Antioxidant Phenylpropanoid Glycosides from Ginkgo biloba Fruit and Identification of a New Phenylpropanoid Glycoside, Ginkgopanoside.
Ginkgo biloba (Ginkgoaceae), well-known as the oldest living plant species and often referred to as a "living fossil," is a famous medicinal plant that has been used in multiple countries to improve numerous illnesses, including anxiety, dementia, peripheral artery disease, and eye problems. We conducted a phytochemical exploration of G. biloba fruit, commonly consumed as a functional food as part of an ongoing natural product chemical research for the discovery of bioactive phytochemicals with novel structures. The natural product chemical analysis of the methanol extract of G. biloba fruit using column chromatography and high-performance liquid chromatography separation under the guidance of a liquid chromatography-mass spectrometry (LC/MS)-based analysis identified six phenylpropanoid glycosides (1-6), including one new compound, ginkgopanoside (1). The structures of the isolated compounds were elucidated by nuclear magnetic resonance spectroscopic data and LC/MS analysis, and the absolute configuration of compound 1 was established by chemical reactions followed by the application of Snatzke's method. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activities of the isolated compounds 1-6 and the aglycone 1a of 1 were evaluated, and we found that compounds 1-5 exhibited antioxidant activities with IC50 values in the range 32.75-48.20 μM, while the aglycone 1a exhibited greater radical scavenging activity (IC50 = 5.23 μM) comparable to that of ascorbic acid (IC50 = 2.54 μM), a positive control, implying that the present of glucose may decrease the DPPH scavenging activity. These findings provide experimental information that the active phenylpropanoid glycosides could represent natural antioxidants for use in pharmaceuticals and functional foods.


Gabapentin drug misuse signals: A pharmacovigilance assessment using the FDA adverse event reporting system.
Although there have been increasing reports of intentional gabapentin misuse, epidemiological evidence for the phenomenon is limited. The purpose of this study was to determine whether there are pharmacovigilance abuse signals for gabapentin. Using FDA Adverse Events Reporting System reports from January 1, 2005 to December 31, 2015, we calculated pharmacovigilance signal measures (i.e., reporting odds ratio, proportional reporting ratio, information component, and empirical Bayes geometric mean) for abuse-related adverse event (AR-AE)-gabapentin pairs. Loglinear modeling assessed the frequency of concurrent reporting of abuse-related and abuse-specific AEs (AS-AEs) associated with gabapentin. Findings were compared to a positive (pregabalin) and negative (duloxetine) control. From 2005-2015 there were 5,951,229 unique AE reports submitted to the FDA including 99,977 for gabapentin, 73,977 for duloxetine, and 97,813 for pregabalin. Significant drug-AR-AE pair signals involving gabapentin included: drug abuser, multiple drug overdose, and substance-induced psychotic disorder. Significant drug AR-AE signals involving gabapentin and pregabalin, but not duloxetine, were: ataxia, dependence, drug abuse, increased drug tolerance, and overdose. Compared to duloxetine, gabapentin had significantly greater odds of a co-report for an AS-AE with drug withdrawal syndrome (OR: 6.55), auditory hallucinations (OR: 4.57), delusions (OR: 2.36), euphoric mood (OR: 5.45), ataxia (OR: 2.85), drug abuser (OR: 3.01), aggression (OR: 1.98), psychotic disorder (OR: 1.96), and feeling abnormal (OR: 1.31). We identified abuse-related signals for gabapentin and highlighted several CNS effects that may be associated with its abuse. Gabapentin prescribers should be aware of the drug's abuse liability and effects that may accompany its use.


Moving beyond frailty: Obesity paradox persists in lung resection.
The apparent protective effect of high body mass index on postoperative outcomes, termed the "obesity paradox," has been postulated to reflect the relative frailty of patients without obesity. We wanted to examine the independent association between body mass index and outcomes after anatomic lung resection. All adults undergoing elective lung resection for cancer were identified in the 2012-2020 National Surgical Quality Improvement Program. The modified Frailty Index quantified degree of patient frailty. Malnutrition was defined as a preoperative serum albumin <3.5g/dL. Multivariable regressions were used to examine the independent association of body mass index and major adverse events, analyzed as a composite of 30-day mortality, postoperative complications, and unplanned reoperation. Of an estimated 20,099 patients meeting study criteria, 6,424 (32.0%) had obesity. Relative to others, patients with obesity were significantly younger (49.3 vs 50.3 years), more commonly White (78.1 vs 74.9%), and more frequently frail (modified Frailty Index >1: 35.7 vs 22.5%, all P < .001). There was no significant difference in malnutrition rates (7.6 vs 8.4%, P = .05) or extent of resection between groups. After adjustment, obesity was associated with decreased odds of major adverse events (adjusted odds ratio 0.86, 95% confidence interval 0.78-0.94). The present findings uphold the canonical obesity paradox in anatomic lung resection, despite adjustment for frailty and malnutrition. Further studies are warranted to characterize the nature of this association; however, our results may inform efforts to optimize risk stratification and patient selection for surgical intervention.


Calcium dobesilate in the treatment of diabetic retinopathy.
The incidence of diabetic retinopathy is still increasing in developed countries. Tight glycemic control and laser therapy reduce vision loss and blindness, but do not reverse existing ocular damage and only slow the progression of the disease. New pharmacologic agents that are currently under development and are specifically directed against clearly defined biochemical targets (i.e. aldose reductase inhibitors and protein kinase C-beta inhibitors) have failed to demonstrate significant efficacy in the treatment of diabetic retinopathy in clinical trials. In contrast, calcium dobesilate (2,5-dihydroxybenzenesulfonate), which was discovered more than 40 years ago and is registered for the treatment of diabetic retinopathy in more than 20 countries remains, to our knowledge, the only angioprotective agent that reduces the progression of this disease. An overall review of published studies involving calcium dobesilate (CLS 2210) depicts a rather 'non-specific' compound acting moderately, but significantly, on the various and complex disorders that contribute to diabetic retinopathy. Recent studies have shown that calcium dobesilate is a potent antioxidant, particularly against the highly damaging hydroxyl radical. In addition, it improves diabetic endothelial dysfunction, reduces apoptosis, and slows vascular cell proliferation.


Novel endocrine therapies: What is next in estrogen receptor positive, HER2 negative breast cancer?
Endocrine therapy (ET) is the cornerstone of management in hormone receptor (HR)+ breast cancer (BC). Indeed, targeting the estrogen receptor (ER) signaling at different levels is a successful strategy, since BC largely relies on the ER signaling as a driver of tumorigenesis and progression. In metastatic BC, progression of disease typically occurs due to either ligand-independent ER signaling, which favors tumor proliferation and survival in the absence of hormonal stimuli, or an ER-independent signaling, which exploits alternative transcription pathways. For instance, estrogen receptor 1 (ESR1) mutations induce constitutive ER activity, in turn upregulating ER-dependent gene transcription and causing resistance to estrogen depleting therapies. The largest unmet need lies after progression on ET + cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, where fulvestrant alone provides an average 2-3-month PFS. In this context, novel oral selective estrogen receptor degraders (SERDs) and other next-generation ETs are being investigated, both as single agents and in combination with targeted therapies. Elacestrant, the next generation ET in most advanced clinical development and the first to be FDA approved, demonstrated improved outcomes compared to standard ETs in ET pre-treated HR+/HER2- metastatic BC in the phase 3 EMERALD clinical trial. Additionally, other agents are showing promising results in both preclinical and early phase clinical settings. In this review, emerging data related to oral SERDs and other novel ETs in managing HR+/HER2- BC are presented. Major challenges and future perspectives related to the optimal sequence of therapeutic options and the molecular landscape of endocrine resistance are also provided.


PSA targeted dual-modality manganese oxide-mesoporous silica nanoparticles for prostate cancer imaging.
Studies have shown the potential of nanomaterials for the accurate and early detection of cancer. The aim of the present study was to design and evaluate the value of prostate-specific membrane antigen (PSA)-targeted manganese oxide-mesoporous silica nanoparticles (Mn-Msns) for the detection of prostate cancer. Mn-Msns were prepared, and then conjugated with the PSA antibody and Cy7 to create the multimodality PSA-Mn-Msn-Cy7. Their particle size, zeta potential, stability and magnetic resonance imaging (MRI) features of the nanoparticles were characterized. Optical and MR imaging were evaluated in cell and tumor-bearing mouse models. The Mn in tissues was measured by inductively coupled plasma mass spectrometry. The fabricated nanoparticles were stable and showed good T1relaxivity. The targeted nanoparticles accumulated to a great extent in prostate cancer cells in vitro but not in noncancerous cells. In vivo studies further demonstrated a targeted distribution of PSA-Mn-Msn-Cy7 to cancer tissues as shown by high optical and T1 signals. The targeted distribution was also confirmed by determining the Mn content in the cancer tissues. Our data demonstrate that PSA targeted fluorescence and MR dual-functional nanoparticle can visualize prostate cancer and can be used as NIRF/MR contrast agents.


Characterization and evolutionary dynamics of complex regions in eukaryotic genomes.
Complex regions in eukaryotic genomes are typically characterized by duplications of chromosomal stretches that often include one or more genes repeated in a tandem array or in relatively close proximity. Nevertheless, the repetitive nature of these regions, together with the often high sequence identity among repeats, have made complex regions particularly recalcitrant to proper molecular characterization, often being misassembled or completely absent in genome assemblies. This limitation has prevented accurate functional and evolutionary analyses of these regions. This is becoming increasingly relevant as evidence continues to support a central role for complex genomic regions in explaining human disease, developmental innovations, and ecological adaptations across phyla. With the advent of long-read sequencing technologies and suitable assemblers, the development of algorithms that can accommodate sample heterozygosity, and the adoption of a pangenomic-like view of these regions, accurate reconstructions of complex regions are now within reach. These reconstructions will finally allow for accurate functional and evolutionary studies of complex genomic regions, underlying the generation of genotype-phenotype maps of unprecedented resolution.


Brain-to-blood partition and in vivo inhibition of 5-hydroxytryptamine reuptake and quipazine-mediated behaviour of nefazodone and its main active metabolites in rodents.
The brain/plasma partition of nefazodone, hydroxynefazodone (OHNFZ) and m-chlorophenyl-piperazine (mCPP) and their antagonism of p-chloroamphetamine (PCA)-induced 5-hydroxytryptamine (5-HT) depletion and quipazine-induced head twitches were compared in rodents. Nefazodone (30 mg kg(-1), i.p.) rapidly entered the brain but concentrations were exceeded by mCPP, the metabolic ratio being 47 and 10 in the mouse and rat respectively. OHNFZ was detectable in plasma but never in brain. Brain concentrations of OHNFZ in the mouse (30 mg kg(-1), i.p.) were less than 10% of those in plasma, confirming a poor blood-brain barrier penetration. Concentrations of its metabolite mCPP were similar to those after 5 mg kg(-1)(i.p.) mCPP. In the mouse, nefazodone (30 mg kg(-1)) antagonized the 5-HT depleting effect of PCA 2 h after dosing, when it had disappeared from brain but when mCPP concentrations were similar to those after 5 mg kg(-1) (i.p.) mCPP. However, mCPP antagonized PCA less than nefazodone. In the rat, nefazodone pretreatment (30 mg kg(-1), 15 min) prevented (97% of inhibition) quipazine-induced head twitches. The effect was weaker (65% of inhibition) but significant when only mCPP was detected in brain. Analysis of brain concentrations of the two compounds after their ED50 against quipazine indicated that both contributed to the effect, although nefazodone was more active than mCPP in terms of concentrations required to obtain a comparable reduction of twitches. These findings show that mCPP concentrates in the brain following injection of nefazodone and may play a role in preventing quipazine-induced behaviour and PCA-induced 5-HT depletion. In contrast OHNFZ poorly enters the brain and its in vivo activity is mostly due to its biotransformation to mCPP.


Occlusion of the abdominal aorta caused by enlargement of the false lumen after graft replacement for a DeBakey type IIIb dissecting aneurysm: report of a case.
We report herein a case of abdominal aorta occlusion caused by enlargement of the false lumen after a graft replacement. The patient was a 70-year-old man who underwent a graft replacement of the descending thoracic aorta for a DeBakey type IIIb dissecting aneurysm. Digital subtraction angiography performed on postoperative day 18 revealed an abdominal aorta occlusion caused by enlargement of the false lumen. A new intimal defect was found in the aortic wall 2 cm distal to the suture line, the cause of which was suspected to be clamp injury during the initial operation. Graft replacement of the abdominal aorta was subsequently carried out. Postoperatively, he had no complications, and digital subtraction angiography showed excellent reconstruction of the abdominal aorta. The patient was discharged from hospital 1 month after his second operation.


Mechanisms of disease: the impact of antithrombotic therapy in cancer patients.
Venous thromboembolism is a common complication in patients with malignant disease. It is associated with a systemic hypercoagulable state that is secondary to tumor elaboration of tissue factor (the physiological initiator of blood coagulation), activation of other procoagulant mechanisms and downregulation of anticoagulant mechanisms. The consequent generation of activated coagulation serine protease in the peritumoral environment influences tumor growth, invasion, metastasis and angiogenesis. The use of antithrombotic agents, such as the low-molecular-weight heparins, might influence survival in cancer patients through several mechanisms. These mechanisms include a reduction in the frequency of overt and silent fatal thromboembolic events, interference with the activation of blood coagulation and generation of coagulation serine proteases that affect the tumor phenotype, and direct cellular effects of heparin on both epithelial and endothelial tumor elements.


Silencing SMYD3 in hepatoma demethylates RIZI promoter induces apoptosis and inhibits cell proliferation and migration.
To investigate the role of SMYD3 in hepatocellular carcinoma (HCC) development and progression and to verify whether its regulation activity was through RIZ1 inactivation. Expression of SMYD3 in HCC cell lines and tissues were measured; silencing of SMYD3 by RNA interference (RNAi) was effectuated, hepatoma cell proliferation, migration and apoptosis were tested, with RIZ1 CpG promoter methylation, and corresponding mRNA expression were investigated. SMYD3 over-expression in HCC was associated with RIZ1 hypermethylation and mRNA down-expression. Suppression of SMYD3 expression de-methylated RIZ1 CpG promoter (P < 0.01) and increased RIZ1 mRNA expression (P < 0.01). Consequently, SMYD3 down-expression with RIZ1 de-methylation strongly inhibited hepatoma cell growth (MTT inhibitory rates: Pgenesil-1-s1 60.95% +/- 7.97%, Pgenesil-1-s2 72.14% +/- 9.68% vs Pgenesil-1-hk 6.89% +/- 4.12%, P < 0.01) and migration (Pgenesil-1-s1 4.24% +/- 1.58%, Pgenesil-1-s1 4.87% +/- 0.73% vs Pgenesil-1 19.03% +/- 4.63%, Pgenesil-1-hk 19.95% +/- 5.21%, P < 0.01) and induced apoptosis (FCM subG1 phase Pgenesil-1-s1 19.07% +/- 1.78%, Pgenesil-1-s2 17.68% +/- 2.36% vs Pgenesil-1 0.47% +/- 0.12%, Pgenesil-1-hk 1.46% +/- 0.28%, P < 0.01. TUNEL-positive cells: Pgenesil-1-s1 40.24% +/- 5.18%, Pgenesil-1-s2 38.48% +/- 4.65% vs Pgenesil-1 2.18% +/- 1.34%, Pgenesil-1-hk 2.84% +/- 1.22%, P < 0.01) in HepG2 cells. These results demonstrate that SMYD3 plays a critical role in the carcinogenesis and progression of HCC. The proliferation, migration induction and apoptosis inhibition activities of SMYD3 may be mediated through RIZ1 CpG promoter hypermethylation.


Assessment of therapy for toxoplasma encephalitis. The TE Study Group.
Toxoplasma encephalitis has been reported as a life-threatening opportunistic infection among patients with the acquired immune deficiency syndrome. The TE Study Group was established to address clinical questions about Toxoplasma encephalitis by retrospectively reviewing available data. The medical centers selected were those reporting Toxoplasma encephalitis to the Centers for Disease Control or to one of the principal investigators. Sixty-eight histologically confirmed cases of Toxoplasma encephalitis were reported by investigators at 31 medical centers; 61 of the patients received some therapy. Overall prognosis was poor. The median survival following initiation of therapy was four months. Patients described as "alert" at initiation of therapy survived significantly longer than those described as "lethargic" or "stuporous." No beneficial or harmful effects could be attributed to the use of corticosteroids. Toxicity attributed to pyrimethamine and sulfonamide therapy was reported in 60 percent of patients. Leukopenia, rash, and thrombocytopenia were common during therapy. A clinical relapse of Toxoplasma encephalitis was reported in 50 percent of patients discharged from the hospital.


Randomized controlled trial of pulse/synchronization cyclophosphamide/apheresis for proliferative lupus nephritis.
To assess the efficacy of pulse/synchronization cyclophosphamide/apheresis in patients with proliferative lupus nephritis. Eighteen patients with Class III or IV renal biopsies and chronicity indices <6 were prospectively randomized to receive 6 courses of parenteral cyclophosphamide over 8 months along with prednisone. Nine of these patients also received 3 daily plasmaphereses prior to each of the 6 courses of cyclophosphamide. Assessments compiled at 6 and 24 months included serum creatinine, albumin, anti DNA, 24-hour urine protein, and C3 complement along with SLAM scores. Two out of nine patients in each group evolved end stage renal disease and 3/9 patients in each group went into a renal remission at 24 months. Serum albumin, C3 complement, and SLAM scores improved in both groups, and anti-DNA improved in the pulse/synchronization patients (P < 0.025). No intergroup comparisons were significant. The addition of pulse/synchronization apheresis to cyclophosphamide therapy does not improve the course of patients with proliferative lupus nephritis.


Cardiac pathology in death from electrocution.
To better characterize the morphologic changes in electrocution, morphologic changes in the hearts of 21 subjects, who died instantaneously of electrocution, were compared to the hearts of decedents with different types of death. Sixteen myocardial samples per heart were processed for histological examination, and sections were prepared with a variety of specific stains. The frequency, location and extent of myocellular segmentation (stretching and/or rupture) of intercalated discs and associated changes of myocardial bundles and single myocells [myofibre break-up (MFB)] were recorded, quantitatively analysed and statistically evaluated. The frequency of MFB was maximal in cases of electrocution (90%). The findings show that MFB is an ante-mortem change and may be a distinct finding in electrocution.


Plant-derived natural products targeting ion channels for pain.
Chronic pain affects approximately one-fifth of people worldwide and reduces quality of life and in some cases, working ability. Ion channels expressed along nociceptive pathways affect neuronal excitability and as a result modulate pain experience. Several ion channels have been identified and investigated as potential targets for new medicines for the treatment of a variety of human diseases, including chronic pain. Voltage-gated channels Na+ and Ca2+ channels, K+ channels, transient receptor potential channels (TRP), purinergic (P2X) channels and acid-sensing ion channels (ASICs) are some examples of ion channels exhibiting altered function or expression in different chronic pain states. Pharmacological approaches are being developed to mitigate dysregulation of these channels as potential treatment options. Since natural compounds of plant origin exert promising biological and pharmacological properties and are believed to possess less adverse effects compared to synthetic drugs, they have been widely studied as treatments for chronic pain for their ability to alter the functional activity of ion channels. A literature review was conducted using Medline, Google Scholar and PubMed, resulted in listing 79 natural compounds/extracts that are reported to interact with ion channels as part of their analgesic mechanism of action. Most in vitro studies utilized electrophysiological techniques to study the effect of natural compounds on ion channels using primary cultures of dorsal root ganglia (DRG) neurons. In vivo studies concentrated on different pain models and were conducted mainly in mice and rats. Proceeding into clinical trials will require further study to develop new, potent and specific ion channel modulators of plant origin.


Responsiveness of Section GG Scores in Tracking Post-Stroke Functional Recovery From Inpatient Rehabilitation Admission to 90-Day Follow-Up.
To evaluate the responsiveness and scale-to-sample targeting of Section GG of the Inpatient Rehabilitation Facility-Patient Assessment Instrument in measuring the trajectory of functional recovery in patients with stroke from inpatient rehabilitation admission to 90 days after discharge. Retrospective cohort study. 150-bed inpatient rehabilitation facility. Patients with stroke (N=1087) discharged between December 2019 to April 2021. Not applicable. Admission and discharge self-care and mobility scores from Section GG were analyzed for the Inpatient Only group (n= 817). Admission, discharge and 90-day post-discharge Section GG scores from telephone interviews with patients or caregivers were analyzed for the Follow-Up group (n=270). Standardized response means (SRM) determined responsiveness of the tool for each group and time interval. Score means, standard deviations, and floor/ceiling effects illustrated scale-to-sample targeting of the tool. Self-care and mobility scores improved significantly from admission to discharge (P<.001) for both groups and from discharge to 90 days (P<.001) for the Follow-Up group. Large SRM existed from admission to discharge for self-care and mobility scores in both groups. A small-to-moderate SRM was seen from discharge to 90 days for self-care (0.46) and a moderate SRM was observed for mobility (0.68). Overall floor effects were minor at admission for self-care (9.8%) and mobility (7.2.%). Overall ceiling effects were minor at discharge for self-care (11.2%) and mobility (4.6%) and significant at follow-up for both self-care (45.2%) and mobility (32.2%). Section GG is responsive to change and appropriately measures patients' functional ability during inpatient rehabilitation. More study is required for telephone follow-up after discharge from inpatient rehabilitation.


Concurrent white and gray matter degeneration of disease-specific networks in early-stage Alzheimer's disease and behavioral variant frontotemporal dementia.
This study investigates regional coherence between white matter (WM) microstructure and gray matter (GM) volume and perfusion measures in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) using a correlational approach. WM-GM coherence, compared with controls, was stronger between cingulum WM and frontotemporal GM in AD, and temporoparietal GM in bvFTD. In addition, in AD compared with controls, coherence was stronger between inferior fronto-occipital fasciculus WM microstructure and occipital GM perfusion. In this first study assessing regional WM-GM coherence in AD and bvFTD, we show that WM microstructure and GM volume and perfusion measures are coherent, particularly in regions implicated in AD and bvFTD pathology. This indicates concurrent degeneration in disease-specific networks. Our methodology allows for the detection of incipient abnormalities that go undetected in conventional between-group analyses.


FAT10ylation as a signal for proteasomal degradation.
The Nobel prize has been awarded for the discovery of ubiquitin as a transferable signal for the degradation of proteins by the 26S proteasome. While isopeptide linkage of a protein with a single ubiquitin does not serve as a degradation signal for the proteasome, poly-ubiquitylation via several different lysine residues within ubiquitin leads to efficient proteasomal degradation. Ubiquitin-like modifiers have not been shown to directly mediate proteasomal degradation except for the cytokine inducible modifier HLA-F adjacent transcript 10 (FAT10), which consists of two ubiquitin-like domains. FAT10 ends with a free diglycine motif at its C-terminus which is required for isopeptide linkage to hundreds of different substrates. In contrast to ubiquitin, a single FAT10 suffices to bind to the 26S proteasome and to efficiently mediate proteasomal degradation in a ubiquitin-independent manner. Here we review the data on ubiquitin-independent degradation by FAT10, on how FAT10 is conjugated to its substrates, how FAT10 binds to the 26S proteasome, and how the ubiquitin-like (UBL)-ubiquitin-associated (UBA) protein NUB1L accelerates FAT10 mediated proteolysis. Finally, with a glimpse on recently identified substrates, we will discuss the currently emerging knowledge about the biological functions of FAT10. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.


The impact of antigenic molecular mimicry on anti-cancer T-cell immune response.
Individuals are exposed to intracellular pathogens (i.e. viruses and intracellular bacteria) and intestinal microbiota, collectively microorganisms (MOs), which enter the body during the host's lifetime. Altogether, MOs are a natural source of non-self antigens (MoAs) expressed by host's cells in the context of the HLA class I molecules, inducing a wide pool of specific memory CD8+ T cell clones. Such MoAs have been shown in selected cases to share sequence and structural homology with cellular self-antigens (molecular mimicry), possibly inducing autoimmune reactions leading to autoimmune diseases (ADs). We have recently shown that a molecular mimicry may be found also to self-antigens presented by cancer cells (i.e. tumor-associated antigens, TAAs). Consequently, memory CD8+ T cell clones specific for the MoAs may turn out to be a natural "anti-cancer vaccination" if a nascent tumor lesion should express TAAs similar or identical to MoAs. We postulate that selecting MoAs with high homology to TAAs would greatly improve the efficacy of cancer vaccines in both preventive and therapeutic settings. Indeed, non-self MoAs are potently immunogenic because not affected by central immune tolerance. Unravelling the impact of the antigenic molecular mimicry between MoAs and TAAs might pave the way for novel anti-cancer immunotherapies with unprecedented efficacy.


[2,5-Bis(di-propyl-amino)-4-(hy-droxy-meth-yl)phen-yl]methanol.
The centrosymmetric title compound, C22H36N2O2, was prepared in five steps from diethyl succinate. The di-propyl-amino groups are almost orthogonal to the central phenyl-enedi-methanol ring [dihedral angle = 87.62 (9)°]. In the crystal, the mol-ecules are connected by O-H⋯N hydrogen bonds, forming (101) layers separated by the propyl chains.


Carbon isotope ratios of soil organic matter and their use in assessing community composition changes in Curlew Valley, Utah.
Stable carbon isotope ratios of roots and soil organic matter were measured in Curlew Valley, Utah to determine if changes in the relative dominance of two shrub species had occurred in this salt-desert community. Measurements were made on soil cores along transects stretching from monospecific stands of Ceratoides lanata, a C3 shrub, to monospecific stands of Atriplex confertifolia, a C4 shrub. δ13C values of roots and soil organic matter under Ceratoides cover appeared to be in equilibrium with the current plant community. By contrast, δ13C values of roots and soils under Atriplex portions of the transects were more negative than would be expected for a C4-dominated community. These results indicate that a change in relative C3/C4 dominance has occurred, and suggest that the C4 shrub Atriplex confertifolia is increasing in importance in this salt-desert community.


Effects of creatine and creatinine content on the mutagenic activity of meat extracts, bouillons and gravies from different sources.
Thirteen commercial meat-flavour samples were analysed for creatine and creatinine content and tested for mutagenicity in the Ames Salmonella/microsome test. In most samples, more than 50% of the creatine had been converted to creatinine. Mutagenicity was related to the creatinine content: 150 mumol creatinine/g dry matter (gdm) gave upwards of 2500 revertants/gdm, concentrations of 15-40 mumol/gdm gave about 100 revertants/gdm and concentrations of 1-10 mumol/gdm gave only low or no significant mutagenicity. No relationship was apparent between coloration and mutagenicity. Beef steaks (initial weight c. 500 g) baked at oven temperatures between 115 and 245 degrees C only showed significant mutagenicity--135 revertants/100 gE (initial raw weight)--in the crust when baked at the highest temperature (245 degrees C). The gravies (meat-juice drip) collected during baking showed a linear increase in mutagenicity with baking temperatures up to 180 degrees C (48-828 revertants/100 gE) and a very sharp increase in mutagenicity for the gravy collected from beef steak baked at 245 degrees C (28,300 revertants/gdm or 19,800 revertants/100 gE). At this high temperature, the brown coloration and the proportion of creatinine to total creatine and creatinine were also dramatically increased, because this gravy dried up completely during the baking procedure.


General practitioner prescribing trends among pediatric patients in the United Kingdom: 1998-2018.
To describe the prescribing trends of 17 therapeutic drug categories and the specific drug classes of systemic antibiotics, analgesics, and antidepressants in children and adolescents in the United Kingdom between 1998 and 2018. A population-based retrospective cohort study including children and adolescents aged 018 years. Overall and annual prescription rates per 10 000 person-years and corresponding 95% confidence intervals (CIs) were calculated. Rate ratios and 95% CIs were calculated to assess changes in prescription rates during the study period using Poisson regression. Among 4 075 527 children and adolescents during the study period from 1998 to 2018, the prescribing rates increased by 15% for attention deficit hyperactivity disorder drugs (rate ratio: 1.15, 95% CI: 1.12-1.18), 14% for anxiolytics and hypnotics (rate ratio: 1.14, 95% CI: 1.13-1.16), and 8% for drugs for gastroesophageal reflux disease (GERD) (rate ratio: 1.08, 95% CI: 1.07-1.09). Prescribing rates decreased by 6% for cough preparations (rate ratio: 0.94, 95% CI: 0.92-0.95) and by 3% for analgesics (rate ratio: 0.97, 95% CI: 0.96-0.99). No meaningful changes were observed for systemic antibiotics (rate ratio: 1.02, 95% CI: 0.99-1.04). Among specific drug classes, prescribing rates decreased for broad-spectrum penicillins and cephalosporins, and they increased for selective serotonin reuptake inhibitors, opioids, and drugs for migraine. Between 1998 and 2018, the prescribing of centrally acting drugs and drugs for GERD increased among pediatric patients, whereas prescribing of cough preparations and analgesics declined in this population.


Characterization of a Novel Alkalophilic Lipase From Aneurinibacillus thermoaerophilus: Lid Heterogeneity and Assignment to Family I.5.
Recent investigations of Aneurinibacillus thermoaerophilus strains have allowed identification of a unique solvent tolerant lipase, distinct from known lipases. This work reports the expression and purification of this lipase (LipAT) and the first characterization of its structure and temperature and pH-dependent behaviour. LipAT has a secondary structural content compatible with the canonical lipase α/β hydrolase fold, and is dimeric at neutral pH. The protein was folded from pH 5 to 10, and association into folded aggregates at pH 7 and 8 likely protected its secondary structures from thermal unfolding. The enzyme was active from 25 to 65 °C under neutral pH, but its maximal activity was detected at pH 10 and 45 °C. The ability of LipAT to recover from high temperature was investigated. Heating at 70 °C and pH 10 followed by cooling prevented the restoration of activity, while similar treatments performed at pH 8 (where folded aggregates may form) allowed recovery of 50% of the initial activity. In silico analyses revealed a high conservation (85% or more) for the main lipase signature sequences in LipAT despite an overall low residue identity (60% identity compared to family I.5 lipases). In contrast, the active site lid region in LipAT is very distinct showing only 25% amino acid sequence identity to other homologous lipases in this region. Comparison of lids among lipases from the I.5 family members and LipAT reveals that this region should be a primary target for elucidation, optimisation and prediction of structure-function relationships in lipases.


Acceleration of natural killer (NK) cell recovery by a glucan, sizofiran, in anti-asialoGM1 antibody-treated mice.
The proportion of asialoGM1 positive cells and NK activity of murine splenic cells was reduced to almost zero one day after intravenous injection of rabbit anti-asialoGM1 antibody. The cells and the activity started to increase at the latest 3 days after the injection, although the proportion was far below that of the normal control. The proportion of asialoGM1 positive cells and NK activity increased more remarkably when 1,3-beta glucan, sizofiran, was administered intramuscularly one day after the antibody injection. The increases were dose related (50-1000 micrograms/mouse). The fact that sizofiran hastened the recoveries of splenic NK activity and asialoGM1 positive cells suggests sizofiran may have the activity to accelerate the differentiation of asialoGM1 positive NK cells.


Effects of pregnancy and fasting on muscle glucose utilization in the rabbit.
The effects of fasting on maternal glucose metabolism were investigated in nonpregnant and 29-day pregnant conscious rabbits. Pregnancy decreased the glucose metabolic index by 60% in maternal red postural muscles. Fasting induced similar modifications in nonpregnant rabbits and exaggerated the changes observed in fed pregnant animals. These data suggest that the decreased glucose utilization by maternal red muscles observed during pregnancy and fasting is related to the increase in circulating fat-derived substrates, because the fall in plasma insulin concentration is a specific adaptation to fasting.


Long-term follow-up of three individuals with Kabuki syndrome.
Long-term follow-up of three individuals with Kabuki syndrome indicates their phenotype becomes less striking as adults. It is characterized by short stature, obesity, and relatively large head. Long palpebral fissures persist, as does mild to moderate mental retardation. Independent daily living skills are achieved but a sheltered living environment is needed.


Direct versus conventional stent implantation in patients with acute coronary syndrome just before the era of drug-eluting stents.
Direct stent implantation in patients, who undergo elective percutaneous coronary intervention (PCI) can be performed with a high success rate and clinical results that are comparable to those after predilatation. It was the aim of this prospective study to compare clinical, angiographic and procedural parameter of direct stent implantation (DS) and conventional stent implantation (CS) in patients with acute coronary syndrome (ACS). We analysed 194 patients with ACS (ST-elevation myocardial infarction 66%, non-ST-elevation myocardial infarction 18%, unstable angina 16%), in whom primary PCI was performed between January and December 2002. In 156 (80%) patients glycoprotein IIb/IIIa inhibitors were administered during the procedure. In 73 patients (38%) direct stent implantation could be performed successfully. In 12 patients (6%) direct stent implantation failed due to the inability to pass the stenosis. In 121 patients (62%) the stent was implanted after predilatation. The clinical parameters were comparable in both groups. Reference luminal diameter before stent implantation did not differ in both groups (DS 3.01+/-0.54 vs. CS 2.84+/-0.43 mm). The final minimal luminal diameter was significantly higher in the DS group (DS 2.95+/-0.45 vs. CS 2.77+/-0.47 mm, p=0.01). The procedural time (DS 41.0+/-14.1 vs. CS 46.8+/-16.9 min, p=0.02), radiation exposure time (DS 7.3+/-4.6 vs. CS 8.9+/-4.6 min, p=0.002) and the amount of contrast agent (DS 216+/-90 vs. CS 235+/-79 ml, p=0.03) could be decreased by the technique of direct stent implantation. The incidence of major adverse cardiac events (death, myocardial infarction, CABG) during hospitalization was 4.1% in the DS group and 11.5% in the CS group (p=0.11). Direct stent implantation is safe and feasible in patients with acute coronary syndromes. The procedural time, radiation exposure time and the amount of contrast agent can be significantly decreased using the technique of direct stent implantation. The incidence of major adverse cardiac events was not significantly different in this subset of patients.


Shared mechanisms mediate the explore-exploit tradeoff in macaques and humans.
Ancestors of macaques and humans separated into distinct lineages 25 million years ago. Despite this long separation, Hogeveen et al. (2022) show, in this issue of Neuron, that they mediate the explore-exploit tradeoff, which must be managed by any agent adapting to a dynamic environment, using similar computational and neural mechanisms.


Survival affects decision making for fenestrated and branched endovascular aortic repair.
Repair options for complex abdominal and thoracoabdominal aortic aneurysms (TAAAs) are evolving with increased experience and availability of less invasive endovascular techniques. Identifying risk factors for mortality after fenestrated and branched endovascular aortic repair (F/B-EVAR) could improve patient selection and facilitate decision making regarding who may benefit from prophylactic F/B-EVAR. We evaluated 1091 patients in a prospective investigational device exemption trial who underwent F/B-EVAR from August 2001 to June 2015 for complex aortic aneurysms (CAAs). Multivariable analysis of risk factors for death was performed using a nonproportional hazards model and a nonparametric analysis using random survival forest technology. Operative mortality after F/B-EVAR was low (3.7%), with high CAA-related survival at 30 day and 5 years (96.8% and 94.0%, respectively). All-cause 5-year survival, however, was 46.2% and older age, heart failure, chronic obstructive pulmonary disease, renal disease, anemia, and coagulation disorders were risk factors. Risk was highest for those undergoing type I/II TAAA repairs and those with larger aneurysms. Patients with multiple comorbidities and those undergoing type I or II TAAA repair are at greatest risk of mortality; however, in this high-risk population, F/B-EVAR offers greater survival compared with that reported for the natural history of untreated aneurysms. Operative and early mortality is lower than the best-reported open repair outcomes, even in this high-risk population, suggesting a potential benefit in extending the use of F/B-EVAR to low-to-average risk CAA patients.


Data supporting Arf6 regulation of Schwann cell differentiation and myelination.
The data is related to the research article entitled "Arf6 mediates Schwann cell differentiation and myelination" [1]. To further investigate the role of Arf6 in promoting myelination by Schwann cells in vivo, we have characterized an another line (#2) of small-hairpin (sh)RNA transgenic mice targeting Arf6. The number of transgenes per one allele in this line was very low (2 transgenes), comparing with high copies in the previous line (#1, 20 transgenes) [1]. In 4 days of neonatal age, transgenic mice exhibited decreased myelin thickness; however, decreased levels were not as much as those in the line #1, likely depending on transgene copy number. In 60-day-old mice, the difference became smaller. On the other hand, transgene׳s effect was not related to cell proliferation and apoptosis. These data support the key role of Arf6 in Schwann cell myelination, especially in the initiation.


Insight into synergetic effects of serum albumin and glucose on the biodegradation behavior of WE43 alloy in simulated body fluid.
The biodegradation rate of Mg alloy medical devices, such as screws and plates for temporary bone fracture fixation or coronary angioplasty stents, is an increasingly important area of study.In vitromodels of the corrosion behavior of these devices use revised simulated body fluid (m-SBF) based on a healthy individual's blood chemistry. Therefore, model outputs have limited application to patients with altered blood plasma glucose or protein concentrations. This work studies the biodegradation behavior of Mg alloy WE43 in m-SBF modified with varying concentrations of glucose and bovine serum albumin (BSA) to (1) mimic a range of disease states and (2) determine the contributions of each biomolecule to corrosion. Measurements include the Mg ion release rate, electrolyte pH, the extent of hydrogen evolution (as a proxy for corrosion rate), surface morphology, and corrosion product composition and effects. BSA (0.1 g l-1) suppresses the rate of hydrogen evolution (about 30%) after 24 h and-to a lesser degree-Mg2+release in both the presence and absence of glucose. This effect gets more pronounced with time, possibly due to BSA adsorption on the Mg surface. Electrochemical studies confirm that adding glucose (2 g l-1) to the solution containing BSA (0.1 g l-1) caused a decrease in corrosion resistance (by around 40%), and concomitant increase in the hydrogen evolution rate (from 10.32 to 11.04 mg cm-2d-1) to levels far beyond the tolerance limits of live tissues.


Pharmacokinetics and metabolism of the anilide local anaesthetics in neonates. 11 Etidocaine.
The urinary elimination of etidocaine and several of its metabolites was investigated in neonates whose mothers had received one or more doses of etidocaine during labour. The urine collection period ranged among the neonates from 21.4 to 47.0 h post-partum. The total amounts of etidocaine and its metabolites recovered in neonatal urine represented a mean of 0.12% of the maternal dose. Some differences in the pattern of urinary metabolites were observed between neonates and adults. Mean half-life of elimination of etidocaine calculated from sigma-minus plots of the neonatal urinary data was 6.42 h. This is greater than that previously reported following intravenous administration of etidocaine to adults (2.6 h). The slower rate of elimination in neonates is probably due to an increased neonatal volume of distribution since there is evidence to show that etidocaine is extensively metabolised by the neonate.


Inactivation by ionizing radiation of ion channels formed by polyene antibiotics amphotericin B and nystatin in lipid membranes: an inverse dose-rate behavior.
The phenomena reported are part of a study about the effects of ionizing radiation on membrane transport. We found that the conductance of lipid membranes in the presence of the polyene-antibiotics nystatin or amphotericin B is reduced to virtually zero following irradiation. Ion channels formed by these substances seem to represent extremely sensitive structures being inactivated by radiation doses in the range of a few Centigray (1 cGy = 1 rad) at sufficiently small dose rates. Inactivation shows a so-called inverse dose-rate behavior, i.e., at constant radiation dose the effect increases with decreasing dose rate. Similar to radiation-induced lipid peroxidation the phenomenon may be understood on the basis of a radical chain mechanism initiated by free radicals of water radiolysis. The process--via peroxidation of the polyene part of the molecules--is suggested to modify the hydrophobic exterior and to destabilize the barrel-like structure of the ion channels.


Prognostic factors for trabeculectomy failure in a Cuban population.
To identify the prognostic factors for mid-term trabeculectomy failure. A prospective cohort study was conducted on 113 eyes (113 patients) that had undergone a trabeculectomy for primary open or closed angle, pigmentary, or juvenile glaucoma. Surgical failure was defined if intraocular pressure was equal or more than 18mmHg with medication (two or more drops), after 1-4 postoperative years. The relative risk was calculated and a logistic regression analysis was performed. Previous trabeculectomy, preoperative intraocular pressure ≥ 31mmHg, black race, and advanced glaucoma increased the failure risk by 7.9 times (P=.036), 5.3 times (P=.011) and 4.7 times (P=.028, and P=.027), respectively. The addition of two or more factors increased the risk by 6.4 times (P<.001). It was not affected by age, sex, pre-operative drops, or surgical complication. Previous trabeculectomy, pre-operative intraocular pressure ≥ 31mmHg, black race, and advanced glaucoma are prognostic factors for trabeculectomy failure, in decreasing order of their association with surgical failure. The addition of two or more factors increased the risk of failure. In those situations, the use of trans- operative anti-metabolites is suggested.


PET analysis of alcohol interaction with the brain disposition of [11C]flumazenil.
Acute alcohol administration to rats has in preliminary studies been reported to drastically increase the binding of the benzodiazepine (BZ) receptor antagonist [3H]flumazenil (Ro 15-1788) to central BZ receptors. In the present study the effect of acute alcohol ingestion on the disposition of [11C]flumazenil in the human brain and plasma was examined by positron emission tomography (PET) in four healthy volunteers. Neocortex, cerebellum and pons (reference region) were delineated using X-ray computerized tomography (CT). Alcohol did not increase either total radioactivity uptake or specific [11C]flumazenil binding in neocortex or cerebellum. However, alcohol had a small but significant effect on [11C]flumazenil in arterial blood. After alcohol the plasma radioactivity peak was higher, more narrow and occurred earlier than in the control experiments. The present experiments contradict the view that alcohol directly affects central BZ receptor binding in man. Thus the dramatic increase of flumazenil binding in rat brain reported previously could not be observed in the human brain.


The relationship between previous hamstring injury and the concentric isokinetic knee muscle strength of Irish Gaelic footballers.
Hamstring injury is one of the most common injuries affecting gaelic footballers, similar to other field sports. Research in other sports on whether residual hamstring weakness is present after hamstring injury is inconsistent, and no study has examined this factor in irish gaelic footballers. The aim of this study was to examine whether significant knee muscle weakness is present in male Irish gaelic footballers who have returned to full activity after hamstring injury. The concentric isokinetic knee flexion and extension strength of 44 members of a university gaelic football team was assessed at 60, 180 and 300 degrees per second using a Contrex dynamometer. Fifteen players (34%) reported a history of hamstring strain, with 68% of injuries affecting the dominant (kicking) limb. The hamstrings were significantly stronger (p < 0.05) on the dominant limb in all uninjured subjects. The previously injured limbs had a significantly lower (p < 0.05) hamstrings to quadriceps (HQ) strength ratio than all other non-injured limbs, but neither their hamstrings nor quadriceps were significantly weaker (p > 0.05) using this comparison. The previously unilaterally injured hamstrings were significantly weaker (p < 0.05) than uninjured limbs however, when matched for dominance. The hamstring to opposite hamstring (H:oppH) strength ratio of the previously injured players was also found to be significantly lower (p < 0.05) than that of the uninjured players. Hamstring muscle weakness was observed in male Irish gaelic footballers with a history of hamstring injury. This weakness is most evident when comparisons are made to multiple control populations, both within and between subjects. The increased strength of the dominant limb should be considered as a potential confounding variable in future trials. The study design does not allow interpretation of whether these changes in strength were present before or after injury.


Therapeutic hypothermia and reliability of somatosensory evoked potentials in predicting outcome after cardiopulmonary arrest.
The loss of the N20 component on testing median somatosensory evoked potentials (SSEP) has been established as the most reliable indicator of unfavorable prognosis in post-cardiopulmonary arrest patients. With the intervention of therapeutic hypothermia in the management of patients who remain comatose following cardiopulmonary arrest that association is now in dispute. Abandoning SSEP as a key prognostic indicator of neurologic outcome would be a serious loss and cannot be justified.


Fatigue among HIV-infected patients in the era of highly active antiretroviral therapy.
To describe the prevalence of operationally defined fatigue in an ethnically diverse HIV-infected population in south London, and to examine the association of fatigue with demographic characteristics, stage of disease, antiretroviral therapy and psychological factors. A descriptive comparative cross-sectional study of HIV-infected patients attending a London HIV clinic over a 5-month period in 2002 was performed. Demographic and clinical data were obtained from the local database. Participants completed four self-administered questionnaires-the Chalder Fatigue Scale (CFS), a measure of physical and mental fatigue; the General Health Questionnaire (GHQ-12) to detect anxiety and depression; the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) to measure functional status, and the Illness Perception Questionnaire (IPQ). Fatigue 'cases' were defined as those scoring at least 4 on the CFS. Multivariate logistic regression was used to identify factors associated with the presence of fatigue. Two hundred and five patients were approached and 148 (72%) agreed to participate. Overall, 65% of patients were defined as fatigued. Significant psychological distress on the GHQ-12, functional impairment on the SF-36 and a higher CD4 count were all independently associated with the presence of fatigue. There was no association with use of antiretroviral therapy or demographic characteristics. The presence of fatigue in HIV-infected patients is most strongly associated with psychological factors and not with more advanced HIV disease or the use of highly active antiretroviral therapy. This highlights the importance of investigation and management of underlying depression and anxiety in patients presenting with fatigue.


Serum fructosamine level and the risk of hip fracture in elderly women: a case-cohort study within the study of osteoporotic fractures.
While a high serum fructosamine level may be an indicator of undiagnosed diabetes, a low level may be indicative of poor nutrition or frailty. As malnutrition is a risk factor for osteoporosis, low serum fructosamine levels may be associated with an increased risk of osteoporotic fracture. We examined the association between serum fructosamine levels and the risk of subsequent hip and vertebral fracture. We performed a case-cohort study within the Study of Osteoporotic Fractures. Subjects were elderly, ambulatory, community-dwelling, Caucasian, women. Fructosamine levels were measured in baseline serum. Incident vertebral fractures were identified by comparing baseline spinal radiographs to those obtained an average of 3.5 years later. Hip fractures were confirmed by radiograph. We randomly selected 101 women who suffered a hip fracture, 100 women who developed a vertebral fracture, and 276 controls. We compared fructosamine levels in women with subsequent osteoporotic fractures to controls. All analyses were adjusted for age, weight, and use of estrogens. Women with fructosamine levels in the lowest decile (< or = 223 micromol/L) had a three-fold increase in the risk of hip fracture (95% confidence interval 1.4-6.4), compared with all other women. Adjustment for markers of frailty, including smoking, functional status, and serum albumin levels, reduced the strength of this association. No clear association was observed between serum fructosamine level and the risk of vertebral fracture. Low serum fructosamine levels, which likely reflect frailty or malnutrition, may be a useful clinical tool to identify women at risk for hip fracture.


Gestational diabetes mellitus. Heterogeneity of maternal age, weight, insulin secretion, HLA antigens, and islet cell antibodies and the impact of maternal metabolism on pancreatic B-cell and somatic development in the offspring.
We have examined gravida with gestational diabetes mellitus (GDM), as defined by the National Diabetes Data Group (Diabetes 1979; 28:1039), for phenotypic and genotypic heterogeneity. Fasting plasma glucose (FPG) at diagnosis was used for further stratification of GDM according to putative metabolic severity into class A1 (FPG less than 105 mg/dl [N = 129]), class A2 (FPG 105-129 mg/dl [N = 47]), and class B1 (FPG greater than or equal to 130 mg/dl [N = 23]). All GDM classes tended to be older and heavier than consecutive gravida with documented normal glucose tolerance (controls, N = 148). Subdivision into "lean" and "obese" indicated that plasma immunoreactive insulin (IRI) was greater after overnight fast in the obese of all groups except B1. However, absolute increases in IRI above fasting levels in response to glucose during OGTT were significantly enhanced by obesity only in class A2 gravida. Adjustment for the effects of age and weight by covariate analysis indicated that the IRI response to glycemic stimulation is usually attenuated in all forms of GDM. Mean values for increases in IRI above fasting values during the first 15 min and IRI increments relative to the increases in plasma glucose throughout the 180-min OGTT were below control values in all GDM groups and progressively so, i.e., A1 less than A2 less than B1. The absolute insulinopenia was not invariable; a small number of gravida from all GDM groups displayed well-preserved IRI responses to oral glucose. Genotypic evaluation of the GDM population disclosed an increased occurrence of "markers" known to be associated with type I diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)


Free radical scavenging activity of silibinin in nitrite-induced hemoglobin oxidation and membrane fragility models.
Free radical formation in heme proteins is recognized as a factor in mediating the toxicity of many drugs. Xenobiotics and drug therapy-related toxicity, due to oxidative modification of hemoglobin (Hb), has been attributed in part to the uncontrolled oxidative reactions. A variety of antioxidant strategies to ameliorate potential oxidative damage in vivo have been suggested. The present study was designed to evaluate the dose-response relationship of the free radical scavenging properties of silibinin dihemisuccinate (SDH) in nitrite-induced Hb oxidation in vitro and in vivo. Different concentrations of SDH were added, before and after different intervals of inducing Hb oxidation in erythrocytes lysate, and formation of methemoglobin (MetHb) was monitored spectrophotometrically; the same approach was utilized to evaluate the effect of the same doses of SDH on the integrity of erythrocytes after induction of hemolysis. Moreover, the most effective dose of SDH was administered in rats before challenge with toxic dose of sodium nitrite, and MetHb formation was monitored as mentioned before. The results showed that in both in vitro and in vivo models, SDH successfully attenuates Hb oxidation after challenge with sodium nitrite; this protective effect was not related to the stage of the catalytic stage of Hb oxidation, though the effect was more prominent when the compound was administered before nitrite. In conclusion, SDH can effectively, in concentration-dependent pattern, attenuate sodium nitrite-induced Hb oxidation and maintain integrity of red blood cells both in vitro and in vivo.


QSRR modeling of the chromatographic retention behavior of some quinolone and sulfonamide antibacterial agents using firefly algorithm coupled to support vector machine.
Quinolone and sulfonamide are two classes of antibacterial agents with an opulent history of medicinal chemistry features that contribute to their bacterial spectrum, efficacy, pharmacokinetics, and adverse effect profiles. The urgent need for their use, combined with the escalating rate of their resistance, necessitates the development of suitable analytical methods that accelerate and facilitate their analysis. In this study, the advanced firefly algorithm (FFA) coupled with support vector regression (SVR) was used to select the most significant descriptors and to construct two quantitative structure-retention relationship (QSRR) models using a series of 11 selected quinolone and 13 sulfonamide drugs, respectively, to predict their retention behavior in HPLC. Precisely, the effect of the pH value and acetonitrile composition in the mobile phase on the retention behavior of quinolones and sulfonamides, respectively, were studied. The obtained QSRR models performed well in both internal and external validations, demonstrating their robustness and predictive ability. Y-randomization validation demonstrated that the obtained models did not result by statistical chance. Moreover, the obtained results shed the light on the molecular features that influence the retention behavior of these two classes under the current chromatographic conditions.


Strong deshielding in aromatic isoxazolines.
Very strong proton deshielding was found in di/tri-aromatic isoxazoline regioisomers prepared from acridin-4-yl dipolarophiles and stable benzonitrile oxides (BNO). Three alkenes, (acridin-4-yl)-CH=CH-R (R = COOCH3, Ph, and CONH2), reacted with three BNO dipoles (2,4,6-trimethoxy, 2,4,6-trimethyl, 2,6-dichloro) to give pairs of target isoxazolines with acridine bound to C-4 or C-5 carbon of the isoxazoline (denoted as 4-Acr or 5-Acr). Regioselectivity was dependent on both the dipolarophile and dipole character. The ester and amide dipolarophile displayed variable regioselectivity in cycloadditions whereas the styrene one afforded prevailing 4-Acr regioisomers. 2,4,6-Trimethoxy-BNO was most prone to form 5-Acr isoxazolines while mesitonitrile oxide gave major 4-Acr isoxazolines. Basic hydrolysis of the amide cycloadduct led to an unexpected isoxazolone product. The structure of the target compounds was studied by NMR, MS, and X-ray crystallography.


Gender composition and wage gaps in the Canadian health policy research workforce in comparative perspective.
Gendered challenges have been shown to persist among health practitioners in countries at all levels of development. Less is known about non-clinical professionals, that is, those who do not deliver services directly but are essential to health systems performance, such as health policy researchers. This national observational study examined gender occupational segregation and wage gaps in the Canadian health policy research workforce using a cross-domain comparative labour market analysis approach. Sourcing data from the 2016 population census, we applied linear regression and Oaxaca-Blinder decomposition techniques to assess wage differentials by sex, traditional human capital measures (e.g., age, education, place of work), and social identity variables intersecting with gender (household head, childcare, migrant status) among health policy researchers aged 25-54. We compared the gender composition and wage gap with seven non-health policy and programme domains, as mapped under the national occupational classification by similarity in the types of work performed. The health policy research workforce (N = 19 955) was characterized by gender segregation: 74% women, compared with 58% women among non-health policy research occupations (N = 102 555). Women health policy researchers earned on average 4.8% (95% CI 1.5‒8.0%) less than men after adjusting for other professional and personal variables. This gap was wider than among education policy researchers with similar gender composition (75% women; adjusted wage gap of 2.6%). Wages among health policy researchers were 21.1% (95% CI 19.4‒22.8%) lower than their counterparts in the male-dominated economics policy domain, all else being equal. Overall, women's earnings averaged 3.2% lower than men's due to factors that remained unexplained by policy domain or other measured predictors. This investigation found that the gender inequalities already widely seen among clinical practitioners are replicated among health policy researchers, potentially hindering the competitiveness of the health sector for attracting and retaining talent. Our findings suggest intersectoral actions are necessary to tackle wage gaps and devaluation of female-dominated health professions. Accountability for gender equity in health must extend to the professionals tasked with conducting equity-informative health policy research.


[Beta 2 microglobulin in the blood pf patients with chronic renal failure treated by hemodialysis and kidney transplantation].
Beta 2-microglobulin serum concentration was measured in 25 patients on chronic haemodialysis with end stage renal failure, in 52 patients with renal transplant and in 26 healthy control subjects. In hemodialysed patients with end stage renal failure the concentration of beta 2-microglobulin was 15-20 times, and in patients with renal transplant 3-4 times that of healthy controls. Elevated serum beta 2-microglobulin concentration in patients with renal transplant seems to depend not only on the kind of immunosuppression applied but also on other factors, such as, for instance, the functional efficiency of the transplanted kidney.


Haematological disorders associated with feline retrovirus infections.
Feline oncornavirus and lentivirus infections have provided useful models to characterize the virus and host cell factors involved in a variety of marrow suppressive disorders and haematological malignancies. Exciting recent progress has been made in the characterization of the viral genotypic features involved in FeLV-associated diseases. Molecular studies have clearly defined the causal role of variant FeLV env gene determinants in two disorders: the T-lymphocyte cytopathicity and the clinical acute immunosuppression induced by the FeLV-FAIDS variant and the pure red cell aplasia induced by FeLV-C/Sarma. Variant or enFeLV env sequences also appear to play a role in FeLV-associated lymphomas. Additional studies are required to determine the host cell processes that are perturbed by these variant env gene products. In the case of the FeLV-FAIDS variant, the aberrant env gene products appear to impair superinfection interference, resulting in accumulation of unintegrated viral DNA and cell death. In other cases it is likely that the viral env proteins interact with host products that are important in cell viability and/or proliferation. Understanding of these mechanisms will therefore provide insights to factors involved in normal lymphohaematopoiesis. Similarly, studies of FeLV-induced haematological neoplasms should reveal recombination or rearrangement events involving as yet unidentified host gene sequences that encode products involved in normal cell growth regulation. These sequences may include novel protoncogenes or sequences homologous to genes implicated in human haematological malignancies. The haematological consequences of FIV are quite similar to those associated with HIV. As with HIV, FIV does not appear to directly infect myeloid or erythroid precursors, and the mechanisms of marrow suppression likely involve virus, viral antigen, and/or infected accessory cells in the marrow microenvironment. Studies using in vitro experimental models are required to define the effects of each of these microenvironmental elements on haematopoietic progenitors. As little is known about the molecular mechanisms of FIV pathogenesis, additional studies of disease-inducing FIV strains are needed to identify the genotypic features that correlate with virulent phenotypic features. Finally, experimental FIV infection in cats provides the opportunity to correlate in vivo virological and haematological changes with in vitro observations in a large animal model that closely mimics HIV infection in man.


A clinical evaluation of all-ceramic bridges placed in patients attending UK general dental practices: three-year results.
To report the results at year three of an evaluation of fixed-fixed all-ceramic bridges, constructed in a yttria oxide stabilized tetragonal zirconium oxide polycrystal (Y-TZP) substructure, placed in adult patients in UK general dental practices and luted using a self-adhesive resin-based cement. Ethical approval was obtained. Four UK general dental practitioners were asked to recruit patients in accordance with the trial protocol. After obtaining informed written consent, appropriate vitality and radiographic assessments were completed and the pre-operative status of the gingival tissues noted. The teeth were prepared and bridges constructed in accordance with the manufacturer's instructions. Each bridge was reviewed annually within 3 months of the anniversary of its placement by a calibrated examiner, together with the clinician who had placed the restoration. The examiners evaluated the integrity of the restoration, its anatomic form, marginal adaptation, surface quality, sensitivity, the condition of the adjacent gingivae, and the presence or absence of secondary caries. A total of 34 bridges were examined at the three-year review. All Y-TZP frameworks were intact and no bridge retainers had debonded. Two veneering ceramic chips, in total, were detected over the three-year period of observation: the patients in whom this had occurred were unconcerned. A further abutment tooth had been successfully endodontically treated, through an occlusal access cavity, in addition to the two already reported at year one. At year three, the 34 Lava Y-TZP fixed-fixed bridges, placed in patients attending UK general dental practices, were found to be performing satisfactorily.


The Friedrich-Lively Instrument to Assess the Impact of Schizophrenia on Siblings (FLIISS): Part I--instrument construction.
Siblings of persons with schizophrenia may provide primary or secondary care for their sibling and support to parents who are primary care givers. These siblings experience stress and the accompanying sequelae of decreased quality of life, grief, chronic illness, and symptoms of depression and anxiety. Comprehensive measures of sibling stress have not been published. Before interventions to help siblings can be created, health professionals need such an assessment. The Friedrich-Lively Instrument to Assess the Impact of Schizophrenia on Siblings (FLIISS) has been developed to meet the needs of both health workers and siblings. The instrument has a strong conceptual basis adapted from Pearlin's model of stress in caregiving and was preceded by pilot work that evaluated both quantitative and qualitative data. In this article, (Part I), the development of the instrument and its relationships to the conceptual model are described. Health professionals can use the instrument for collecting information that will increase their ability to identify sources of stress faced by siblings of persons with schizophrenia, and from this assessment they may develop interventions for this underserved population.


Quantifying the increase in average human heterozygosity due to urbanisation.
The human population is undergoing a major transition from a historical metapopulation structure of relatively isolated small communities to an outbred structure. This process is predicted to increase average individual genome-wide heterozygosity (h) and could have effects on health. We attempted to quantify this increase in mean h. We initially sampled 1001 examinees from a metapopulation of nine isolated villages on five Dalmatian islands (Croatia). Village populations had high levels of genetic differentiation, endogamy and consanguinity. We then selected 166 individuals with highly specific personal genetic histories to form six subsamples, which could be ranked a priori by their predicted level of outbreeding. The measure h was then estimated in the 166 examinees by genotyping 1184 STR/indel markers and using two different computation methods. Compared to the value of mean h in the least outbred sample, values of h in the remaining samples increased successively with predicted outbreeding by 0.023, 0.038, 0.058, 0.067 and 0.079 (P<0.0001), where these values are measured on the same scale as the inbreeding coefficient (but opposite sign). We have shown that urbanisation was associated with an average increase in h of up to 0.08-0.10 in this Croatian metapopulation, regardless of the method used. Similar levels of differentiation have been described in many populations. Therefore, changes in the level of heterozygosity across the genome of this magnitude may be common during isolate break-up in humans and could have significant health effects through the established genetic mechanism of hybrid vigour/heterosis.


Effects of recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) in grade III open tibia fractures treated with unreamed nails-A clinical and health-economic analysis.
Recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) is licensed in Europe for open tibia fractures treated with unreamed nails. However, there is limited data available on the specific use of rhBMP-2 in combination with unreamed nails for open tibia fractures. The intention of the current study was to evaluate the medical and health-economic effects of rhBMP-2 in Gustilo-Anderson grade III open tibia fractures treated with unreamed nails based on individual patient data from two previously published studies. Linear regression analysis was performed on raw data of 90 patients that were either treated by standard of care with soft tissue management and unreamed nailing (SOC group) (n=50) or with rhBMP-2 in addition to soft tissue management and unreamed nailing (rhBMP-2 group) (n=40). For all types of revision, a significant lower percentage of patients (27.5%) of the rhBMP-2 group had to be revised compared to 48% of the patients of the SOC group (p=0.04). When only invasive secondary interventions such as bone grafting and nail exchange were considered, there was also a statistically significant reduction in the rhBMP-2 group with a revision rate of 10.0% (4 of 40 patients) compared to the SOC group with a revision rate of 28.0% (14 of 50 patients) (p=0.01). Mean fracture healing time of 228 days in the rhBMP-2 compared to 266 days in the SOC group was not statistically significant (p=0.24). Health-economic analysis based on a societal perspective with calculation of overall treatment costs after initial surgery and including productivity losses revealed savings of €6,239 per patient for Germany and €4,752 for the UK in favour of rhBMP-2 which was mainly driven by reduction of productivity losses. In conclusion, rhBMP-2 reduces secondary interventions in patients with grade III open tibia fractures treated with an unreamed nail and its use leads to financial savings for Germany and the UK from a societal perspective.


Short biphasic pulses from 90 microfarad capacitors lower defibrillation threshold.
For defibrillation between right ventricular and retropectoral patch electrodes using truncated exponential pulses, the stored energy defibrillation threshold (DFT) is lower for short pulses from small 60-microF capacitors than for conventional pulses from 120-microF capacitors, but 60-microF pulses frequently require higher voltages than are currently used. The goal of this study was to determine if DFT could be reduced by intermediate size 90-microF capacitors. This study compared biphasic waveform DFTs for 120 microF-65% tilt pulses, 90 microF-65% tilt pulses, and 90 microF-50% tilt pulses in 20 patients at defibrillator implantation. The 90 microF-50% tilt pulses were selected because their duration is half that of 120 microF-65% tilt pulses. The stored energy DFT for 90 microF-50% tilt pulses (9.1 +/- 4.3 J) was less than both the DFT for 120 microF-65% tilt pulses (12.0 +/- 5.5 J, P < 0.005) and the DFT for 90 microF-65% tilt pulses (11.6 +/- 5.8 J, P < 0.005). There was no significant difference between the latter two values. The voltage DFTs for 90 microF-50% pulses (436 +/- 113 V) and 120 microF-65% tilt pulses (436 +/- 104 V) were not statistically different; the voltage DFT for 90 microF-65% tilt pulses was higher than for either of the other two pulses (490 +/- 131, P < 0.005). The DFT was 20 J or greater in three patients for both 120 microF-65% tilt pulses and 90 microF-65% tilt pulses, but it was 16 J or less in all patients for 90 microF-50% tilt pulses. When pathways were dichotomized by the median resistance of 71 omega, 90 microF-50% tilt pulses significantly reduced DFTs compared to 120 microF-65% tilt pulses for higher resistance pathways (9.2 +/- 4.0 J vs 13.0 +/- 6.2 J, P = 0.002), but not lower resistance pathways (9.0 +/- 4.8 J vs 10.9 +/- 4.6 J, P = NS). For the electrode configuration tested, biphasic 90 microF-50% tilt pulses reduce stored energy DFT in comparison with 120 microF-65% tilt pulses without increasing voltage DFT. However, 90 microF-65% tilt pulses provide no benefit.


Cost implications of different surgical management strategies for primary hyperparathyroidism.
Controversy exists about optimal management of patients with primary hyperparathyroidism. To date, no studies have explored the cost implications of variation in practice. Results from a national survey of endocrine surgeons were combined with results from a survey of endocrinologists and financial data from Medicare. Patterns of use of resources were identified, annual costs for the surgical management of primary hyperparathyroidism in the United States were calculated, and the financial impact of variation in practice was estimated. Survey respondents (n = 109) were experienced endocrine surgeons, performing an average of 33 parathyroidectomies annually. Seventy-five percent of patients undergo localization before initial exploration for primary hyperparathyroidism. In order of preference, these studies were sestamibi (43%), ultrasonography (28%), and sestamibi with single-photon emission computed tomography (26%). Although there is variation in preoperative and postoperative practice, in-hospital costs have the greatest influence on total cost. An estimated $282 million is spent annually in the United States on operations for primary hyperparathyroidism. National health expenditures could range by more than $70 million, depending on whether management strategies involving low or high use of resources are employed. Substantial variation among endocrine surgeons in the management of primary hyperparathyroidism has important cost implications. Implementation of evidence-based guidelines to optimize clinical and economic performance should be considered.


The effect of dose fractionation on the frequency of ethylnitrosourea-induced dominant cataract and recessive specific locus mutations in germ cells of the mouse.
A combined dominant cataract-recessive specific locus mutation experiment for fractionated exposure to ethylnitrosourea (2 X 80 mg/kg, 24-h fractionation interval) was designed to determine if lower doses of ethylnitrosourea are more effective in inducing dominant cataract mutations as suggested by previous results. This observation was not confirmed by the present experiment. The extensive, statistically more reliable specific locus results indicate an additive effect of fractionated ethylnitrosourea treatment. A saturable repair system for ethylnitrosourea-induced DNA damage has been previously documented (Karran et al., 1979; Sega et al., 1986; Van Zeeland et al., 1985). Two parameters inherent to a saturable system, the minimal time required for the saturated system to recover and the minimal dose to saturate the system are important, and results of experiments employing a fractionation exposure protocol must be interpreted relative to these two parameters. Longer fractionation intervals or smaller doses result in a reduced mutagenic effect. Due to the inherently lower experimental variability of the specific locus mutation assay as compared to the dominant cataract assay, the specific locus assay is the test of choice to determine factors affecting the mammalian germ cell mutation rate. The dominant cataract test requires a larger investment of experimental resources to achieve a comparable degree of accuracy. The dominant cataract mutation test is important in assessing the mutation rate to dominant alleles in germ cells of mammals. Due to the immediate expression of the mutant phenotype in newly occurring dominant mutations, a dominant mutation assay screens a genetically relevant endpoint in an assessment of the mutagenic hazard for man in mouse experiments. A multi-endpoint design screening specific locus, dominant cataract, and biochemical mutational endpoints (Ehling et al., 1985) allows a systematic comparison of mutagenic results for different classes of mutations in the same animals.


The complete mitochondrial genomes of Aporia crataegi, Gonepteryx rhamni, and Appias remedios (Lepidoptera, Pieridae) and phylogenetic relationship of other Pieridae species.
Pieridae is a butterfly family whose higher classification has not yet been settled. In this research, we used completed mitochondrial genome sequence to identify and analyze the relationship of three subfamilies of Pieridae (Dismorphiinae, Coliadinae and Pierinae). We have sequenced the complete mitogenomes of Aporia crataegi, Gonepteryx rhamni, and Appias remedios, which are 15,148 bp, 15,118 bp and 15,223 bp in length, respectively. These three mitogenomes have a typical set of 37 genes and an A+T-rich region. The protein-coding genes, excluding the cox1 gene, in the three mitogenomes are initiated by the typical ATN codons. The putative initiation codon for the cox1 gene in the three species is CGA. tRNA genes in the three Pieridae mitogenomes show typical clover leaf structures, except tRNASer(AGN) which lacks the dihydrouridine (DHU) stem. The length of A+T-rich region varies in the three species, which leads to the variation in the mitochondrial genome size. The characterizations of the three mitogenomes enrich our knowledge on the Lepidopteran mitogenome and provide us genetic information to reconstruct the phylogenetic tree. Finally, the phylogenetic analyses using mitogenome data showed that the relationship among three subfamilies of Pieridae is (Dismorphiinae + (Coliadinae + Pierinae)).


Gaining insight into genotoxicity with the comet assay in inhomogenoeous exposure scenarios: The effects of tritiated steel and cement particles on human lung cells in an inhalation perspective.
The comet assay was recently applied for the first time to test the genotoxicity of micrometric stainless steel and cement particles, representative of those produced in the dismantling of nuclear power plants. A large dataset was obtained from in vitro exposure of BEAS-2B lung cells to different concentrations of hydrogenated (non-radiative control) and tritiated particles, to assess the impact of accidental inhalation. Starting from the distributions of the number of nuclei scored at different extent of DNA damage (% tail DNA values), we propose a new comet data treatment designed to consider the inhomogeneity of the action of such particles. Indeed, due to particle behavior in biological media and concentration, a large fraction of cells remains undamaged, and standard averaging of genotoxicity indicators leads to a misinterpretation of experimental results. The analysis we propose reaches the following goals: genotoxicity in human lung cells is assessed for stainless steel and cement microparticles; the role of radiative damage due to tritium is disentangled from particulate stress; the fraction of damaged cells and their average level of DNA damage are assessed separately, which is essential for carcinogenesis implications and sets the basis for a better-informed risk management for human exposure to radioactive particles.


Cross-cultural adaptation for Brazil and validity of a guide to assist nursing students' clinical reasoning.
To assess the validity of a Written Clinical Reasoning Prompt (WCRP) to help nursing students' clinical reasoning (CR). This is a methodological study of translation and cross-cultural adaptation into Brazilian Portuguese of instruments that aim to promote CR improvement, composed of (1) WCRP; (2) two case studies; (3) a questionnaire about students' perceptions during decision-making in case studies; (4) a scoring rubric for correcting case studies. For translation and cross-cultural adaptation, stages 1-8 of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Consortium Network were adopted. Agreement values among experts >80% and content validity coefficient (CVC) > 0.8 were considered satisfactory. For the pretest, a randomized clinical trial was carried out with 24 nursing students (intervention group, n = 14, using the WCRP to solve case studies; control group, n = 10, without using the WCRP). The WCRP was translated and adapted into Brazilian Portuguese, requiring minimal adjustments to obtain agreement among the judges above 80% and CVC above 0.80. Regarding face validation, an adequate agreement was obtained in the assessment by students. There was no difference in the accuracy of nursing diagnoses between the intervention and control groups in the pretest. The WCRP was translated and adapted into Brazilian Portuguese and had adequate face and content validity estimates; however, there was no association with improving nursing students' diagnostic accuracy. The translated and adapted versions of all instruments into Brazilian Portuguese had adequate evidence of content and face validity. The use of WCRP was not associated with a significant improvement in nursing students' diagnostic accuracy. New studies with larger samples, a sample power of at least 80%, and a level of significance of 5% are needed.


The Bologna bladder neck suspension procedure for treatment of stress urinary incontinence associated with cystocele.
The object was to study retrospectively the perioperative complications and results of the Bologna procedure for the treatment of stress urinary incontinence associated with cystocele grade 2 or more. In the study, 80 patients underwent a repair of all defects of pelvic support plus the Bologna procedure. Mean duration of follow-up was 40.2 months (range 3-127). The incidence of operative complications was 2.5% for inadvertent cystostomy and for hemorrhage. Mean hospital stay was 7.2 days (range 2-17). At 2-year follow-up 85% of the patients were completely free of incontinence symptoms (95% CI: 75-92) and 76% at 3-year follow-up (95% CI: 66-86). None of the parameters tested in a univariate analysis was independently linked with surgical failure. Further studies are needed to establish the place of this technique in the surgical management of urinary incontinence associated with genital prolapse.


Domestic pigs (Sus scrofa) engage in non-random post-conflict affiliation with third parties: cognitive and functional implications.
In social mammals, conflict resolution involves the reunion of former opponents (aggressor and victim) after an aggressive event (reconciliation) or post-conflict triadic contacts with a third party, started by either opponent (solicited-TSC) or spontaneously offered by the third party (unsolicited-TUC). These post-conflict strategies can serve different functions, including consolation (specifically when TUCs reduce the victim's anxiety). We investigated the possible presence and modulating factors of such strategies on semi-free ranging pigs (Sus scrofa; N = 104), housed at the ethical farm Parva Domus (Cavagnolo, Italy). Kinship was known. Reconciliation was present and mainly occurred between weakly related pigs to possibly improve tolerant cohabitation. Triadic contacts (all present except aggressor TSCs) mostly occurred between close kin. TSCs enacted by victims reduced neither their post-conflict anxiety behaviors nor further attacks by the previous aggressor, possibly because TSCs remained largely unreciprocated. TUCs towards aggressors did not reduce aggressor post-conflict anxiety but limited aggression redirection towards third parties. TUCs towards the victim reduced the victim but not the third-party's anxiety. However, TUCs may also provide inclusive fitness benefits to third parties by benefiting close kin. In sum, pigs engaged in non-random solicited/unsolicited triadic contacts, which suggests that pigs might possess socio-emotional regulation abilities to change their own or others' experience and elements of social appraisal, necessary to detect the emotional arousal of relevant others and (in case of TUCs) take the agency to restore homeostasis.


[Trace effects of short-term cooling and their importance in the adaptation to cold].
The thermoregulation traces (O2 consumption, electrical activity of cervical muscles deep rectal temperature and subcutis temperature) were observed to 30 min. at ambient temperatures + 20--24 degrees and + 6--7 degrees through 1, 5, 10 and 30 days after cooling. The after-effect (traces) of cooling depends on conditions of cooling. Single or double cooling followed by a fall in core temperature to 30 degrees as well as intermittent cold exposures (15 two-min. exposures at--20 degrees) without the core temperature falling and a cold long--term (4--5 weeks) exposure at + 2--4 degrees cause a prolonged after. The short-term cooling increases the trace reactions throuth 5--10 days after cooling. Their traces are similar to changes in a cold acclimation rats.


Changes in intracellular amino acids and organic acids induced by nitrogen starvation and nitrate or ammonium resupply in the cyanobacterium Phormidium laminosum.
In Phormidium laminosum cells, nitrogen starvation caused a decrease in the intracellular levels of all amino acids, except glutamate, and an increase in the total level of the analyzed organic acids. The addition of nitrate or ammonium to N-starved cells resulted in substantial increases in the pool size of most amino acids. Upon addition of ammonium the total level of organic acids diminished, whereas it increased upon addition of nitrate, after a transient decay during the first minutes. Nitrogen resupply stimulated amino acid synthesis, the effect being faster and higher when ammonium was assimilated. The data indicate that nitrate and ammonium assimilation induced an enhancement of carbon flow through the glycolytic and the tricarboxylic-acid pathways to amino acid biosynthesis, with a concurrent decrease in the carbohydrate reserves. The results suggest that the availability of carbon skeletons limited the rate of ammonium assimilation, whereas the availability of reducing equivalents limited the rate of nitrate assimilation.


Antimicrobial activity of endemic Crataegus tanacetifolia (Lam.) Pers and observation of the inhibition effect on bacterial cells.
Up to now an increasing number of antibiotic-resistant bacteria have been reported and thus new natural therapeutic agents are needed in order to eradicate these pathogens. Through the discovery of plants such as Crataegus tanacetifolia (Lam.) Pers that have antimicrobial activity, it will be possible to discover new natural drugs serving as chemotherapeutic agents for the treatment of nosocomial pathogens and take these antibiotic-resistant bacteria under control. The objective of the present study was to determine antimicrobial activity and the activity mechanism of C. tanacetifolia plant extract. The leaves of C. tanacetifolia, which is an endemic plant, were extracted using methanol and tested against 10 bacterial and 4 yeast strains by using a drop method. It was observed that the plant extract had antibacterial effects on Bacillus subtilis, Shigella, Staphylococcus aureus, and Listeria monocytogenes among the microorganisms that were tested. Minimum inhibitory concentration (MIC) results obtained at the end of an incubation of 24 h were found to be > or =6.16 mg ml(-1) for B. subtilis, < 394 mg ml(-1) for Shigella, and > or =3.08 mg ml(-1) for L. monocytogenes and S. aureus and minimum bactericidal concentration (MBC) were found as > or =24.63 mg ml(-1) for B. subtilis, > or =394 mg ml(-1) for Shigella, > or =6.16 mg ml(-1) for L. monocytogenes, and > or =98.5 mg ml(-1) for S. aureus. According to the MBC results, it was found that the plant extract had bactericidal effects and in order to explain the activity mechanism and cell deformation of bacterial strains treated with plant extract, the scanning electron microscopy (SEM) was used. The results of SEM showed that the treated cells appeared shrunken and there was degradation of the cell walls. This study, in which the antibacterial effect of C. tanacetifolia was demonstrated, will be a base for further investigations on advanced purification and effect mechanism of action of its active compounds.


No dose-dependent tubulotoxicity of 5-aminosalicylic acid: a prospective study in patients with inflammatory bowel diseases.
Elevated levels of renal tubular markers in the urine are found in 20-30% of patients with chronic inflammatory bowel diseases. We investigated whether this reflects a dose-dependent tubulotoxicity of 5-aminosalicylic acid (5-ASA). In an open, prospective, multicenter study 18 patients with Crohn's disease and 29 with ulcerative colitis were treated with 3 g 5-ASA or more daily as the sole drug for 6 weeks. Clinical activity (CDAI, CAI) and renal tubular markers [beta-N-acetyl-D-glucosaminidase (beta-NAG) and other proteins in urine] were monitored. We examined whether the proportion of patients with elevated beta-NAG is more than 15% higher (absolute difference) than that prior to treatment. The proportion decreased from 19.2% to 12.8% in the intention-to-treat analysis (n=47) and from 24.3% to 13.5% in the per-protocol analysis (n=37), which was not more than 15% higher than at baseline. Mean CDAI decreased from 222 to 146 and mean CAI from 7.3 to 3.1 (intention-to-treat analysis). Response to therapy was shown by 61% of patients with Crohn's disease and 66% of patients with ulcerative colitis. The cumulative dose of 5-ASA was not correlated with beta-NAG level in the urine. This study largely rules out that 5-ASA at 3 g or higher per day for 6 weeks induces renal tubular damage. Elevated renal tubular markers reflect inflammatory activity or an extraintestinal manifestation of inflammatory bowel diseases.


Prevalence of myopia and high myopia, and the association with education: Shanghai Child and Adolescent Large-scale Eye Study (SCALE): a cross-sectional study.
To report on: (a) overall myopia and high myopia prevalence, and (b) the impact of education on the spherical equivalent refractive error in children across Shanghai. Cross-sectional study. Across all 17 districts of Shanghai. 910 245 children aged 4-14 years from a school-based survey conducted between 2012 and 2013. Data of children with non-cycloplegic autorefraction, visual acuity assessment and questionnaire were analysed (67%, n=6 06 476). Prevalence of myopia (≤-1.0 D) and high myopia (≤-5.0 D) was determined. We used a regression discontinuity design to determine the impact of school entry cut-off date (1 September) by comparing refractive errors at each age, for children born pre-September to post-1 September, and performed a multivariate analysis to explore risk factors associated with myopia. Data analysis was performed in 2017-2018. Prevalence rates of myopia and high myopia were 32.9% (95% CI: 32.8% to 33.1%) and 4.2% (95% CI: 4.1% to 4.2%), respectively. From 6 years of age onwards, children born pre-September were more myopic compared with those born post-1 September (ahead in school by 1 year, discontinuity at 6 years: -0.19 D (95% CI: -0.09 to -0.30 D); 14 years: -0.67 D (95% CI: -0.21 to -1.14 D)). Our findings suggest that myopia is associated with education, that is primarily focused on near-based activities. Efforts to reduce the burden should be directed to public awareness, reform of education and health systems.


Clinical features of ankylosing spondylitis may correlate with HLA-B27 polymorphism.
The objective of this study is to investigate the relationship between clinical features of ankylosing spondylitis (AS) and HLA-B27 status or its subtypes. Clinical data and blood samples were collected with patients' informed consent. Luminex liquid array combining polymerase chain reaction-sequence specific oligonucleotide probe was used to do the low-resolution HLA-B genotype typing. Polymerase chain reaction-sequence specific primer was applied to do the high resolution HLA-B27 typing. In 98 subjects, 93 were HLA-B27 positive, of which three subtypes were detected: B*2704 (n = 76), B*2705 (n = 12), and B*2715 (n = 5). The onset age for B27 negative and positive group was 28 +/- 7.9 and 21.1 +/- 6.2 years, respectively (chi(2) = -2.047, P = 0.041). The onset age for B*2704, B*2705 and B*2715 group was 20.45 +/- 4.50, 26.67 +/- 9.95 and 17.8 +/- 11.12 years, respectively (chi(2) = 7.888, P = 0.019). No significant difference was found between B27 positive and negative group, or among three B27 subtypes groups for other clinical features. In conclusion, the clinical features of AS may be correlated with HLA-B27 status and its polymorphism.


Reproducible imaging of rat corticothalamic pathway by longitudinal manganese-enhanced MRI (L-MEMRI).
Manganese-enhanced MRI (MEMRI) has been described as a powerful tool to depict the architecture of neuronal circuits. The aim of the present study was to optimize the experimental conditions of MEMRI that permits the study of insult-induced alterations of the somatosensory pathway in a longitudinal way, and to provide functional information on rat corticothalamic connectivity or disturbances thereof. A guidance screw was implanted in the skull of the rats, over the forelimb representation area of the primary somatosensory cortex (S1fl), allowing repetitive injections at the same stereotactic coordinates. MnCl2 (200 nL, 0.3 M) was injected 1.5 mm below the dura using a calibrated microcapillary. Animals received MnCl2 injections 3 times at 15 day intervals. Spatiotemporal patterns showed a significant hyperintensity on T1-weighted images induced by manganese transport in structures related to the somatosensory pathway, i.e. globus pallidus, caudate putamen, thalamus and substantia nigra. 7 days after MnCl2 injection hyperintensity was only evident at some points surrounding the injection site. Complete loss of manganese-induced contrast was achieved after 15 days after injection. Functional MRI (fMRI) experiments were performed under the same conditions, 24 h after MnCl2 injection. Activation of S1fl was observed showing that fMRI and MEMRI studies are compatible and can be performed in parallel in the same animals. The present study shows, for the first time, a robust and reproducible technique to perform longitudinal MEMRI (L-MEMRI) experiments and to study the time course of alterations of the corticothalamic connections following stroke in the rat.