Cardiovascular remodeling in active and controlled acromegaly: association with sleep-disordered breathing.
We hypothesized that an unfavorable cardiovascular profile in acromegaly is associated with sleep-disordered breathing (SDB), while acromegaly control improves both respiratory sleep characteristics and the cardiovascular profile. The patients underwent the assessment of breathing during sleep and cardiovascular profile assessment at the start of the study including arterial stiffness, blood pressure, echocardiography, nocturnal heart rate variability (HRV). The assessment was repeated in patients with acromegaly at 1 year after transsphenoidal adenectomy (TSA). A total of 47 patients with acromegaly and 55 control subjects were enrolled. At one year after TSA, 22 patients with acromegaly were reassessed. Multiple linear regression analysis with adjustment for age, sex and body mass index (BMI) showed the associations of insulin growth-like factor 1 (IGF-1) with obstructive apnea index (OAI: β=0.035/h, p<0.001), but not with cardiovascular parameters, in patients with acromegaly. The analysis of combined acromegaly and control dataset with adjustment for age, sex and BMI showed the association the presence of acromegaly with diastolic blood pressure (DBP; β=17.99 mmHg, p<0.001), ejection fraction (EF; β=6.23%, p=0.009), left heart remodeling (left ventricle posterior wall: β=0.81 mm, p=0.045) and the association of the presence of SDB (apnea-hypopnea index≥15/h) with left ventricular function (EF: -4.12%, p=0.040; end systolic volume: 10.12 ml, p=0.004). Control of acromegaly was accompanied by the decrease in OAI (5.9 [0.8, 14.5]/h and 1.7 [0.2, 5.1]/h, p=0.004) and nocturnal heart rate (66.1 [59.2, 69.8] bpm and 61.7 [54.0, 67.2] bpm, p=0.025) and by the increase in blood pressure (DBP: 78.0 [70.3, 86.0] mm Hg and 80.0 [80.0, 90.0] mm Hg, p=0.012). The comorbidities of acromegaly, including sleep-disordered breathing, appear to have a long-term effect on cardiovascular remodeling in active acromegaly. Future studies should investigate the applicability of the treatment of SDB for the reduction of cardiovascular risk in acromegaly.


Microvascular decompression and aneurysm clipping for a patient with hemifacial spasm and ipsilateral labyrinthine artery aneurysm: A rare case report and literature review.
Preoperative MRI results showed a vascular anomaly at the REZ of the left facial nerve (Figure A) and an anomaly at the internal auditory canal (Figure B). The left AICA was identified as the offending vessel compressing the left facial nerve at the REZ (Figure C). After the artery was dissociated and Teflon felt was placed between the involved vessel and the facial nerve (Figure D), electrophysiological monitoring indicated that the AMR had disappeared (Figure E).


Investigating the synergic role of asynchronous dosed protease and lysozyme for facilitating excess sludge solubilization and acidogenic fermentation.
Improving the anaerobic fermentation (AF) efficiency of excess sludge (ES) is essential for attaining biosolid minimization, stabilization, resource recovery, and carbon-emission reduction. Along these lines, here, the synergistic mechanism of protease and lysozyme for enhancing hydrolysis and AF efficiency with better recovery of volatile fatty acids (VFAs) was thoroughly investigated. Single lysozyme was capable of reducing the zeta potential and fractal dimension when dosed into the ES-AF system, which was beneficial for increasing the contact probability between proteases and extracellular proteins. Moreover, the weight-averaged molecular weight of the loosely-bound extracellular polymeric substance (LB-EPS) reduced from 1867 to 1490 in the protease-AF group, which facilitated the penetration of EPS by the lysozyme. The soluble DNA and extracellular DNA (eDNA) of the enzyme cocktail pretreated group increased by 23.24 % and 77.09 %, and the cell viability decreased after 6-hour hydrolysis, demonstrating a better hydrolysis efficiency. Remarkably, the asynchronous dosed enzyme cocktail pretreatment was proven a better strategy to enhance both the solubilization and hydrolysis processes since the synergistic effect of these two enzymes can exclude the mutual interference. As a result, the VFAs were increased by 1.26 times higher than the blank group. The underlying mechanism of an environmental-friendly and effective strategy was examined to promote ES hydrolysis and acidogenic fermentation, which was beneficial for the recovery of VFAs and carbon-emission reduction.


Phospholipid metabolism in cancer cells monitored by 31P NMR spectroscopy.
Addition of choline, ethanolamine, or hemicholinium-3 (a choline kinase inhibitor) to the perfusate of human breast cancer cells monitored by 31P NMR spectroscopy resulted in significant changes to phosphomonoester (PME) and phosphodiester (PDE) signals. These results enable us to assign the PMEs to phosphcholine (PC) and phosphoethanolamine (PE), the PDEs to glycerophosphorylcholine and glycerophosphorylethanolamine, and to define the pathways producing them. The PMEs are products of choline and ethanolamine kinases, the first steps in phospholipid synthesis; and the PDEs are substrates of glycerophosphorylcholine phosphodiesterase, the last step in phospholipid catabolism. Furthermore, PC and PE peaks are twice as intense in cells at log phase versus confluency. We also observed these signals in vivo in human colon and breast tumors grown in mice. Since PMEs are low in most nonproliferating tissues, they could form a basis for noninvasive diagnosis. Also, PE and PC are situated between the control enzymes of two major synthetic pathways and will allow noninvasive 31P NMR studies of these pathways in intact cells and in vivo.


Increased paediatric emergency mental health and suicidality presentations during COVID-19 stay at home restrictions.
Anecdotal reports indicate an increase in mental health presentations and acuity to EDs during the COVID-19 pandemic and associated stay at home restrictions. Paediatric and adolescent data to confirm this are unavailable in the Australian setting. Retrospective electronic medical record review of all ED patients with mental health discharge codes at a large tertiary children's hospital in Australia during the period of stay at home restrictions from 1 April to 30 September 2020 compared with the same dates in 2019. We found a 40% decrease in ED presentations (18 935-11 235) with a concurrent 47% increase in mental health presentations (809-1190) to ED during the study periods between 2019 and 2020. This resulted in an increase of 100 mental health admissions from ED. Diagnoses with greatest percentage increases were eating disorders, social issues and suicidality. We found suicidality presentation numbers were highest in June to September 2020 compared with 2019. Patients with a diagnosis of suicidality had a higher rate of re-presentation in 2020 (1.83 presentations per patient) compared to 2019 (1.38 presentations per patient). Despite an overall decrease in ED presentations, the absolute increase in mental health presentations for children and adolescents during the stay at home restriction period was pronounced. It is unclear how sustained this change and the impact on mental health resource use will be post-pandemic.


Simultaneous spectrophotometric estimation of thorium and calcium in urine.
A simple and rapid method for the simultaneous estimation of thorium and calcium in urine was developed. Thorium and calcium were coprecipitated as oxalates at pH 3-4 and were determined using Thoronol as reagent. A multi-wave-length linear regression analysis procedure was applied. Thorium recovery was found to be 78.3% +/- 5.1% (1 sigma) and that of calcium was 93.7 +/- 3.0% (1 sigma). The minimum detection limit for thorium was found to be 2.54 mBq/dm3. The analytical results of calcium agree very well with those determined by EDTA titrimetry.


Detection and characterization of chicken anemia virus from commercial broiler breeder chickens.
Chicken anemia virus (CAV) is the causative agent of chicken infectious anemia (CIA). Study on the type of CAV isolates present and their genetic diversity, transmission to their progeny and level of protection afforded in the breeder farms is lacking in Malaysia. Hence, the present study was aimed to detect CAV from commercial broiler breeder farms and characterize CAV positive samples based on sequence and phylogenetic analysis of partial VP1 gene. A total of 12 CAV isolates from different commercial broiler breeder farms were isolated and characterized. Detection of CAV positive embryos by the PCR assay in the range of 40 to 100% for different farms indicated high level of occurrence of vertical transmission of viral DNA to the progeny. CAV antigen was detected in the thymus and in the bone marrow but not in spleen, liver, duodenum, ovary and oviduct by indirect immunoperoxidase staining. The 12 CAV isolates were characterized based on partial sequences of VP1 gene. Six isolates (MF1A, MF3C, M3B5, NF4A, P12B and P24A) were found to have maximum homology with previously characterized Malaysian isolate SMSC-1, four isolates (M1B1, NF3A, PYT4 and PPW4) with isolate BL-5 and the remaining two (NF1D and NF2C) have maximum homology both with isolates 3-1 and BL-5. Meanwhile, seven of the isolates with amino acid profile of 75-I, 97-L, 139-Q and 144-Q were clustered together in cluster I together with other isolates from different geographical places. The remaining five isolates with amino acid profile of 75-V, 97-M, 139-K and 144-E were grouped under cluster II. All the CAV isolates demonstrated omega values (Ka/Ks) of less than one (the values ranging from 0.07 to 0.5) suggesting the occurrence of purifying (negative) selection in all the studied isolates. The present study showed that CAV is widespread in the studied commercial broiler breeder farms. The result also indicated the occurrence of genetic variability in local CAV isolates that can be divided at least into two groups based on characteristic amino acid substitutions at positions 75, 97, 139 and 144 of the VP1 protein.


Mycobacteria and dendritic cell differentiation: escape or control of immunity.
Human monocytes can differentiate into dendritic cells (DC) according to the nature of environmental signals. Pathogenic mycobacteria have been demonstrated interfere with this process to generate a not fully competent DC population. This mechanism is not common to non-pathogenic mycobacteria and could be correlated with bacterial virulence. However, it could represents a new mechanism of immune escape by persistent pathogens or a control mechanism of immune system to preserve the life of the organ against persistent infections.


Effects of gender and cigarette smoking on reactivity to psychological and pharmacological stress provocation.
We examined the influence of gender and smoking status on reactivity in two human laboratory stress paradigms. Participants were 46 (21 men, 25 women) healthy individuals who completed the Trier Social Stress Task (i.e., performed speech and math calculations in front of an audience) and a pharmacological stress provocation (i.e., administration of corticotrophin releasing hormone (CRH)) after an overnight hospital stay. Approximately half (53%) of the participants were smokers. Cortisol, adrenocorticotrophin hormone (ACTH), physiologic measures (heart rate, blood pressure), and subjective stress were assessed at baseline and at several time points post-task. Men demonstrated higher baseline ACTH and blood pressure as compared to women; however, ACTH and blood pressure responses were more pronounced in women. Women smokers evidenced a more blunted cortisol response as compared to non-smoking women, whereas smoking status did not affect the cortisol response in men. Finally, there was a more robust cardiovascular and subjective response to the Trier as compared to the CRH. Although preliminary, the findings suggest that women may be more sensitive than men to the impact of cigarette smoking on cortisol response. In addition, there is some evidence for a more robust neuroendocrine and physiologic response to acute laboratory stress in women as compared to men.


Expedient synthesis of the alpha-C-glycoside analogue of the immunostimulant galactosylceramide (KRN7000).
[Structure: see text] Key reactions in a concise synthesis of an alpha-C-galactosylceramide analogue of KRN7000 include a diastereoselective alkenylalane addition to an N-tert-butanesulfinyl imine and the use of an epoxidation/carbamate ring opening sequence to install the aminodiol stereotriad.


Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett's esophagus without grossly recognizable neoplastic lesions.
There is uncertainty regarding the value of endoscopic biopsy surveillance in Barrett's esophagus because, in retrospective studies, some patients with high-grade dysplasia in endoscopic biopsy specimens have had unexpected advanced adenocarcinoma discovered at the time of esophageal resection. We compared the accuracy of preoperative endoscopic biopsy diagnoses with the final pathologic diagnoses in esophagectomy specimens in 4 patients who had both high-grade dysplasia and intramucosal carcinoma and 4 other patients who had only high-grade dysplasia preoperatively. The histologic lesions in all 8 patients were documented in intact mucosa with no gross evidence of neoplasia by endoscopy. The preoperative diagnoses were defined with an endoscopic biopsy protocol in which specimens were taken with large-channel biopsy forceps at least every 2 cm throughout the length of Barrett's epithelium. Final pathologic diagnoses derived from detailed analysis of the resected specimens confirmed high-grade dysplasia without carcinoma in 4 patients and intramucosal carcinoma in 2 patients. The remaining 2 patients with a preoperative diagnosis of intramucosal carcinoma had focal submucosal invasion by carcinoma in the resected specimens, but no involvement of the muscularis propria or adventitial lymph nodes. Because the natural history of high-grade dysplasia is not known, the decision to operate on patients with this lesion must be carefully weighed and individualized for each patient. Two of our patients who underwent esophageal resection for high-grade dysplasia without cancer died, one immediately postoperatively and the other 9 mo later after a postoperative stroke. Once intramucosal carcinoma is documented, surgery should be considered if the patient is an acceptable operative risk. We conclude that systematic preoperative endoscopic biopsy of intact mucosa in Barrett's esophagus can correctly detect high-grade dysplasia, either alone or in combination with early, treatable adenocarcinoma.


The safety of central line placement prior to treatment of pediatric acute lymphoblastic leukemia.
Central venous lines are placed in children with acute lymphoblastic leukemia at diagnosis, despite significant cytopenias, to facilitate the administration of chemotherapy and blood sampling. The present study aimed to determine the safety of central line placement in these patients. We reviewed the charts of 115 consecutive patients treated during a 10-year period. Data abstracted comprised age, gender, presenting and preoperative blood counts, type of central line, blood products transfused preoperatively, duration of neutropenia (absolute neutrophil count [ANC], <500/microl), treatment, and central line-associated complications. There were 66 male and 49 female patients with a median age of 4 years. Seventy-one patients were classified as standard-risk and 44 as high-risk. Respective median blood counts at diagnosis and prior to surgery were white cell count (microl), 4,200 and 5,550; hemoglobin (g/dl), 7.7 and 9.4; platelet count (microl), 63,000 and 72,000; and ANC (microl), 3,950 and 4,900. The median duration of neutropenia was 15 days in the standard-risk group and 18 days in the high-risk group. Thirty-eight patients were not transfused preoperatively. There were no episodes of bacteremia. Seven patients (7%) with life-ports experienced a complication: in four blood could not be aspirated, two ports needed realignment, and one a wound infection developed without dehiscence. Four patients (27%) with external lines had a complication: one each with line occlusion, accidental removal by patient, line rupture, and line leakage at insertion site. The complication rate between ports and external lines was different (P = 0.045). Central line placement prior to anti-leukemia treatment is safe. Most complications are mechanical and not due to leukemia, chemotherapy, or cytopenias.


Biofilm-forming capacity of blood-borne Candida albicans strains and effects of antifungal agents.
Infections related to Candida albicans biofilms and subsequent antifungal resistance have become more common with the increased use of indwelling medical devices. Regimens for preventing fungal biofilm formation are needed, particularly in high-risk patients. In this study, we investigated the biofilm formation rate of multiple strains of Candida albicans (n=162 clinical isolates), their antifungal susceptibility patterns, and the efficacy of certain antifungals for preventing biofilm formation. Biofilm formation was graded using a modified Christensen's 96-well plate method. We further analyzed 30 randomly chosen intense biofilm-forming isolates using the XTT method. Minimum biofilm inhibition concentrations (MBIC) of caspofungin, micafungin, anidulafungin, fluconazole, voriconazole, posaconazole, itraconazole, and amphotericin B were determined using the modified Calgary biofilm method. In addition, the inhibitory effects of antifungal agents on biofilm formation were investigated. Our study showed weak, moderate, and extensive biofilm formation in 29% (n=47), 38% (n=61), and 23% (n=37) of the isolates, respectively. We found that echinocandins had the lowest MBIC values and that itraconazole inhibited biofilm formation in more isolates (26/32; 81.3%) than other tested agents. In conclusion, echinocandins were most effective against formed biofilms, while itraconazole was most effective for preventing biofilm formation. Standardized methods are needed for biofilm antifungal sensitivity tests when determining the treatment and prophylaxis of C. albicans infections.


Creating and Managing a Phototherapy Center.
Phototherapy is a safe and effective treatment for many benign and malignant inflammatory cutaneous diseases. Treatment courses require consistent visits over the course of weeks to months, and one barrier for patients in accessing this treatment is the lack of a geographically convenient phototherapy center. To expand access, new phototherapy centers can be created, and this can be done in a series of steps. These include considering the physical space, anticipating the finances, laying the operational groundwork, and establishing a consent and education process.


[kappa-light chain amyloidosis of the liver, a rare cause of liver enzyme elevation].
A 69-year-old man was admitted to the department of gastroenterology having for months had persistently elevated liver enzymes after discontinuing systemic antimycotic therapy. He reported loosing five kilogram of body weight in the past six months. No macroscopic or microscopic abnormalities had been found on esophago-gastroduodenoscopy. Congo-red staining of the liver biopsy revealed massive sinusoidal amyloidosis of the liver. Immunoelectrophoresis of the urine and serum, as well as bone marrow biopsy, ruled out multiple myeloma or Waldenström's disease. Immunohistochemical staining identified the amyloid protein as a IgG kappa light chain (KLC). The free light chain (FLC) test confirmed KLC monoclonal gammopathy with an abnormal free kappa to lambda chain (KLLC) ratio. Systemic KLC amyloidosis in this patient older than 65 years was given chemotherapy with melaphalan and dexamethasone (M-Dex). After three courses of M-Dex the renal clearance deteriorated and the serum N-terminal probrain natriuretic peptide (T-proBNP) had increased. The patient was included in a phase II clinical trial which evaluates the use of bortezomib in patients with amyloidosis. Normalization of the free KLLC ratio and the NT-proBNP level will serve as important prognostic indicators. KLC amyloidosis is a rare cause of elevated liver enzymes. The nonspecific symptoms often delay the diagnosis. FLC testing is a helpful tool in identifying monoclonal gammopathies, even when immunoelectrophoretic tests are normals.


[Somatization disorder - an overdiagnosed but underestimated illness].
Physical symptoms often occur in the absence of physical illness. This is termed somatization when the symptoms are caused by psychic factors. When abundant symptoms affect the functional capacity and cause subjective harm and seeking healthcare services, a psychic disorder may be in question. Somatization may be associated with numerous psychic disorders. It may, however, also be a question of a somatoform disorder having a physical symptom picture. Somatization disorder is one of the somatoform disorders. Recognition of the disorder is often the problem in its treatment. Establishing a long-term treatment relationship actually forms the basis for therapy.


Light regimes differentially affect baseline transcript abundance of stress-axis and (neuro)development-related genes in zebrafish (Danio rerio, Hamilton 1822) AB and TL larvae.
Many strains of zebrafish (Danio rerio) are readily available. Earlier we observed differences between AB and Tupfel long-fin (TL) larvae regarding baseline hypothalamus-pituitary-interrenal (HPI) axis activity and (neuro)development. Light regimes, i.e. 14 h light:10 h dark and 24 h continuous dark or light, affect hatching rate and larval growth. Here, we assessed baseline transcript abundance of HPI-axis-related genes and (neuro)development-related genes of AB and TL larvae (5 days post fertilisation) using these light regimes. A principal component analysis revealed that in AB larvae the baseline expression of HPI-axis-related genes was higher the more hours of light, while the expression of (neuro)development-related genes was higher under 14 h light:10 h dark than under both continuous light or dark. In TL larvae, a complex pattern emerged regarding baseline expression of HPI-axis-related and (neuro)development-related genes. These data extend data of earlier studies by showing that light regimes affect gene-expression in larvae, and more importantly so, strengthen the notion of differences between larvae of the AB and TL strain. The latter finding adds to the growing database of phenotypical differences between zebrafish of the AB and TL strain.


Expectancies and memory for spatiotemporal events in 5-month-old infants.
Five-month-old infants were trained to fixate four event locations, and recall was assessed following training in three experiments. Memory for four events was demonstrated in the first two studies, and memory for these events was also found to be robust following a 6- to 7-day delay. Infants demonstrated that they can anticipate upcoming events during training: they increased anticipatory behaviors during latter training trials, and they appeared to form expectancies of future events during periods of both stimulus onset and stimulus offset. Results are interpreted as consistent with a script representational view of memory for spatiotemporal events.


Silk fibroin as biomaterial for bone tissue engineering.
Silk fibroin (SF) is a fibrous protein which is produced mainly by silkworms and spiders. Its unique mechanical properties, tunable biodegradation rate and the ability to support the differentiation of mesenchymal stem cells along the osteogenic lineage, have made SF a favorable scaffold material for bone tissue engineering. SF can be processed into various scaffold forms, combined synergistically with other biomaterials to form composites and chemically modified, which provides an impressive toolbox and allows SF scaffolds to be tailored to specific applications. This review discusses and summarizes recent advancements in processing SF, focusing on different fabrication and functionalization methods and their application to grow bone tissue in vitro and in vivo. Potential areas for future research, current challenges, uncertainties and gaps in knowledge are highlighted. Silk fibroin is a natural biomaterial with remarkable biomedical and mechanical properties which make it favorable for a broad range of bone tissue engineering applications. It can be processed into different scaffold forms, combined synergistically with other biomaterials to form composites and chemically modified which provides a unique toolbox and allows silk fibroin scaffolds to be tailored to specific applications. This review discusses and summarizes recent advancements in processing silk fibroin, focusing on different fabrication and functionalization methods and their application to grow bone tissue in vitro and in vivo. Potential areas for future research, current challenges, uncertainties and gaps in knowledge are highlighted.


Influence of vitamin E administration on platelet functions in hormonal contraceptive users.
Platelet functions (aggregation, clotting activity), platelet lipid biosynthesis, sterol composition and phospholipid fatty acids were studied in relation to plasma lipids and fatty acids as well as dietary habits at day 5 and 21 of the menstrual cycle in 30 women having used hormonal contraceptive for several years. The women were studied again on day 21 of the second cycle after they had taken for two months 200 mg vitamin E per day in addition to the contraceptive. At day 21 (after 3 weeks of hormonal contraceptive) as compared to day 5, there was a significant increase in the clotting activity of platelets and the response to ADP-induced aggregation concomitant with a decrease in plasma vitamin E. After vitamin E administration, platelet activity at day 21 was markedly decreased, being similar to the activity at day 5, with a significant increase in the level of vitamin E in plasma and platelets. The high response of platelets to aggregation in women using contraceptives does not seem to be associated with the intake of saturated fat but rather with that of 18:2. The aggregation to thrombin was mostly related to lanosterol biosynthesis and the aggregation to ADP to platelet cholesterol, but not to plasma lipids or apoproteins. The present pilot study suggests that the platelet hyperactivity of long-term hormonal contraceptive users might be dependent upon a low level of platelet alpha-tocopherol which can be rapidly overcome by giving a supplement of vitamin E.


Concise Review: Reprogramming, Behind the Scenes: Noncanonical Neural Stem Cell Signaling Pathways Reveal New, Unseen Regulators of Tissue Plasticity With Therapeutic Implications.
Interest is great in the new molecular concepts that explain, at the level of signal transduction, the process of reprogramming. Usually, transcription factors with developmental importance are used, but these approaches give limited information on the signaling networks involved, which could reveal new therapeutic opportunities. Recent findings involving reprogramming by genetic means and soluble factors with well-studied downstream signaling mechanisms, including signal transducer and activator of transcription 3 (STAT3) and hairy and enhancer of split 3 (Hes3), shed new light into the molecular mechanisms that might be involved. We examine the appropriateness of common culture systems and their ability to reveal unusual (noncanonical) signal transduction pathways that actually operate in vivo. We then discuss such novel pathways and their importance in various plastic cell types, culminating in their emerging roles in reprogramming mechanisms. We also discuss a number of reprogramming paradigms (mouse induced pluripotent stem cells, direct conversion to neural stem cells, and in vivo conversion of acinar cells to β-like cells). Specifically for acinar-to-β-cell reprogramming paradigms, we discuss the common view of the underlying mechanism (involving the Janus kinase-STAT pathway that leads to STAT3-tyrosine phosphorylation) and present alternative interpretations that implicate STAT3-serine phosphorylation alone or serine and tyrosine phosphorylation occurring in sequential order. The implications for drug design and therapy are important given that different phosphorylation sites on STAT3 intercept different signaling pathways. We introduce a new molecular perspective in the field of reprogramming with broad implications in basic, biotechnological, and translational research. Reprogramming is a powerful approach to change cell identity, with implications in both basic and applied biology. Most efforts involve the forced expression of key transcription factors, but recently, success has been reported with manipulating signal transduction pathways that might intercept them. It is important to start connecting the function of the classic reprogramming genes to signaling pathways that also mediate reprogramming, unifying the sciences of signal transduction, stem cell biology, and epigenetics. Neural stem cell studies have revealed the operation of noncanonical signaling pathways that are now appreciated to also operate during reprogramming, offering new mechanistic explanations.


Effects of clove extract on oxidative stability and sensory attributes in cooked beef patties at refrigerated storage.
The antioxidant effects of clove extract (CE) by comparing with BHT and ascorbic acid (AA) in cooked beef patties were assessed at refrigerated storage. Four kinds of patties were formulated: without antioxidants (control), with added 0.02% BHT, 0.05% AA, and 0.1% CE. Addition of BHT, AA, and CE resulted in a significant (p < .05) decrease in thiobarbituric acid reactive substance (TBARS) value, carbonyl content, and hue angle; increasing of redness value; and improvement of the stability of sensory attributes. Addition of CE showed reduced protein and lipid oxidation when compared with BHT (p < .05). Moreover, CE presented lower lipid oxidation, and a higher redness value and overall color score than the AA (p < .05). Sensory assessment regarding overall color, discoloration, and odor showed that CE inclusion in patties extended the storage life up to 10 days. Therefore, the application of CE as a natural antioxidant can result in reduced protein and lipid oxidation and enhance the quality of cooked beef patties.


Apoptosis effects of Xrel3 c-Rel/Nuclear Factor-kappa B homolog in human cervical cancer cells.
Cervical cancer is considered a common yet preventable cause of death in women. In this report, we studied the role of the NF-kappaB gene family in HeLa human cervical cancer cells, using the Xrel3 c-Rel homologue of Xenopus laevis. The expression of Xrel3/c-Rel slowed cell growth 6-fold, consistent with an upregulated expression of the cell cycle inhibitor p21. The activated PARP apoptosis effector was significantly increased (P<0.01). Based on cell viability assays Xrel3 provided an anti-apoptotic effect in 1 microM cisplatin, and this was associated with significantly lower levels of the apoptotic proteins Bax and MDM-2 (P<0.05). Furthermore, there was a 3-fold drop in the level of the tumor suppressor protein p53. In 5 microM cisplatin, expression of HeLa Xrel3 enhanced apoptosis by significantly increasing the expression of the apoptotic proteins Bax and MDM-2 (P<0.05). However, the tumor suppressor protein p53 showed a significant decrease (P<0.05) relative to the control. Thus, c-Rel/NF-kappaB may potentially be of clinical significance, especially in tumors exhibiting resistance to high-level chemotherapy.


The midterm effects of diabetes mellitus on quadriceps and patellar tendons in patients with knee arthrosis: a comparative radiological study.
We sought to evaluate the effects of diabetes on the physical properties of the patellar and quadriceps tendons using radiological techniques. Twenty-seven diabetic and 34 nondiabetic patients with primary osteoarthritis of the right knee were studied. All patients had anteroposterior and lateral knee radiographs. The lengths of the patella and the patellar tendon were measured. The width and thickness of the patellar tendon were determined by ultrasound (US) examination at midpoint. The increase in the thickness of the patellar tendon sheath was graded qualitatively. The length of the quadriceps and patellar tendons, and the thickness and width of tendons in mid-length were measured by magnetic resonance imaging (MRI). Buckling of tendons and increase in intensities were also evaluated. The mean age in the diabetic group was 57.6 +/- 10.1 years, and the mean age in the control group was 52.6 +/- 9.1 years. The mean duration of diabetes was 104.1 +/- 67.1 months. X-ray, US, and MRI measurements did not reveal any differences between the two groups. Quadriceps buckling was more prevalent in diabetic patients (P=.025). In both groups, the width of the patellar tendon was greater in men than in women (P=.001). In conclusion, we found no significant structural changes in the patellar and quadriceps tendons in diabetic patients in midterm. On MRI examination, the quadriceps tendons had more buckling in diabetic patients.


Shared genetic architecture between metabolic traits and Alzheimer's disease: a large-scale genome-wide cross-trait analysis.
A growing number of studies clearly demonstrate a substantial link between metabolic dysfunction and the risk of Alzheimer's disease (AD), especially glucose-related dysfunction; one hypothesis for this comorbidity is the presence of a common genetic etiology. We conducted a large-scale cross-trait GWAS to investigate the genetic overlap between AD and ten metabolic traits. Among all the metabolic traits, fasting glucose, fasting insulin and HDL were found to be genetically associated with AD. Local genetic covariance analysis found that 19q13 region had strong local genetic correlation between AD and T2D (P = 6.78 × 10- 22), LDL (P = 1.74 × 10- 253) and HDL (P = 7.94 × 10- 18). Cross-trait meta-analysis identified 4 loci that were associated with AD and fasting glucose, 3 loci that were associated with AD and fasting insulin, and 20 loci that were associated with AD and HDL (Pmeta < 1.6 × 10- 8, single trait P < 0.05). Functional analysis revealed that the shared genes are enriched in amyloid metabolic process, lipoprotein remodeling and other related biological pathways; also in pancreas, liver, blood and other tissues. Our work identifies common genetic architectures shared between AD and fasting glucose, fasting insulin and HDL, and sheds light on molecular mechanisms underlying the association between metabolic dysregulation and AD.


Lichen striatus and blaschkitis: reappraisal of the concept of blaschkolinear dermatoses.
Blaschkitis (BL) and lichen striatus (LS) are rare dermatoses occurring along the Blaschko lines of the skin with preferential occurrence in distinct age categories. Controversy exists regarding the pathogenesis and classification of BL and LS within the spectrum of blaschkolinear dermatoses. To describe the clinicopathological characteristics of six cases of BL/LS with special emphasis on immunophenotyping the inflammatory infiltrate. Additionally, we review and critically discuss current concepts of the blaschkolinear dermatoses. Skin biopsies from six patients with BL and LS were analysed retrospectively. The immunophenotypes of the inflammatory cells were determined and related to clinical features. The clinical characteristics of the diseases occurred equally in both genders and all ages. BL and LS had similar histopathological findings with respect to epidermal changes and composition of the inflammatory infiltrates. Characteristically, a lichenoid lymphocytic infiltrate with exocytosis of inflammatory cells and obvious alterations of the interface zone was observed. We characterize the two main blaschkolinear dermatoses BL and LS sensu stricto morphologically and open new insights into the pathogenesis of these diseases. We propose the concept of a wide spectrum of blaschkolinear dermatoses with BL and LS located somewhere within the spectrum. We do not think that it is helpful for clinicians to enlarge the spectrum of blaschkolinear diseases and to create numerous 'new' entities. Rather, our aim was to unify diseases with similar clinical and histopathological features and common genetic pathomechanisms underlying phenotypic variations.


Further studies of effects of chlorpromazine on the contingent negative variation.
The effect of 25 mg of chlorpromazine (CPZ) on the contingent negative variation (CNV) at Cz and Oz was studied in nine male subjects. Two kinds of warning stimulus (S1)--imperative stimulus--and motor response (MR) were used. A click as S1 was common to both, while either flashes or electrical stimulation was used as S2. Simultaneously with CNV recording, the reaction time of the finger movement as MR to S2 was measured in five of nine subjects. The results obtained were as follows. 1) CNV amplitudes after CPZ administration were decreased significantly both at Cz and Oz when S2 was flashes and only at Cz when S2 was electrical stimulation. 2) Significant positive correlations of CNV amplitudes between Cz and Oz were found both before and after the drug administration. 3) Reaction times to flashes and electrical stimulation as S2 were not affected by CPZ administration. 4) The reaction time to flashes was significantly shorter than that to electrical stimulation irrespective of pre- and post-administration of CPZ.


Market structure and conduct in the pharmaceutical industry.
The pharmaceutical industry offers the world's population alleviation and cure from a variety of medical conditions, while also contributing to the economic performance of many countries. The potential importance of these characteristics have made the industry an area of intense debate, criticism and praise. This review aims to clarify some of the arguments surrounding the industry on both sides of the fence, and by doing so, to provide a balanced introduction on which opinions may be made.


A double-masked comparison of carteolol and timolol in ocular hypertension.
We performed a double-masked study in which 98 patients with ocular hypertension who had been previously treated with timolol received either timolol 0.25% or carteolol 1%, a beta-blocker with intrinsic sympathomimetic activity. The drugs were administered topically twice daily for one month after a one-week washout period. Intraocular pressure was measured at baseline and after one and four weeks of treatment. The appearance of the fundus, external eye, visual fields, tear secretion, blood pressure, and pulse were recorded. Adverse symptoms were elicited using a menu-type questionnaire and an overall judgment of therapy was recorded. Carteolol was as effective as timolol in reducing intraocular pressure. There were significantly fewer patients reporting adverse events overall (P = .019), and eye irritation specifically (P = .02), in the group treated with carteolol.


Ionic liquid-promoted ring-closure reactions between 1,4-dihydroxyanthraquinone and diamines.
The reaction of 1,4-Dihydroxyanthraquinone with diamines was carried out in the presence of CuCl(2), CuCl in the ionic liquid [Bmim]PF(6), [Bmim]BF(4) or [Bmim]Cl x CuCl.


Clinical profile and mortality of Sars-Cov-2 infection in cancer patients across two pandemic time periods (Feb 2020-Sep 2020; Sep 2020-May 2021) in the Veneto Oncology Network: The ROVID study.
We analyzed a cohort of patients with cancer and Sars-Cov-2 infection from the Veneto Oncology Network registry across two pandemic time periods. 761 patients with cancer and SARS-CoV-2 infection were included. 198 patients were diagnosed during the first pandemic time period (TP1; February 2020 September 2020), 494 during TP2 before the vaccination campaign (TP2/pre-vaccination; September 2020-21 February 2021) and 69 in TP2/post-vaccination (22 February 2021-15 May 2021). TP2 vs TP1 patients were younger (p = 0.004), showed more frequently a good performance status (p < 0.001) and <2 comorbidities (p = 0.002), were more likely to be on active anticancer therapy (p = 0.006). Significantly fewer patients in TP2 (3-4%) vs TP1 (22%) had an in-hospital potential source of infection (p < 0.001). TP2 patients were more frequently asymptomatic (p = 0.003). Significantly fewer patients from TP2 were hospitalized (p < 0.001) or admitted to intensive care unit (p = 0.006). All-cause mortality decreased from 30.3% in TP1, to 8.9% and 8.7% in the two TP2 periods (p < 0.001), reflected by a significant reduction in Sars-Cov-2-related mortality (15.2%, 7.5% and 5.8% in the three consecutive time periods, p = 0.004). Differences in clinical characteristics and features of Sars-Cov-2 infection between TP1 and TP2 reflect the effects of protective measures and increased testing capacity. The lower mortality in TP2 is in line with a less frail population. However, the vast majority of death events in TP2 were related to COVID-19, reinforcing the priority to protect cancer patients.


An improved and simple method for determining diene conjugation in autoxidized polyunsaturated fatty acids.
The autoxidation of linolenic acid was produced at room temperature in a rotating apparatus by passing a stream of dry air over a thin layer of polyunsaturated fatty acid (PUFA). During these experiments, volatile thiobarbituric acid positive product(s), were recovered. The extent of fatty acid autoxidation was measured either (a) by the production of malonaldehyde (MDA) or (b) by the height of the peak at 233 nm of the second derivative spectrum, corresponding to the hidden maximum at 235 nm in the normal absorbance spectra of autoxidized PUFA. The identification of the conjugated double bond structure, arising from the autoxidation of linolenic acid was further confirmed by 1H-NMR spectrometric determinations.


Health care professional's perceived stress levels and novel brief COPE-4 factor structure-based assessment of coping methods during COVID-19 pandemic in India: A multi-modal cross-sectional study.
SARS-CoV-19 or popularly known as COVID-19 is recognized as a global public health emergency and a pandemic necessitating readiness of the health system and its operational work force to address the unprecedent challenge. To assess perceived stress and coping methods using novel brief COPE-4 factor structure and narrate thematic testimonials among health care professionals involved in COVID care in India. Health care settings and multi-state cross-sectional study. A cross sectional mixed-methods study, with multi-modal aids was undertaken during April-May, 2020 using a novel brief COPE-4 Factor structure. Oral informed consent was obtained to document narrative testimonials verbatim from interviews among doctors, nurse practitioners. The web-survey data from Google forms analyzed using STATA (Ver 12.0) statistical package. The interview content was subjected to manual inductive thematic coding, grouped into piles to identify broad themes as main categories. Among total 218 respondents, 75 (34.4%) were female and 143 (65.6%) male, mean age of 34.71 (SD = 8.9) years. Majority of the respondents were medical post-graduates on duty (38%) followed by nurses (25%) and public health professionals (14%). Slightly higher levels of stress seen among respondents involved in COVID-19 duty, compared to those not involved (p < 0.001) and positive thinking is the major coping method adopted. Appraising the coping mechanisms of health care professionals reveals positive outlook amidst medium levels of perceived stress while providing COVID-19 pandemic related health care services.


Changes in plasma concentrations of osteoprotegerin before and after levothyroxine replacement therapy in hypothyroid patients.
Recent study has shown that overt hypothyroidism (oHT) is associated with increased plasma osteoprotegerin (OPG) levels. Our objective was to examine the plasma OPG level alteration before and after levothyroxine (L-T4) treatment in oHT and subclinical hypothyroidism (sHT). The study subjects included oHT and sHT patients and healthy individuals (20 subjects in each group). All patients were given L-T4 therapy to maintain a euthyroid state. Plasma OPG concentration was measured in duplicate by a sandwich ELISA. Plasma OPG levels in oHT and sHT before treatment were significantly higher than levels in controls (P < 0.01). After normalization of thyroid function, OPG levels in both groups decreased markedly (P < 0.01). The absolute changes in OPG showed a significant positive correlation with the changes in TSH (P < 0.05) and negative correlation with the changes in endothelium-dependent arterial dilation (P < 0.01) in hypothyroid patients during the course of treatment. OPG may be involved in the development of vascular dysfunction in hypothyroid patients.


A computer simulation for behavior therapy training.
Computer simulation technology has been applied to a wide variety of learning tasks; however, behavior therapy training has not been among them. A computer simulation has recently been developed for use in behavior therapy training. The simulation written for Apple II microcomputers reflects possible referral, assessment, and intervention procedures encountered by a behavior therapist in a mental health center. Forty-two pieces of assessment information may be drawn from 8 general areas, while 6 different interventions may be chosen after a diagnosis is reached. Simulation content and utility were rated highly by both practicing behavior therapists and trainees.


Pentobarbital, diazepam, and ethanol abolish the interphase diminution of pain in the formalin test: evidence for pain modulation by GABAA receptors.
There are two phases to the behavioral response to injection of formalin. After an initial vigorous response, a period of reduced pain occurs 10 to 15 min after formalin, followed by reemergence of pain-related behaviors. These phases are believed to represent acute chemical stimulation of afferent neurons followed by injury-related inflammatory pain. Pentobarbital (10, 15, or 25 mg/kg), diazepam (0.5, 1.5, or 5.0 mg/kg), or ethanol (0.5, 1.0, or 1.5 g/kg) attenuated the diminution of pain between the two phases, so that pain was continuous throughout 60 min of testing, but had no effect on pain scores during the peaks of either phase. The effects of pentobarbital and diazepam were blocked by picrotoxin (2.5 mg/kg), which itself had no effect. Ro 15-1788 also blocked the effect of diazepam. Picrotoxin did not effectively antagonize the effect of ethanol. A high dose of picrotoxin (5.0 mg/kg) caused seizures in some rats and also eliminated the interphase depression of pain. The results suggest that the biphasic time course of formalin pain is produced by a central antinociceptive mechanism that is inhibited by GABAA receptors.


Alteration of cell membrane proteoglycans impairs FSH receptor/Gs coupling and ERK activation through PP2A-dependent mechanisms in immature rat Sertoli cells.
During the pre-pubertal life, the cessation of Sertoli cell proliferation and the onset of differentiation are associated with a shift in the FSH-mediated signaling leading to inhibition of the ERK-mitogenic pathway and to a concomitant sensitization of cAMP/PKA pathway. To highlight the role of cell proteoglycans (PGs) in the shift of FSH signaling, both FSH-induced cAMP production and ERK1/2 inactivation were studied in untreated and sodium chlorate PG-depleted cultured Sertoli cells from 20day-old rats. Depletion of cell membrane PGs by sodium chlorate reduced FSH-, but not cholera toxin-stimulated cAMP production as well as basal ERK phosphorylation through an okadaic acid (OA)-sensitive mechanism. Involvement of PP2A was further substantiated by a marked decrease in membrane- associated PP2A activity under SC conditions and by the OA-induced restoration of PKA-dependent ERK inactivation in SC-treated cells. In 20-day-old rat Sertoli cells, transmembrane cell PGs, through tethering/activation of PP2A activity exerts regulatory control on both FSH receptor/Gs coupling and ERK phosphorylation. Besides their antiproliferative roles, cell PGs such as syndecan-1, could be involved in the increase in cAMP response to FSH occurring in Sertoli cells at the time of transition between proliferative and differentiated states.


Postnatal development of synaptophysin immunoreactivity in the rat nucleus tractus solitarii and caudal ventrolateral medulla.
Synaptophysin (SY) is a major integral membrane protein of small synaptic vesicles. In the present study, SY immunohistochemistry was used to investigate the postnatal development of the rat nucleus tractus solitarii (NTS) and nucleus ambiguus/ventrolateral medulla (NA/VLM). Whatever the age of the animal, SY immunoreactivity showed a typical pattern of punctate staining reminiscent of presynaptic terminal labeling. In the NTS and the NA/VLM, SY immunoreactive puncta were few at birth and increased in number during the first postnatal days. These changes were quantified by measuring the volumetric fraction occupied by SY immunoreactive puncta at various postnatal ages. Using volumetric fraction data, an index of the total volume occupied SY immunoreactivity in each region was then calculated. Between birth and adulthood, this index increased by 6-fold in the NTS and by 7-fold in the NA/VLM, suggesting that most of the synaptic development of these regions occurs postnatally.


Experimental confirmation of effectiveness of fenestration in acute aortic dissection.
Aortic fenestration is used clinically to treat organ ischemia in acute descending aortic dissection. However, fenestration has not been studied experimentally. This study does so using an animal model. Descending aortic dissection was created in six dogs, with subsequent fenestration of the infrarenal aorta. Blood flow (femoral, cephalic, and renal), blood pressure (femoral and carotid), and aortic distensibility were measured at baseline, after dissection, and after fenestration. Values were compared using paired t tests. Baseline femoral, cephalic, and renal arterial flows were 53+/-37, 78+/-65, and 83+/-52 mL/min, respectively. Baseline femoral and carotid pressures were 82+/-13 and 81+/-11 mm Hg, respectively. After dissection, femoral, cephalic, and renal arterial flow decreased to 20+/-21 (p < 0.05), 38+/-26, and 56+/-36 mL/min, respectively. Femoral blood pressure decreased to 28+/-17 mm Hg (p < 0.05). With fenestration, femoral, cephalic, and renal flows increased to 60+/-37 (p < 0.05), 78+/-51, and 80+/-48 mL/min, respectively. Femoral blood pressure increased to 85+/-28 mm Hg (p < 0.05). Carotid pressure remained unchanged with dissection and fenestration (77+/-17 mm Hg, 82+/-17 mm Hg, respectively). Baseline aortic distensibility (21%) decreased significantly after dissection (to 1.4%, p < 0.05) and increased after fenestration (to 12%, p < 0.05). Experimental aortic fenestration restored blood pressure and flow to hypoperfused organs in acute descending aortic dissection. The continued clinical application of fenestration is supported.


Coccidioidomycosis and blastomycosis: advances in molecular diagnosis.
Clinical isolates of Coccidioides spp. and Blastomyces dermatitidis can be identified by chemiluminescent DNA probes and PCR assays targeting multicopy genes. In fixed tissue samples, cells of the two fungi are specified by in situ hybridization and PCR assays targeting 18S rDNA but sequencing of the products is mandatory. Nested PCR assays targeting genes encoding species- or genus-specific proteins like proline rich antigen of Coccidioides spp. and B. dermatitidis adhesin facilitate amplification of specific DNA from fixed tissue samples. The value of DNA amplification from native specimens of suspected cases of coccidioidomycosis or blastomycosis still needs to be determined.


Relation between graded, subcritical impairments of coronary flow reserve and regional myocardial dysfunction induced by isoproterenol infusion in dogs.
Isoproterenol has been used experimentally and clinically to elicit ischemia. The usefulness of this approach, however, in eliciting regional dysfunction in the presence of mild to moderate single-vessel coronary disease quantitated on the basis of coronary flow reserve measurements has not been previously defined. Open-chest, anesthetized dogs were instrumented with an electromagnetic flow probe, high-fidelity micromanometers, and subendocardial ultrasonic crystals. A rigid, screw occluder was used to produce five subcritical coronary stenoses in each dog associated with varying impairment of postocclusion reactive hyperemia at rest but no impairment of resting coronary blood flow. Regional function at rest and in response to the isoproterenol challenge (0.25 micrograms/kg/min) in nonstenotic and stenotic conditions was assessed. Relative regional function was maintained during the infusion until nearly total loss of coronary flow reserve. With this near-critical stenosis, function was lower than in the nonstenotic state but remained greater than resting control values. Moderate impairments of coronary flow reserve were not associated with isoproterenol-induced deterioration of regional function. In conclusion, detection of impaired coronary flow reserve at rest is a more sensitive index of the severity of a coronary stenosis than is detection of regional dysfunction during isoproterenol challenge. Failure to maintain the expected isoproterenol-induced increase in regional function is manifested only when stenoses are associated with nearly total loss of resting coronary flow reserve. This suggests that the clinical use of isoproterenol challenge is not effective in eliciting regional dysfunction when mild coronary disease is present.


Ultrastructural alterations of neuronal cells in a brain stem ganglioglioma.
A brain stem ganglioglioma in a 9-year-old female was examined ultrastructurally. The constituent neuronal (ganglion) cells displayed various ultrastructural features of neuronal degeneration including Hirano, Lafora and zebra bodies, inclusion-like aggregates of neurofilaments and large dilatations of rough endoplasmic reticulum. Although similar observations have been reported in peripheral neuronal tumors, this is the first reported occurrence in ganglioglioma, an uncommon tumor in the central nervous system. The coincidence of these alterations in the present tumor appeared to be of great interest, however, their exact etiology remained uncertain.


Primary Lymphoma of the Distal Femur Presenting as Spontaneous Deep Vein Thrombosis and Knee Monoarthritis: A Case Report.
A 68-year-old man with a history of unprovoked deep vein thrombosis (DVT) presented with recurrent knee effusions after the initiation of anticoagulation. Radiographs showed soft-tissue swelling without a distinct skeletal lesion. Magnetic resonance imaging, however, showed a marrow-replacing process in the distal femur. Subsequent biopsy demonstrated B-cell lymphoma. This is a rare case of a primary lymphoma of bone mimicking synovial disease. It also highlights the fact that an unprovoked DVT may be a harbinger of an undiagnosed underlying malignancy.


Differential Effects of a Behavioral Treatment Probe on Social Gaze Behavior in Fragile X Syndrome and Non-Syndromic Autism Spectrum Disorder.
The purpose of this study was to examine potential differences in social learning between individuals with fragile X syndrome (FXS), the leading known inherited cause of intellectual disability, and individuals with non-syndromic autism spectrum disorder (ASD). Thirty school-aged males with FXS and 26 age and symptom-matched males with non-syndromic ASD, were administered a behavioral treatment probe designed to improve levels of social gaze during interactions with others. The treatment probe was administered by a trained behavior therapist over two days in our laboratory and included reinforcement of social gaze in two alternating training conditions - looking while listening and looking while speaking. Prior to each session, children in each group were taught progressive muscle relaxation and breathing techniques to counteract potential increased hyperarousal. Measures included the rate of learning in each group during treatment, in addition to levels of social gaze and heart rate obtained during administration of a standardized social conversation task administered prior to and following the treatment probe. Results showed that learning rates obtained during administration of the treatment probe were significantly less steep and less variable for males with FXS compared to males with non-syndromic ASD. Significant improvements in social gaze were also observed for males with FXS during the social conversation task. There was no effect of the treatment probe on heart rate in either group. These data reveal important differences in social learning between the two groups and have implications for early interventions in the two conditions.


Presynaptic inhibition of spontaneous acetylcholine release mediated by P2Y receptors at the mouse neuromuscular junction.
At the neuromuscular junction, ATP is co-released with the neurotransmitter acetylcholine (ACh) and once in the synaptic space, it is degraded to the presynaptically active metabolite adenosine. Intracellular recordings were performed on diaphragm fibers of CF1 mice to determine the action of extracellular ATP (100 muM) and the slowly hydrolysable ATP analog 5'-adenylylimidodiphosphate lithium (betagamma-imido ATP) (30 muM) on miniature end-plate potential (MEPP) frequency. We found that application of ATP and betagamma-imido ATP decreased spontaneous secretion by 45.3% and 55.9% respectively. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A(1) adenosine receptor antagonist and alpha,beta-methylene ADP sodium salt (alphabeta-MeADP), which is an inhibitor of ecto-5'-nucleotidase, did not prevent the inhibitory effect of ATP, demonstrating that the nucleotide is able to modulate spontaneous ACh release through a mechanism independent of the action of adenosine. Blockade of Ca(2+) channels by both, Cd(2+) or the combined application of nitrendipine and omega-conotoxin GVIA (omega-CgTx) (L-type and N-type Ca(2+) channel antagonists, respectively) prevented the effect of betagamma-imido ATP, indicating that the nucleotide modulates Ca(2+) influx through the voltage-dependent Ca(2+) channels related to spontaneous secretion. betagamma-Imido ATP-induced modulation was antagonized by the non-specific P2 receptor antagonist suramin and the P2Y receptor antagonist 1-amino-4-[[4-[[4-chloro-6-[[3(or4)-sulfophenyl] amino]-1,3,5-triazin-2-yl]amino]-3-sulfophenyl] amino]-9,10-dihydro-9,10-dioxo-2-anthracenesulfonic acid (reactive blue-2), but not by pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt (PPADS), which has a preferential antagonist effect on P2X receptors. Pertussis toxin and N-ethylmaleimide (NEM), which are blockers of G(i/o) proteins, prevented the action of the nucleotide, suggesting that the effect is mediated by P2Y receptors coupled to G(i/o) proteins. The protein kinase C (PKC) antagonist chelerythrine and the calmodulin antagonist N-(6-aminohexil)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) occluded the effect of betagamma-imido ATP, while the protein kinase A (PKA) antagonist KT-5720 and the inhibitor of the calcium/calmodulin-dependent protein kinase II (CAMKII) KN-62 failed to do so. betagamma-Imido ATP did not affect 10, 15 and 20 mM K(+)-evoked release and application of reactive blue-2 before incubation in high K(+) induced a higher asynchronous secretion. Thus, our results show that at mammalian neuromuscular junctions, ATP induces presynaptic inhibition of spontaneous ACh release due to the modulation of Ca(2+) channels related to tonic secretion through the activation of P2Y receptors coupled to G(i/o) proteins. We also demonstrated that at increasing degrees of membrane depolarization evoked by K(+), endogenously released ATP induces presynaptic inhibition as a means of preventing excessive neurotransmitter secretion.


From Myzocytosis to Cytostomal Nutrient Uptake and Transport by Intracellular Plasmodium Species.
Plasmodium falciparum causes severe and lethal malaria [...].


[Detection of epidermal growth factor receptor gene amplification in human laryngeal carcinomas by means of fluorescence in situ hybridization].
To detect epidermal growth factor receptor(EGFR) gene amplification in human laryngeal carcinoma Hep-2 cell line and laryngeal carcinoma tissues. The technique of fluorescence in situ hybridization(FISH). The EGFR gene amplification of a laryngeal carcinoma Hep-2 cell line and 5 laryngeal carcinoma tissues were detected by FISH. In the metaphase chromosome and interphase nuclei of Hep-2 cell line and 2 laryngeal carcinoma tissues, distinct cluster and multiple dot signals were found. In the interphase nuclei of the other 3 laryngeal carcinoma tissues, no increase in the number or extent of the hybrid signals was found. Compared with normal diploid cell, the EGFR gene amplification was observed at different levels ranging from 2 to 8 folds in metaphase chromosome and interphase nuclei of Hep-2 cell line and 2 laryngeal carcinoma tissues while no amplification was observed in the other 3 laryngeal carcinoma tissues. The results demonstrate that quantitative detection of amplified gene by FISH in the metaphase chromosome and interphase nuclei is useful for detection of laryngeal carcinoma tissues.


The impact of genetics and genomics on public health.
Public health practice has to date concerned itself with environmental or social determinants of health and disease and has paid scant attention to genomic variations within the population. The advances brought about by genomics are changing these perceptions. In the long run, this knowledge will enable health promotion messages and disease prevention programmes to be specifically directed at susceptible individuals and families, or at subgroups of the population, based on their genomic risk profile. As the controversial discourse in science and health politics shows, the integration of genomics into public health research, policy and practice is one of the major challenges that our health-care system is currently facing.


"I AM NOT A VIRUS": COVID-19, Anti-Asian Hate, and Comics as Counternarratives.
Ever since the global spread of the COVID-19 pandemic in 2020, East Asians across the globe have been ostracized, othered, pathologized, and subjected to numerous anti-Asian hate crimes. Despite contemporary China's rapid modernization, the country is still perceived as an Oriental and primitive site. Taking these cues, the current article aims to investigate the Sinophobic attitudes in the wake of COVID-19 through a detailed analysis of sequential comics and cartoons by artists of East Asian descent, such as Laura Gao and Lisa Wool-Rim Sjöblom. Drawing theoretical insights from Alexandre White's "epidemic orientalism" and Priscilla Wald's "medicalized nativism," this essay investigates how these chosen comics function as counternarratives through first-person storytelling. In so doing, these comics, while reinstating the dignity of East Asians, also challenge and resist the naturalized methods of seeing that justify violence and dehumanization. The article further argues that Sinophobia and anti-Asian hate crimes are motivated as much by the origins of COVID-19 in China as by the political, economic, and technological variables that have shaped modern China.


Treatment of childhood T-cell lymphoblastic lymphoma according to the strategy for acute lymphoblastic leukaemia, without radiotherapy: long term results of the EORTC CLG 58881 trial.
From June 1989 through to November 1998, 121 children with newly diagnosed T-cell lymphoblastic lymphoma (T-LBL) were included in the EORTC 58881 trial conducted by the Children's Leukaemia Group. The therapy regimen was based on a Berlin-Frankfurt-Munster protocol, for a total duration of 24 months. Cranial irradiation, prophylactic cranial and local, was omitted, even for patients with central nervous involvement at diagnosis. In total, 119 patients were evaluable. The median follow-up was 6.7 years. The overall event-free survival (EFS) rate at 6 years was 77.5% (standard error (SE)=4%). Median time of relapse was 1 year after complete remission (range 0.2-5.9 years). Only two (1.8%) patients had an isolated central nervous system relapse. For patients with complete response (n=16) to the 7-day prephase, the EFS rate at 6 years was 100% versus 14% (P<0.001) for patients with no response (n=7). Overall survival rate at 6 years was 86% (SE=3%). An intensive acute lymphoblastic leukaemia type chemotherapy regimen without irradiation leads to a high cure and survival rate in childhood T-LBL without an increased CNS recurrence. This suggests that prophylactic cranial irradiation can safely be omitted. Response to the prephase appeared to be a strong prognostic factor for EFS.


Sjogren's syndrome in optometric practices in North America.
To describe the presentation of dry eye in Sjogren's syndrome (SS) in optometric practices, to report on the methodology used in dry eye monitoring and to explore the level of corneal staining versus age and time of disease. Records of SS patients were reviewed in 6 optometric sites. A standardized abstraction tool was developed to collect data from the records including: health history, medications and symptoms and signs of dry eye. The methods of testing symptoms and signs of dry eye were recorded. Variables were recorded at each site and collated at the University of Waterloo. The first visit after January 1, 2000 was selected for description in this paper. 123 charts were included. The average time since diagnosis was 7.2 years ±5.1 years. Symptoms of dryness were present in 110/123 = 89.4% of charts. Corneal fluorescein staining was present in 96/123 = 78% of charts. MGD was present in 52% of charts. There were significant differences in the protocols and grading systems used in these 6 sites. Corneal staining levels did not change with greater age or length of disease. These 123 SS patients presented with a large variation in their symptoms and signs. Symptoms of dryness and corneal fluorescein staining were the most commonly recorded presentations. There was a great deal of inconsistency in dry eye protocols among offices. Future prospective research with standardized testing will contribute to our understanding of the best dry eye protocols for SS patients.


Construction and validation of web-based nomograms for detecting and prognosticating in prostate adenocarcinoma with bone metastasis.
Bone metastasis (BM) is one of the most common sites of metastasis in prostate adenocarcinoma (PA). PA with BM can significantly diminish patients' quality of life and result in a poor prognosis. The objective of this study was to establish two web-based nomograms to estimate the risk and prognosis of BM in PA patients. From the Surveillance, Epidemiology, and End Results (SEER) database, data on 308,332 patients diagnosed with PA were retrieved retrospectively. Logistic and Cox regression, respectively, were used to determine independent risk and prognostic factors. Then, We constructed two web-based nomograms and the results were validated by receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA) , and the Kaplan-Meier analyses. The independent risk factors for BM in PA patients included race, PSA, ISUP, T stage, N stage, brain, liver, lung metastasis, surgery, radiation and chemotherapy. The independent prognostic predictors for overall survival (OS) were age, marital status, PSA, ISUP and liver metastasis. Both nomograms could effectively predict risk and prognosis of BM in PA patients according to the results of ROC curves, calibration, and DCA in the training and validation sets. And the Kaplan-Meier analysis illustrated that the prognostic nomogram could significantly distinguish the population with different survival risks. We successfully constructed the two web-based nomograms for predicting the incidence of BM and the prognosis of PA patients with BM, which may assist clinicians in optimizing the establishment of individualized treatment programs and enhancing patients' prognoses.


A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis-ichthyosis-deafness (KID) syndrome.
Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal disorder, caused by heterozygous missense mutation in GJB2, encoding the gap junction protein connexin 26. The commonest mutation is the p.Asp50Asn mutation, and only a few other mutations have been described to date. To report the fatal clinical course and characterize the genetic background of a premature male neonate with the clinical and histological features of KID syndrome. Genomic DNA was extracted from peripheral blood and used for PCR amplification of the GJB2 gene. Direct sequencing was used for mutation analysis. The clinical features included hearing impairment, ichthyosiform erythroderma with hyperkeratotic plaques, palmoplantar keratoderma, alopecia of the scalp and eyelashes, and a thick vernix caseosa-like covering of the scalp. On histological analysis, features characteristic of KID syndrome, such as acanthosis and papillomatosis of the epidermis with basket-weave hyperkeratosis, were seen. The skin symptoms were treated successfully with acitretin 0.5 mg/kg. The boy developed intraventricular and intracerebral haemorrhage, leading to hydrocephalus. His condition was further complicated by septicaemia and meningitis caused by infection with extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Severe respiratory failure followed, and the child died at 46 weeks of gestational age (13 weeks postnatally). Sequencing of the GJB2 gene showed that the child was heterozygous for a novel nucleotide change, c.263C>T, in exon 2, leading to a substitution of alanine for valine at position 88 (p.Ala88Val). This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome.


Paroxysmal cold haemoglobinuria coexisting with cold agglutinins in a patient with syphilis resulting in peripheral gangrene: a case report.
Cold-reactive antibodies may cause peripheral ischaemia, occasionally proceeding to gangrene on exposure to cold. A 46-year-old male with syphilis, presented with an unusual combination of both paroxysmal cold haemoglobinuria and cold agglutinin disease, resulting in peripheral gangrene and requiring bilateral below knee amputations.


Effect of the muscarinic agonist carbachol on pial arteries in vivo after endothelial damage by air embolism.
Reactions of pial arteries to the muscarinic agonist carbachol were tested in vivo in chloralose anesthetized cats before and after endothelial damage. Moderate endothelial damage was induced by arterial air embolism and verified by electron microscopy for the vessels tested. The experiments had three phases; First, the normal reactivity of pial arteries to carbachol (10(-7) to 10(-5) M) was tested using the microapplication technique, then, after air embolism, the reactivity was reinvestigated at the same vessel. Finally, pial arteries were taken out for scanning electron microscopy. The results show carbachol (10(-6) and 10(-5) M) induced significant dilations under control conditions, also after repetition at the same vessel. After air embolism, the reactions to carbachol were abolished. Morphologic data revealed that whereas control pial arteries showed intact endothelium, the embolized vessels revealed various degrees of endothelial alterations. All showed flattening of endothelial nuclei, to a greater or lesser degree, and in many cases, the endothelium had a wrinkled appearance; several arteries showed severe degradation of the intercellular junctions. It is concluded that (a) carbachol-induced muscarinic vasodilatation of pial arteries in vivo can be abolished after a morphologically verified endothelial lesion--thus confirming in vitro studies in larger arteries and (b) disturbed vascular function does not require rubbing of the endothelium, but occurs already with moderate endothelial damage.


Optimising cell temperature and dispersion field strength for the screening for putrescine and cadaverine with thermal desorption-gas chromatography-differential mobility spectrometry.
Biogenic amines, and putrescine and cadaverine in particular, have significant importance in the area of food quality monitoring, and are also potentially important markers of infection, for cancer, diabetes, arthritis and cystic fibrosis. A thermal desorption-gas chromatograph-heated differential mobility spectrometer was constructed and the significant effect of interactions between cell temperature and dispersion field strength on the observed responses studied. The experiment design was a Box-Wilson central composite design (CCD) over the levels of 10-24 kVcm(-1) for dispersion field strength and 100-130 degrees C for cell temperature. The optimum values were estimated to be 16.22 kVcm(-1) and 116 degrees C for putrescine and 14.78 kVcm(-1) and 112 degrees C for cadaverine, respectively with an ammonia dopant at 19 mgm(-3). An amine test atmosphere generator was constructed and produced stable concentrations of putrescine (7 mgm(-3)) and cadaverine (4 mgm(-3)) vapours at 50+/-0.5 degrees C. Tenax TA-Carbotrap adsorbent tubes were used to sample putrescine and cadaverine vapour standards and a linear response function over the range of sample masses 5-20 ng was obtained at 15.0 kVcm(-1) 115 degrees C, with a R(2) of 0.99 for both putrescine and cadaverine. The sample mass at the limit of detection was estimated to be 3 ng for putrescine and cadaverine. Preliminary data from sampling the headspace of chicken meat revealed a 62% increase in the recovered masses of putrescine from 0.84 to 1.36 ng in the sampled air.


¹¹¹In-DTPA⁰-octreotide (Octreoscan), ¹³¹I-MIBG and other agents for radionuclide therapy of NETs.
This paper is a critical review of the literature on NET radionuclide therapy with (111)In-DTPA(0)-octreotide (Octreoscan) and (131)I-MIBG, focusing on efficacy and toxicity. Some potential future applications and new candidate therapeutic agents are also mentioned. Octreoscan has been a pioneering agent for somatostatin receptor radionuclide therapy. It has achieved symptomatic responses and disease stabilization, but it is now outperformed by the corresponding β-emitter agents (177)Lu-DOTATATE and (90)Y-DOTATOC. (131)I-MIBG is the radionuclide therapy of choice for inoperable or metastatic phaeochromocytomas/paragangliomas, which avidly concentrate this tracer via the noradrenaline transporter. Symptomatic, biochemical and tumour morphological response rates of 50-89%, 45-74% and 27-47%, respectively, have been reported. (131)I-MIBG is a second-line radiopharmaceutical for treatment of enterochromaffin carcinoids, mainly offering the benefit of amelioration of hormone-induced symptoms. High specific activity, non-carrier-added (131)I-MIBG and meta-astato((211)At)-benzylguanidine (MABG) are tracers with potential for enhanced therapeutic efficacy, yet their integration into clinical practice awaits further exploration. Amongst other promising agents, radiolabelled exendin analogues show potential for imaging and possibly therapy of insulinomas, while preclinical studies are currently evaluating DOTA peptides targeting the CCK-2/gastrin receptors that are overexpressed by medullary thyroid carcinoma cells.


Patterns of nicotine dependence in four Eastern European countries.
Evidence of patterns of nicotine dependence, although crucial for developing and implementing effective tobacco control strategies, is limited in the Eastern European countries. The purpose of this study was to evaluate the correlates of high nicotine dependence among adults in Poland, Romania, the Russian Federation and Ukraine. The data used in the current analysis is available from the Global Adult Tobacco Survey (2009-2011). Nicotine dependence was assessed using the Heaviness of Smoking Index (HSI), which covers two measures: reported cigarettes smoked per day and time to the first cigarette upon waking. Based on a six-point scale of HSI, nicotine dependence was categorized into low to moderate (score 0-3), and high dependence (score 4-6). Out of 31,936 completed interviews, we used data from 8229 daily smokers. The study results indicate that more than 25 % of daily smokers were highly dependent on nicotine. Higher odds of high nicotine dependence were identified for males (OR = 1.5 in Poland and Romania, OR = 2.7 in Russia; p ≤ 0.001), people between 50-59 years of age (the highest odds in Romania; OR = 4.8; p ≤ 0.001) and those who had started smoking at a young age (the highest odds in Romania, OR = 5.0; p ≤ 0.001). Having fewer restrictions on smoking at home was significantly associated with a high level of nicotine dependence (the highest odds in Romania, OR = 3.0; p ≤ 0.001). A high proportion of the participants had no interest in quitting smoking, with a statistically significantly higher percentage observed among smokers highly dependent on nicotine compared to the less addicted (p ≤ 0.01). Smokers highly dependent on nicotine constitute a quarter of the Romanian group of daily smokers and even more in the remaining three analyzed countries. Similar patterns of nicotine dependence were observed in all of the investigated countries showing that male gender, younger age at the smoking onset, and fewer restrictions on smoking at home were significantly associated with higher nicotine dependence. The study highlighted the fact that a high proportion of the participants had no interest in quitting smoking. These results underscore importance of policy measures as well as prevention and cessation interventions for smokers who are highly dependent on nicotine, which need to take into account the social gradient in smoking patterns.


Adoption of E-health platforms by medical practitioners: Mediating effect of attitude on E-health platforms usage.
This study considers Theory of Reasoned Action and Technology Acceptance Model frameworks to test the mediating role of attitude towards using E-health platforms. 224 medical practitioners' responses are collected in the online mode. The mediation analysis supports the full mediation role of attitude towards using the E-health platforms in the relationship between perceived usefulness and intentions to use with (indirect effect = .15, SE = 0.03, LLCI = 0.09, and ULCI = .22). E-health platform developers should take active measures to improve the attitude of medical practitioners towards using such platforms, to derive the best results of the added features.


The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis.
To explore the roles of Annexin A2 (ANXA2) on hepatocyte pyroptosis and hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and underlying molecular mechanism. Bioinformatics analyses were performed on transcriptome data of liver tissues from mice and patients with liver fibrosis for screening the hepatocyte pyroptosis-related differential genes. The in vivo NASH mouse model and in vitro NASH cellular model were established. The expression levels of Anxa2/ANXA2 were quantified. Then, the upstream transcription factor of Anxa2 was screened by ChIP-Seq and experimentally verified. The effects of the p-STAT3/ANXA2 axis on Caspase-1 mediated pyroptosis and fibrosis were explored by in vivo and in vitro experiments. Bioinformatics analyses suggested that the expression of Anxa2/ANXA2 was significantly up-regulated in liver tissues of both NASH mice and patients scoring with high pyroptotic activity. Experimental data showed that the ANXA2 expression was positively associated with the development of hepatocyte pyroptosis and fibrosis. As a transcription factor of ANXA2, p-STAT3 can bind to the promoter of Anxa2 and promote its transcription. The inhibition of p-STAT3 can significantly suppress hepatocyte pyroptosis and fibrosis, which was significantly reversed after the over-expression of Anxa2. Caspase-1 was verified as the player of the p-STAT3/ANXA2 axis to promote pyroptosis and fibrosis. By specifically inhibiting Caspase-1, the promotion effect of the p-STAT3/ANXA2 axis on pyroptosis and fibrosis can be significantly weakened. The p-STAT3 promoted Anxa2 expression at the transcription level, thus activating the Caspase-1 mediated hepatocyte pyroptosis and fibrosis in NASH.


MAPK-regulated transcription: a continuously variable gene switch?
Switching mechanisms that control genes could be viewed either as stable binary switches, in which genes exist in 'on' or 'off' states; or as quantitative rheostat-like switches, in which the rate of transcription is continuously variable and coupled directly to the strength of intracellular signalling events. Here, we discuss the biological need for quantitative gene regulation and, using mitogen-activated protein kinase (MAPK)-controlled transcription as a model, assess the evidence for its existence and postulate mechanisms by which it might occur.


Commentary: the cellular condensation of dying plant cells: programmed retraction or necrotic collapse?
In this commentary we argue that the recent renaming of all types of plant programmed cell death (PCD) into two categories of vacuolar cell death and necrosis is premature and does not fully take into account different forms of cell death that may operate in plant cells. Specifically, we believe that the condensed protoplast morphology associated with many instances of PCD may come about due to an active cell death-associated cellular retraction rather than simple rupture of the plasma membrane. We argue that it is important to be able to distinguish between cells that have died having undergone this protoplast retraction and those which have died without protoplast retraction. In our opinion this differentiation is essential as the control of these two types of death may differ in several respects.


Effects of nutritional lithium deficiency on behavior in rats.
To demonstrate whether nutritional lithium deficiency is associated with behavioral changes, male Sprague-Dawley rats were placed on a lithium-deficient diet (Li content < .01 ppm). A lithium-deprived group, receiving drinking water containing 31 microM NaCl, were compared to a control group receiving drinking water containing 31 microM LiCl. Growth and general appearance were the same in both groups. However, lithium-deficient animals demonstrated decreased aggression in social interactions with other rats and also in response to handling. The phase of wheel-running activity was delayed by 0.8 h and exhibited decreased amplitude (p < .05). Other behaviors, including acquisition and retention of a passive avoidance response, were unaffected by lithium deprivation.


HCV core protein interacts with Dicer to antagonize RNA silencing.
RNA silencing is a form of nucleic acid-based immunity against viruses in plants and invertebrate animals. Successful viral infection requires evasion or suppression of gene silencing. Here, we report that the core protein of Hepatitis C virus (HCV) acts as a potent suppressor of RNA silencing (SRS). We have found that the HCV core protein inhibits RNA silencing induced by short hairpin RNAs (shRNAs) but not by synthetic small interfering RNAs (siRNAs) in various mammalian cells. We have further demonstrated that HCV core protein directly interacts with Dicer, an RNase enzyme that generates siRNA in host cells. The HCV core protein has been shown to inhibit the function of Dicer to process double-stranded RNAs (dsRNAs) into siRNAs. Through deletion analysis, we have found that the N-terminal domain is required for core protein to antagonize RNA silencing activity of Dicer enzyme. Thus, our results suggest that HCV core protein may abrogate host cell RNA silencing defense by suppressing the ability of Dicer to process precursor dsRNAs into siRNAs. This anti-Dicer ability of core protein may contribute to the persistent viral infection and pathogenesis of HCV.


Aortic smooth muscle TRPV4 channels regulate vasoconstriction in high salt-induced hypertension.
Recent studies have focused on the contribution of vascular endothelial transient receptor potential vanilloid 4 (TRPV4) channels to hypertension. However, in hypertension, TRPV4 channels in vascular smooth muscle remain unexplored. In the present study, we performed wire myograph experiments in isolated aortas from endothelial cell specific TRPV4 channel knockout (TRPV4EC-/-) mice to demonstrate that GSK1016790A (a specific TRPV4 channel agonist) triggered aortic smooth muscle-dependent contractions from mice on a normal-salt diet, and the contractions were enhanced in high-salt diet (HSD) mice. Intracellular Ca2+ concentration ([Ca2+]i) and Ca2+ imaging assays showed that TRPV4-induced [Ca2+]i was significantly higher in aortic smooth muscle cells (ASMCs) from HSD-induced hypertensive mice, and application of an inositol trisphosphate receptor (IP3R) inhibitor markedly attenuated TRPV4-induced [Ca2+]i. IP3R2 expression was enhanced in ASMCs from HSD-induced hypertensive mice and the contractile response induced by TRPV4 was inhibited by the IP3R inhibitor. Whole-transcriptome analysis by RNA-seq and western blot assays revealed the involvement of interferon regulatory factor 7 (IRF7) in TRPV4-IRF7-IP3R2 signaling in HSD-induced hypertension. These results suggested that TRPV4 channels regulate smooth muscle-dependent contractions in high salt-induced hypertension, and this contraction involves increased [Ca2+]i, IP3R2, and IRF7 activity. Our study revealed a considerable effect of TRPV4 channels in smooth muscle-dependent contraction in mice during high-salt induced hypertension.


Delayed genomic and acute nongenomic action of glucocorticosteroids in seasonal allergic rhinitis.
Glucocorticosteroids are effective in the treatment of allergic rhinitis, a disease characterized by a variety of symptoms, e.g. rhinorrhea and itching. The time course of symptomatic relief for allergic rhinitis by steroids has not been examined in detail to date, although the onset of steroid action is one of the main discriminations between genomic and nongenomic actions of steroids. We therefore investigated the time course of subjective and objective measures of nasal affection after steroid administration in patients with allergic rhinitis following specific allergen challenge. Six female and 18 male volunteers (median age 26 years) with a history of allergic rhinitis but currently free of symptoms were included in this randomized, placebo-controlled, double-blind, three-period crossover study. A single dose of either betamethasone (60 mg), methylprednisolone (400 mg) or placebo was given intravenously, 5 min after intranasal allergen provocation. After 10, 20, 60, 150 and 240 min, nasal itching and nasal obstruction were assessed using a standardized visual analogue scale. In addition, nasal airflow was measured by anterior rhinomanometry. Nasal itching was markedly reduced following either of the two steroids within 10 min after administration of study drug. Itching was depressed by 38% following betamethasone (P<0.05) and by 18% following methylprednisolone (P=0.07) compared with placebo. Nasal airflow and nasal obstruction were not significantly altered by steroids during the first 2 h of the study. However, after 150 min, nasal airflow was 21% rsp. 19% higher after methylprednisolone and betamethasone (P<0.05) compared with placebo. After 240 min, nasal airflow was increased by 20% following betamethasone (P<0.05) and by 19% following methylprednisolone. Nasal obstruction was also beneficially affected by both steroids 150 and 240 min after administration compared with placebo (P<0.05 for both time points following betamethasone). This study for the first time shows rapid in vivo effects of external glucocorticosteroids in humans. Itching, a pathophysiologically complex sensation, is favourably influenced by steroids within 10 min, therefore presumably via nongenomic mechanisms. Though no detailed mechanisms can be derived from this study, steroid interaction with receptors in the central nervous system may play an important role in mediating this effect.


Serum uric acid is independently associated with hypertension in patients with rheumatoid arthritis.
Hypertension (HT) is highly prevalent in rheumatoid arthritis (RA). Serum uric acid (SUA) has been associated with HT in the general population. The mutual exclusion of gout and RA, and the systemic inflammatory component of RA may alter this association in this patient population. We explored a potential association between SUA levels and HT in RA and evaluated whether this association is independent of HT risk factors, RA characteristics and relevant drugs. A total of 400 consecutive RA patients were assessed. SUA and complete biochemical profile were measured. Demographic, HT-related factors, RA characteristics and drugs were assessed as potential covariates. Results were analysed using binary logistic models to test the independence of the association between SUA and HT. SUA levels were higher in hypertensive compared to normotensive RA patients (5.44+/-1.6 mg dl(-1) (323.57+/-95.17 micromol l(-1)) vs 4.56+/-1.1 mg dl(-1) (271.23+/-65.43 micromol l(-1)), P<0.001). When adjusted for HT risk factors, renal function, RA characteristics, non-steroidal anti-inflammatory drugs, oral prednisolone, cyclosporine, leflunomide and low-dose aspirin, the odds of being a hypertensive RA patient per 1 mg dl(-1)(59.48 micromol l(-1)) SUA increase were significantly increased: OR=1.59 (95% CI: 1.21-2.1, P=0.001). This was also significant for the subgroup of patients who were not on diuretics (OR=1.5, 95% CI: 1.1-2.05; P=0.011). This cross-sectional study suggests that SUA levels are independently associated with HT in RA patients. Prospective longitudinal studies are needed to confirm and further explore the causes and implications of this association.


Near-zero ventilator-associated pneumonia rates after implementation of a multimodal preventive strategy in a Mexican hospital.
A multimodal preventive strategy consisting of a ventilator-associated pneumonia (VAP) preventive bundle plus 3 additional sequential interventions (noninvasive ventilation, reeducation of health care workers, and early weaning) was associated with a marked reduction in VAP rates in a Latin American hospital, including 6 consecutive months without VAP cases. A positive association between the percentage of intubated patients and VAP rates was observed.


Metformin and combined oral contraceptive pills in the management of polycystic ovary syndrome: a systematic review and meta-analysis.
Polycystic ovary syndrome (PCOS) is affecting more than every tenth woman. As part of the 2023 International PCOS Guidelines update, comparisons between combined oral contraceptive pills (COCP), metformin and combination treatment were evaluated. Ovid Medline, Embase, PsycINFO, All EBM and CINAHL were searched. Women with PCOS included in randomized controlled trials (RCT). We calculated mean differences (MD) and 95% confidence intervals (CI) regarding anthropometrics, metabolic and hyperandrogenic outcomes. Meta-analyses and quality assessment using GRADE was performed. The search identified 1660 publications, 36 RCTs were included. For hirsutism no differences were seen when comparing metformin versus COCP, nor when comparing COCP versus combination treatment with metformin and COCP. Metformin was inferior on free androgen index (FAI) (7.08, 95% CI 4.81; 9.36), sex hormone binding globulin (SHBG) (-118.61 nmol/l, 95% CI -174.46; -62.75) and testosterone (0.48 nmol/l,95% CI 0.32; 0.64) compared with COCP. COCP was inferior for FAI (0.58, 95% CI 0.36; 0.80) and SHBG (-16.61 nmol/L, 95% CI -28.51; -4.71) compared with combination treatment, whereas testosterone did not differ. Metformin lowered insulin (-27.12 pmol/l, 95%CI -40.65; -13.59) and triglycerides (-0.15 mmol/l, 95%CI -0.29; -0.01) compared with COCP. COCP was inferior for insulin (17.03 pmol/l, 95%CI 7.79; 26.26) and insulin resistance (0.44, 95%CI 0.17; 0.70) compared with combination treatment. The choice of metformin or COCP treatment should be based on symptoms, noting that there are some biochemical benefits from combination treatment, targeting both major endocrine disturbances seen in PCOS; hyperinsulinemia and hyperandrogenism.


Impact of duct-to-mucosa pancreaticojejunostomy with external drainage of the pancreatic duct after pancreaticoduodenectomy.
A variety of different techniques are established for the management of the pancreatic remnant after partial pancreaticoduodenectomy. Although pancreaticojejunostomy is one of the most favored methods, technical details are still under discussion. We report about a series of duct-to-mucosa pancreaticojejunostomies with total external drainage of the pancreatic duct. Between 1998 and 2007 257 patients underwent surgical therapy for malignant disease of the pancreas and the periampullary region and for chronic pancreatitis. Of these, 153 partial pancreaticoduodenectomies (85 pylorus preserving resections and 68 Whipple's procedures) were performed. In all of these cases, the pancreatic remnant was drained by a duct-to-mucosa pancreaticojejunostomy with external drainage of the pancreatic duct. Presence of postoperative pancreatic fistula (PPF) was defined according to the International Study Group on Pancreatic Fistula (ISGPF). Postoperative mortality was 1.9%. The incidence of postoperative pancreatic fistula (PPF) was 19.6% according to the ISGPF criteria. Only one patient required re-laparotomy for complications caused by PPF. Patients with PPF had a significantly longer operation time (7.3 h versus 6.6 h; P=0.041). Incidence of PPF was not influenced by histology. In all cases the fistulas resolved under conservative treatment. Duct-to-mucosa PJ with external drainage is a safe procedure to enteralize the pancreatic stump after partial pancreaticoduodenectomy.


A novel mitochondrial DNA-like sequence insertion polymorphism in Intron I of the FOXO1A gene.
The human forkhead box O1A (FOXO1A) gene belongs to the human forkhead gene family and acts downstream of the human insulin signalling pathway. In this study, polymorphisms of the Intron I of FOXO1A gene were studied in Italian healthy people and insulin resistant subjects. No significant association between the germ-line variability in the Intron I of FOXO1A and insulin resistance was observed. Interestingly, during the study, a new 39-bp sequence insertion polymorphism in Intron I of FOXO1A gene was described. The polymorphism was found to co-segregate in a co-dominant Mendelian fashion and to be present in an ethnically distinct population (Greeks). A BLAST search showed that the sequence shares 100% identity with a mtDNA (mitochondrial DNA) sequence coding for the ATP synthase 8 (ATPase8) and ATP synthase 6 (ATPase6) genes. Hence, FOXO1A Intron I is a polymorphic nuclear region involved in the exchange of DNA material between mitochondrial and genomic DNA, which is a well-established mechanism of evolutionary change in eukaryotes.


Carbon quantum dots as fluorescence resonance energy transfer sensors for organophosphate pesticides determination.
Carbon quantum dots (CQDs) obtained from natural organics attract significant attention due to the abundance of carbon sources, varieties of heteroatom doping (such as N, S, P) and good biocompatibility of precursor. In this study, tunable fluorescence emission CQDs originated from chlorophyll were synthesized and characterized. The fluorescence emission can be effectively quenched by gold nanoparticles (Au NPs) via fluorescence resonance energy transfer (FRET). Thiocholine, which was produced from acetylthiocholine (ATC) by the hydrolysis of butyrylcholinesterase (BChE), could cause the aggregation of Au NPs and the corresponding recovery of FRET-quenched fluorescence emission. The catalytic activity of BChE could be irreversibly inhibited by organophosphorus pesticides (OPs), thus, the recovery effect was reduced. By evaluating the fluorescence emission intensity of CQDs, a FRET-based sensing platform for OPs determination was established. Paraoxon was studied as an example of OPs. The sensing platform displayed a linear relationship with the logarithm of the paraoxon concentrations in the range of 0.05-50μgL-1 and the limit of detection (LOD) was 0.05μgL-1. Real sample study in tap and river water revealed that this sensing platform was repeatable and accurate. The results indicate that the OP sensor is promising for applications in food safety and environmental monitoring.


Treatment with Idelalisib in Patients with Relapsed or Refractory Follicular Lymphoma: The Observational Italian Multicenter FolIdela Study.
Follicular lymphoma (FL) is an indolent hematological disease, often responsive to the first line of treatment, but characterized by repeated relapses. The therapeutic algorithm for relapsed/refractory FL patients comprises phosphatidylinositol 3-kinase inhibitors. Idelalisib showed anticancer activity, while inducing a significant rate of toxicities. Since the evidence in the literature on its use in normal clinical practice is scarce, a retrospective multicenter study was conducted to evaluate effectiveness and tolerability in a real-life context. Seventy-two patients with a median age at diagnosis of 57.2 years-mostly with an advanced stage (88.9%) and relapsed to the most recent therapy (79.1%)-were enrolled. The median number of prior therapies was three (20.8% refractory to the last therapy before idelalisib). With a median number of 4 months of treatment, the overall response rate was 41.7% (20.8% complete responses). Median disease-free survival and overall survival were achieved at 8.4 months and at 4 years, respectively. Forty-four percent of patients experienced at least one drug-related toxicity: 6.9% hematological ones and 43% non-hematological. The study confirmed that idelalisib has anticancer effectiveness and an acceptable safety profile in relapsed/refractory FL with unfavorable prognostic characteristics, even in the context of normal clinical practice.