Early angiographic changes after laser treatment of choroidal neovascularisation in age-related macular degeneration.
To describe angiographic features detectable on fluorescein angiography (FA) and indocyanine green angiography (ICGA) early after laser photocoagulation of choroidal neovascularisation (CNV) in age-related macular degeneration (AMD). Thirty-five eyes of patients with AMD and juxtafoveal or extrafoveal CNV referred to the angiographic centre of the Eye Clinic of Trieste were considered. Ophthalmological assessment included FA and ICGA performed 2 days before and 30 min after laser treatment, and then 1, 2, 7, 14, 21 and 28 days after photocoagulation. Further clinical angiographic examinations were carried out 2, 3, 4 and 6 months after treatment. Photocoagulation was performed for classic CNV on FA and occult CNV on FA, appearing as well-defined focal spot on ICGA. Our results show that interpretation of early post-treatment angiographic examinations may be awkward because diffuse leakage on FA and hot spots on ICGA are normally detectable soon after laser treatment and thereafter during the first 2 weeks. Later, at the 3-week control, leakage on FA and hot spots on ICGA are visible in 62.8% and in 37% of cases respectively; they disappear completely by the 4-week control. Difficulty in analysing FA and ICGA in the early post-photocoagulation period underlines the importance of the decision regarding when to perform the first reliable post-laser control and how to improve its interpretation. We suggest that the first angiographic control be performed 3 weeks after treatment, strictly monitoring those eyes showing leakage or marginal hot spots over the following weeks. Overlapping the post-laser hypofluorescent area on the pre-laser lesion can ensure the complete coverage of CNV, and analysis of the retinal and choroidal vascular pattern inside and near the photocoagulated area during the different angiographic phases, albeit difficult, is essential for the interpretation of the angiographic lesions.


Suppression of dopamine-related side effects of morphine by aripiprazole, a dopamine system stabilizer.
Dopamine receptor antagonists are commonly used to counter the adverse effects of opioids such as hallucinations, delusions and emesis. However, most of these agents themselves have side effects, including extrapyramidal symptoms. Here, we investigated the effect of the dopamine system stabilizer aripiprazole on morphine-induced dopamine-related actions in mice. Morphine-induced hyperlocomotion and reward were significantly suppressed by either the dopamine receptor antagonist prochlorperazine or aripiprazole. Catalepsy was observed with a high dose of prochlorperazine, but not with an even higher dose of aripiprazole. The increased level of dialysate dopamine in the nucleus accumbens stimulated by morphine was significantly decreased by pretreatment with aripiprazole. These results suggest that the co-administration of aripiprazole may be useful for reducing the severity of morphine-induced dopamine-related side effects.


Targeted delivery of PROTAC-based prodrug activated by bond-cleavage bioorthogonal chemistry for microneedle-assisted cancer therapy.
Proteolysis-targeting chimera (PROTAC) is emerging as a new strategy to degrade target proteins in a precise way by taking advantage of the cellular ubiquitin-proteasome system. However, the potential cytotoxicity of PROTAC should be avoided to mitigate the off-target degradation of proteins in healthy tissues or cells. To address this issue, we herein present a strategy to cage a PROTAC with 4-(vinyloxy) benzyl carbonate (MZ1-O), which can be eliminated through a 3,6-dimethyl-1,2,4,5-tetrazine (Tz)-mediated inverse electron-demand Diels-Alder (iEDDA) reaction to generate a BRD4 (bromodomain-containing protein 4) degrader, MZ1. We further propose a dissolvable microneedle-assisted strategy for site-specific activation of MZ1-O that is delivered by a targeted delivery vector through systemic route in vivo, and demonstrate such a bioorthogonal strategy is efficient and precise for tumor treatment. Our study suggests that the bioorthogonal activation of PROTAC-based prodrug offers a highly specific and precise approach for cancer therapy.


Translation and Cross-Cultural Validation of the Danish Version of the Family Health Scale-Long Form: A Psychometric Study.
The Family Health Scale is a new instrument for evaluating family health. The instrument is reported as valid and reliable in investigating family health among different types of adult family members. This study aimed to translate the Family Health Scale into Danish and investigate its validity and reliability in families with a family member affected by chronic or serious illness. Translation was performed through forward and backward bilingual practice consisting of 10 steps. A cross-sectional study included 406 participants, of whom 94 also participated in a follow-up study within 3 weeks for the test-retest. Content validity was examined by conducting cognitive interviews with nine family members. Internal consistency reliability was assessed using Cronbach α. The test-retest reliability was evaluated using intraclass correlation coefficients. Model fit was assessed using confirmatory factor analysis. The Family Health Scale demonstrated good content validity and a moderate model fit. Both Internal consistency reliability and test-retest reliability were satisfying. Cronbach α ranged from 0.73 to 0.89, while the intraclass correlation coefficient value was 0.88. The confirmatory factor analysis estimated a satisfying model fit, with an acceptable root-mean-square error of 0.076 and a moderate comparative fit index of 0.794. The Family Health Scale instrument has the potential to identify vulnerable families or families affected by chronic or serious illnesses, such as cancer. The assessment tool can consequently be used to target interventions to promote family health and improve the health of both the individual and his/her family.


Inducibility of nuclear Rad51 foci after DNA damage distinguishes all Fanconi anemia complementation groups from D1/BRCA2.
Fanconi anemia (FA) is a cancer susceptibility disorder characterized by chromosomal instability and hypersensitivity to DNA cross-linking agents. So far 11 complementation groups have been identified, from which only FA-D1/BRCA2 and FA-J are defective downstream of the central FANCD2 protein as cells from these groups are capable of monoubiquitinating FANCD2. In this study we show that cells derived from patients from the new complementation groups, FA-I, FA-J and FA-L are all proficient in DNA damage induced Rad51 foci formation, making the cells from FA-D1/BRCA2 patients that are defective in this process the sole exception. Although FA-B patient HSC230 was previously reported to also have biallelic BRCA2 mutations, we found normal Rad51 foci formation in cells from this patient, consistent with the recent identification of an X-linked gene being mutated in four unrelated FA-B patients. Thus, our data show that none of the FA proteins, except BRCA2, are required to sequester Rad51 into nuclear foci. Since cells from the FA-D1 and FA-J patient groups are both able to monoubiquitinate FANCD2, the "Rad51 foci phenotype" provides a convenient assay to distinguish between these two groups. Our results suggest that FANCJ and FANCD1/BRCA2 are part of the integrated FANC/BRCA DNA damage response pathway or, alternatively, that they represent sub-pathways in which only FANCD1/BRCA2 is directly connected to the process of homologous recombination.


Prices, availability, and affordability of national essential medicines in public primary hospitals: A cross-sectional survey in poverty-stricken rural areas in China.
This study aimed to determine the prices, availability, and affordability of national essential medicines in public primary hospitals in poverty-stricken areas of Anhui province, China. A cross-sectional study was conducted in 143 public primary hospitals in Anhui province, eastern China. Data on access to 44 essential medicines was evaluated using the standardized methodology available in the World Health Organization and Health Action International manual. Median price rates show that 46.51% (21 of 44) of the lowest price generics and 100% of the originator brands were more expensive than the international reference price. The median availability of the 44 medicines was 31.47%, and 65.91% (29 of 44) of the medicines had less than 50% availability. The majority of the medicines were affordable as they would cost less than a day's income in sample areas. Suppliers could respond to 88.27% of the procuring orders raised by the 143 hospitals in the study, but this ranged from 43.96% to 99.86%. There is poor availability and non-ideal response rate of medicine delivery in public primary hospitals in poverty-stricken areas in eastern China. Further implementation of national essential medicine policy needs to focus on improving both availability and distribution efficiency in these areas.


Clinical characteristics of community-acquired acute pyelonephritis caused by ESBL-producing pathogens in South Korea.
The aim of this study was to determine the risk factors and clinical characteristics of community-acquired acute pyelonephritis (CA-APN) caused by extended-spectrum β-lactamase (ESBL)-producing organisms. From March 2010 to February 2011, patients with CA-APN were recruited in 11 hospitals in South Korea. Clinical and microbiological data were collected prospectively, and the ESBLs and multilocus sequence types of the ESBL-producing Escherichia coli were characterized. Comparison between CA-APN caused by ESBL-producing Enterobacteriaceae and those by non-ESBL-producing organisms was performed. A total of 566 patients were recruited. Enterobacteriaceae were detected in 526 patients. Forty-six isolates (46/526, 8.7 %) were positive for ESBLs. Clinical and microbiological failure did not differ between the two groups, despite there being fewer patients with ESBL-positive isolates provided with appropriate antibiotics initially (19.6 vs. 93.8 %, p < 0.001). However, the duration of hospitalization was longer in the ESBL group (10.5 vs. 7.0 days, p = 0.012). In a logistic regression model, Charlson score ≥1 point [odds ratio (OR) 3.4, 95 % confidence interval (CI) 1.6-7.0, p = 0.001], antibiotics usage during the previous year (OR 3.1, 95 % CI 1.4-7.2, p = 0.008), and urinary catheterization during the previous month (OR 4.4, 95 % CI 1.1-17.6, p = 0.035) were associated with the risks of CA-APN by ESBL producers. CTX-M-15 (48 %) and CTX-M-14 (38 %) were the most common ESBLs. ST131 was the most common clone (7/24, 29.1 %), which was more frequently resistant to cefepime, fosfomycin, and temocillin. The risk factors for CA-APN by ESBL producers were Charlson score ≥1 point, antibiotics usage during the previous year, and urinary catheterization during the previous month.


Casting a wider protective net: Anti-infective vaccine strategies for patients with hematologic malignancy and blood and marrow transplantation.
Patients who have hematologic malignancies are at high risk for infections but vaccinations may be effective prophylaxis. The increased infection risk derives from immune defects secondary to malignancy, the classic example being CLL, and chemotherapies and immunotherapy used to treat the malignancies. Therapy of hematologic malignancies is being revolutionized by introduction of novel targeted agents and immunomodulatory medications, improving the survival of patients. At the same time those agents uniquely change the infection risk and response to immunizations. This review will summarize current vaccine recommendations for patients with hematologic malignancies including patients who undergo hematopoietic cell transplant.


A brief guide to situating the neuroscience of Black and White civilian arrests in a broader social context.
This commentary provides some guidance to reading and interpreting the results reported in Dang et al. (2022). In light of the recent events of police violence and the public interest such important topics, we believe it is warranted to provide some guidance to interpreting the findings of this article for readers from the broader scientific community and the general public. We focus on the distinction between the reported results and their interpretation, conveying the scientific method's subtleties to the larger audience, and situating the findings in a broader context.


90K/LGALS3BP expression is upregulated in COVID-19 but may not restrict SARS-CoV-2 infection.
Glycoprotein 90K, encoded by the interferon-stimulated gene LGALS3BP, displays broad antiviral activity. It reduces HIV-1 infectivity by interfering with Env maturation and virion incorporation, and increases survival of Influenza A virus-infected mice via antiviral innate immune signaling. Its antiviral potential in SARS-CoV-2 infection remains largely unknown. Here, we analyzed the expression of 90K/LGALS3BP in 44 hospitalized COVID-19 patients at multiple levels. We quantified 90K protein concentrations in serum and PBMCs as well as LGALS3BP mRNA levels. Complementary, we analyzed two single cell RNA-sequencing datasets for expression of LGALS3BP in respiratory specimens and PBMCs from COVID-19 patients. Finally, we analyzed the potential of 90K to interfere with SARS-CoV-2 infection of HEK293T/ACE2, Calu-3 and Caco-2 cells using authentic virus. 90K protein serum concentrations were significantly elevated in COVID-19 patients compared to uninfected sex- and age-matched controls. Furthermore, PBMC-associated concentrations of 90K protein were overall reduced by SARS-CoV-2 infection in vivo, suggesting enhanced secretion into the extracellular space. Mining of published PBMC scRNA-seq datasets uncovered monocyte-specific induction of LGALS3BP mRNA expression in COVID-19 patients. In functional assays, neither 90K overexpression in susceptible cell lines nor exogenous addition of purified 90K consistently inhibited SARS-CoV-2 infection. Our data suggests that 90K/LGALS3BP contributes to the global type I IFN response during SARS-CoV-2 infection in vivo without displaying detectable antiviral properties in vitro.


Rehabilitating Cough Dysfunction in Parkinson's Disease: A Randomized Controlled Trial.
Disorders of airway protection (cough and swallowing) are pervasive in Parkinson's disease (PD) resulting in a high incidence of aspiration pneumonia and death. However, there are no randomized controlled trials comparing strength and skill-based approaches to improve airway protection in PD. The aim of this study was to compare expiratory muscle strength training (EMST) and sensorimotor training for airway protection (smTAP) to improve cough-related outcomes in people with PD. Participants with PD and dysphagia were recruited for this prospective phase II randomized-blinded controlled clinical trial. Participants completed baseline assessment, 5 weeks of EMST or smTAP, and a post-training assessment. Primary outcome measures included maximum expiratory pressure (MEP) and voluntary cough peak expiratory flow rate (PEFR). Mixed effects models were used to assess the effects of EMST and smTAP on outcomes. A total of 65 participants received either EMST (n = 34) or smTAP (n = 31). MEP improved from pre- to post-treatment for smTAP (P < 0.001, d = 0.19) and EMST (P < 0.001, d = 0.53). Voluntary PEFR increased from pre- to post-treatment for smTAP (P < 0.001, d = 0.19) and EMST (P < 0.001, d = 0.06). Moreover, reflex cough PEFR (P < 0.001, d = 0.64), reflex cough expired volume (P < 0.001, d = 0.74), and urge to cough (P = 0.018, OR = 2.70) improved for the smTAP group but not for the EMST group. This clinical trial confirmed the efficacy of smTAP to improve reflex and voluntary cough function, above and beyond EMST, the current gold standard. © 2022 International Parkinson and Movement Disorder Society.


Effects of reduced graphene oxide on humic acid-mediated transformation and environmental risks of silver ions.
The reduction of Ag+ mediated by natural organic matters has been demonstrated to be an important process of Ag+ transformation and would influence the risks of Ag+ and Ag-containing materials in aquatic environment. Considering the large production of carbon nanomaterials (CNMs) and their inevitable release into the environment, the effects of CNMs on Ag transformation are of considerable interest. This study demonstrated that the humic acid-mediated reduction of Ag+ to free Ag nanoparticles (AgNPs) in aqueous phase was suppressed by coexisting reduced graphene oxide (rGO). A large amount of Ag+ was reduced on rGO surface, resulting in the generation of AgNPs-rGO composites. rGO at concentrations of 1-2 orders of magnitude lower than those of Ag+ would exhibit significant effects. The X-ray absorption fine structure spectroscopy study showed that Ag+ was first adsorbed on rGO surface cooperatively with humic acid and then rapidly reduced to AgNPs. The hydroxylic-OH on rGO could participate in the AgNPs formation and was oxidized to carbonyl during the reduction of Ag+. Additionally, the formed AgNPs-rGO had a relatively lower environmental risk compared to AgNPs or rGO alone. Overall, these results improve our understanding of the interaction between CNMs and Ag+ in aquatic systems.


Multidrug resistance 1 (MDR1) 3435C/T genotyping in childhood drug-resistant epilepsy.
A mutation at nucleotide position 3435 in exon 26 of the multidrug resistance 1 (MDR1) gene is the most frequently studied polymorphism in relation to multidrug resistance. However, there are conflicting data as to whether the CC or TT genotype of the 3435C>T polymorphism is associated with drug resistance. We investigated the association between this polymorphism in drug-resistant childhood epilepsy by comparison with drug-responsive patients. In total, 59 patients with drug-resistant epilepsy, defined as having four or more seizures within a 12-month period while using three or more AEDs, 60 children with drug-responsive epilepsy who had remained seizure-free for 12months on their current AED regimen and 76 healthy children were involved in this study. Genotype frequencies in drug-resistant patients were as follows: 32.2% CC, 44.1% CT, 23.7% TT; in the drug-responsive group: 20.0% CC, 50.0% CT, 30.0% TT; in the control group: 24.3% CC, 50.0% CT, 25.7% TT. Comparison of drug-resistant and drug-responsive patients revealed no significant difference in genotype frequency. The findings of the epilepsy patients were not significantly different from those of the healthy control subjects. Our study does not support any significant association between the MDR1 polymorphism and drug-resistant childhood epilepsy.


Glass fiber reinforced composite resin space maintainer: case reports.
Glass fiber reinforced composite resins (GFRCR) are new to the pediatric dental market and can be an alternative to conventional space maintenainers. GFRCRs have been developed for dental applications during the past several years. This preliminary clinical study described the treatment of patients whose missing primary molars were restored with everStick, a semimanufactured product made of glass fibers, thermoplastic polymer, and lightcuring resin matrix for reinforcing dental polymer. everStick was applied as a space maintainer when there was a loss of 1 or 2 teeth in the maxillary or mandibular arch. This study showed that the GFRCR space maintainers functioned well during a short period. The clinical advantages of the GFRCR space maintainers were that they: provided cost and time savings; did not require a cast model; did not require a second visit; were easy to apply; provided reliable adhesive bonding; provided long-term retention; were used when there was an indication of metal allergy; were easy to clean; had a natural feel and were esthetic. GFRCR space maintainers can be a new alternative to the conventional space maintainers used in pediatric dentistry.


Potential usefulness of otoscopy in the evaluation of hanging deaths: A report of two cases.
The significance of examination of the tympanic membrane (TM) has been previously reported in cases of strangulation, traumatic asphyxia, and drowning. We report otoscopic findings in two victims of suicidal hanging, including hemotympanum, bleeding from superficial vessels of the TM, perforation of the TM, and gross bulging of the pars-tensa with a bluish hue. These two cases also show petechial hemorrhages in the TM, which is a previously reported finding in cases of hanging. Postmortem otoscopic examination of victims of hanging may provide information useful in the determination of vitality of hanging.


Increased transgene integration efficiency upon microinjection of DNA into both pronuclei of rabbit embryos.
Transgenic rabbits provide a useful biological model for the study of the regulation of mammalian genes. However, transgene integration efficiency has generally been low. Here we present a first attempt to increase the integration rate of exogenous DNA into the rabbit genome, using a double pronuclei microinjection method. Pronuclear stage rabbit embryos were recovered from superovulated NZW females, 19-20 h after hCG injection. About 5 microg/mL of exogenous DNA solution was microinjected either into one pronucleus (single microinjection, SM) or into both pronuclei (double microinjected, DM). The transgene consisted of a 2.5 kb murine whey acidic protein promoter (mWAP), 7.2 kb cDNA of the human clotting factor VIII (hFVIII), and 4.6 kb that of 3' flanking sequences of the mWAP gene. The in vitro survival of DM embryos to the blastocyst stage was lower than that of SM embryos (68 vs. 89%). Similar results were obtained using EGFP as a control gene construct. However, there was no difference in the percentage of embryos that developed into live offspring using DM (25%) vs. SM (26%). The integration frequency of mWAP-hFVIII into the genome of transgenic rabbits was 3.3% (1/30) upon SM and 8.1% (4/49) at DM (p < 0.05). All founders transmitted the transgene to their offspring in a Mendelian fashion. The SM founder female secreted 87.4 microg/mL rhFVIII in milk, with an activity of 0.594 IU/mL. The DM founder female produced 118 microg/mL rhFVIII, with activity values of 18 IU/ mL. This is the first report of transgenic rabbit production using a double microinjection technique. Our preliminary results suggest that this method can increase the efficiency of production of transgenic rabbit founders, giving a higher integration rate than single microinjection.


A proactive approach to prevention of health care-acquired Legionnaires' disease: the Allegheny County (Pittsburgh) experience.
The Allegheny County Health Department (ACHD) in Pennsylvania distributed the first guidelines for prevention and control of health care-acquired Legionnaires' disease (LD) by 1995. The proactive approach advocated in the guidelines differed notably from that of the Centers for Disease Control and Prevention (CDC) by recommending routine environmental testing of the hospital water distribution system even when cases of health care-acquired Legionnaires' disease had never been identified. Our purpose was to (1) evaluate the impact of the ACHD guidelines on the Legionella diagnostic and preventive practices of health care facilities in Allegheny and surrounding counties and (2) compare the incidence of health care-acquired LD before and after issuance of the ACHD guidelines. CDC case reports of LD from 1991 to 2001 were tabulated and compiled by the ACHD Infectious Disease Unit and the Association for Professionals in Infection Control and Epidemiology, Inc, Three Rivers Chapter. A survey was distributed to 110 hospitals and long-term care facilities in the region. The results were analyzed as occurring either in the preguideline period (1991-1994) or postguideline period (1995-2001). A significant decrease in the number of health care-acquired cases was demonstrated between the preguideline (33%) and postguideline (9%) periods (P=.0001). In contrast, community-acquired cases increased from 67% pre guideline to 91% post guideline. A total of 71% of the facilities were colonized with Legionella. Disinfection of the water distribution system was initiated by 44% of facilities. Use of urinary antigen testing significantly increased from 40% pre guideline to 79% post guideline (P=.0001). Health care-acquired LD declined significantly after the issuance of guidelines for prevention and control of health care-acquired LD. The decline was associated with health care facilities performing routine environmental monitoring of their water distribution systems followed by the initiation of disinfection methods if indicated. Two unanticipated benefits were (1) cases of LD in the community and long-term care facilities were uncovered as a result of increased availability of Legionella tests and (2) litigation and unfavorable publicity involving ACHD hospitals ceased.


Diversity of cytoplasmic functions for the 3' untranslated region of eukaryotic transcripts.
The 3' untranslated region (3' UTR) can control gene expression by affecting the localization, stability and translation of mRNAs. The recent finding that 3' UTRs can control the decapping rate of mRNAs, in combination with their ability to influence the initiation of translation, suggests that 3' UTRs act through a direct or indirect interaction between the 3' and 5' ends of mRNAs.


Is quality in the eye of the beholder?
Relatively ignored in the literature on quality improvement (QI) in health care is the question of who defines the issues in quality of care and decides how those issues will be addressed. In late 1992, 669 hospital administrators, quality assurance (QA) coordinators, physicians, and nurses in 72 hospitals in six states were surveyed by telephone. Respondents were asked to identify the most serious issue related to quality of care in their hospital. Of all the respondents, hospital administrators were most likely to identify quality issues related to organizational/institutional issues. QA coordinators, most of whom had nursing backgrounds, were most likely to identify organizational and patient care issues. Physician responses were distributed approximately evenly across issues related to physicians, to the organization, and to patient care. Nurses were most likely to identify issues related to patient care and patient satisfaction. The findings validate the viewpoint that "quality is in the eye of the beholder" and that the eye is conditioned by the discipline in which hospital staff have been trained and socialized. As total quality management and continuous quality improvement approaches are implemented, and participants from many disciplines are involved in QI, a wide range of issues that have both a direct and indirect effect on patient care are likely to be addressed. The findings of this study suggest that surveys that specifically target certain disciplinary groups may yield important information about issues related to quality of care.


Effect of intra-arterial CO2 insuffflation on occlusive arterial disease in the lower leg.
Twenty patients with a mean age of 79 years were followed over a period of 6 months after intra-arterial insufflation of CO2 in the lower extremity. All patients had severe peripheral occlusive arterial disease caused by atherosclerosis and were scheduled for amputation. A significant increase of the distal perfusion pressure was obtained in the majority of the cases resulting in pain relief and healing of ulcers and gangrenes.


Protein and lipid disturbances in rat liver microsomal membranes after bile duct ligation.
An analysis of proteins, phospholipids and cholesterol from liver microsomal membranes was performed in normal and post-cholestatic rats. Bile duct ligated rats showed a progressive decrease of these membrane constituents. Minor changes in peptide analysis, a marked decrease of phosphatidylcholine and phosphatidylinositol, disappearance of phosphatidylethanolamine and sphingomyelin, and a clear increment of phosphatidylserine was observed in post-cholestatic as compared to normal group. It was concluded that extra-hepatic cholestasis produces structural changes on the liver microsomes, particularly on phospholipid profile.


First Detection of OXA-10 Extended-Spectrum Beta-Lactamases and the Occurrence of mexR and nfxB in Clinical Isolates of Pseudomonas aeruginosa from Nigeria.
The characterization of β-lactamase production in Pseudomonasaeruginosa is rarely reported in Nigeria. The objective of this study was to investigate the occurrence and characterize the different β-lactamases as well as mechanisms of fluoroquinolones resistance among P. aeruginosa isolated from various clinical sources from Nigeria. Isolates were investigated using PCR, RFLP and sequencing for the detection of various β-lactamases and efflux pump regulator genes. The prevalence of OXA-10, AmpC, CTX-M and SHV in P. aeruginosa was 80, 70, 5 and 5%, respectively. The coexistence of blaOXA-10 with blaAmpC, blaSHV and blaCTX-M was reported in 40, 5 and 5% of isolates, respectively. The efflux pump regulator genes mexR and nfxB were both amplified in 45% of the OXA-10-positive isolates. This is the first report of the characterization of OXA-10 extended-spectrum β-lactamases and occurrence of mexR and nfxB efflux regulator genes in clinical isolates of P. aeruginosa in Nigeria.


The action of puromycin and cycloheximide on the initiation of rapid axonal transport in amphibian dorsal root neurones.
1. Amphibian dorsal root ganglia-sciatic nerve preparations were incubated in vitro and the rapid axonal transport of radioactive labels was studied with a position-sensitive detector and by conventional liquid scintillation analysis. Protein was labelled by exposure of the ganglia to [(35)S]methionine or [(3)H]leucine and lipid was labelled using [(32)P]orthophosphoric acid.2. Protein synthesis was interrupted by exposure of the ganglia to either cycloheximide or puromycin. When ganglia were exposed to either inhibitor prior to or simultaneously with a label, the somal export of both protein and lipid to the axon was reduced by two to three orders of magnitude.3. Using the position-sensitive detector, [(35)S]methionine was observed to be exported from the ninth dorsal root ganglia of Rana catesbiana 3.49+/-1.56 h (+/- S.D.) after exposure, and [(32)P]phosphate 4.46+/-1.85 h after exposure.4. Export of [(35)S]methionine or [(32)P]phosphate was disrupted 3.32+/-1.21 h (+/- S.D.) or 1.93+/-1.04 h respectively after exposure of the ganglia to cycloheximide or puromycin.5. For a given preparation the time required for [(35)S]methionine to be exported was statistically equal to the time required for cycloheximide or puromycin to disrupt export. No such correlation was found to exist for the export of [(32)P]phosphate.6. Analysis revealed that materials labelled with either [(35)S]methionine or [(32)P]phosphate continue to be exported from the ganglia for several hours after the initial disruption in outflow caused by the inhibitors.7. The results do not provide support for the hypothesis of Ambron, Goldman & Schwartz (1975) that a ;key' newly synthesized, and non-storable, polypeptide is added to an already assembled structure to allow rapid axonal transport to be initiated.


Bromocriptine-induced changes in dopamine and gamma aminobutyric acid in haloperidol withdrawn rats.
1. Daily administration of haloperidol (2 mg/kg, i.p.) for 35 days significantly decreased tyrosine hydroxylase activity as well as homovanillic acid in the corpus striatum of rats. 2. Long-term treatment with haloperidol significantly elevated (17%) glutamic acid decarboxylase activity as well as gamma-aminobutyric acid level in the corpus striatum. 3. Withdrawal of rats for 3 and 5 days after 32 and 30 days of haloperidol treatment increased the locomotor activity to 279% and to 211%, respectively, of control values. While haloperidol withdrawal decreased tyrosine hydroxylase activity, it produced no further change in glutamic acid decarboxylase activity and gamma-aminobutyric acid. 4. Daily injection of bromocriptine (2 mg/kg, i.p.) for 5 days in haloperidol-withdrawn rats decreased locomotor activity and dopamine release as evidenced by increased endogenous levels of dopamine and decreased homovanillic acid in striatum of rats. No further increase in striatal glutamic acid decarboxylase activity and GABA levels were reported after bromocriptine treatment. 5. Our data suggest that bromocriptine may elicit its beneficial effect in tardive dyskinesia patients by modifying dopamine turnover in the striatum.


SAIC: an iterative clustering approach for analysis of single cell RNA-seq data.
Research interests toward single cell analysis have greatly increased in basic, translational and clinical research areas recently, as advances in whole-transcriptome amplification technique allow scientists to get accurate sequencing result at single cell level. An important step in the single-cell transcriptome analysis is to identify distinct cell groups that have different gene expression patterns. Currently there are limited bioinformatics approaches available for single-cell RNA-seq analysis. Many studies rely on principal component analysis (PCA) with arbitrary parameters to identify the genes that will be used to cluster the single cells. We have developed a novel algorithm, called SAIC (Single cell Analysis via Iterative Clustering), that identifies the optimal set of signature genes to separate single cells into distinct groups. Our method utilizes an iterative clustering approach to perform an exhaustive search for the best parameters within the search space, which is defined by a number of initial centers and P values. The end point is identification of a signature gene set that gives the best separation of the cell clusters. Using a simulated data set, we showed that SAIC can successfully identify the pre-defined signature gene sets that can correctly separated the cells into predefined clusters. We applied SAIC to two published single cell RNA-seq datasets. For both datasets, SAIC was able to identify a subset of signature genes that can cluster the single cells into groups that are consistent with the published results. The signature genes identified by SAIC resulted in better clusters of cells based on DB index score, and many genes also showed tissue specific expression. In summary, we have developed an efficient algorithm to identify the optimal subset of genes that separate single cells into distinct clusters based on their expression patterns. We have shown that it performs better than PCA method using published single cell RNA-seq datasets.


The Ebola Vaccine, Iatrogenic Injuries, and Legal Liability.
Amir Attaran and Kumanan Wilson propose a compensation system for vaccine injuries, based on no-fault principles, to ensure that recipients of Ebola vaccines are fairly compensated in cases of iatrogenic harm.


Somatostatin receptor scintigraphy in patients with rheumatoid arthritis and secondary Sjögren's syndrome treated with Infliximab: a pilot study.
Human T lymphocytes infiltrating tissues in autoimmune diseases are known to express somatostatin receptors amongst other activation markers. In this study, we evaluated whether somatostatin receptor scintigraphy (SRS) using a radiolabelled somatostatin analogue ((99m)Tc-EDDA/tricine-HYNIC-tyr(3)-octreotide ((99m)Tc-EDDA/HYNIC-TOC)) is able to detect the presence of immune-mediated processes in patients with rheumatoid arthritis and secondary Sjögren's syndrome. We also aimed to evaluate whether positivity to SRS was predictive of therapeutic response and if SRS could be used for monitoring the efficacy of immunomodulatory treatment. Eighteen patients with rheumatoid arthritis and secondary Sjögren's syndrome not responding to conventional treatment were recruited for treatment with infliximab, a monoclonal antibody against TNF-α. All patients had complete blood cell count, renal and liver function tests, measurements of ESR, CRP, ANA, ENA, and anti-dsDNA antibodies, functional salivary gland scintigraphy, labial biopsy, and ophthalmologic assessment with Schirmer's test and tear film break-up time (BUT). Diagnosis was made according to the revised criteria of the American-European Consensus Group. All patients underwent SRS at baseline and after 3-6 months of therapy with infliximab. Eleven out of 18 had repeat SRS images. Images of the salivary glands and major joints were acquired 3 h after injection of 370 MBq of (99m)Tc-EDDA/HYNIC-TOC. Image analysis was performed semi-quantitatively. All patients showed uptake of (99m)Tc-EDDA/HYNIC-TOC in the joints. Salivary glands also showed variable radiopharmaceutical uptake in 12 out of 18 patients, but all patients showed presence of lymphocytic infiltration at labial salivary gland biopsy. All patients, who repeated the study after treatment, showed significant reduction of somatostatin uptake in the joints but not in the salivary glands. SRS using (99m)Tc-EDDA/HYNIC-TOC may be a useful imaging tool to assess disease activity and extent in patients with rheumatoid arthritis and may help to detect secondary Sjögren's syndrome. It may also aid therapy decision-making with anti-TNFα antibodies in the joints but not in salivary glands.


Normal vertebral dimensions and normal variation in serial measurements of vertebrae.
A total of 568 lateral spine radiographs of 191 generally healthy white perimenopausal women were used to determine the limits of normal for shape and dimensions of the vertebral bodies most often involved in osteoporotic fracture. Anterior and posterior vertebral heights for T7-L4 were used to compute wedge shape, relative posterior height, and relative serial change. Wedge shape was defined as anterior height minus posterior height divided by posterior height. Relative posterior height was defined as the posterior height of a vertebra minus the posterior height of the vertebra superior divided by the posterior height of the vertebra superior. The degree of normal wedging depended on position: wedge values progressed down the spine, from a mean of -0.106 at T7 to 0.048 at L4. The minimum normal wedge value ranged from -0.209 at T7 to -0.083 at L4. Radiographs on a cohort of 28 osteoporotic women were evaluated both by ordinary clinical reading of the radiographs and by using the standards developed from the normal subjects. Initial agreement between the two modes of assessment was 85.4%, and in resolving the remaining disagreements the clinician agreed that he had initially misread the films in all but 3.2%. On the basis of this limited experience, we conclude that the use of such objective standards, in a computer-operated algorithm, is more accurate than routine radiographic assessment. Serial x-rays spanning a 15-20 year period in these women permitted determination of both reproducibility and longitudinal change in vertebral dimensions in the perimenopause. The mean relative serial change was not significantly different from zero for all vertebrae.(ABSTRACT TRUNCATED AT 250 WORDS)


On the 2D-transition, hysteresis and thermodynamic equilibrium of Kr adsorption on a graphite surface.
The adsorption and desorption of Kr on graphite at temperatures in the range 60-88K, was systematically investigated using a combination of several simulation techniques including: Grand Canonical Monte Carlo (GCMC), Canonical kinetic-Monte Carlo (C-kMC) and the Mid-Density Scheme (MDS). Particular emphasis was placed on the gas-solid, gas-liquid and liquid-solid 2D phase transitions. For temperatures below the bulk triple point, the transition from a 2D-liquid-like monolayer to a 2D-solid-like state is manifested as a sub-step in the isotherm. A further increase in the chemical potential leads to another rearrangement of the 2D-solid-like state from a disordered structure to an ordered structure that is signalled by (1) another sub-step in the monolayer region and (2) a spike in the plot of the isosteric heat versus density at loadings close to the dense monolayer coverage concentration. Whenever a 2D transition occurs in a grand canonical isotherm it is always associated with a hysteresis, a feature that is not widely recognised in the literature. We studied in details this hysteresis with the analysis of the canonical isotherm, obtained with C-kMC, which exhibits a van der Waals (vdW) type loop with a vertical segment in the middle. We complemented the hysteresis loop and the vdW curve with the analysis of the equilibrium transition obtained with the MDS, and found that the equilibrium transition coincides exactly with the vertical segment of the C-kMC isotherm, indicating the co-existence of two phases at equilibrium. We also analysed adsorption at higher layers and found that the 2D-coexistence is also observed, provided that the temperature is well below the triple point. Finally the 2D-critical temperatures were obtained for the first three layers and they are in good agreement with the experimental data in the literature.


Complete Genome Coding Sequences of Artashat, Burana, Caspiy, Chim, Geran, Tamdy, and Uzun-Agach Viruses (Bunyavirales: Nairoviridae: Orthonairovirus).
The bunyaviral monogeneric family Nairoviridae currently includes 12 species for 35 distinct viruses. Here, we present the complete genome coding sequences of an additional seven nairoviruses. Five of them can be assigned to established species, whereas two of them (Artashat and Chim viruses) ought to be assigned to two novel species.


Gastric acid secretion in gastric fistula dogs after antral denervation and antrectomy.
Acid secretion in Pavlov pouches in dogs is known to increase after antrectomy in response to histamine and gastrin. Dogs with gastric fistulae were tested with histamine and tetragastrin as a control study. The vagal nerve fibers to the antrum were divided and the dogs underwent repeat testing. Finally an antrectomy was performed and final dose-response data were collected. After antrectomy there was an increased acid response to histamine and tetragastrin. We postulate that the vagal fibers innervating the antrum are probably not a factor in this increase. Furthermore, we believe that the increased acid secretion after antrectomy observed in the dog and the decrease known to occur in the human being is a species difference and is not related to the pouch method of study used in earlier studies of the antrectomized dog.


ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine.
Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II. Hence, reduced intracellular phosphoethanolamine causes mitochondria hyperactivation, ROS production, and DNA damage. Treatment with phosphoethanolamine is able to counteract complex II hyperactivation and to restore a normal phenotype.


2,6-Diphenyl-3-(prop-2-en-1-yl)piperidin-4-one.
In the title compound, C20H21NO, the dihedral angle between the phenyl ring is 47.5 (1)° and the piperidine ring adopts a chair conformation. In the crystal, mol-ecules are linked by C-H⋯π inter-actions into dimers with the mol-ecules related by twofold symmetry.


Interference of blast cell fragments with automated platelet counting.
Automated haematology analysers may inaccurately determine platelet counts in several circumstances. Spuriously elevated automated platelet counts have been reported in some acute leukaemia (AL) cases because of fragmentation of circulating blast cells (pseudoplatelets). Haemorrhagic diathesis is a common manifestation of AL, which is often caused by severe thrombocytopenia. Therefore, overestimation of the actual platelet count in patients with AL can affect its clinical management. We aimed to detect the frequency of pseudoplatelets in patients with AL. Complete blood cell counts were performed on 86 AL patients with three automated analysers (ADVIA 2120, Coulter LH 750 and Sysmex XE-2100D). Platelet counts were also performed by quantitative flow cytometry (QFC). The platelet counts of the automatic analysers were compared to the platelet counts by QFC. Blood smears were checked for the presence of pseudoplatelets. The automated analysers overestimated the platelet count due to the presence of pseudoplatelets in patients with AL. Pseudoplatelets were observed in the blood smears of 11 patients (13%). Three of these patients were near the prophylactic platelet transfusion threshold. Spurious increases in automated platelet counts by blast cell fragments are little known but frequent artefacts that should be ruled out by careful examination of peripheral blood smears.


Traumatic death in urban children.
Trauma has remained one of the leading causes of death in children in spite of improved medical care. A review of 911 pediatric trauma deaths which occurred over a 5 yr period in an urban setting revealed that almost 50% of these children died before receiving medical care. A significant improvement of the trauma mortality can thus only be accomplished by reducing the number of "DOAs". We therefore analyzed the cause and type of injury and its relationship to age, sex, race, seasonal occurrence, and sociological circumstances. The following four categories are merely part of the overall material developed in this review. Even with improved medical care of trauma patients the overall pediatric trauma mortality cannot be significantly reduced unless the number of DOAs is decreased through prevention. Educational and family assistance programs can be designed for specific problem areas to reach identified susceptible groups through existing channels such as day care centers, schools, or welfare agencies. Statistical data, such as presented here (but not previously available) are essential to analyze the particular problems of specific geographic and sociologic areas. Since the vast majority of pediatric trauma deaths fall within the interest sphere of the pediatric surgeon, our active participation in accident prevention is essential to achieve a significant reduction of pediatric trauma mortalities.


Nerve fiber density differences in the temporal dura mater: An explanation for headache after temporal lobectomy? An anatomical study.
Patients who undergo a temporal lobectomy for drug-resistant epilepsy more frequently complain about postoperative headache compared to patients who undergo a craniotomy in any other region. The pathophysiological mechanism is not well understood. It is hypothesized that a relatively high density of sensory nerve fibers in the temporomesial dura underlies a higher sensitivity to pain upon stimulation. The objective of this study was to address this hypothesis by comparing the nerve fiber density in the temporomesial dura to that in the temporolateral dura. Temporomesial (n = 6) and temporolateral (n = 6) dura mater samples (2.5 × 2 cm) were dissected from the middle cranial fossa of 5 formalin fixed human cadavers. Paraffin embedded specimens were cut in a sagittal direction into 5 µm sections (temporomesial group n = 106, temporolateral group n = 113), and immunohistochemically stained for S100 as a marker of myelinated nerve fibers. The number of S100-immunoreactive nerve fiber bundles was counted in an anterior-posterior direction by a blinded observer, expressed as mean ± standard error of the mean per cm for each group, and statistically analyzed by a linear mixed-effects model. To assess potential observer bias, a randomized subset of the sections (n = 28) was evaluated by a second blinded observer and statistically analyzed by intraclass correlation coefficient (ICC). The temporomesial dura expressed 4.1 ± 2.1 and the temporolateral dura displayed 1.0 ± 0.7 nerve fiber bundles per cm (β = 3.2, SE= 0.30, 95% CI [2.6, 3.8], p < 0.001). There is a significant decrease in nerve fiber bundle density in the mesial to lateral direction (mean difference -0.1, SE= 0.0, 95% CI [-0.1, -0.2], p < 0.001). The ICC was 0.69. The density of myelinated nerve fiber bundles is about 4 times higher in the temporomesial dura, than in the temporolateral dura. Assuming that dural innervation primarily consists of sensory trigeminal fibers, this observation suggests that a summation of stimuli to surpass the threshold to convey pain is reached sooner in the temporomesial than in the temporolateral dura mater.


The influence of attachment and emotional support in end-stage cancer.
The impact of attachment style and emotional support on negative affect in 67 end-stage cancer patients was examined via self-report inventory. Path analysis revealed high levels of both attachment anxiety and attachment avoidance were associated with lower levels of emotional support which, in turn, had a major adverse influence on patients' negative affect. In addition, attachment anxiety was also directly associated with distress. The discussion emphasises the importance of attachment theory and emotional support within the context of terminal cancer.


Maternal Deaths from COVID-19 in Brazil: Increase during the Second Wave of the Pandemic.
To compare death rates by COVID-19 between pregnant or postpartum and nonpregnant women during the first and second waves of the Brazilian pandemic. In the present population-based evaluation data from the Sistema de Informação da Vigilância Epidemiológica da Gripe (SIVEP-Gripe, in the Portuguese acronym), we included women with c (ARDS) by COVID-19: 47,768 in 2020 (4,853 obstetric versus 42,915 nonobstetric) and 66,689 in 2021 (5,208 obstetric versus 61,481 nonobstetric) and estimated the frequency of in-hospital death. We identified 377 maternal deaths in 2020 (first wave) and 804 in 2021 (second wave). The death rate increased 2.0-fold for the obstetric (7.7 to 15.4%) and 1.6-fold for the nonobstetric groups (13.9 to 22.9%) from 2020 to 2021 (odds ratio [OR]: 0.52; 95% confidence interval [CI]: 0.47-0.58 in 2020 and OR: 0.61; 95%CI: 0.56-0.66 in 2021; p < 0.05). In women with comorbidities, the death rate increased 1.7-fold (13.3 to 23.3%) and 1.4-fold (22.8 to 31.4%) in the obstetric and nonobstetric groups, respectively (OR: 0.52; 95%CI: 0.44-0.61 in 2020 to OR: 0.66; 95%CI: 0.59-0.73 in 2021; p < 0.05). In women without comorbidities, the mortality rate was higher for nonobstetric (2.4 times; 6.6 to 15.7%) than for obstetric women (1.8 times; 5.5 to 10.1%; OR: 0.81; 95%CI: 0.69-0.95 in 2020 and OR: 0.60; 95%CI: 0.58-0.68 in 2021; p < 0.05). There was an increase in maternal deaths from COVID-19 in 2021 compared with 2020, especially in patients with comorbidities. Death rates were even higher in nonpregnant women, with or without comorbidities.


Small bowel esophagoplasty without vascular microanastomosis: a preliminary report.
An intestinal segment through staged augmentation of its blood supply can be well suited to bridge a gap in the esophagus from the abdomen to the neck.


Green Synthesized Silver Nanoparticles-Mediated Cytotoxic Effect in Colorectal Cancer Cells: NF-κB Signal Induced Apoptosis Through Autophagy.
Green synthesized silver nanoparticles (Ag-NPs) have demonstrated promising effects, including cytotoxicity and anticancer potential, in different cell lines. Therefore, in our previous study, Ag-NPs were synthesized from the reduction of AgNO3 using Brassica rapa var. japonica (Bj) leaf extract as a reducing and stabilizing agent. The synthesized Ag-NPs were spherical in shape, with a size range of 15-30 nm. They had phase-centered cubic structure with strong growth inhibition potential against some bacteria. In continuation with our previous study, in the present study, we aimed to investigate the autophagy-regulated cytotoxic effect of Ag-NPs against human epithelial colorectal adenocarcinoma cells (Caco-2 cells). We found that the Bj leaf aqueous extract facilitated Brassica silver nanoparticles (Brassica Ag-NPs)-induced NF-κB mediated autophagy in Caco-2 cells. Results showed that Ag-NPs reduced cell viability of Caco-2 cells by inducing oxidative stress and DNA damage. Therefore, to understand the mechanism underlying the death-promoting activity of Ag-NPs in Caco-2 cells, western blotting was performed. Western blot analysis showed decreased expression of NFκB and increased expression of IκB, which is a sign of autophagy initiation. In addition, autophagosome formation was accelerated by the activity of p53 and light chain 3 (LC3) II. In addition, inhibition of Akt and mTOR also played a pivotal role in autophagy formation. Finally, excessive expansion of autophagy promoted apoptosis, which subsequently resulted in necrosis. These findings support a novel cell death-promoting function of autophagy by Ag-NPs in Caco-2 cells.


Autologous hematopoietic stem cell transplantation for relapsed/refractory systemic anaplastic large cell lymphoma. A retrospective analysis of the lymphoma working party (LWP) of the EBMT.
Systemic anaplastic large cell lymphoma (sALCL) is a rare histological entity expressing the CD30 antigen that comprises around 11% of peripheral T-cell lymphoma. We analysed the outcome of patients with relapsed/refractory sALCL treated with autologous stem cell transplantation (auto-HCT). We included 65 adult patients (42 males; median age, 44 years); 24 patients had an ALK-ve sALCL. Fifty-one patients had chemosensitive disease at the time of transplant. Ten patients (15%) were treated with brentuximab vedotin (BV) before auto-HCT (median number of doses: 5). The median follow-up for surviving patients was 35 months (3-71). Three-year cumulative incidence of nonrelapse mortality and of relapse were 1.7% and 34%, respectively. Three-year progression-free survival and overall survival were 64% and 73%, respectively. No prognostic factors for any of the outcomes analysed were found in univariate analysis. There were no significant differences in any of the outcomes between patients who had received BV and the remainder. This is the largest analysis presented so far analysing the role of auto-HCT in patients with relapsed/refractory sALCL, showing a promising PFS and OS in this high-risk population. The potential impact of the administration of BV as salvage strategy before the procedure needs to be further elucidated.


Brain gamma-aminobutyric acid measurement by proton double-quantum filtering with selective J rewinding.
An optimized single-shot proton double-quantum (DQ) filter for the quantification of gamma-aminobutyric acid (GABA) levels in human brain is reported. It is demonstrated that creation of DQ coherences following dual-resonance-selective refocusing gives a theoretical editing efficiency of 50% for the detection of the GABA resonance at 3.01 ppm. The sequence times are optimized with both numerical and experimental analyses of the editing performance, giving an experimental editing efficiency of 42%. It is acknowledged that homocarnosine is partially coedited, leading to a 20% contribution to the edited signal; however, macromolecule contamination is negligible in vivo under these experimental conditions. The GABA concentration in human prefrontal cortex is estimated to be 0.8 +/- 0.1 micromol/g (mean +/- SD, n = 6), with reference to the internal standard creatine at 9 micromol/g.


Characterization of autochthonal Hafnia spp. strains isolated from Spanish soft raw ewe's milk PDO cheeses to be used as adjunct culture.
The present work was performed to study the enterobacteria involved in the ripening of the artisanal raw ewe's milk PDO cheeses 'Torta del Casar' and 'Queso de la Serena' produced in Extremadura (Spain). These isolates were strain-typed, safety tested and characterized for some important technological properties. A total of 485 enterobacterial isolates were clustered by RAPD-PCR and subsequently identified by partial sequencing of the 16S rRNA gene. Among the 17 different species identified, Hafnia paralvei was the predominant species; H. alvei and Lelliottia amnigena were present to a lesser extent. Therefore, 55 Hafnia spp. strains, selected according to their genetic profile and dairy origin, were tested for the safe application. Overall, they were able to produce the biogenic amines putrescine and cadaverine under favourable conditions, presented α-haemolytic activity and did not produce cytolytic toxin active against HeLa cells or contain virulence genes. In addition, antibiotic susceptibility profiles showed that 17 Hafnia spp. strains were less resistant to the 33 antibiotics tested; subsequently, they were further technologically characterized. Although they showed differences, in general, they were well adapted to the stress conditions of cheese ripening. Among them, two strains, H. alvei 544 and 1142, are highlighted mainly due to their proteolytic activity at refrigeration temperatures and their low or null gas production. Although further studies are necessary before industrial application, these two strains are proposed for potential use as adjunct cultures to favour the homogeneity of these PDO cheeses, preserving their unique sensory characteristics.


Reduction of arginine vasopressin binding sites in mouse lateral septum by treatment with 6-hydroxydopamine.
The neuropeptide arginine vasopressin modulates neuroadaptive processes, including memory consolidation and functional tolerance to ethanol, by actions at CNS V1 receptors. Noradrenergic systems play a role in these actions of the peptide. To assess whether vasopressin may act presynaptically on catecholamine neurons, vasopressin receptors were measured by quantitative autoradiography in the lateral septum, an area that is innervated by catecholaminergic neurons and has a high density of V1 receptors, of control and 6-hydroxydopamine-treated mice. Vasopressin receptors were distributed non-uniformly throughout the lateral septum, with greater binding in the more caudal regions. Treatment with 6-hydroxydopamine lowered septal catecholamine levels and vasopressin binding, with a greater effect on binding in the intermediate and caudal portions of the lateral septum. Pretreatment with desmethylimipramine reversed the depletion of norepinephrine, and attenuated the effect of 6-hydroxydopamine on vasopressin binding in the intermediate region, but was less effective in the caudal region of the lateral septum. The results suggest that a portion of septal vasopressin receptors are localized on the terminals of noradrenergic and, possibly, dopaminergic neurons, consistent with the hypothesis that certain neuroadaptive responses to vasopressin could be mediated by modulation of neurotransmitter release. In contrast to the results with 6-hydroxydopamine, treatment of mice with 5,7-dihydroxytryptamine, to destroy serotonergic terminals, did not alter vasopressin binding in the lateral septum.


β-Estradiol unmasks metabotropic receptor-mediated metaplasticity of NMDA receptor transmission in the female rat dentate gyrus.
Loss of estrogen in women following menopause is associated with increased risk for cognitive decline, dementia and depression, all of which can be prevented by estradiol replacement. The dentate gyrus plays an important role in cognition, learning and memory. The gatekeeping function of the dentate gyrus to filter incoming activity into the hippocampus is modulated by estradiol in a frequency-dependent manner and involves activation of metabotropic glutamate receptors (mGluR). In the present study, we investigated whether estradiol (EB) modulates the metaplastic effect of inducing synaptic long-term potentiation (LTP) on subsequent propensity for expression of LTP in the dentate gyrus. At medial perforant path-dentate granule cell synapses in hippocampal slices of ovariectomized female rats, EB replacement was critical for an initial induction of LTP to enhance the magnitude of subsequent LTP elicited by a second high-frequency stimulation, metaplasticity, which was not present in slices from oil-treated control animals. EB enhanced expression of group I mGluRs, and the metaplastic effect of EB on LTP required activation of group I mGluRs that led to Src-family tyrosine kinase-mediated phosphorylation of NR2B subunits of N-methyl-d-aspartate receptors (NMDAR) that enhanced the magnitude of NMDAR-dependent LTP. Our data show that EB effects on LTP in the hippocampal dentate gyrus require activation of group I mGluRs, which in turn leads to functional metaplastic regulation of NR2B subunit-containing NMDARs, as opposed to direct effects of EB on NMDARs.


[Image-guided and -controlled percutaneous laser disc decompression by cross-sectional imaging and pathology ex vivo].
Nearly 65-70% of the population over the age of 40 years may be affected by lumbar pain. The aim of the author was to detect the impact of percutaneous laser disc decompression in intervertebral discs. For the model 27 ex vivo lumbar intervertebral discs were used. Constant laser light energy to the nucleus pulposus was delivered using diode laser. Computed tomography and fluoroscopy were performed to compare the accuracy of the procedure. For the detection of the physical effect of the laser procedure, magnetic resonance imaging was performed after the laser procedure. To demonstrate morphological tissue changes, histopathological studies were conducted. 2 mm accuracy was reached by cross-sectional imaging aided surgical navigation. The radiation exposure time to the staff was reduced. Measurable tissue changes were detected and different physical effects were verified in the nucleus pulposus after the laser procedure magnetic resonance imaging. The applied study is feasible for modeling percutaneous laser disk decompression PLDD with cross sectional imaging aided surgical navigation. The physical effect was detectable by magnetic resonance measurements which could be used to control in vivo human applications in the future.


Senescence-induced increases in intracellular oxidative stress and enhancement of the need for ascorbic acid in human fibroblasts.
Many studies have suggested that there is a close correlation among declines in internal ascorbic acid (AsA) levels, various disorders, and senescence. To clarify the relationships between age-associated changes in intracellular AsA levels and the effects of AsA administration on intracellular reactive oxygen species (ROS) levels, we investigated aging-related changes in AsA uptake, ROS levels, and the effects of AsA administration on intracellular ROS levels in young and old (senescent) human fibroblasts. Our results demonstrated that AsA uptake was increased in old cells compared with young cells, although mRNA and protein expression of sodium-dependent vitamin C transporter 2 was barely altered between the young and old cells. We also demonstrated that the intracellular superoxide anion level was higher in young cells, whereas the level of intracellular peroxides was significantly increased in old cells under both normal and oxidative stress conditions. Moreover, AsA administration markedly decreased the augmentation of intracellular peroxides in old cells, whereas there was no effect of AsA treatment in young cells under both normal and oxidative stress conditions. Therefore, our results also indicate that AsA could play an important role in regulating the intracellular ROS levels in senescent cells and that the need for AsA is enhanced by cellular senescence.


Trends in selected obstetric complications from University Hospital, Kuala Lumpur, Malaysia.
Trends in selected pregnancy complications from 1969 to 1987 in a tertiary hospital in Malaysia are presented. Complications reviewed were abortion, ectopic pregnancy, anemia, hypertension, hyperemesis, antepartum and postpartum hemorrhage. Possible explanations for the observed trends were discussed, including the role of improved obstetric care and changes in the characteristics of the childbearing population. The data presented give some indication of maternal morbidity in the childbearing population served by this tertiary center and should lead to improvements in provision of services as well as in health data collection in the future.


Surgical factors associated with patient-reported quality of life outcomes after free flap reconstruction of the oral cavity.
To determine which surgical factors are associated with quality-of-life (QOL) outcomes in oral cavity cancer survivors after free flap reconstruction of the oral cavity. A cross-sectional study was conducted from a multidisciplinary head and neck cancer (HNC) survivorship clinic. Oral cavity cancer survivors with at least 6-months of postoperative follow-up from ablation and free flap reconstruction were included. Primary outcome measures were validated patient-reported outcome measures (PROMs) including the Eating Assessment Tool-10 (EAT-10) measure of swallowing-specific QOL, University of Washington Quality of Life (UW-QOL) physical and social-emotional subscale scores and feeding tube dependence. Extent of tongue resection was associated with EAT-10 and the UW-QOL Physical subscale scores. Patients with oral tongue defects reported worse scores than with composite defects in the EAT-10 and UW-QOL physical domain (p = 0.0004, 0.0025, respectively). This association no longer applies when controlling for differences in extent of tongue resection. Patients with anterior composite resections reported worse EAT-10 scores than lateral resections (p = 0.024). This association no longer applies when controlling for extent of tongue resection (p = 0.46). Gastric tube dependence demonstrates similar trends to PROMs. Extent of tongue resection was strongly associated with poor QOL outcomes after free tissue reconstruction of the oral cavity and mediates the associations between other defect characteristics and QOL. These findings demonstrate the need for emphasis on expected oral tongue defects when counseling patients and highlight the need to address QOL in a multidisciplinary fashion post-operatively.


Hope and PTSD.
This paper reviews the present literature examining how hope relates to PTSD and broader functioning after a trauma, including potential underlying mechanisms and significant factors impacting these relationships and the role of hope as a mechanism of change within interventions for PTSD. First, the ways in which trauma impacts hope are discussed. Afterwards, an overview is provided of cross-sectional and prospective research indicating that greater hope reduces the risk of PTSD and promotes positive outcomes of adversity. Next, potential underlying mechanisms and determinants of the relationship between hope and adjustment are explored, including adaptive appraisals, productive coping, and social support. Finally, evidence supporting the role of hope as a mechanism of change in treatments for PTSD is reviewed.


A comparison of frontal electromyographic biofeedback training, trapezius electromyographic biofeedback training, and progressive muscle relaxation therapy in the treatment of tension headache.
This study is the first systematic examination of a trapezius EMG biofeedback training regimen with tension headache sufferers. It evaluated the differential effects of three psychophysiological treatments for tension headache: (1) a standard 12-session frontal EMG biofeedback training regimen (n = 8), (2) a 12-session upper trapezius EMG biofeedback training regimen (n = 10), and (3) a standard seven-session progressive muscle relaxation therapy regimen (n = 8). Posttreatment assessment at 3 months following cessation of treatment revealed clinically significant decreases in overall headache activity (50% or greater) in 50% of subjects in the frontal biofeedback group, 100% in the trapezius biofeedback group, and 37.5% in the relaxation therapy group. Chi-squared analyses indicated that the trapezius biofeedback group was more effective in obtaining significant clinical improvement than the frontal biofeedback and relaxation therapy groups (which did not differ from each other). The three treatments did not differ on secondary measures of headache improvement (number of headache-free days, peak headache activity, and medication index). Implications for the psychophysiological treatment of tension headache, as well as future research directions, are discussed.


Leishmaniasis in Bolivia. II. The involvement of Psychodopygus yucumensis and Psychodopygus llanosmartinsi in the selvatic transmission cycle of Leishmania braziliensis braziliensis in a lowland subandean region.
An epidemiological survey of the vectors of cutaneous leishmaniasis ("espúndia" type) was carried out in the Alto Beni region of Bolivia, an area of Andean foothills at the Eastern limit of the Amazonian lowlands. The climate is typical wet tropical (15 degrees S latitude). Anthropophilic phlebotomine sandfly species were sampled at 20 sites, all forested. The importance of species from the Psychodopygus group, already suspected as a vector in the transmission of Leishmania from the braziliensis complex, was confirmed by: the aggressiveness and diversity of the species encountered (83% of catches, nine species), the discovery of a new anthropophilic species, P. yucumensis and the isolation of a strain of Leishmania braziliensis braziliensis indistinguishable from human strains from the same area, from two species, P. llanosmartinsi and P. yucumensis.


[Mechanisms of action of glucocorticoids].
Glucocorticoids exert their actions at nuclear levels through genomic mechanisms including both transcriptional activation (transactivation) and gene expression repression (transrepression). Transactivation mechanisms are mediated by transcription factors, the main one being the activated glucocorticoid receptor (GR). These mechanisms contribute to both powerful therapeutic effects of glucocorticoids on inflammatory and immune diseases, and adverse effects than can be harmful on vital functions. Non-genomic mechanisms, which act faster than genomic ones, have also been explored. They also involve the GR in different membranous and cytosolic sites. The phenomenon of glucocorticoid resistance is also complex and several different mechanisms may mediate this phenomenon. Among them are alterations in number, binding affinity or phosphorylation status of the GR, changes in capacity of cellular apoptosis, polymorphic changes or expression of proteins involved in the genomic actions of glucocorticoids. Finally, some proteins, which mediate glucocorticoid activity could be therapeutic targets for reducing glucocorticoid-induced adverse effects.


The bidirectional interactions between addiction, behaviour approach and behaviour inhibition systems among adolescents in a prospective study.
Internet addiction is a worldwide mental health problem among adolescents. This study aimed to evaluate the prediction of the Behaviour Inhibition System (BIS) and the Behaviour Approach System (BAS) on the occurrence of Internet addiction, and determine whether Internet addiction would make any difference on the development of BIS/BAS among adolescents. Adolescents in grade 7 were recruited to complete assessment for Internet addiction and BIS/BAS. Then, a follow-up was performed 1 year later. The results demonstrated that higher BAS and BAS fun seeking predicted the occurrence of Internet addiction. Adolescents with Internet addiction decreased more on BAS and BIS 1 year later than the non-addiction group. These results suggest that higher BAS and fun seeking are risk factors for Internet addiction among adolescents. Besides, interventions for Internet addiction should pay attention to the disturbed development of BAS and BIS.


Firing up Cold Tumors-Targeting the Epigenetic Machinery to Enhance Cancer Immunotherapy.
Cancer immunotherapy using monoclonal antibodies targeting immune checkpoint proteins, such as PD-L1 or PD-1 (i [...].


The acute cutaneous inflammatory response is attenuated in Slug-knockout mice.
We previously reported ultraviolet radiation (UVR) induction of Slug, a Snail family zinc-finger transcription factor, in the epidermis of mice; we now report that Slug-knockout mice are, unexpectedly, more resistant to sunburn than wild-type mice. There was a marked difference between the cutaneous inflammatory response in the skin of Slug-knockout and wild-type mice from 12 h to 1 week following a single exposure to 3 minimal erythemal doses of UVR. Slug-knockout mice showed a much reduced immediate increase in skin thickness and neutrophil infiltration compared to wild-type mice. However, there were as many or more intraepidermal T cells, dermal mast cells, and dermal blood vessels in the UVR-exposed skin of Slug-knockout mice as in the skin of wild-type mice. Differences in cytokine and chemokine expression following UVR appeared to account for at least some differences between the genotypes in cutaneous inflammatory response. Despite the reported antiapoptotic and antiproliferative role for Slug in some cell types, we observed little difference between the genotypes in UVR-induced keratinocyte apoptosis or proliferation. Our findings indicate an unexpected but important role for Slug in the acute cutaneous inflammatory response to UVR.


Successful cord blood transplantation for myelodysplastic syndrome complicated by Mycobacterium kansasii pneumonia.
Non-tuberculous mycobacterial (NTM) disease is a rare cause of neutropenic fever in patients with hematological malignancies. There are few studies on the optimal management for such patients with NTM. We report a case of myelodysplastic syndrome (MDS) treated by umbilical cord blood transplantation (CBT) after Mycobacterium kansasii (M kansasii) pneumonia. A 38-year-old man diagnosed with MDS developed severe pneumonia during induction chemotherapy. Repeated sputum culture uncovered mycobacterium infection. Then, by the polymerase chain reaction of the bronchial lavage fluid, M kansasii infection was proven. After 140 days of anti-NTM therapy, CBT was successfully carried out and the patient recovered without recurrence of NTM infection. This case provides valuable evidence that hematopoietic stem cell transplantation is feasible after a reliable diagnosis and continuous anti-NTM therapy.


Renal Outcomes of Antidiabetic Treatment Options for Type 2 Diabetes-A Proposed MARE Definition.
One of the most critical long-term complications of type 2 diabetes is nephropathy, currently termed diabetic kidney disease. Although the prevalence is increasing, renal outcomes are heterogeneously defined. Intensive glucose control is effective for the prevention of microvascular complications, including kidney disease. However, the impact of specific drugs on renal outcome measures such as the incidence of kidney disease, albuminuria, progression to end-stage kidney disease, or death of renal cause remains unclear. Comparison of agents or drug classes is impossible, as renal outcomes are inconsistently defined in trials. Recent publications include more stringent criteria, but use only composite endpoints, which can reveal significant results driven by a single surrogate marker but not clinical events of true relevance to patients. This review discusses renal outcomes related to antidiabetic agents for type 2 diabetes, in an attempt to determine the influence of specific drugs on the incidence of diabetic kidney disease and various renal outcomes. There are marked differences among the various agents, but direct comparisons are difficult due to heterogeneous measures. Statements from Kidney Disease Improving Global Outcomes (KDIGO) or European Renal Best Practice (ERBP) highlight that "standardized outcome reporting is key to achieving evidence-based guidance and improving clinical care for patients." Renal outcome studies including a well-defined, standardized core set of patient-relevant outcomes are needed. Here, we propose to define and establish major adverse renal events (MARE) as the outcome measure for future studies.


Alterations in surface activity of pulmonary surfactant in Gould's wattled bat during rapid arousal from torpor.
The small microchiropteran bat, Chalinolobus gouldii, undergoes large daily fluctuations in metabolic rate, body temperature, and breathing pattern. These alterations are accompanied by changes in surfactant composition, predominantly an increase in cholesterol relative to phospholipid during torpor. Furthermore, the surface activity changes, such that the surfactant functions most effectively at that temperature which matches the animal's activity state. Here, we examine the surface activity of surfactant from bats during arousal from torpor. Bats were housed at 24 degrees C on an 8:16h light:dark cycle and their surfactant was collected during arousal (28<T(b)<32 degrees C). Surface activity was examined with a Captive Bubble Surfactometer at 24 and 37 degrees C. Surfactant from arousing bats was more active at 37 degrees C than at 24 degrees C, indicated by a lower ST(min) and reduced film area compression required to reach ST(min). It appears that the arousal-induced changes in surfactant composition, i.e., lower levels of cholesterol, inhibit adsorption of surfactant at 24 degrees C. Furthermore, the alterations in surfactant composition during arousal are very rapid, such that the mixture behaves more like surfactant from warm-active bats, and therefore, functions more effectively at 37 degrees C.


Methicillin-resistant Staphylococcus aureus from dental school clinic surfaces and students.
Methicillin-resistant Staphylococcus aureus (MRSA) isolated from frequently touched dental school clinic surfaces were compared with MRSA isolated nasal cultures of dental students. Sixty-one dental students and 95 environmental surfaces from 7 clinics were sampled using SANICULT (Starplex Scientific Inc, Etobicoke, Ontario, Canada) swabs. Antimicrobial susceptibility testing was performed, and pulsed-field gel electrophoresis analysis, the mecA gene, multilocus sequence type, and SCCmec type were determined by polymerase chain reaction and sequencing. Thirteen (21%) dental students and 8 (8.4%) surfaces were MRSA positive. Three MRSA strains were SCCmec type IV, whereas 3 were nontypeable isolates and Panton-Valentine leukocidin positive (PVL+), and none were USA300. One surface and 1 student isolate shared the same multilocus sequence type ST 8 and were 75% related. Two groups of students carried the same MRSA strains. The MRSA-positive samples were from 4 of 7 dental clinics. In addition, 21% of the dental students carried MRSA, which is > 10 times higher than the general public and twice as frequent as in other university students. This is the first study to characterize MRSA from dental clinic surfaces and dental students and suggests that both may be reservoirs for MRSA. Further studies are needed to verify this premise.


Analysis of visual quality after multifocal intraocular lens implantation in post-LASIK cataract patients.
With the development of refractive corneal surgery, excimer laser in situ keratomileusis (LASIK) has become a common refractive surgery procedure. However, post-LASIK patients are at increased risk of developing cataracts as they age and often require IOL implantation. The choice of IOLs is particularly important for these patients, who have smaller residual refractive error and have higher requirements for post-cataract vision recovery and visual quality than the general population. Multifocal IOLs are widely used in clinical practice for patients with high visual acuity needs, such as cataract patients after refractive keratomileusis, due to their advantages of providing excellent near and distance visual acuity; however, compared to monofocal IOLs, multifocal IOLs can lead to postoperative problems related to visual quality such as increased higher order aberrations and decreased contrast sensitivity. Therefore, whether multifocal IOLs have advantages for post-LASIK cataract patients, such as improving the visual quality of such patients, has attracted attention. In this paper, we analyze the current status of research on the implantation of multifocal IOLs in post-LASIK cataract patients by domestic and foreign experts, review and summarize the relevant literature, and propose further discussion in the context of the actual situation of postoperative visual quality and vision recovery.


Identification and characterization of microRNAs in the liver of rainbow trout in response to heat stress by high-throughput sequencing.
MicroRNAs (miRNAs) play key roles in the stress response in animals. The rainbow trout is a widely cultivated cold-water fish species that usually encounters heat stress, which affects its growth and may cause diseases. However, there is limited information on the miRNAs involved in heat stress in this species. To identify the heat-responsive miRNAs at the genome level in rainbow trout, we conducted high-throughput sequencing of 6 small RNA libraries from the liver tissues of rainbow trout specimens under control and heat-treated conditions. A total of 363 conserved miRNAs and 638 novel miRNAs were identified, among which 39 (21 conserved and 18 novel) miRNAs were differentially expressed in response to heat stress. Eight important miRNAs were further validated using quantitative real-time PCR. GO enrichment and KEGG pathway analyses of the potential target genes of the DE miRNAs, revealed DNA replication and protein folding and unfolding were affected by heat stress. Several key pathways involved in the heat stress response were characterized, such as protein processing in the endoplasmic reticulum, NOD-like receptor signaling pathway, and progesterone-mediated oocyte maturation. In addition, 20 important functional interaction pairs among the 65 negatively correlated miRNA-mRNA pairs were identified using integrated miRNA-mRNA analysis and miRNA prediction algorithms, which including potential important miRNAs and target genes such as miR-301a, miR-301d, let-7c, novel_1181 and HSP90BA, HSP90BB, HSP40, PDIA3. This study showed that the identified miRNAs probably play important roles in the heat stress response and lay a foundation for further studies on the thermal adaptation mechanisms in rainbow trout.


Clinical characteristics and early outcomes of very elderly patients in the reperfusion era.
Not much data is available regarding "real-world" clinical experience of very elderly patients with acute myocardial infarction (AMI) in the reperfusion era. We reviewed 483 patients (26%) between the ages of 75 and 85 from the 1855 patients with AMI. We analyzed 264 patients treated with reperfusion therapy (55%) and 219 patients treated with conservative therapy (45%) on their clinical characteristics and early outcomes. Patients treated with reperfusion therapy were slightly younger (79.0 vs. 80.0 years, P=0.01), presented earlier (205 vs. 400 minutes, P<0.01) and had higher peak creatine kinase values (2634 vs. 1407 IU/l, P<0.01) than those treated with conservative therapy. Other clinical profiles including sex, prior myocardial infarction, hypertension, diabetes, and infarct location were similar to each other. There was a 92% success for reperfusion therapy. The incidence of recurrent ischemia, cardiac rupture, and cerebral hemorrhage was not significantly different between the two groups. In-hospital mortality in this study was 20.5%. In-hospital mortality was not significantly different between the two groups (19% vs. 23%, P=0.25). The multivariate analysis showed that age, infarct location, and Killip class were correlated to in-hospital mortality. The leading cause of in-hospital death was pump failure. Older age and late presentation were correlated to conservative therapy in very elderly patients with AMI. Early outcomes were similar between the two treatment groups. In-hospital mortality seemed to be associated with impaired myocardial reserve.


Gene sequences coding for S-adenosylmethionine decarboxylase are present on human chromosome 6 and the X and are not amplified in colon neoplasia.
Sequences for human S-adenosylmethionine decarboxylase, an enzyme involved in polyamine biosynthesis, which is elevated in tumors, have been localized on chromosome 6 and the X.


The relationship between mixed venous and regional venous oxygen saturation during cardiopulmonary bypass.
The relationship between mixed venous and regional venous saturation during cardiopulmonary bypass (CPB), and whether this relationship is influenced by temperature, has been incompletely elucidated. Thirty patients undergoing valve and/or coronary surgery were included in a prospective, controlled and randomized study. The patients were allocated to two groups: a hypothermic group (28 degrees C) and a tepid group (34 degrees C). Blood gases were analysed in blood from the hepatic vein and the jugular vein and from mixed venous blood collected before surgery, during hypothermia, during rewarming, and 30 min after CPB was discontinued. Oxygen saturation in the hepatic vein was lower than in the mixed venous blood at all times of measurement (-24.0 +/- 3.0% during hypothermia, -36.5 +/- 2.9% during rewarming, and -30.5 +/- 3.0% postoperatively, p < 0.001 at all time points). In 23% of the measurements, the hepatic saturation was <25% in spite of normal (>60%) mixed venous saturation. There was a statistical correlation between mixed venous and hepatic vein oxygen saturation (r=0.76, p < 0.0001). Jugular vein oxygen saturation was lower than mixed venous saturation in all three measurements (-21.6 +/- 1.9% during hypothermia, p < 0.001; -16.7 +/- 1.9% during rewarming, p < 0.001; and -5.6 +/- 2.2% postoperatively, p = 0.037). No significant correlation in oxygen saturation could be detected between mixed venous and jugular vein blood (r = 0.06, p = 0.65). Systemic temperature did not influence the differences in oxygen saturation between mixed venous and regional venous blood at any time point. In conclusion, regional deoxygenation occurs during CPB, in spite of normal mixed venous saturation. Mixed venous oxygen saturation correlates with hepatic, but not with jugular, vein saturation. The level of hypothermia does not influence differences in oxygen saturation between mixed venous and regional venous blood.


Leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase-mediated parallel activation of prostaglandin and constitutive nitric oxide synthase pathways.
Leptin, a pleiotropic cytokine secreted by adipocytes but also identified in salivary glands and saliva, is recognized as an important element of oral mucosal defense. Here, we report that in sublingual salivary glands leptin protects the acinar cells of against ethanol cytotoxicity. We show that ethanol- induced cytotoxicity, characterized by a marked drop in the acinar cell capacity for NO production, arachidonic acid release and prostaglandin generation, was subject to suppression by leptin. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with cyclooxygenase inhibitor, indomethacin and nitric oxide synthase (cNOS) inhibitor, L-NAME, as well as PP2, an inhibitor of Src kinase. Indomethacin, while not affecting leptin-induced arachidonic acid release, caused the inhibition in PGE2 generation, pretreatment with L-NAME led to the inhibition in NO production, whereas PP2 exerted the inhibitory effect on leptin-induced changes in NO, arachidonic acid, and PGE2. The leptin-induced changes in arachidonic acid release and PGE2 generation were blocked by ERK inhibitor, PD98059, but not by PI3K inhibitor, wortmannin. Further, leptin suppression of ethanol cytotoxicity was reflected in the increased Akt and cNOS phosphorylation that was sensitive to PP2. Moreover, the stimulatory effect of leptin on the acinar cell cNOS activity was inhibited not only by PP2, but also by Akt inhibitor, SH-5, while wortmannin had no effect. Our findings demonstrate that leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase-mediated parallel activation of MAPK/ERK and Akt that result in up-regulation of the respective prostaglandin and nitric oxide synthase pathways.


Pathogenesis and treatment of edema.
Edema results from excess accumulation of interstitial fluid. This may be due to increased transfer of fluid across the capillary membranes or excess retention of salt and water. The kidneys play a significant role in promoting salt and water homeostasis. Correction of the primary disorder should be the main goal in the management. Diuretics aid in promoting increased excretion of salt and water.


National Institutes of Health diversity supplements: Perspectives from administrative insiders.
The NIH Diversity Administrative Supplement is a funding mechanism that provides support for diverse early-stage researchers. There is limited guidance on how to apply for these awards. We describe perspectives of NIH program/diversity officers and university research administrators offering recommendations for diversity supplement submission. This article is the product of a working group exploring diversity in research. Nursing faculty from an R2 Historically Black College and University and an R1 research intensive university conducted stakeholder interviews with NIH program/diversity officers and university research administrators. We used content analysis to categorize respondents' recommendations. Recommendations centered on harmonizing the applicant with the program announcement, communication with program/diversity officers, mentor/mentee relationship, scientific plan, and systematic institutional approaches to the diversity supplement. Successful strategies in submitting diversity supplements will facilitate inclusion of diverse researchers in NIH-sponsored programs. Systematic approaches are needed to support development of diverse voices to enhance the scientific community.


Enterotoxigenicity among Salmonella typhimurium strains isolated in France.
Twenty strains of Salmonella typhimurium isolated in France from patients with diarrhea were tested for enterotoxins and cytotoxic factors by conventional bioassays. Eighteen of the strains produced enterotoxins to varying degrees and did not react with antisera to Escherichia coli heat-labile enterotoxin. Cytotoxic factors were present in two strains. These findings suggest that efforts to elucidate the virulence mechanisms of Salmonella spp. isolated in different parts of the world should be renewed.


Surgical cytoreduction in patients with metastatic uterine leiomyosarcoma at the time of initial diagnosis.
To determine whether cytoreduction is associated with improved outcome in patients newly diagnosed with metastatic uterine leiomyosarcoma (LMS). We retrospectively identified all patients treated at our institution for high-grade uterine LMS with extrauterine disease at the time of initial diagnosis from 7/1/82 to 7/31/07. Pattern of disease spread was classified as intraperitoneal (IP) or extraperitoneal (EP). Progression-free survival (PFS) and overall survival (OS) were determined from date of initial surgery using Kaplan-Meier estimates. We identified 96 cases. Median age was 54 years (range, 23-81). IP disease was seen in 48 (50%) and EP in 48 (50%). A complete gross resection of all tumor was achieved in 41/84 (49%). Recurrence or progression was noted in 93 (97%); 81 (84%) have died. Median PFS and OS for the entire cohort was 9.7 months (range, 6.7-10.9) and 20.2 months (range, 15.5-24.8), respectively. All 8 non-surgical cases died within 30 months of diagnosis. Median PFS was 14.2 months (range, 11.4-16.9) for those with a complete gross resection versus 6.8 months (range, 4.1-9.5) for those with any residual disease (P=0.002). Median OS was 31.9 months (range, 3.3-60.4) versus 20.2 months (range, 11.8-28.6), respectively (P=0.04). On multivariate analysis, no residual disease was independently associated with PFS when adjusting for disease distribution (IP vs EP) and the use of chemotherapy but not OS. Surgical cytoreduction of metastatic uterine LMS was independently associated with PFS but not OS in cases selected for surgery. The improvement in PFS must be weighed against the morbidity of surgery.


Large conductance Ca2+-activated K+ (BKCa) channels are involved in the vascular relaxations elicited by piceatannol isolated from Rheum undulatum rhizome.
We previously reported that piceatannol isolated from the rhizome extract of RHEUM UNDULATUM has a potent vasorelaxant activity. In the present study, the mechanisms underlying the direct vascular relaxant effect of piceatannol were investigated in isolated rat aorta. Piceatannol induced a concentration-dependent relaxation in aortic preparations precontracted with phenylephrine (EC (50) : 2.4 +/- 0.4 microM), which was completely inhibited by endothelial removal, N(omega)-nitro- L-arginine (nitric oxide synthase inhibitor), methylene blue and 1 H- oxadiazolo [4,3- A]quinoxalin-1-one (guanylyl cyclase inhibitor). The piceatannol-induced relaxation was also blocked by raising the extracellular K (+) (45 mM), 4-aminopyridine (voltage-sensitive K (+) channel blocker) and tetraethylammonium [the non-selective Ca (2+)-activated K (+) (K (Ca)) channel blocker] but not by indomethacin (cyclooxygenase inhibitor), atropine (muscarinic receptor antagonist), propranolol (beta-adrenoceptor antagonist), verapamil and nifedipine (L-type voltage-gated Ca (2+) channel blocker), barium chloride (inward rectifier K (+) channel inhibitor) and glibenclamide (ATP-sensitive K (+) channel blocker). In further studies investigating the role of Ca (2+)-activated K (+) (K (Ca)) channels, piceatannol-induced relaxant responses were decreased by charybdotoxin [large (BK (Ca))- and intermediate (IK (Ca))-conductance K (Ca) channel blocker], iberiotoxin (selective BK (Ca) channels blocker), but not by apamin [small-conductance K (Ca) (SK (Ca)) channel blocker], TRAM-34 [intermediate-conductance K (Ca) (IK (Ca)) channel blocker]. The present results demonstrate that piceatannol-induced vascular relaxation in rat aorta may be mediated by an endothelium-dependent nitric oxide signaling pathway, at least partially, through the activation of BK (Ca).


High-frequency oscillatory ventilation combined with intermittent mandatory ventilation in critically ill neonates: 3 years of experience.
A heterogeneous group of 45 neonates with severe pulmonary disease and inadequate gas exchange on conventional intermittent mandatory ventilation (IMV) was treated with a high-frequency oscillator combined with an IMV (HFO-IMV) system (Emerson Airway Vibrator connected to a BABYBird 1 ventilator). The mean gestational age was 33 weeks (25.5-43) and mean birth weight 2.02 kg (0.66-4.24). Primary diagnoses included respiratory distress syndrome (RDS; 23), pneumonia (12), persistent fetal circulation (PFC; 6), diaphragmatic hernia/hypoplastic lungs (4). The IMV rate was reduced from 78 to 29 BPM (P less than or equal to 0.0005), while maintaining lower partial pressure of carbon dioxide (PaCO2) (P less than 0.005) and higher partial pressure of oxygen (PaO2) (P less than or equal to 0.0025). Active air leaks were present in 20 infants and these infants responded most favourably to HFO-IMV. HFO-IMV failed to improve ventilation in neonates with diaphragmatic hernia/hypoplastic lungs. Complications during HFO-IMV were increased pulmonary secretions (11), worsening or recurrence of pre-existing air leaks (11), or occurrence of new air leaks (10). In 4 patients death was related to major air leak complications. Twenty-four infants died, 18 of them of a respiratory cause. Twenty-one infants finally survived. We assembled a well-tolerated system to provide HFO-IMV and to successfully ventilate neonates with severe respiratory disease, who failed to respond to conventional IMV. Initiation of HFO-IMV earlier in the course of the disease in this type of infant may improve survival.


Evaluating Resource Utilization for In-Person and Virtual Joint Classes in Total Joint Arthroplasty: An Analysis of Attendance Patterns at a Large Metropolitan Health System.
Provider-run "joint classes" educate total joint arthroplasty (TJA) patients on how to best prepare for surgery and maximize recovery. There is no research on potential healthcare inequities in the context of joint classes or on the impact of the recent shift toward telehealth due to coronavirus disease 2019 (COVID-19). Using data from a large metropolitan health system, we aimed to (1) identify demographic patterns in prepandemic joint class attendance and (2) understand the impact of telehealth on attendance. We included data on 3,090 TJA patients from three centers, each with a separately operated joint class. Attendance patterns were assessed prepandemic and after the resumption of elective surgeries when classes transitioned to telehealth. Statistical testing included standardized differences (SD > 0.1 indicates significance) and a multivariate linear regression. The in-person and telehealth attendance rates were 69.9% and 69.2%, respectively. Joint class attendance was significantly higher for non-White, Hispanic, non-English primary language, Medicaid, and Medicare patients (all SD > 0.1). Age was a determinant of attendance for telehealth (SD > 0.1) but not for in-person (SD = 0.04). Contrastingly, physical distance from hospital was significant for in-person (SD > 0.1) but not for telehealth (SD = 0.06). On a multivariate analysis, distance from hospital (P < .05) and telehealth (P < .0001) were predictors of failed class attendance. This work highlights the relative importance of joint classes in specific subgroups of patients. Although telehealth attendance was lower, telehealth alleviated barriers to access related to physical distance but increased barriers for older patients. These results can guide providers on preoperative education and the implementation of telehealth.


The novel HLA-A*30:172 allele identified in a donor from the Colombian bone marrow donor registry.
HLA-A*30:172 differs from HLA-A*30:01:01:01 by a single nucleotide in codon 153 in exon 3.


Remodeling of dorsal column nuclear efferents to the basilar pontine gray after cortical ablations in newborn rats.
In view of previous reports documenting corticopontine remodeling in response to neonatal cerebral cortical lesions, we examined possible alterations of ascending pontine afferents from the dorsal column nuclei after the same types of neonatal lesion. Two anterograde tracing techniques, autoradiography and the Fink-Heimer silver degeneration method, were combined to facilitate a topographic analysis. The distribution patterns of cuneo- and gracilopontine terminations appeared expanded in response to neonatal sensorimotor cortical lesions, as compared to non-lesioned animals.