Acquired uterine arterio-venous malformation post molar pregnancy suction-curettage: 2 case reports.
Acquired uterine AVM is an abnormal and non-functional connection between uterine arteries and veins. It is reported as a consequence of uterine trauma as curettage procedures, pelvic surgery. The authors report 2 cases of uterine AVM post suction-curettage procedure on molar pregnancy incidentally discovered in ultrasound screening in the usual follow-up of this disease, diagnosed in the Department of Maternity of Mother and Child University Hospital Abderrahim Harouchi of Casablanca. Uterine AVMs are extremely rare and should be considered in cases of heavy and persistent uterine bleeding. Uterine AVMs are either acquired or, more rarely, congenital, due to abnormal differentiation of the primary vascular structures during embryogenesis. The invasive technique allows confirmation of the diagnosis and identification of the major feeding vessels when embolization may be indicated as a treatment option. Acquired uterine arteriovenous malformation is the result of uterine trauma; it presents as uterine bleeding through the vagina that can be life threatening, the rarity of the condition makes it difficult to diagnose, however the evolution of investigative techniques helps in the diagnostic process.


The result of replacement of partial or total collateral ligaments with Marlex mesh in the knees of dogs.
Marlex mesh is a synthetic material which has been used clinically to replace ligamentous structures. It serves as a scaffold for infiltration of the fibroblasts eventually becoming mature fibrocytes. In dogs, almost totally mature fibrocytes appear within the framework of the Marlex mesh prosthesis by the end of 3 months of healing.


Antitumor promoting activities of 3-O-acyl-(-)epigallocatechins.
As an exploratory investigation of antitumor promoting compounds, 3-O-acyl-(-)-epigallocatechins possessing a straight-, branched-, phenyl-inserted- or 1,4-phenylene-inserted-acyl chain of varying length from C4 to C18 were synthesized and evaluated their inhibitory effects against the activation of the Epstein-Barr virus early antigen (EBV-EA). It was indicated that the epigallocatechin derivatives having the straight- or branched-acyl chain of C8 to C11 carbon atoms achieve marked effects.


Effects of the imidazobenzodiazepine Ro 15-4513 on saccharin choice and acceptance, and on food intake, in the rat.
The general aim of the present series of experiments was to investigate the effects of the imidazobenzodiazepine, Ro 15-4513, on ingestional behavior in the rat. The more specific aims were to test its effects on preference for sweet taste, to determine if it acts as a benzodiazepine-receptor inverse agonist, and if it selectively reduces sweetness preference. The results indicated that Ro 15-4513 (1.0-10 mg/kg, i.p.) abolished the preference for a 0.05% sodium saccharin solution in a two-choice test. Water intake in the same test was unaffected. Second, at 10 mg/kg, it suppressed saccharin ingestion in an acceptance test; this effect was completely reversed by the selective benzodiazepine antagonist, Ro 15-1788 (20 mg/kg). Third, Ro 15-4513 (1.0-10 mg/kg) reduced palatable food consumption in non-deprived rats, an effect which was also antagonized by Ro 15-1788. The results are consistent the bidirectional modulation of ingestional responses to palatable taste stimuli as a consequence of drug actions at benzodiazepine receptors. Furthermore, they emphasize that any reduction in consummatory responses produced by Ro 15-4513 is likely to reflect inverse agonist characteristics, as distinct from any putative ethanol antagonist property.


Electrophysiologic effects of intravenous and oral sotalol for sustained ventricular tachycardia secondary to coronary artery disease.
The electrophysiologic effects of intravenous sotalol (1.5 mg/kg load followed by 0.008 mg/kg maintenance, mean dose 150 +/- 23 mg) and oral sotalol (mean dose 583 +/- 204 mg daily) were prospectively evaluated in 16 patients undergoing electrophysiologic evaluation for sustained ventricular tachycardia (VT) secondary to coronary artery disease. Electrocardiographic intervals, indexes of sinus and atrioventricular node function and indexes of atrial and ventricular function were assessed. Inducibility or noninducibility of sustained VT and characteristics of the induced arrhythmia were also evaluated. Intravenous and oral sotalol exerted similar beta-blocking effects, which included significant prolongation of sinus cycle length (baseline 820 +/- 165 ms, intravenous sotalol 1,077 +/- 206 ms, oral sotalol 1,141 +/- 306 ms), AH interval (baseline 126 +/- 43, intravenous sotalol 169 +/- 42, oral sotalol 197 +/- 55 ms) and Wenckebach cycle length (baseline 375 +/- 70, intravenous sotalol 460 +/- 84, oral sotalol 449 +/- 68 ms). Both intravenous and oral sotalol also prolonged repolarization and refractoriness including significant increases in QT interval (baseline 338 +/- 47, intravenous sotalol 417 +/- 35, oral sotalol 450 +/- 70 ms), atrial effective refractory period (baseline 240 +/- 38, intravenous sotalol 330 +/- 71, oral sotalol 299 +/- 26 ms) and right ventricular effective refractory period (baseline 241 +/- 16, intravenous sotalol 289 +/- 35, oral sotalol 291 +/- 22 ms).(ABSTRACT TRUNCATED AT 250 WORDS)


Nervous tract-bioinspired multi-nanoyarn model system regulating neural differentiation and its transcriptional architecture at single-cell resolution.
Bioinspired by native nervous tracts, a spinal cord-mimicking model system that was composed of multiple nanofibrous yarns (NYs) ensheathed in a nanofibrous tube was constructed by an innovative electrospinning-based fabrication and integration strategy. The infilling NYs exhibited uniaxially aligned nanofibrous architecture that had a great resemblance to spatially-arranged native nervous tracts, while the outer nanofibrous tubes functioned as an artificial dura matter to provide a stable intraluminal microenvironment. The three-dimensional (3D) NYs were demonstrated to induce alignment, facilitate migration, promote neuronal differentiation, and even phenotypic maturation of seeded neural stem and progenitor cells (NSPCs), while inhibiting gliogenesis. Single-cell transcriptome analysis showed that the NSPC-loaded 3D NY model shared many similarities with native spinal cords, with a great increase in excitatory/inhibitory (EI) neuron ratio. Curcumin, as a model drug, was encapsulated into nanofibers of NYs to exert an antioxidant effect and enhanced axon regeneration. Overall, this study provides a new paradigm for the development of a next-generation in vitro neuronal model system via anatomically accurate nervous tract simulation and constructs a blueprint for the research on NSPC diversification in the biomimetic microenvironment.


Deposition, microstructure and nanoindentation of multilayer Zr nitride and carbonitride nanostructured coatings.
Nitrides, carbides, and carbonitrides of transition metal elements like Zr, W, Ti, etc. are generally employed to produce hard coatings. Zirconium-based hard coatings have shown useful applications in the areas of tribology, biomedicine and electrical due to their high thermal stability, hardness, biocompatibility, good erosion, wear, and corrosion resistance. In this study, we created homogeneous and tenacious nanostructured hard coatings based on Zr with good mechanical properties. The magnetron sputter deposition technique was utilized to coat stainless steel 316L substrates with multilayers of Zr/ZrN and ZrN/ZrCN with individual layer thicknesses of 250 and 500 nm for each coating composition. The deposition conditions were adjusted to create two different coating thicknesses of 2 and 3 µm. The thickness of the coating was confirmed using Calotest and the coatings' morphology and elemental composition were determined utilizing the atomic force microscope and scanning electron microscope equipped with energy dispersive x-ray spectrometer. Coating thickness and adhesion were measured using cross-sectional samples and XRD was utilized to analyze the coatings structure. Nanoindenter was employed to determine the instrumental nanoindentation hardness and elastic modulus. The influence of coating thickness on tribological behavior was further investigated using the ratio of nanohardness-to-elastic modulus (H/E). No evidence of decohesion was observed at the substrate/coatings interface, and the grains of all the coatings were observed to show columnar growth which were homogeneous, compact and dense. The grains of the ZrN/ZrCN coatings were observed to be denser, finer and more compact compared to those of the Zr/ZrN coatings. Correspondingly, higher hardness, modulus and H/E values were exhibited by ZrN/ZrCN than Zr/ZrN coatings. This suggests that the ZrN/ZrCN coatings are capable of exhibiting better wear resistance and fracture toughness. The coatings developed in this investigation are anticipated to be suitable for applications in tribology due to their excellent hardness and H/E properties.


Impact of COVID-19 anxiety on functional foods consuming intention: role of electronic word of mouth.
The COVID-19 pandemic, which involving mass quarantines in many nations, has affected consumer health consciousness behaviors, including food consumption. This study aimed to investigate the impact of COVID-19 anxiety on functional food consumption within the framework of changes in health concerns and electronic word-of-mouth communication through digital platforms, paying special attention to the moderating effect of trust on eWOM information. /methodology/approach: This cross-sectional study included 527 participants. The data were analyzed using a structural equation modeling approach. Mediating moderating effects were tested using bootstrapping and multigroup methods. Anxiety about the COVID-19 virus has a great impact on individuals' health concerns, word-of-mouth information seeking, and functional food consumption intention. Mediating effects of health consciousness and eWOM on functional food consumption intention were also observed. The anxiety about the COVID-19 virus and health consciousness triggers eWOM communication, and is a strong driver of intention to purchase functional foods if people trust the eWOM information source. While scholars have demonstrated the impact of COVID-19 on human behavior, a largely uninvestigated issue is the effect of COVID-19 virus anxiety on health product consumption. This is one of the first studies to examine the interrelationships among COVID-19 anxiety, health consciousness, eWOM, and functional food consumption intention.This study provides valuable insights into consumer behavior during the COVID-19 pandemic. Future research should consider the effect of COVID-19 virus anxiety on health-related issues and nutritional behavioral consequences. Based on the results, implications for managers and researchers are proposed.


Role of Vitamins B-3 and C in the fashioning of granules in UASB reactor sludge.
Whereas a myriad of possible factors have been reported which effect the formation of granules in a upflow anaerobic sludge blanket (UASB) reactor and influence their properties, there is no study on the effect of vitamins on the granulation of UASB reactor sludge. The present study was undertaken to bridge this gap. It was seen that vitamins helped in better granule formation--as reflected by favorable size distribution, sludge volume index, and settling velocity--compared to controls. The vitamin-spiked reactors also achieved >85% COD removal efficiency in half the number of days the unspiked reactors took. The vitamin supplements were effective at concentrations ≤ 1 mg/l. Hence, their use in expediting granule formation as also in developing better-quality granules appears economically viable.


Permeability studies on liposomes formed from polymerizable diacetylenic phospholipids and their potential applications as drug delivery systems.
We have investigated the permeability and entrapment characteristics of liposomes formed from a group of polymerizable phospholipids, containing diacetylenic groups in one or both of their acyl chains. Permeability was assessed by the release of an entrapped dye, 6-carboxyfluorescein. Diacetylenic phosphatidylcholine (PC) liposomes were found to exhibit a wide range of permeability properties, depending on: the nature of the diacetylenic lipid, i.e. mixed-chain (mc) or identical-chain (id), the extent of polymerisation, vesicle size, and cholesterol content. Ultraviolet-initiated polymerisation affected a significant decrease in the permeability of C25idPC liposomes. The increase in permeability of liposomes formed from four other diacetylenic lipids (C25mcPC, C23idPC, C23mcPC and C20idPC) after polymerisation was attributed to disturbances in the packing of lipid molecules, and/or the limited ability of small unilamellar vesicles to accommodate long polymers. The C20idPC lipid is atypical, forming irregular monomeric and polymeric vesicles. The permeability of C25idPC liposomes was also assessed by the release of [3H]inulin. C25idPC liposomes exhibited low permeabilities to [3H]inulin in their monomeric and polymeric states. Incubation of C25idPC liposomes in human plasma caused a substantial increase in the permeability of monomeric vesicles to both carboxyfluorescein and [3H]inulin. The permeability of polymerised C25idPC liposomes, however, was unaffected in the presence of plasma, with vesicles retaining most of their entrapped [3H]inulin after 50 h. These findings demonstrate that polymeric C25idPC liposomes exhibit high resistance to the destructive actions of plasma components, such as high-density lipoproteins (HDLs). Polymeric C25idPC liposomes may have an application in drug delivery systems.


HPAC, a new human glucocorticoid-sensitive pancreatic ductal adenocarcinoma cell line.
A new human pancreatic cancer (HPAC) cell line was established from a nude mouse xenograft (CAP) of a primary human pancreatic ductal adenocarcinoma. In culture, HPAC cells form monolayers of morphologically heterogenous, polar epithelial cells, which synthesize carcinoembryonic antigen, CA 19-9, CA-125, cytokeratins, antigens for DU-PAN-2, HMFG1, and AUA1, but do not express chromogranin A or vimentin indicative of their pancreatic ductal epithelial cell character. In the presence of serum, HPAC cell DNA synthesis was stimulated by insulin, insulin growth factor-I, epidermal growth factor, and TGF-α but inhibited by physiologic concentrations of hydrocortisone and dexamethasone. Dose-dependent inhibition of DNA synthesis was limited to steroids with glucocorticoid activity. The inhibitory effect of dexamethasone was abolished by the glucocorticoid antagonist RU 384862 Binding of [3H] dexamethasone to cytosolic proteins was specific and saturable at 4 degrees C. Scatchard analysis of binding data demonstrated a single class of high-affinity binding sites (K(d) = 3.8 ± 0.9 nM; B(max) = 523 ± 128 fmol/mg protein). Western blot analysis revealed a major protein band that migrated at a M(r) of 96 kDa. Northern blot analysis identified an mRNA of approximately 7 kilobases which hybridized with a specific glucocorticoid receptor complementary-DNA probe (OB7). These findings support a role for glucocorticoids in the regulation of human malignant pancreatic cell function.


Malignant melanoma of the skin. I. The association of tumor depth and type, and patient sex, age, and site with survival.
The occurrence and behavior of cutaneous melanomas in a group of 1123 patients studied prospectively, is described in terms of histologic type, tumor thickness and levels of invasion, the patients' sex and age, and the anatomic location of the primary tumors. Associations amongst these attributes, and with survival, are also examined. The characteristics of the patients in this study (who on average are somewhat younger, and have better prognoses and survivals than those reported by most other groups) are compared with data obtained (primarily over the past decade) in other geographical areas, and with different patient populations. Evidence is presented that sex, tumor location, and age (in the case of males) are also predictive of survival.


1,3,4-Thiadiazole-Containing Azo Dyes: Synthesis, Spectroscopic Properties and Molecular Structure.
Three series of azo dyes derived from 2-amino-5-aryl-1,3,4-thiadiazoles and aniline, N,N-dimethylaniline and phenol were synthesized in high yields by a conventional diazotization-coupling sequence. The chemical structures of the prepared compounds were confirmed by 1H-NMR, 13C-NMR, IR, UV-Vis spectroscopy, mass spectrometry and elemental analysis. In addition, the X-ray single crystal structure of a representative azo dye was presented. For explicit determination of the influence of a substituent on radiation absorption in UV-Vis range, time-dependent density functional theory calculations were performed.


The Minichromosome Maintenance Complex Component 2 (MjMCM2) of Meloidogyne javanica is a potential effector regulating the cell cycle in nematode-induced galls.
Root-knot nematodes Meloidogyne spp. induce enlarged multinucleate feeding cells-galls-in host plant roots. Although core cell-cycle components in galls follow a conserved track, they can also be usurped and manipulated by nematodes. We identified a candidate effector in Meloidogyne javanica that is directly involved in cell-cycle manipulation-Minichromosome Maintenance Complex Component 2 (MCM2), part of MCM complex licensing factor involved in DNA replication. MjMCM2, which is induced by plant oxilipin 9-HOT, was expressed in nematode esophageal glands, upregulated during parasitic stages, and was localized to plant cell nucleus and plasma membrane. Infected tomato hairy roots overexpressing MjMCM2 showed significantly more galls and egg-mass-producing females than wild-type roots, and feeding cells showed more nuclei. Phylogenetic analysis suggested seven homologues of MjMCM2 with unknown association to parasitism. Sequence mining revealed two RxLR-like motifs followed by SEED domains in all Meloidogyne spp. MCM2 protein sequences. The unique second RxLR-like motif was absent in other Tylenchida species. Molecular homology modeling of MjMCM2 suggested that second RxLR2-like domain is positioned on a surface loop structure, supporting its function in polar interactions. Our findings reveal a first candidate cell-cycle gene effector in M. javanica-MjMCM2-that is likely secreted into plant host to mimic function of endogenous MCM2.


Endoscopic Transorbital Approach for Spheno-Orbital Tumors: Case Series and Systematic Review of Literature.
Transorbital neuroendoscopic surgery (TONES) comprises a group of approaches with indications expanding from orbital tumors to more complex skull base lesions. We analyzed the role of the endoscopic transorbital approach (eTOA) for spheno-orbital tumors, reporting the results of our clinical series and of a systematic review of the literature. All patients operated on from 2016 to 2022 at our institution for a spheno-orbital tumor through an eTOA were included in a clinical series, and a systematic review of the literature was performed. Our series consisted of 22 patients (16 females, mean age 57 ± 13 years). Gross tumor removal was achieved in 8 patients (36.4%) after the eTOA and in 11 (50.0%) after a multistaged strategy combining the eTOA with the endoscopic endonasal approach. Complications included 1 chronic subdural hematoma and 1 permanent extrinsic ocular muscle deficit. Patients were discharged after 2.4 ± 1.3 days. The most common histotype was meningioma (86.4%). Proptosis improved in all cases, visual deficit in 66.6%, and diplopia in 76.9%. These results were confirmed by the review of the 127 cases reported in the literature. Despite its recent introduction, a significant number of spheno-orbital lesions treated with an eTOA are being reported. Its main advantages are favorable patient outcome and optimal cosmetic results, with minimal morbidity and quick recovery. This approach can be combined with other surgical routes or adjuvant therapies for complex tumors. However, it is a technically demanding procedure, requiring specific skills in endoscopic surgery, that should be reserved to dedicated centers.


Highly selective etching of SiNxover SiO2using ClF3/Cl2remote plasma.
Highly selective etching of silicon nitride over silicon oxide is one of the most important processes especially for the fabrication of vertical semiconductor devices including 3D NAND (Not And) devices. In this study, isotropic dry etching characteristics of SiNxand SiO2using ClF3/Cl2remote plasmas have been investigated. The increase of Cl2percent in ClF3/Cl2gas mixture increased etch selectivity of SiNxover SiO2while decreasing SiNxetch rate. By addition of 15% Cl to ClF3/Cl2, the etch selectivity higher than 500 could be obtained with the SiNxetch rate of ∼8 nm min-1, and the increase of Cl percent to 20% further increased the etch selectivity to higher than 1000. It was found that SiNxcan be etched through the reaction from Si-N to Si-F and Si-Cl (also from Si-Cl to Si-F) while SiO2can be etched only through the reaction from Si-O to Si-F, and which is also in extremely low reaction at room temperature. When SiNx/SiO2layer stack was etched using ClF3/Cl2(15%), extremely selective removal of SiNxlayer in the SiNx/SiO2layer stack could be obtained without noticeable etching of SiO2layer in the stack and without etch loading effect.


Peritoneal and serum tumor markers predict recurrence and survival of patients with resectable gastric cancer.
BACKGROUND: Laparoscopy has become a useful adjunct for the staging of gastric cancer; yet, other than standard TNM staging, few additional variables can be used to predict survival. This study evaluated the utility of serum and peritoneal tumor markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA]-125) as predictors of locoregional recurrence and distant disease-free survival in patients with gastric cancer.METHODS: During the period June 1990 to February 1994, 86 patients with gastric cancer were evaluated and deemed resectable by preoperative imaging studies. Serum levels of CEA and CA-125 were determined, and all patients underwent laparoscopic staging. Peritoneal washings were obtained from all patients, and 56 of these samples were evaluated for levels of CEA and CA-125.RESULTS: Sixteen (19%) of the 86 patients were found to have metastatic disease at laparoscopy; 67 of the remaining 70 patients underwent potentially curative gastrectomy. Serum CEA and CA-125 levels were predictive of survival in the entire group of patients. In patients who underwent curative gastrectomy, serum CEA predicted survival, whereas peritoneal CA-125 predicted peritoneal recurrence.CONCLUSIONS: Elevated serum levels of CEA and CA-125 are predictive of decreased survival in patients with gastric cancer. Furthermore, determination of peritoneal CA-125 helps to identify those patients at an increased risk for recurrent peritoneal disease.


Nanoconjugates based on a novel organic-inorganic hybrid silsesquioxane and gold nanoparticles as hemocompatible nanomaterials for promising biosensing applications.
A new hybrid organic-inorganic silsesquioxane material, 3-n-propyl(2-amino-4-methyl)pyridium chloride (SiAMPy+Cl-), was synthesized and successfully applied for the synthesis of stable nanoconjugates with gold nanoparticles (AuNPs-SiAMPy+). SiAMPy+Cl- was obtained through a simple sol-gel procedure by using chloropropyltrimetoxysilane and tetraethylorthosilicate as precursors and 2-amino-4-methylpyridine as the functionalizing agent. The resulting material was characterized by employing FTIR, XRD, and 1H-, 13C-, and 29Si-NMR spectroscopy. The synthesis of AuNPs-SiAMPy+ nanoconjugates was optimized through a 23 full factorial design. UV-VIS, FTIR, TEM, DLS, and ζ-potential measurements were used to characterize the nanoconjugates, which presented a spherical morphology with an average diameter of 5.8 nm. To investigate the existence of toxic effects of AuNPs-SiAMPy+ on blood cells, which is essential for their future biomedical applications, toxicity assays on human erythrocytes and leukocytes were performed. Interestingly, no cytotoxic effects were observed for both types of cells. The nanoconjugates were further applied in the construction of electrochemical immunosensing devices, aiming the detection of anti-Trypanosoma cruzi antibodies in serum as biomarkers of Chagas disease. The AuNPs-SiAMPy+ significantly enhanced the sensitivity of the biodevice, which was able to discriminate between anti-T. cruzi positive and negative serum samples. Thus, the AuNPs-SiAMPy+-based biosensor showed great potential to be used as a new tool to perform fast and accurate diagnosis of Chagas disease. The promising findings described herein strongly confirm the remarkable potential of SiAMPy+Cl- to obtain nanomaterials, which can present notable biomedical properties and applications.


Differential hippocampal protein expression between normal mice and mice with the perioperative neurocognitive disorder: a proteomic analysis.
To compare differential expression protein in hippocampal tissues from mice of perioperative neurocognitive disorder (PND) and normal control mice and to explore the possible mechanism of PND. Mice were randomly divided into a PND group (n = 9) and a control group (n = 9).The mice in the PND group were treated with open tibial fracture with intramedullary fixation under isoflurane anesthesia, while the mice in the control group received pure oxygen without surgery. The cognitive functions of the two groups were examined using Morris water maze experiment, Open field test and Fear conditioning test. The protein expression of the hippocampus of mice was analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore the principal functions of dysregulated proteins. A total of 21 proteins were differentially expressed between PND and control mice on days 1, 3, and 7 after the operation. These proteins were involved in many pathological processes, such as neuroinflammatory responses, mitochondrial oxidative stress, impaired synaptic plasticity, and neuronal cell apoptosis. Also, the dysregulated proteins were involved in MAPK, AMPK, and ErbB signaling pathways. The occurrence of PND could be attributed to multiple mechanisms.


Comparison of three methods for respiratory virus detection between induced sputum and nasopharyngeal aspirate specimens in acute asthma.
Viral respiratory tract infections are associated frequently with acute exacerbations of asthma. Nasopharyngeal aspirates and bronchoalveolar lavage specimens are used extensively for detecting viral respiratory tract infections, but not sputum. The aim of the study was to determine the efficiency of viral detection in induced sputum versus nasopharyngeal aspirate obtained during acute exacerbations of asthma, comparing three laboratory methods of viral diagnosis. Paired samples of induced sputum and nasopharyngeal aspirate obtained from 32 adults admitted to hospital with acute asthma were subjected to reverse transcription-polymerase chain reaction (RT-PCR), viral culture, and immunofluorescence assay. The results show that RT-PCR was associated with significantly higher rates of viral detection than culture (P=0.005) or immunofluorescence (P=0.001), without significant differences in the rates of viral detection between induced sputum and nasopharyngeal aspirate. It is concluded that induced sputum specimens are feasible for detection of viral respiratory tract infections by RT-PCR during acute exacerbations of asthma.


Establishment of a 5-gene risk model related to regulatory T cells for predicting gastric cancer prognosis.
Gastric cancer (GC) is one of the high-risk cancers that lacks effective methods for prognosis prediction. Therefore, we searched for immune cells related to the prognosis of GC and studied the role of related genes in GC prognosis. In this study, we collected the mRNA data of GC from The Cancer Genome Atlas (TCGA) database and studied the immune cells that were closely related to the prognosis of GC. Spearman correlation analysis was performed to show the association between immune cell-related genes and the differentially expressed genes (DEGs) of GC. Univariate and multivariate Cox regression analyses were conducted on the immune cell-related genes with a high correlation with GC. A prognostic risk score model was constructed and the most significant feature genes were identified. Kaplan-Meier method was then used to compare the overall survival (OS) of patients with high-risk and low-risk, and receiver operating characteristic (ROC) analysis was used to assess the accuracy of the risk model. In addition, GC patients were grouped according to the median expression of the features genes, and survival analysis was further carried out. It was noted that regulatory T cells (Tregs) were significantly correlated with the prognosis of GC, and 172 genes related to Tregs were found to be closely associated with GC. An optimal prognostic risk model was constructed, and a 5-gene (including LRFN4, ADAMTS12, MCEMP1, HP and MUC15) signature-based risk score was established. Survival analysis showed significant difference in OS between low-risk and high-risk samples. ROC analysis results indicated that the risk model had a high accuracy for the prognosis prediction of samples (AUC = 0.717). The results of survival analysis on each feature gene based on expression levels were consistent with the results of multivariate Cox analysis for predicting the risk rate of the 5 genes. These results proved that the 5-gene signature-based risk score could be used to predict the survival of GC patients, and these 5 genes were closely related to Tregs. These findings are of great significance for studying the role of immune cells and related immune factors in regulating the prognosis of GC.


Organic fluorescent nanoprobes with NIR-IIb characteristics for deep learning.
Illumination of biological events with near-infrared II sub-channel (NIR-IIb, 1500-1700 nm) enhances the transparency of biological tissues, which is very attractive for deep imaging. Due to the long-wavelength, which reduces optical damage, suppresses autofluorescence, and obviates light scattering, NIR-IIb nanoprobes afford deep tissue penetration with unprecedented spatiotemporal resolution. Hence, NIR-IIb imaging facilitates deep learning and decipherment of biological proceedings in living organisms with astounding high clarity. In comparison to its predecessors in the visible-near-infrared spectrum, imaging in the NIR-IIb has shown great potential for tissue imaging and extrapolating imaging applications for clinical studies. However, the use of organic fluorescent nanoprobes (OFNPs) in the NIR-IIb region is still rare since it is in its early stages. Thus, herein we aim to survey the recent development of different organic fluorescent nanomaterials with NIR-IIb characteristics, their unique photophysical properties, and their utilization in deep imaging in animal models. Further, practical researches on organic fluorescent nanoprobes with NIR-IIb emission and their transition to clinical applications are highlighted.


Contribution of CYP19A1, CYP1A1, and CYP1A2 polymorphisms in coronary heart disease risk among the Chinese Han population.
The previous study has pointed to that endogenous CYP metabolites play an important role in the pathogenesis of coronary heart disease (CHD). The study aimed to identify the association of CYP19A1, CYP1A1, and CYP1A2 polymorphisms with CHD susceptibility in a Chinese Han population. A total of 960 genetically unrelated participants consist of 480 CHD patients and 480 healthy controls were enrolled. Nine SNPs in CYP19A1, CYP1A1, and CYP1A2 were randomly selected and genotyped using the Agena MassARRAY platform. Logistic regression analysis was used for the relationship between selected SNPs and CHD susceptibility by calculating odds ratios (OR) with 95% confidence intervals (CI) adjusted for age and gender. The distribution of clinical characteristics in different genotypes was evaluated by one-way analysis of variance (ANOVA). CYP1A2 rs2470890 TT genotype had a higher CHD risk compared with CC genotype (OR = 3.06, p = 0.032) or CC-CT genotype (OR = 3.04, p = 0.033). Moreover, the contribution of CYP19A1 and CYP1A2 polymorphisms to CHD susceptibility was associated with age, gender, and clinical phenotypes (course of the disease and Gensini score). Besides, CYP1A2 rs762551 was related to serum levels of red blood cell, triglyceride, total cholesterol, and low-density lipoprotein cholesterol (LDL-C, p < 0.05). Our findings provided scientific evidence about CYP19A1, CYP1A1, and CYP1A2 polymorphisms on CHD incidence.


Advanced nutrient root-feeding system for conveyor-type cylindrical plant growth facilities for microgravity.
A compact and reliable automatic method for plant nutrition supply is needed to monitor and control space-based plant production systems. The authors of this study have designed a nutrient root-feeding system that minimizes and regulates nutrient and water supply without loss of crop yields in a space greenhouse. The system involves an ion-exchange fibrous artificial soil (AS) BIONA-V3(TM) as the root-inhabited medium; a pack with slow-release fertilizer as the main source of nitrogen, phosphorus, and potassium; and a cartridge with granular mineral-rich ionite (GMRI) as a source of calcium, magnesium, sulfur, and iron. A controller equipped with an electrical conductivity meter controls the solution flow and concentration of the solution in the mixing tank at specified values. Experiments showed that the fibrous AS-stabilized pH of the substrate solution within the range of 6.0-6.6 is favorable to the majority of crops. The experimental data confirmed that this technique allowed solution preparation for crops in space greenhouses by means of pumping water through the cartridge and minimization of the AS stock onboard the space vehicle.


Sonic hedgehog inhibits the terminal differentiation of limb myoblasts committed to the slow muscle lineage.
The proliferation, differentiation, and fusion of a small number of myogenic precursor cells must be precisely regulated during development to ensure the proper size, organization, and function of the limb musculature. We have examined the role of Sonic hedgehog (Shh) in these processes by both augmentation and inhibition of the Shh-mediated signaling pathway. Our data show that Shh regulates muscle development by repressing the terminal differentiation of early myogenic precursor cells and does not function as a myoblast mitogen. Shh function in hypaxial muscle appears to be spatially restricted to the early myoblast population within the ventral muscles of the posterior region of the limb. Furthermore, Shh appears to act as a permissive, rather than an inductive, signal for slow MyHC expression in myoblasts. Our data thus provide the foundation for a new hypothesis for Shh function in hypaxial skeletal muscle development.


The nature of the stabilizing functions of skeletal muscles.
The paper defines the term coordination interval (CI), suggesting that it should replace the term electromechanical delay (EMD), if this parameter is determined in vivo for a muscle functioning in a biomechanical system with considerable mobility, but not in a kinematic pair with one degree of rotational freedom (DOF). It was adopted that CI is the time elapsing between the moment of exertion of the resultant muscular force to the surroundings by the ending of the biokinematic chain with many DOFs, and the onset of myopotential in the muscle involved in its actuation. Tested at the same time was the utility efficiency of the system: man--unstable external object with adjustable mobility, as well as the participation and coordination patterns of the upper extremity muscles engaged in stabilizing and motor activities. Twelve adult men, students of physical education, took part in the experiment. The experimental set-up was in the form of a 3.08 m long physical pendulum with the inertial moment of 574 kg m2 and with an exchangeable ending that served as a handle. Three endings were used with zero, one or two DOFs in relation to the pendulum shaft. The subjects of the test were told to push the pendulum ending with maximum force using the upper extremity, so as to impart to it the highest possible kinetic energy, irrespective of its stability type and mobility. The muscles straightening the upper extremity and stabilizing the wrist joint were tested in the EMG measurements. As a result of the experiment, it was found that (1) the utility efficiency of the organism in relation to the force and muscular power exerted on the surroundings decreases to 80 and 60%, respectively, if a driven object requires stabilization, and (2) the patterns of muscular synergism expressed by sequences and frequencies of muscular activation by the nervous system, on the grounds of CI, undergo characteristic changes if a driven object becomes unstable.


Distribution of H2S synthesis enzymes in the walls of cerebral arteries in rats.
The distribution of two enzymes involved in H(2)S synthesis, cystationine β-synthase (CBS) and cystationine γ-liase (CSE), was studied in the walls of the internal carotid artery, order I-V branches of the middle cerebral artery basin, and intracerebral vessels of adult Wistar rats. Immunohistochemical staining showed the presence of CBS in the endothelium of small pial arteries (order IV-V branches) and intracerebral arterioles and in the capillary walls, neurons, and vascular nerves. As for CSE, in the internal carotid artery and large (order I-II) pial branches it was found mainly in the tunica media myocytes, in order III-IV vessels in myocytes and endothelium, and in smaller pial and intracerebral vessels in the endothelium. Along with enzyme-positive vessels, many pial and intracerebral arteries contained no these enzymes in the walls.


Emerging roles for TNIP1 in regulating post-receptor signaling.
A vast number of cellular processes and signaling pathways are regulated by various receptors, ranging from transmembrane to nuclear receptors. These receptor-mediated processes are modulated by a diverse set of regulatory proteins. TNFα-induced protein 3-interacting protein 1 is such a protein that inhibits both transduction by transmembrane receptors, such as TNFα-receptor, EGF-R, and TLR, and nuclear receptors' PPAR and RAR activity. These receptors play key roles in regulating inflammation and inflammatory diseases. A growing number of references have implicated TNIP1 through GWAS and expression studies in chronic inflammatory diseases such as psoriasis and rheumatoid arthritis, although TNIP1s exact role has yet been determined. In this review, we aim to integrate the current knowledge of TNIP1s functions with the diseases in which it has been associated to potentially elucidate the role this regulator has in promoting or alleviating these inflammatory diseases.


Asymptomatic bacteriuria in men with orthotopic ileal neobladders: possible relationship to nocturnal enuresis.
To assess prospectively the incidence with time of asymptomatic bacteriuria in patients with orthotopic ileal neobladders, and the possible effect on neobladder function. In all, 47 patients (mean age 52.7 years, sd 8.7, range 31-68) with uncomplicated orthotopic ileal neobladders were prospectively evaluated. With no antibiotic manipulation, consecutive urine cultures were assessed monthly. Continence was assessed by direct information from the patients at each follow-up visit. Overall, 797 samples were cultured from the 47 patients (mean 17.6, sd 7.1). There was a steady decrease in the incidence of positive cultures, from 74.5%, to 35.6% and 6.7% at 1, 6 and 18 months, respectively. While there was persistently sterile urine in only eight patients (17%), 32 had occasional and seven had persistent bacteriuria. Escherichia coli was the commonest organism (76.6%) followed by Klebsiella pneumonia (15.7%); 54% of E. coli and 38% of K. pneumonia infections were sensitive to nitrofurantoin. Diurnal continence was achieved in 98% of the patients at 6 months after surgery. There was a gradual decrease in the frequency of nocturnal enuresis (NE) with time, from 87%, to 42%, 28% and 27% at 1, 6, 12 and 18 months, respectively. There was a significant correlation between the presence of bacteriuria and NE during the first 6 months, but it was not sustained after that. The age of the patients was also related significantly to the incidence of NE; at 6 months, only one of 18 men aged < or = 50 years had NE, while 19 of 29 aged > 50 years had (P < 0.001). At 1 year all patients aged < or = 50 years were nocturnally continent, while half of those aged > 50 years had NE (P = 0.001). Ileal neobladders are associated with a high incidence of asymptomatic bacteriuria during the first year after surgery. There was spontaneous clearance of bacteriuria with time, with no antimicrobial manipulation. Soon after surgery there was a significant association between bacteriuria and NE. The effect of antimicrobials on patients with NE should be evaluated.


Panitumumab Treatment for Advanced Penile Squamous Cell Carcinoma When Surgery and Chemotherapy Have Failed.
Patients with metastatic penile squamous cell carcinoma (SCC) have a poor prognosis and treatment options are needed when chemotherapy treatment fails. We present the final results of panitumumab treatment from our original series. Eligibility included patients with unresectable or metastatic penile SCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and failure of at least 1 chemotherapy regimen. Patients received panitumumab 6.0 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Response was assessed by clinical examination or Response Evaluation Criteria in Solid Tumors version 1.1 criteria every 6 weeks, when applicable. Descriptive statistics were calculated and univariable Cox proportional hazards regression analysis was conducted. Between October 2010 and July 2013, 11 patients were treated. After a median of 5 panitumumab administrations (range, 1-11), we recorded 1 case of Grade 3 cutaneous toxicity and diarrhea each, and 2 cases of Grade 3 mucositis. One patient discontinued treatment because of skin toxicity. Two patients had a complete remission of skin nodules and of skin and nodal metastases, respectively. One patient had a partial regression of skin metastases, and 2 patients stable disease (clinical benefit: 45.5%). Median progression-free survival was 1.9 months (interquartile range [IQR], 0.9-3.0 months) and median overall survival (OS) was 9.5 months (IQR, 4.9-12.6). The presence of visceral metastases showed a trend for association with worse OS (P = .098). Panitumumab was active and safe in patients with highly pretreated penile SCC. The design of combination or sequential strategies with chemotherapy and in an earlier disease stage is warranted.


[Medicosocial rehabilitation of disabled patients with impaired vision at a sanatorium].
Proper studies of the needs of the blind and weak-eyed patients in corrective measures at different stages of rehabilitation basing on both health status and subjective preferences raise efficacy of rehabilitation justifying an individual approach to each patient's needs in vision correction.


Pyridine Derivative of Succinic Acid Hydroxylamide Enhances the Cytotoxic Effect of Cisplatin and Actinomycin D.
We studied the possibility of inhibition of histone deacetylases (HDAC) in the nuclear extract of HeLa cells by N1-hydroxy-N4-(pyridin-4-yl)succinamide (compound 1). Compound 1 inhibits HDAC and showed low toxicity for A-172, HepG2, HeLa, MCF-7, and Vero cells. HeLa cells were most sensitive to the compound. Increasing the interval between administration of compound 1 and the chemotherapeutic agent to 8 h led to an increase in the cytotoxic effect of cisplatin (actinomycin D) on HeLa cells. The combination of compound 1 with cisplatin (actinomycin D) reduced the cytotoxic effect of these drugs for non-tumor Vero cells.


Occult well differentiated thyroid carcinoma presenting as cervical node disease.
Records of 92 patients with differentiated thyroid carcinoma presenting as cervical adenopathy without a palpable mass were reviewed to identify prognostic factors and to evaluate therapy. Patients were treated between 1940 and 1990 and were observed for 3 to 48 years (median 18 years). Follow-up data were obtained by chart review, correspondence, and telephone contact. Among the group, 20 patients had unilateral and 72 bilateral thyroid lobectomy, with node dissection in 77. Thyroid hormone was used in 50 patients and radioactive iodine in 20. Patients were younger than the overall population of patients with differentiated thyroid carcinoma, with more men and more multifocal thyroid disease. Risk group defined by age and sex was the most important determinant of survival. All women 50 years of age or younger and all men 40 or younger (low risk group) survived independent of the type of initial operation or use of thyroid-stimulating hormone suppression or radioactive iodine. Of the low-risk patients, 16% had recurrent disease but were treated successfully with surgery or radioactive iodine; 28% of the older patients (high risk) died of disease. A trend for better survival was noted in high risk patients undergoing bilateral thyroidectomy and in patients receiving thyroid suppression. Of the high risk patients, 26% had recurrent disease, with a 71% mortality rate. Age and sex are the primary determinants of survival. Therapy should be based on risk factors. Low risk patients should have conservative thyroid surgery and modified or limited node dissection.(ABSTRACT TRUNCATED AT 250 WORDS)


Bioinformatic analysis of RecQ4 helicases reveals the presence of a RQC domain and a Zn knuckle.
RecQ helicases play essential roles in the maintenance of genome stability and contain a highly conserved helicase region generally followed by a characteristic RecQ-C-terminal (RQC) domain, plus a number of variable associated domains. Notable exceptions are the RecQ4 helicases, where none of these additional regions have been described. Particularly striking was the fact that no RQC domain had been reported, considering that the RQC domain had been shown to play an essential role in the catalytic mechanism of most RecQ family members. Here we present the results of detailed bioinformatic analyses of RecQ4 proteins that identify, for the first time, the presence of a putative RQC domain, including some of the key residues involved in DNA binding and unwinding. We also describe the presence of a novel "Zn knuckle" domain, as well as an additional Sld2-homology region, providing new insights into the architecture, function and evolution of these enzymes.


Opioid-neuroleptic interaction in brainstem self-stimulation.
Injection of morphine into the ventral tegmental area (but not dorsal to it) induced a dose-dependent decrease in the frequency threshold for midline metencephalic brain stimulation reward. Facilitating doses of ventral tegmental morphine also reversed, in 4 of 6 animals, the threshold-increasing effects of pimozide (0.35 mg/kg, i.p.). This reversal was itself reversed by naloxone (2 mg/kg, i.p.), suggesting a direct action of morphine at ventral tegmental opiate receptors. These data fit with electrophysiological evidence that ventral tegmental morphine stimulates or disinhibits dopamine impulse flow, which would result in increased synaptic dopamine concentrations and decreased synaptic pimozide effectiveness. In the remaining two animals, the combined neuroleptic-opiate treatment resulted in a complete cessation of responding that was not reversed by a 5-fold increase in stimulation frequency. This finding suggested a complete inactivation of the reward mechanism, which might be expected from the interaction of high doses of two drugs that are each known to be capable of producing depolarization inactivation of dopaminergic neurons. These data confirm that brainstem self-stimulation, like medial forebrain bundle self-stimulation, depends critically on the function of the mesocorticolimbic dopamine system.


Relationship between the responsiveness of maternal and foetal lymphocytes to phytohaemagglutinin and to microbial antigens.
The response of 105 maternal-foetal lymphocyte pairs to specific and non-specific stimulation were evaluated using a newly defined method of analysis. There were no significant differences in the responses of maternal or foetal lymphocytes to phytohaemogglutinin (PHA) or the various antigens as a function of concentration over the ranges tested. The maternal lymphocytes were stimulated by all of the antigens and responded to PHA three--five times more strongly than to the antigens. The foetal lymphocytes were stimulated by PHA and tetanus toxoid only and were suppressed by streptokinase-streptodornase (SKSD). They responded to stimulation by antigens at a lower level than did the maternal lymphocytes, but they responded at a much higher level to PHA. Unstimulated cultures of foetal lymphocytes incorporated more isotope than did those of maternal lymphocytes in both autologous and AB plasma. The data were cross-classified to determine whether the responses of the foetal lymphocytes varied concordantly with the responses of the maternal lymphocytes in both autologous and AB plasma by the Chi-square test for independence and by rank correlation analysis. There was no significant correlation in either plasma to stimulation with the antigens. Thus, the presence of antigen reactive lymphocytes in the circulation of the mother does not mean that the foetus is sensitized to that antigen. Comparison of the lymphocyte responses in autologous plasma with those in AB plasma provided evidence for the presence of circulating immunoregulatory substances. Autologous maternal plasma suppressed the lymphocyte responses to high concentrations of candida and SKSD and stimulated the response to mumps, varicella and tetanus toxoid. Autologous fetal plasma suppressed the lymphocyte responses to candida, varicella and SKSD and stimulated the response to PHA. The responsiveness of maternal lymphocytes to PHA was less in foetal plasma than in autologous maternal or AB plasma.


Subcellular integrities in Chroococcidiopsis sp. CCMEE 029 survivors after prolonged desiccation revealed by molecular probes and genome stability assays.
Desiccation-tolerant cells must either protect their cellular components from desiccation-induced damage and/or repair it upon rewetting. Subcellular damage to the anhydrobiotic cyanobacterium Chroococcidiopsis sp. CCMEE 029 stored in the desiccated state for 4 years was evaluated at the single-cell level using fluorescent DNA strand breakage labelling, membrane integrity and potential related molecular probes, oxidant-sensing fluorochrome and redox dye. Covalent modifications of dried genomes were assessed by testing their suitability as PCR template. Results suggest that desiccation survivors avoid/and or limit genome fragmentation and genome covalent modifications, preserve intact plasma membranes and phycobiliprotein autofluorescence, exhibit spatially-reduced ROS accumulation and dehydrogenase activity upon rewetting. Damaged cells undergo genome fragmentation, loss of plasma membrane potential and integrity, phycobiliprotein bleaching, whole-cell ROS accumulation and lack respiratory activity upon rewetting. The co-occurrence of live and dead cells within dried aggregates of Chroococcidiopsis confirms that desiccation resistance is not a simple process and that subtle modifications to the cellular milieu are required to dry without dying. It rises also intriguing questions about the triggers of dead cells in response to drying. The capability of desiccation survivors to avoid and/or reduce subcellular damage, shows that protection mechanisms are relevant in the desiccation tolerance of this cyanobacterium.


Hemodynamic and prognostic value of thallium-201 myocardial imaging in patients with dilated cardiomyopathy.
We studied 70 patients with dilated cardiomyopathy to determine whether extent of perfusion defect on thallium imaging could be related to the hemodynamics and prognosis of the patients. Patients were divided into three groups according to the extent of perfusion defect, i.e., Grade I: no perfusion defect (n = 19), Grade II: apical perfusion defect (n = 22), and Grade III: extensive perfusion defect (n = 29). The patients of Grade III demonstrated marked hemodynamic deterioration compared with those of Grade I and II. Three-year survival rate showed lower value in proportion to the extent of perfusion defect (P less than 0.05). Death from progressive heart failure tended to occur in patients with extensive perfusion defect (P less than 0.05). In patients of Grade III, the perfusion defect extended mainly to the posterolateral segment. Although autopsy studies showed increased fibrosis in the left ventricular wall in these patients, the extension of the fibrosis was not related to that of fibrosis. Moreover, the perfusion defect had regressed in three of 18 patients in the follow-up examination. These results indicate that the extent of perfusion defect on thallium imaging may be of value in non-invasive evaluation and prediction of the prognosis in patients with dilated cardiomyopathy. Distribution of the perfusion defect was, however, not related to that of myocardial fibrosis.


Equivalent circuit for coil-patient interactions in magnetic resonance imaging.
An equivalent circuit is presented which accurately models the performance of magnetic resonance imaging receiver coils used with conducting samples. Coil-sample interaction is determined by measuring either the complex impedance or the associated resonant frequency and quality factor when samples of different conductivity are placed in the coil. The equivalent circuit component values are obtained from these data using a global nonlinear least squares fit. This equivalent circuit contains a minimum number of components necessary for understanding and quantifying the detuning and losses caused by electric and magnetic field coupling with the sample.


A retrospective analysis of institutional review board and informed consent practices in EMS research.
To assess the frequency of institutional review board (IRB) review and informed consent in emergency medical services (EMS) research. Two-year, retrospective review of published EMS research. One hundred two studies were analyzed. Seventy-one (70%) were exempt from IRB review; 31 (30%) were not exempt. Seventeen nonexempt studies (55%) did not obtain IRB review. Eight of these did not specify a consent method; one used implied consent and eight used volunteers. Volunteers gave informed consent in one study. Of the 14 nonexempt studies with IRB approval, seven did not specify a consent method. Two used informed consent, one received an informed consent waiver, one used verbal consent, and three involved volunteers. Written parent permission was used once when volunteers were minors. IRB review is often omitted by EMS investigators. This raises ethical concerns about EMS research. Investigators should document their consent method or approval to use an informed consent waiver in their manuscripts. A consent method should be specified for volunteers.


Chemoprevention of oral leukoplakia and chronic esophagitis in an area of high incidence of oral and esophageal cancer.
This intervention trial carried out in Uzbekistan (former USSR) in an area with a high incidence of oral and esophageal cancer involved random allocation of 532 men, 50 to 69 years old, with oral leukoplakia and/or chronic esophagitis to one of four arms in a double-blind, two-by-two factorial design, with active arms defined by the administration of (a) riboflavin; (b) a combination of retinol, beta-carotene, and vitamin E; or (c) both. Weekly doses were 100,000 IU of retinol, 80 mg of vitamin E, and 80 mg of riboflavin. The dose of beta-carotene was 40 mg/d. Men in the trial were followed for 20 months after randomization. The aim of the trial was to determine whether treatment with these vitamins or their combination could affect the prevalence of oral leukoplakia and/or protect against progression of oral leukoplakia and esophagitis, conditions considered to be precursors of cancer of the mouth and esophagus. A significant decrease in the prevalence odds ratio (OR) of oral leukoplakia was observed after 6 months of treatment in men receiving retinol, beta-carotene, and vitamin E (OR = 0.62; 95% confidence interval (CI): 0.39 to 0.98). After 20 months of treatment, no effect of vitamin supplementation was seen when the changes in chronic esophagitis were compared in the four different treatment groups, although the risk of progression of chronic esophagitis was lower in the subjects allocated to receive retinol, beta-carotene and vitamin E (OR = 0.65; 95% CI: 0.29 to 1.48) A secondary analysis not based on the randomized design revealed a decrease in the prevalence of oral leukoplakia in men with medium (OR = 0.45; 95% CI: 0.21 to 0.96) and high (OR = 0.59; 95% CI: 0.29 to 1.20) blood concentrations of beta-carotene after 20 months of treatment. Risk of progression of chronic esophagitis was also lower in men with a high blood concentration of beta-carotene, odds ratios being 0.30 (95% CI: 0.10 to 0.89) and 0.49 (95% CI: 0.15 to 1.58) for medium and high levels, respectively. A decrease in risk, also statistically not significant, was observed for high vitamin E levels (OR = 0.39; 95% CI: 0.14 to 1.10). These results were based on levels of vitamins in blood drawn after 20 months of treatment.


Immunochemical studies on thermal denaturation of ovomucoid.
The thermal denaturation of ovomucoid was investigated by immunochemical methods, namely immunoprecipitation analyses and antibody-Sepharose 4B column chromatography. In the immunoprecipitation analyses, heated ovomucoid (90 degrees C, 90 min, pH 7.2) required about twice the antigen addition of the native protein to approach maximal precipitation with specific antibody, and the maximal immunoprecipitation was decreased to 80% of that by native ovomucoid. However, heated protein inhibited the binding of antibody with native ovomucoid, and 100% inhibition was attained at about 4-times the antigen addition necessary for the native protein. Heated ovomucoid (100 degrees C, 120 min) showed little immunoprecipitation and inhibition. To ovomucoid antigenicity was diminished more slowly than the trypsin inhibitory activity by heating, e.g., heated ovomucoid (90 degrees C, 120 min) retained more than 30% of the antigenicity but little trypsin inhibitory activity. By passing through the immunoaffinity column, heated ovomucoid (90 degrees C, 90 min) was separated into two fractions, either with (fraction II) or without (fraction I) antigenicity. Fraction II contained smaller fractions of ordered secondary structure than native ovomucoid, and trypsin inhibitory activity of fraction II was only 24% of the native one. These results indicated that thermally denatured ovomucoid was heterogeneous regarding the conformational damage caused by heating, and the structure around some antigenic sites in an ovomucoid molecule was retained even after the backbone conformation was partially destroyed and trypsin inhibitory activity was lost.


The many faces of Th17 cells.
Th17 cells have been shown to be strong inducers of tissue inflammation and autoimmune diseases. However, not all Th17 cells are pathogenic and increasing data suggest that Th17 cells may come in different flavors. Thus, Th17 cells cannot be described using a narrow schematic, but instead Th17 cells comprise a wide spectrum with a range of effector phenotypes. Here, we review the key factors that generate such diversity, as well as the cytokines and transcription factors that are differentially expressed in pathogenic and nonpathogenic Th17 cells. This new knowledge can be used to identify molecules that make Th17 cells pathogenic and determine how these cells could be targeted to suppress autoimmune diseases.


Morphological changes induced by androgen blockade in normal prostate and prostatic carcinoma.
Maximal androgen blockade (MAB), combining a luteinizing hormone releasing hormone (LHRH) agonist and a pure or non-steroidal anti-androgen, induces significant morphologic changes in the prostate. The tumor volume, density, capsular penetration, and surgical margin involvement are strongly reduced following such treatment. On histology, normal prostate tissue and tumor undergo marked atrophy and shrinkage. Although residual cancer cells are readily identifiable in most cases, they may often be sparse and easily overlooked. The increased Gleason score apparent after MAB is most likely related to fragmentation of acinar structures, and grading is not recommended following MAB. Residual cancer cells show features of lower activity and increased apoptosis. Such therapy-induced changes may be reversible, although occasional clones of cancer cells are apparently not affected and have probably developed resistance. Finally, MAB leads to marked but reversible morphologic changes and reduction in prevalence and extent of prostatic intra-epithelial neoplasia (PIN). Monotherapy using a variety of agents causes comparable but often less extensive changes.


Comparative transcriptome analysis of ovary and testis reveals potential sex-related genes and pathways in spotted knifejaw Oplegnathus punctatus.
The spotted knifejaw (Oplegnathus punctatus) is a newly emerging fishery species inhabiting the Pacific Ocean around Hawaii, China, Japan and Korean Peninsula. Little information on the mechanism of gonadal development and gametogenesis in this species could be used for research and breeding work. In this study, RNA-seq technology was applied to generate a deep-coverage sequencing data of spotted knifejaw testis and ovary. A total of 262,392,754 reads (ovary 133,403,270, testis 128,989,484) were generated from the cDNA library. After filtering and assembling, a total of 113,794 unigenes were obtained with the N50 of 1658bp. Unigenes were annotated with multiple public databases, including non-redundant protein databases (NR) (42,460, 37.31%), Swiss-Prot (33,632, 29.56%), eukaryotic Orthologus Groups (KOG) (26,195, 23.02%), Kyoto Encyclopedia of Genes and Genomes (KEGG) (10,978, 9.65%), and Gene Ontology (GO) (30,514, 26.82%). By comparing ovary and testis, 4496 differentially expressed unigenes (1986 in female, 2510 in male) were identified, in which 469 were specially expressed in females and 859 in males. The expression levels of 12 unigenes were confirmed by qRT-PCR. In addition, 35,054 simple sequence repeats were identified. By GO and KEGG analyses, a set of unigenes related to gonadal development and gametogenesis were filtered. foxl2 was deduced to be a key regulator for gonadal development and gametogenesis in females and dmrt1 in males. bmp15, nanos3, sox9 and amh were likely to function in the regulation of gonad physiology and germ line cells maintenance in ovary and testis. Interestingly, p53, apoptosis, Jak-STAT and neuroactive ligand-receptor interaction pathways were found to be pivotal in regulating gonadal development and gametogenesis of spotted knifejaw in various aspects. This study provides a fundamental support for further research in reproduction biology, population genetics and functional genomics in spotted knifejaw.


Surviving the sun: repair and bypass of DNA UV lesions.
Structural studies of UV-induced lesions and their complexes with repair proteins reveal an intrinsic flexibility of DNA at lesion sites. Reduced DNA rigidity stems primarily from the loss of base stacking, which may manifest as bending, unwinding, base unstacking, or flipping out. The intrinsic flexibility at UV lesions allows efficient initial lesion recognition within a pool of millions to billions of normal DNA base pairs. To bypass the damaged site by translesion synthesis, the specialized DNA polymerase η acts like a molecular "splint" and reinforces B-form DNA by numerous protein-phosphate interactions. Photolyases and glycosylases that specifically repair UV lesions interact directly with UV lesions in bent DNA via surface complementation. UvrA and UvrB, which recognize a variety of lesions in the bacterial nucleotide excision repair pathway, appear to exploit hysteresis exhibited by DNA lesions and conduct an ATP-dependent stress test to distort and separate DNA strands. Similar stress tests are likely conducted in eukaryotic nucleotide excision repair.


The State of Prescreening Discussions About Prostate-specific Antigen Testing Following Implementation of the 2012 United States Preventive Services Task Force Statement.
To determine if the quality of prescreening discussions has changed following release of the United States Preventive Services Task Force statement against prostate cancer screening. This cross-sectional study used the 2012 and 2014 Behavioral Risk Factor Surveillance System surveys. Respondents were categorized based on the year in which they responded to the Behavioral Risk Factor Surveillance System Survey. Quality of prescreening discussion was operationalized as having discussed only advantages, only disadvantages, both advantages and disadvantages, or neither. Race/ethnicity, education level, income, insurance status, and having a prostate-specific antigen (PSA) level actually drawn after prescreening counseling served as confounders in our multivariate analysis. Among 217,053 men in the analytic sample, 37% were told about only advantages of PSA screening compared to 30% of men who were advised about both advantages and disadvantages. Men who were told about neither advantages nor disadvantages were more likely to be Hispanic, not graduate high school, have low income, and not have insurance. Controlling for covariates, men in 2014 were significantly more likely to have undergone PSA testing without having discussed either advantages or disadvantages than men in 2012. Comprehensive prescreening discussions about advantages and disadvantages of PSA testing are critical to informed decision making about prostate cancer screening. Disparities not only exist with regard to the quality of prescreening discussions that patients receive from their providers prior to PSA testing across categories of race/ethnicity, education, income, and insurance status, but these disparities became more substantial between 2012 and 2014. Further investigation is warranted to elicit more specific reasons behind these variations.


Achieving a multilevel evidence-based approach to improve cancer care in the U.S. post-COVID era: What is the role of management?
In 2013, the Institute of Medicine already had declared the state of U.S. cancer care as "a delivery system in crisis." Beginning in early 2020, the ongoing COVID-19 pandemic has dramatically revealed the fragile nature of the U.S. health system. As a microcosm of that larger health system, cancer care can provide us with opportunities for innovative thinking and new solutions. This paper describes a series of public and private-sector cancer care initiatives that are the building blocks for a multilevel evidence-based approach to improve cancer care in the post-COVID era. Achieving these objectives requires significant managerial policy decisions, some risk taking, and the development of organizational strategies that involve collaboration within the managerial and clinical leadership. Such strategies should reflect adaptability to navigate the complex and changing science, policy and financing environment, while retaining the central values of patient-centered care. As suggested by Edward Deming, an early pioneer in quality-improvement initiatives, the problems are with the system, and the system belongs to management. Though future challenges are undefined and likely to be significant, the foundational elements of a multilevel, evidence-based approach for improving cancer care are established and able to be built upon and will offer application in the post-COVID era.


Perinatal exposure to the xenoestrogen bisphenol-A induces mammary intraductal hyperplasias in adult CD-1 mice.
Humans are routinely exposed to bisphenol-A (BPA), an estrogenic compound that leaches from consumer products. Given the sensitivity of the developing organism to hormones, exposure of fetuses and infants is a concern. Here, CD-1 mice were exposed to environmentally relevant doses of BPA during gestation and the lactational period (gestational day 8 through postnatal day 16). At 3, 9 and 12-15 months of age, mammary glands from exposed offspring were examined for structural changes. BPA-exposed females demonstrated altered mammary phenotypes including the appearance of alveolar buds. Additionally, intraductal hyperplasias were observed exclusively in BPA-exposed females. These lesions had the appearance of "beaded" ducts, with epithelial cells present inside the ductal lumen and increased proliferation indexes compared to normal ducts. Similar structures have also been observed following exposure to other estrogens. These results are further evidence that perinatal BPA exposure can alter the morphology of the rodent mammary gland in adulthood.