Downregulation of Grem1 expression in the distal limb mesoderm is a necessary precondition for phalanx development.
The phalanges are the final skeletal elements to form in the vertebrate limb and their identity is regulated by signaling at the phalanx forming region (PFR) located at the tip of the developing digit ray. Here, we seek to explore the relationship between PFR activity and phalanx morphogenesis, which define the most distal limb skeletal elements, and signals associated with termination of limb outgrowth. As Grem1 is extinguished in the distal chick limb mesoderm, the chondrogenesis marker Aggrecan is up-regulated in the metatarsals and phalanges. Fate mapping confirms that subridge mesoderm cells contribute to the metatarsal and phalanges when subridge Grem1 is down-regulated. Grem1 overexpression specifically blocks chick phalanx development by inhibiting PFR activity. PFR activity and digit development are also disrupted following overexpression of a Gli3 repressor, which results in Grem1 expression in the distal limb and downregulation of Bmpr1b. Based on expression and fate mapping studies, we propose that downregulation of Grem1 in the distal limb marks the transition from metatarsal to phalanx development. This suggests that downregulation of Grem1 in the distal limb mesoderm is necessary for phalanx development. Grem1 downregulation allows for full PFR activity and phalanx progenitor cell commitment to digit fate.


Effects of tibial and parasacral nerve electrostimulation techniques on women with poststroke overactive bladder: study protocol for a randomized controlled trial.
Neurogenic bladder (NB) can affect people after stroke episodes. NB features changes in the normal voiding pattern at the bladder filling and emptying phases. Overactive NB is characterized by urgency symptoms, with or without urinary incontinence, caused by NB. This disorder affects many domains of life (physical, social, psychological, domestic, sexual) that limit personal autonomy and degrade the quality of life. Among the several treatments available, the conservative physical therapy intervention through tibial nerve electrostimulation (TNES) and parasacral electrostimulation (PSES) can help improve patient conditions with a smaller number of collateral effects than those of interventions based on medication. The aim of the present study is to compare the effects of TNES and PSES techniques in women with overactive NB after stroke episodes to assess the impact of urinary incontinence in these women, on their number of incontinence episodes, daytime and nocturnal urinary frequency, and quality of life. This is a prospective clinical study to compare two randomized groups based on parallel and blind conditions. Forty-four women who have had a stroke episode at least 30 days before the trial and who have developed overactive NB will be recruited for the trial. All patients will be subjected to initial evaluation and randomly divided into two groups, TNES and PSES. Subsequently, the two groups will be subjected to a 12-session intervention protocol, twice a week. A new evaluation will be performed after the intervention. The results of this study will contribute to the physiotherapeutic treatment of women with NB after a stroke episode since such results will add information about the benefits of this treatment, urinary control, and the improvements in the quality of life of these women. Brazilian Registry of Clinical Trials (REBEC) RBR-2bn2z4 . Registered on December 11, 2018.


Phosphorylation of the Epstein-Barr virus nuclear antigen 2.
A major in vivo phosphorylation site of the Epstein-Barr virus nuclear antigen 2 (EBNA-2) was found to be localized at the C-terminus of the protein. In vitro phosphorylation studies using casein kinase 1 (CK-1) and casein kinase 2 (CK-2) revealed that EBNA-2 is a substrate for CK-2, but not for CK-1. The CK-2 specific phosphorylation site was localized in the 140 C-terminal amino acids using a recombinant trpE-C-terminal fusion protein. In a similar experiment, the 58 N-terminal amino acids expressed as a recombinant trpE-fusion protein were not phosphorylated. Phosphorylation of a synthetic peptide corresponding to amino acids 464-476 of EBNA-2 as a substrate led to the incorporation of 0.69 mol phosphate/mol peptide indicating that only one of three potential phosphorylation sites within the peptide was modified. The most likely amino acid residues for phosphorylation by CK-2 are Ser469 and Ser470.


Artificial intelligence in foot and ankle surgery: current concepts.
The twenty-first century has proven that data are the new gold. Artificial intelligence (AI) driven technologies might potentially change the clinical practice in all medical specialities, including orthopedic surgery. AI has a broad spectrum of subcomponents, including machine learning, which consists of a subdivision called deep learning. AI has the potential to increase healthcare delivery, improve indications and interventions, and minimize errors. In orthopedic surgery. AI supports the surgeon in the evaluation of radiological images, training of surgical residents, and excellent performance of machine-assisted surgery. The AI algorithms improve the administrative and management processes of hospitals and clinics, electronic healthcare databases, monitoring the outcomes, and safety controls. AI models are being developed in nearly all orthopedic subspecialties, including arthroscopy, arthroplasty, tumor, spinal and pediatric surgery. The present study discusses current applications, limitations, and future prospective of AI in foot and ankle surgery.


Quintuply orthogonal pyrrolysyl-tRNA synthetase/tRNAPyl pairs.
Mutually orthogonal aminoacyl transfer RNA synthetase/transfer RNA pairs provide a foundation for encoding non-canonical amino acids into proteins, and encoded non-canonical polymer and macrocycle synthesis. Here we discover quintuply orthogonal pyrrolysyl-tRNA synthetase (PylRS)/pyrrolysyl-tRNA (tRNAPyl) pairs. We discover empirical sequence identity thresholds for mutual orthogonality and use these for agglomerative clustering of PylRS and tRNAPyl sequences; this defines numerous sequence clusters, spanning five classes of PylRS/tRNAPyl pairs (the existing classes +N, A and B, and newly defined classes C and S). Most of the PylRS clusters belong to classes that were unexplored for orthogonal pair generation. By testing pairs from distinct clusters and classes, and pyrrolysyl-tRNAs with unusual structures, we resolve 80% of the pairwise specificities required to make quintuply orthogonal PylRS/tRNAPyl pairs; we control the remaining specificities by engineering and directed evolution. Overall, we create 924 mutually orthogonal PylRS/tRNAPyl pairs, 1,324 triply orthogonal pairs, 128 quadruply orthogonal pairs and 8 quintuply orthogonal pairs. These advances may provide a key foundation for encoded polymer synthesis.


Recycling silage leachate and biochar for improving nitrate removal by woodchip bioreactor.
Woodchip bioreactor (WBR) is commonly used to remove nitrate from drainage and runoff. However, the efficiency of nitrate removal in WBR is highly variable due to the properties of filling materials. In this study, we investigated the potential of recycling two waste materials, biochar (B) and silage leachate (SL), to enhance nitrate removal by providing a better living habitat and extra available carbon for denitrification. We constructed twelve lab-scale bioreactors with different filling materials (WBR, WBR + B, WBR + SL, WBR + B + SL), hydraulic retention times (HRT: 0.5-24 h), and nitrate concentrations (5.4-33 mg L-1) to test nitrate removal efficiency (NRE) and nitrate removal rate (NRR). Our results showed that the combination of biochar and silage leachate led to the highest NRE and NRR, with improvements of 23% and 48%, respectively, compared to WBR alone. However, the benefits of adding biochar and silage leachate were less apparent at longer HRTs. According to the results of our structural equation modeling (SEM), we have attributed the improved denitrification to several factors. These factors include the decrease in dissolved oxygen, saturated hydraulic conductivity, and pH value, as well as an increase in dissolved organic carbon after the addition of silage leachate. Therefore, our study provides evidence that recycling biochar and silage leachate as an additive to WBR could be a beneficial strategy for enhancing nitrate removal. Overall, this study highlights the potential of a win-win solution to improve the efficiency of nitrate removal in water treatment processes.


Saving sea turtles: the evolution of the IUCN Marine Turtle Group.
When Peter Scott became chairman of the Survival Service Commission of the International Union for the Conservation of Nature and Natural Resources (IUCN) in 1963, he invited Archie Carr to chair the Marine Turtle Group (MTG). A leading authority on the ecology and conservation of sea turtles, Carr believed that the MTG could be the first international forum for sea turtle research and conservation. The assembly of data for the IUCN Red Data Book revealed which species of turtles were threatened with extinction and the array of risks that they faced. Although Carr and Scott differed on what courses of action should be taken in light of this, the MTG did emerge as an important international congress that remains an inspiration to current marine protection efforts.


The effect of desynchronization on meal patterns of humans living in time isolation.
We analyzed the timing of meals in nine subjects who lived for several weeks in a time isolation environment and whose free-running sleep-wake cycles lengthened markedly and lost synchrony with the body temperature rhythm for part of the study. The long sleep-wake periods (SWP) in free-running desynchrony (mean = 34 +/- 3 hours) as compared to free-running synchrony (25 +/- 1 hours) enabled us to compare meal timing in two distinct temporal frameworks and to relate them to the two major oscillators presumed to underlie circadian rhythms in man. We found that when the SWP lengthened in desynchrony, the intermeal interval (IMI) increased significantly. In half the subjects, the increase in IMI was approximately proportional to the increase in the SWP--the IMI "stretched" along with the SWP. Analysis of prelunch and postlunch IMIs indicated that the lengthening of the IMI during desynchrony was comparable in early and later parts of the subjective day. The increase in meal spacing was not due to increased caloric content of meals. The findings support an interpretation of dual regulation of meal timing. Proportional increases in IMI and SWP suggest that the mechanism governing the timing of the sleep-wake cycle also governs meal timing. The less than proportional increase in some cases suggests that an additional, probably metabolic, mechanism tends to limit the intervals between meals.


Hierarchical Bayesian narrative-making under variable uncertainty.
While Conviction Narrative Theory correctly criticizes utility-based accounts of decision-making, it unfairly reduces probabilistic models to point estimates and treats affect and narrative as mechanistically opaque yet explanatorily sufficient modules. Hierarchically nested Bayesian accounts offer a mechanistically explicit and parsimonious alternative incorporating affect into a single biologically plausible precision-weighted mechanism that tunes decision-making toward narrative versus sensory dependence under varying uncertainty levels.


SARS-CoV-2 interacts with renin-angiotensin system: impact on the central nervous system in elderly patients.
SARS-CoV-2 is a recently identified coronavirus that causes the current pandemic disease known as COVID-19. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor, suggesting that the initial steps of SARS-CoV-2 infection may have an impact on the renin-angiotensin system (RAS). Several processes are influenced by RAS in the brain. The neurological symptoms observed in COVID-19 patients, including reduced olfaction, meningitis, ischemic stroke, cerebral thrombosis, and delirium, could be associated with RAS imbalance. In this review, we focus on the potential role of disturbances in the RAS as a cause for central nervous system sequelae of SARS-CoV-2 infection in elderly patients.


Enhancement of central norepinephrine and 5-hydroxytryptamine transmission by tricyclic antidepressants. A comparison.
The relative abilities of 1--3 mg/kg of desipramine (DES), imipramine (IMIP), amitriptyline (AMI), and chlorimipramine (CI-IMIP) to enhance synaptic transmission mediated by either NE or 5-HT were determined by testing their effects directly on NE or 5-HT transmission to sympathetic preganglionic neurons in unanesthetized, spinal cats. Effects on NE transmission were assessed on intraspinal excitatory pathways which utilize NE as a transmitter. Effects on 5-HT transmission were assessed on 5-HT-mediated depression of spinal sympathetic reflexes produced by 30 mg/kg of 5-HTP. Both DES and IMIP markedly enhanced transmission through the intraspinal excitatory NE pathways whereas AMI and CI-IMIP depressed transmission. However, both AMI and CI-IMIP modestly enhanced transmission in cats depleted of central 5-HT by pretreatment with parachlorophenylalanine. The relative potencies of the four drugs on excitatory NE transmission were DES greater than IMIP greater than AMI greater than CI-IMIP. Each of the four drugs also enhanced the 5-HTP-induced depression of spinal sympathetic reflexes, but their relative potencies on 5-HT transmission were just the opposite to those found on NE transmission. Therefore, all four drugs enhanced transmission by both NE and 5-HT, but their relative selectivities for the two transmitters differed markedly and were complementary. In general, the results support those of previous studies based on less direct methods for assessing inhibition of amine reuptake by tricyclic antidepressants.


Development and initial validation of a clinical measure to assess early symptoms of post-stroke depression in the acute stroke patient.
To evaluate a measure specifically developed to clinically assess early symptoms of poststroke depression (PSD) in acute stroke patients. Poststroke depression is associated with elevated rates of morbidity and mortality following a mild-to-moderate stroke. Measures currently used to assess depression in acute poststroke patients can lack the clinical specificity necessary to detect symptoms within 30 days poststroke. A two-round Delphi design was used to estimate symptom consensus. Three panels, healthcare professionals (N = 74), experts (N = 16) and acute poststroke patients (N = 40), evaluated an initial set of symptom-items systematically developed by the research team. Our study yielded consensus for 29 symptom-items. Additional symptoms recommended by acute poststroke patients increased the final number of symptoms to 35. We developed a specific measure of early symptoms of PSD in acute stroke patients with good content validity. The specific clinical relevance of our findings lies in the consensus of health professionals, the Delphi panel and patients regarding core areas of clinical assessment during the acute poststroke phase. And our findings may draw attention to the need to assess and treat acute stroke patients with early symptoms of PSD.


Layer and rhythm specificity for predictive routing.
In predictive coding, experience generates predictions that attenuate the feeding forward of predicted stimuli while passing forward unpredicted "errors." Different models have suggested distinct cortical layers, and rhythms implement predictive coding. We recorded spikes and local field potentials from laminar electrodes in five cortical areas (visual area 4 [V4], lateral intraparietal [LIP], posterior parietal area 7A, frontal eye field [FEF], and prefrontal cortex [PFC]) while monkeys performed a task that modulated visual stimulus predictability. During predictable blocks, there was enhanced alpha (8 to 14 Hz) or beta (15 to 30 Hz) power in all areas during stimulus processing and prestimulus beta (15 to 30 Hz) functional connectivity in deep layers of PFC to the other areas. Unpredictable stimuli were associated with increases in spiking and in gamma-band (40 to 90 Hz) power/connectivity that fed forward up the cortical hierarchy via superficial-layer cortex. Power and spiking modulation by predictability was stimulus specific. Alpha/beta power in LIP, FEF, and PFC inhibited spiking in deep layers of V4. Area 7A uniquely showed increases in high-beta (∼22 to 28 Hz) power/connectivity to unpredictable stimuli. These results motivate a conceptual model, predictive routing. It suggests that predictive coding may be implemented via lower-frequency alpha/beta rhythms that "prepare" pathways processing-predicted inputs by inhibiting feedforward gamma rhythms and associated spiking.


A practical method of autotransfusion in the emergency center.
A new mobile autotransfusion device, modified for use in the Emergency Center, is described. Preliminary usage in thirty trauma patients who underwent autotransfusion of 60 units of blood indicated the device was simple to utilize, efficacious, inexpensive, cost-effective, and safe.


[Treatment of massive endobronchial hemorrhage after cardiopulmonary bypass by selective coil embolization of the bronchial artery].
A 68-year-old woman underwent aortic valve replacement to treat her aortic regurgitation. The operation was performed successfully. Just before coming off cardiopulmonary bypass, massive hemorrhage occurred through the endotracheal tube. Fiberoptic bronchoscopy could not find the bleeding site and 1,350 ml of blood had been lost. Bronchial angiography under percutaneous cardiopulmonary bypass revealed the right middle branch to be the bleeding site. The endotrachial bleeding was treated successfully by selective coil embolization of the bronchial artery. No further bronchial bleeding occurred. Although we found the bleeding site, we could not identify the cause of hemorrhage.


Long-term remission of ocular and extraocular manifestations in Behçet's disease using infliximab.
To investigate the long-term effect of infliximab on ocular and extraocular manifestations in patients with Behçet's disease. Seven patients with active Behçet's disease and treated with infliximab at Aichi Medical University Hospital for more than 18 months were included in the study. We evaluated visual acuity, the average number of uveitis attacks involving the posterior segment, and general disease activity every 2 months. The Behçet's Disease Current Activity Form (BDCAF) was used for an overall index of disease activity. Anti-infliximab antibody levels were examined in the patients' sera. The follow-up period after initial introduction of infliximab ranged from 19 to 40 months (mean ± SD, 32 ± 8.7 months). The number of infliximab infusions ranged from 12 to 24 (19 ± 4.4). By the 2-month follow-up, the frequency of uveitis attacks involving the posterior segment and the BDCAF scores were significantly improved compared to the 2 months before introducing infliximab. Anti-infliximab antibodies were detected in the sera of all examined patients. Significant long-term improvement in both the frequency of uveitis attacks involving the posterior segment and overall disease activity was provided by the administration of infliximab to patients suffering from Behçet's disease, despite the presence of anti-infliximab antibodies.


Extracellular gadolinium contrast agents: differences in stability.
Extracellular gadolinium contrast agents (Gd-CA) are either linear or macrocyclic chelates available as ionic or non-ionic preparations. The molecular structure whether cyclic or linear and ionicity determines the stability of Gd-CA. Linear chelates are flexible open chains which do not offer a strong binding to Gd(3+). In contrast, the macrocyclic chelates offer a strong binding to Gd(3+) by the virtue of being preorganized rigid rings of almost optimal size to cage the gadolinium atom. Non-ionic preparations are also less stable in comparison to the ionic ones as the binding between Gd(3+) with the negatively charged carboxyl groups is stronger in comparison to that with amides or alcohol in the non-ionic preparations. According to stability constants and kinetic measurements, the most stable Gd-CM is the ionic-macrocyclic chelate Gd-DOTA and the least stable agents are the non-ionic linear chelates gadodiamide and gadoversetamide. In vivo data confirmed the low stability of non-ionic linear chelates but no significant difference was observed amongst the macrocyclic agents whether ionic (Gd-DOTA) or non-ionic such as Gd-HP-DO3A and Gd-BT-DO3A. The stability of Gd-CA seems to be an important factor in the pathogenesis of the serious complication of nephrogenic systemic fibrosis. Gd-CA of low stability are likely to undergo transmetallation and release free Gd ions that deposit in tissue and attract circulating fibrocytes to initiate the process of fibrosis. No cases of NSF have been observed so far after the exclusive use of the stable macrocyclic Gd-CA.


Frequency and diversity of molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients of a South West German teaching hospital.
We have determined the frequency and the genetic diversity of methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from inpatients of a South West German teaching hospital. The frequency of primary MRSA isolates remained constant over the two-year surveillance period: 108 of the total number of 1450 S. aureus isolates (7.5%) were MRSA in 2001 and the corresponding figures were 110 MRSA out of 1412 S. aureus isolates (7.8%) in 2002. Six clusters of nosocomial MRSA infection were observed during 2001 and 2002. Cluster infections involved 65 patients on four different wards. Molecular typing of the 65 cluster isolates demonstrated that 51 (79%) belonged to a single predominant clone. The remaining 14 isolates represented seven genetically unrelated MRSA clones. Molecular typing of 50 additional non-cluster, sporadic isolates demonstrated 37 different pulsed-field gel electrophoresis (PFGE) banding patterns. Our results demonstrate that primary MRSA strains from hospitalized patients show a high degree of genetic heterogeneity. In contrast, however, MRSA isolates from nosocomial clusters were mostly derived from a single predominant clone, thus indicating a significant intra-ward and intra-hospital distribution. Molecular typing methods may lead to an improved understanding of MRSA epidemiology and thus allow the establishment of effective preventive measures.


Prenatal alcohol exposure and offspring hyperactivity: effects of physostigmine and neostigmine.
Rats were fed a liquid diet containing ethanol from days 6-19 of gestation. Controls were pair-fed the same diet with sucrose substituted for ethanol, or received ad lib chow and water. The activity of the offspring was observed at 10, 16, 22 or 28 days-of-age. Overall, offspring exposed to alcohol prenatally were hyperactive compared to controls at 16 and 22 days, but not at 10 or 28 days. Administration of physostigmine had no effect on the activity of any group at 10 days. At 16 days, physostigmine enhanced the activity of the alcohol group, had no effect on the sucrose group, but depressed the activity of the chow group. At 22 days it led to a dose-related decrease in activity in controls but had no effect on the activity of the alcohol treated pups. At 28 days, physostigmine decreased the activity of all three groups. Administration of the quaternary derivative, neostigmine, indicated that the effects of scopolamine at 22 days were probably central in origin. These data indicate that a putative cholinergic/inhibitory system becomes functional in control pups before 22 days, but in pups exposed to alcohol prenatally development is delayed by a number of days.


Lysogeny in marine Synechococcus.
Viral infection of bacteria can be lytic, causing destruction of the host cell, or lysogenic, in which the viral genome is instead stably maintained as a prophage within its host. Here we show that lysogeny occurs in natural populations of an autotrophic picoplankton (Synechococcus) and that there is a seasonal pattern to this interaction. Because lysogeny confers immunity to infection by related viruses, this process may account for the resistance to viral infection seen in common forms of autotrophic picoplankton.


New aporphinoid 5-HT2A and α1A antagonists via structural manipulations of nantenine.
A series of C1, C2, C3 and N6 analogs of nantenine (2) was synthesized and evaluated in 5-HT(2A) and α(1A) receptor functional assays. Alkyl substitution of the C1 and N6 methyl groups of nantenine provided selective 5-HT(2A) and α(1A) antagonists, respectively. The C2 alkyloxy analogs studied were generally selective for α(1A) versus 5-HT(2A). The C3 bromo analog 15 is one of the most potent aporphinoid 5-HT(2A) antagonists known presently.


The use of continuous positive airway pressure in COPD-OSA overlap syndrome: A systematic review.
The co-occurrence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD), known as COPD-OSA overlap syndrome, increases morbidity and mortality. The effectiveness of continuous positive airway pressure (CPAP) therapy, a commonly used treatment for OSA, in this patient population remains uncertain. Therefore, we conducted a systematic review to evaluate the efficacy of CPAP therapy in improving clinical outcomes. We conducted a comprehensive systematic review to identify studies that evaluated the impact of CPAP therapy on COPD exacerbation, hospitalization, and mortality in patients with COPD-OSA overlap syndrome. We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis Statement and assessed the quality of each study using the Newcastle-Ottawa quality scale. From the initial 3184 articles identified, we reviewed 365 and included five in the systematic review. Our findings revealed that CPAP therapy improved clinical outcomes, including COPD exacerbation, COPD related hospitalization, and mortality in patients with COPD-OSA overlap syndrome. However, the definition of COPD and OSA varied across studies, and the definition of CPAP usage was not consistent. Our systematic review suggests that CPAP therapy is effective in improving outcomes in patients with COPD-OSA overlap syndrome. Nonetheless, further research is required to establish the efficacy of CPAP therapy by standardizing the definition of COPD, OSA, and CPAP usage.


Investigation of the binding interactions between dimethyl phthalate and its metabolite with bovine serum albumin by multispectroscopy.
To understand the behavior of dimethyl phthalate (DMP) and realize the effect of DMP and its metabolite, monomethyl phthalate (MMP), on the conformation changes of bovine serum albumin (BSA), the interaction mechanisms of DMP and MMP with BSA were investigated by multispectroscopy and molecular docking. The results of the fluorescence quenching experiment showed that the fluorescence quenching of BSA by DMP and MMP was due to the formation of a complex though static quenching, which was also confirmed by time-resolved fluorescence measurements. The binding constants were 8.06 × 104 M-1 and 4.74 × 104 M-1 for DMP-BSA and MMP-BSA, respectively, and the number of binding sites were 1.20 (DMP) and 1.18 (MMP). The thermodynamic parameters showed different binding forces for DMP and MMP with BSA. The binding of DMP to BSA was driven mainly by hydrophobic interactions and hydrogen bonding, and MMP bound to BSA by van der Waals forces and hydrogen bonding, which were in accordance with the results from the molecular docking. The conformation and structural alterations of BSA upon DMP or MMP binding were studied by UV-vis spectroscopy, circular dichroism spectroscopy and synchronous fluorescence spectroscopy. The presence of metabolite did not change the quenching mechanism but decreased the binding affinity of DMP toward BSA as well as shortened the binding distance, which may be attributed to the competition between DMP and MMP for binding to BSA. This study revealed the combined effects of DMP and its metabolite on BSA at the molecular level.


The computer based patient record: a strategic issue in process innovation.
Reengineering of the workplace through Information Technology is an important strategic issue for today's hospitals. The computer-based patient record (CPR) is one technology that has the potential to profoundly modify the work routines of the care unit. This study investigates a CPR project aimed at allowing physicians and nurses to work in a completely electronic environment. The focus of our analysis was the patient nursing care process. The rationale behind the introduction of this technology was based on its alleged capability to both enhance quality of care and control costs. This is done by better managing the flow of information within the organization and by introducing mechanisms such as the timeless and spaceless organization of the work place, de-localization, and automation of work processes. The present case study analyzed the implementation of a large CPR project ($45 million U.S.) conducted in four hospitals in joint venture with two computer firms. The computerized system had to be withdrawn because of boycotts from both the medical and nursing personnel. User-resistance was not the problem. Despite its failure, this project was a good opportunity to understand better the intricate complexity of introducing technology in professional work where the usefulness of information is short lived and where it is difficult to predetermine the relevancy of information. Profound misconceptions in achieving a tighter fit (synchronization) between care processes and information processes were the main problems.


An Examination of the Factors Affecting Community Pharmacists' Knowledge, Attitudes, and Impressions About the COVID-19 Pandemic
Coronavirus disease-2019 (COVID-19)-related cases and deaths are ongoing throughout the world, but there is still no effective drug in its treatment, and the vaccine supply is not adequate for the global population. It is important that pharmacists have sufficient knowledge and awareness to prevent and control the disease. COVID-19 has been widely covered in the media, which has been a source widely used by healthcare professionals. This study aimed to assess the knowledge, attitudes, and impressions of community pharmacists about COVID-19 and the factors affecting them. The questions in this survey were formed using the guideline created by the World Health Organization, a guide composed by the Turkish COVID-19 Scholarly Commission, and data disclosed to the public on the website of the Ministry of Health. The questionnaire was designed with Google forms and then applied to community pharmacists all over Turkey by sharing the survey link. Analyses of 393 questionnaires showed that Ministry of Health/government statements, the internet (scientific sources), and the media were the preferred sources of information (96.7%, 89.6%, and 84%, respectively). "Ways to avoid COVID-19" was the most searched title (96.9%). It was determined that the names of the two drugs most frequently mentioned by the participants to be used in the treatment of COVID-19 in Turkey were hydroxychloroquine and azithromycin (57.5%; 50.1%, respectively). Participants who received information from the media gave less education to patients/customers on personal protection measures against COVID-19 (83.3%) and symptoms of COVID-19 (78.8%); however, their behavior regarding the training of pharmacy personnel was found to be the opposite. It has been determined that about half of the participants (46.6%) mostly trust the Ministry of Health regarding the COVID-19 pandemic. Media and other sources influence the knowledge, behavior and impressions of pharmacists'. Having a high level of knowledge positively affects people's behavior. It is important for pharmacists to have accurate information about COVID-19 and to transfer their knowledge to the community to provide patient education and to prevent/control the spread of COVID-19.


Peptic Ulcer Disease is Associated with Increased Risk of Chronic Urticaria Independent of Helicobacter pylori Infection: A Population-Based Cohort Study.
Some studies showed patients with chronic urticaria have a higher rate of peptic ulcer disease (PUD). Whether PUD is a risk factor for chronic urticaria is unclear. The objective of this study was to evaluate the incidence of and risk factors for chronic urticaria in patients with PUD using the Taiwan National Health Insurance Research Database. We conducted a retrospective nationwide cohort study of the period 2000-2012 and involving 11,901 patients with PUD who underwent Helicobacter pylori (HP) therapy (PUD + HP group) and an equal number of matched patients without HP infection (PUD - HP group). Furthermore, we enrolled 23,802 patients without PUD for comparison (non-PUD group). The Cox proportional hazards regression model was used to analyze chronic urticaria risk after adjusting for potential confounding factors. The mean ages of the three groups were around 50 years. Approximately 42.6% were female. Chronic urticaria incidences in the PUD + HP and PUD - HP groups were both significantly higher than that in the non-PUD group. The hazard ratios of chronic urticaria in the PUD + HP group and the PUD - HP group were 1.34 (95% confidence interval 1.09-1.64) and 1.45 (95% confidence interval 1.19-1.79), respectively. The risk difference became significant 2 years after patients with PUD had the HP infection tests and persisted till the end of follow-up. The risk increase was significant in patients with PUD who were female or aged 40-64 years. There was no difference in the risk comparison between PUD + HP and PUD - HP groups. Peptic ulcer disease, independent of HP infection, is associated with an increased chronic urticaria risk. Patients with PUD who were female or aged 40-64 years are more likely to have chronic urticaria.


Up-regulation of interleukin-12 receptor expression in peripheral blood mononuclear cells of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.
We previously reported elevated levels of serum interleukin-12 (IL-12) in association with increased interferon-gamma (IFN-gamma) levels in patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The interaction between IL-12 and IL-12 receptor (IL-12R) plays an important role in differentiation of the T helper type 1 (Th1) phenotype. In this study, we further examined the IL-12/IL-12R axis by investigating the expression of IL-12R and CD40 ligand (CD40L) in peripheral blood mononuclear cells (PBMC) of 18 HAM/TSP patients, and comparing the levels with those in 25 patients with other neurological disorders, including 4 anti-HTLV-I-seropositive carriers as controls. Two-color analysis by flow cytometry revealed a significantly high percentage of IL-12R beta1+ cells in CD4+ T lymphocytes in HAM/TSP patients compared to the control. Furthermore, IL-12R beta2 mRNA expression in PBMC was detected by reverse-transcriptase polymerase chain reaction in 6 of 18 HAM/TSP patients, but not in any control patients. In contrast, there was no significant difference between the percentage of CD40L+ cells in CD4+ T lymphocytes in HAM/TSP and control patients. Our results suggest Th1 immune activation in patients with HAM/TSP, which leads to chronic inflammation in the spinal cord, mediated by dysregulation of the IL-12/IL-12R axis rather than of the CD40/CD40L interaction.


Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. Systolic Hypertension in China (Syst-China) Collaborative Group.
Isolated systolic hypertension occurs in around 8% of Chinese people aged 60 years or older. In 1988, the Systolic Hypertension in China (Syst-China) Collaborative Group started to investigate whether active treatment could reduce the incidence of stroke and other cardiovascular complications in older patients with isolated systolic hypertension. All patients were initially started on masked placebo. After stratification for centre, sex and previous cardiovascular complications, alternate patients (n=1253) were assigned nitrendipine at 10-40 mg daily, with the addition of captopril at 12.5-50.0 mg daily or hydrochlorothiazide at 12.5-50.0 mg daily, or both, if a sufficient blood pressure fall was not obtained. In the remaining 1141 control patients, matching placebos were administered similarly. At entry, sitting blood pressure averaged 170.5 mmHg systolic and 86.0 mmHg diastolic, age averaged 66.5 years and total serum cholesterol was 5.1 mmol/l. After 2 years of follow-up, sitting systolic and diastolic blood pressures had fallen by 10.9 mmHg and 1.9 mmHg in the placebo group and by 20.0 mmHg and 5.0 mmHg in the active treatment group. The intergroup differences were 9.1 mmHg systolic (95% confidence interval 7.6-10.7 mmHg ) and 3.2 mmHg diastolic (95% confidence interval 2.4-4.0). Active treatment reduced total strokes by 38% (from 20.8 to 13.0 endpoints per 1000 patient-years, P=0.01), all-cause mortality by 39% (from 28.4 to 17.4 endpoints per 1000 patient-years, P=0.003), cardiovascular mortality by 39% (from 15.2 to 9.4 endpoints per 1000 patient-years, P=0.03), stroke mortality by 58% (from 6.9 to 2.9 endpoints per 1000 patient-years, P=0.02), and ail fatal and nonfatal cardiovascular endpoints by 37% (from 33.3 to 21.4 endpoints per 1000 patient-years, P=0.004). Antihypertensive treatment prevents stroke and other cardiovascular complications in older Chinese patients with isolated systolic hypertension. Treatment of 1000 Chinese patients for 5 years could prevent 55 deaths, 39 strokes or 59 major cardiovascular endpoints.


Interventional radiology of male varicocele: current status.
Varicocele is a fairly common condition in male individuals. Although a minor disease, it may cause infertility and testicular pain. Consequently, it has high health and social impact. Here we review the current status of interventional radiology of male varicocele. We describe the radiological anatomy of gonadal veins and the clinical aspects of male varicocele, particularly the physical examination, which includes a new clinical and ultrasound Doppler maneuver. The surgical and radiological treatment options are also described with the focus on retrograde and antegrade sclerotherapy, together with our long experience with these procedures. Last, we compare the outcomes, recurrence and persistence rates, complications, procedure time and cost-effectiveness of each method. It clearly emerges from this analysis that there is a need for randomized multicentre trials designed to compare the various surgical and percutaneous techniques, all of which are aimed at occlusion of the anterior pampiniform plexus.


Selective inhibition of retrograde axonal transport by erythro-9-[3-(2-hydroxynonyl)]adenine.
Retrograde transport of microscopically visible organelles in isolated lobster axons was selectively inhibited by erythro-9-[3-(2-hydroxynonyl)]adenine (EHNA), with little or no effect on anterograde transport. The retrograde velocity was reduced both in living axons and in permeabilized axons in which movement was reactivated with exogenous ATP. This is the first report of an agent that selectively inhibits axonal transport in one direction.


Interaction of plasma lipoproteins with erythrocytes. I. Alteration of erythrocyte morphology.
Intact erythrocytes incubated in the presence of low density lipoproteins (LDL) undergo a time-dependent morphologic transformation from biconcave discs to spherocytes within 4 h. No shape change is observed when erythrocytes are incubated with high density lipoproteins (HDL). The LDL-induced change in erythrocyte morphology occurs without concomitant leakage of hemoglobin from the cell or depletion of intracellular ATP; no change in the distribution of the major lipids of the erythrocyte membranes was detected. The alteration of morphology does require attachment of LDL to the erythrocyte surface. The LDL-induced morphologic alteration is inhibited by HDL, but not by serum albumin. HDL prevent the attachment of LDL to the cell membrane; however, the HDL subfractions, HDL2 and HDL3, are only partially effective. These data suggest that normal erythrocyte morphology and cell function may depend on the concentration and composition of the circulating lipoproteins.


Correction: PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells.
[This corrects the article DOI: 10.1371/journal.pone.0164660.].


Swallowing screening practice patterns for nurses in the cardiac surgery intensive care unit.
The current study surveyed nurse practice patterns for performing swallowing screens in an academic cardiac intensive care unit (ICU). It aimed to index: training and levels of confidence in conducting dysphagia screens; screening methods employed; timing and frequency of implement; and subsequent plan of care in identified high-risk patients. Swallowing impairment (dysphagia) is common following cardiac surgery and associated with significant morbidity and mortality. Early and accurate detection of dysphagia is therefore critical to afford implementation of interventions to optimise patient care. Currently, no validated instruments or guidelines exist for nursing screening of dysphagia in this setting. An anonymous and voluntary 10-item mixed-methods online survey was conducted using Qualtrics software. Nonprobability purposive sampling was utilised to recruit nurses working in an academic 24-bed cardiac ICU. Thematic analysis using operationally defined coding, SRQR checklist and descriptive statistics were employed. Sixty-nine nurses completed the survey during a 1-month period, representing an 84% response rate. Formal training in performing swallowing screens was reported in 18.6% of nurses. In rank order, reported level of confidence was the following: "moderately" (49%); "somewhat" (35%); "not" (13%); and "very" (3%). The majority of nurses performed screens within 1 hr (40.6%) or between 1-4 hr (43.8%) of extubation. Fifteen different methods were utilised to screen swallowing function by nurses who reported a total of 31 different clinical signs indicative of dysphagia. Survey data of practicing nurses in an academic cardiac ICU revealed limited formal training in swallowing screening methodology, a high degree of variability in screening methods employed and low levels of agreement for dysphagia signs. Data highlight a knowledge gap and need for the development of formal education and validated rapid nursing dysphagia screening tools for standardised implementation in the cardiac surgery ICU setting.


Subinhibitory concentrations of pinocembrin exert anti-Staphylococcus aureus activity by reducing α-toxin expression.
Natural products have been used as potentially important sources of novel antibacterials in combating pathogenic Staphylococcus aureus isolates, a major problem around the world. In this study, we aimed to investigate the antibacterial effects of pinocembrin (PNCB) against Staph. aureus pneumonia in a murine model and its influence on the production of Staph. aureus α-haemolysin (Hla). The in vitro activities of PNCB on α-haemolysin production were determined using haemolysis, Western blot and real-time RT-PCR assays. The viability and cytotoxicity assays were performed to evaluate the influence of PNCB on α-toxin-mediated injury of human alveolar epithelial cells. Moreover, through histopathologic analysis, we further determined the in vivo effects of PNCB on Staph. aureus pneumonia in a mouse model. In vitro, PNCB at low concentrations exhibited inhibitory activity against α-haemolysin production and attenuated α-haemolysin-mediated cell injury. Furthermore, the in vivo findings demonstrated that PNCB protected mice from Staph. aureus pneumonia. We have provided new evidence of the effects of PNCB, which suggest that PNCB attenuated α-haemolysin-mediated cell injury and protected mice from Staph. aureus pneumonia. The findings indicate that PNCB may be used as a basis for anti-Staphylococcus agent.


Rapid COVID-19 diagnosis using ensemble deep transfer learning models from chest radiographic images.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes novel coronavirus disease (COVID-19) outbreak in more than 200 countries around the world. The early diagnosis of infected patients is needed to discontinue this outbreak. The diagnosis of coronavirus infection from radiography images is the fastest method. In this paper, two different ensemble deep transfer learning models have been designed for COVID-19 diagnosis utilizing the chest X-rays. Both models have utilized pre-trained models for better performance. They are able to differentiate COVID-19, viral pneumonia, and bacterial pneumonia. Both models have been developed to improve the generalization capability of the classifier for binary and multi-class problems. The proposed models have been tested on two well-known datasets. Experimental results reveal that the proposed framework outperforms the existing techniques in terms of sensitivity, specificity, and accuracy.


Response of anoestrous ewes pre-treated with a single dose of oestradiol-17 beta, or progesterone and oestradiol-17 beta, to the introduction of rams and ewes in oestrus.
To determine if the frequency distribution of time to oestrus observed after the introduction of rams, and additional ewes in oestrus, is affected by the administration of oestradiol- 17beta. To determine if the fertility following mating at the first induced oestrus in progesterone-primed ewes may be increased with administration of oestradiol-17beta. In Experiment 1, ewes received 40 mug oestradiol- 17beta 3 (E3; n=61) or 5 (E5; n=56) days before the introduction of rams; 61 ewes were controls (C1). In Experiment 2, a controlled internal drug-releasing (CIDR) device was inserted in 95 ewes on Day -5 (Day 0 = introduction of rams). In addition, 47 ewes received oestradiol-17beta on Day 0 (CE), and the remaining 48 were controls (C2). In both experiments, additional ewes, brought into oestrus between Days 0 and 2 by hormonal treatments, were introduced with the rams. Onset of oestrus was estimated by visual observation of ewes marked by rams. Pregnancy status of ewes in Experiment 2 was determined using ultrasound, 30 days after oestrus. The total number of ewes detected in oestrus in Experiment 1 was similar between the three groups. The frequency distribution of ewes in oestrus in the E5 group differed from that of ewes in both C1 (p=0.05) and E3 (p<0.001). A similar number of ewes were detected in oestrus between Days 16-20, but the proportion of ewes in oestrus between Days 21-26 was greater for ewes in C1 than E5 or E3. Mean interval to the onset of oestrus was shorter in C1 than E3 which was shorter than E5 ewes (p<0.001). In Experiment 2, the total number of ewes in oestrus were similar between groups. Ewes in oestrus between Days 1-4 (65% and 64% for C2 and CE, respectively) and conception rates over the same period (81% and 80% for C2 and CE, respectively) were also similar between groups. Administration of oestradiol-17beta to anoestrous ewes altered the pattern of onset of oestrus, but it did not affect submission or conception rates, regardless of whether or not a short period of progesterone priming with a new CIDR device was included prior to the introduction of rams.


Implementation of a Contingency Management-Based Intervention in a Community Supervision Setting: Clinical Issues and Recommendations.
A cognitive-behaviorally based substance abuse treatment program was implemented within a Community Supervision setting. This program included a goals group that included a contingency management component and included the probation agent as a part of treatment. This paper describes the contingency management component of the treatment and discusses, in detail, issues that arose throughout the course of the study. Possible causes and solutions to the issues are discussed from a contingency management perspective that can result in improved reinforcements to achieve better probationer outcomes.


A new simultaneous derivatization and microextration method for the determination of memantine hydrochloride in human plasma.
A simple and sensitive method for simultaneous derivatization and hollow fiber liquid phase microextraction (HF-LPME) followed by high performance liquid chromatography-fluorescence detection (HPLC-FL) to determine memantine hydrochloride (MT) in human plasma was developed. The derivatization and microextraction was combined to a single step to ensure the precision. What is more, the derivatization reaction accelerated the mass transfer during the process of microextraction. The hollow fiber was filled with cyclohexane and dansyl chloride (derivatization agent) as acceptor phase and submersed in the alkalinized plasma sample. The system was submitted to stirring at 800rpm for 50min at 40°C. Different experimental parameters were systematically evaluated by response surface methodology. Under the optimized conditions, the calibration curve was linear in the range of 1-100ng/mL (r=0.9991) with a limit of detection of 0.1ng/mL (S/N=3). The precision estimated as the relative standard deviation (RSD) was less than 4.5% and the accuracy was 94.3-100.7%. The present method was successfully applied to determine MT in human plasma samples.


Polymorphisms in the CC-chemokine receptor-2 (CCR2) and -5 (CCR5) genes and risk of coronary heart disease among US women.
Genetic variation in CC-chemokine receptor-2 (CCR2) and -5 (CCR5), and their common haplotypes, acting through inflammatory responses, may affect atherosclerosis and risk of coronary heart disease (CHD). We examined seven common variants in the CCR2 and CCR5 loci and risk of CHD among women in the Nurses' Health Study. During 8 years of follow-up, we documented 248 incident cases of nonfatal myocardial infarction and fatal CHD, and matched controls 2:1 based on age and smoking. The distribution of alleles was similar between cases and controls. The haplotype-specific odds ratios (ORs) were not statistically significant nor was the globally-adjusted p-value (p=0.61). However, there was a statistically significant association for CCR5-Delta32 and A58755G (rs2856758) between cases and controls comparing age of onset <55 and >or=55 years. For Delta32, the OR for having the variant was 0.12 (0.02-0.76) for age <55, and 1.14 (0.69-1.88) for age >or=55 years (p, interaction=0.04). The CCR5-Delta32 was in linkage disequilibrium with 58755G, and a similar association was observed for having the 58755G. In this population, CCR2-CCR5 haplotypes were not associated with risk of CHD. However, our data suggest a strong inverse association for certain CCR5 variants and early age of CHD onset.


Androgen deficiency as a predictor of metabolic syndrome in aging men: an opportunity for intervention?
The prevalence of metabolic syndrome is increasing globally and is an important risk factor for the development of cardiovascular disease. Longitudinal population studies have found that low testosterone status in men is a risk factor for the later development of metabolic syndrome. Men with metabolic syndrome and type 2 diabetes mellitus have a higher incidence of hypotestosteronaemia. Furthermore, in men, testosterone levels are inversely associated with the degree of carotid and aortic atherosclerosis. Early interventional, short-term studies have shown that testosterone replacement therapy has a beneficial effect on visceral obesity, insulin sensitivity, glycaemic control and lipid profiles in men with diagnosed hypogonadism with and without diabetes. The effect of testosterone therapy on atherogenesis in men is unknown; however, animal studies have shown that testosterone is atheroprotective and can ameliorate the degree of atherosclerosis. Testosterone is an arterial vasodilator and has been shown to improve myocardial ischaemia in men with coronary artery disease. This review discusses the role that testosterone may play in the pathogenesis of metabolic syndrome in men and also examines the potential role of testosterone replacement therapy in this condition.


Robotic axial lower leg testing: repeatability and reproducibility.
The purpose of this study was to determine the test-retest reliability and the repeatability over multiple days of a robotic testing device when used to measure laxity of the lower leg during a simulated dial test. Ten healthy subjects were evaluated using an instrumented robotic lower leg testing system over 4 days. Three testing cycles were performed each day. Each leg was rotated into external and then internal rotation by servomotors until a torque threshold of 5.65 N m was reached. Load-deformation curves were generated from torque and rotation data. Both average-measure and single-measure intraclass correlation coefficients (ICC) were compared across the curves. ICC scores were also compared for features of the curves including: maximum external rotation at -5.65 N m of torque, maximum internal rotation at 5.65 N m of torque, rotation at torque 0, compliance (slope of load-deformation curve) at torque 0, endpoint compliance in external rotation, endpoint compliance in internal rotation, and play at torque 0. Play at torque 0 was defined as the width of the hysteresis curve at torque 0. Average-measure ICC scores and test-retest scores were >0.95 along the entire load-deformation curve except around zero torque. ICC scores at maximum internal and external rotation ranged from 0.87 to 0.99 across the left and right knees. ICC scores for the other features of the curves ranged from 0.61 to 0.98. The standard error of the mean ranged from 0.0497 to 1.1712. The robotic testing device in this study proved to be reliable for testing a subject multiple times both within the same day and over multiple days. These findings suggest that the device can provide a level of reliability in rotational testing that allows for clinical use of test results. Objective laxity data can improve consistency and accuracy in diagnosing knee injuries and may enable more effective treatment.


The role of library and information services in the modular curriculum.
Radical changes in nurse education, accompanied by advances in library and information services (LIS), set against a background of ever-expanding nursing literature and information, have favoured the development of good practices in curriculum development and student-centred learning. This paper discusses the experience at Keele University of enhanced collaborative effort between curriculum planners and LIS staff, and aims to show how LIS can facilitate student learning and contribute to curriculum planning and delivery, quality resource provision, evaluation processes and life-long learning.


A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration.
Zebrafish and mammalian neonates possess robust cardiac regeneration via the induction of endogenous cardiomyocyte (CM) proliferation, but adult mammalian hearts have very limited regenerative potential. Developing small molecules for inducing adult mammalian heart regeneration has had limited success. We report a chemical cocktail of five small molecules (5SM) that promote adult CM proliferation and heart regeneration. A high-content chemical screen, along with an algorithm-aided prediction of small-molecule interactions, identified 5SM that efficiently induced CM cell cycle re-entry and cytokinesis. Intraperitoneal delivery of 5SM reversed the loss of heart function, induced CM proliferation, and decreased cardiac fibrosis after rat myocardial infarction. Mechanistically, 5SM potentially targets α1 adrenergic receptor, JAK1, DYRKs, PTEN, and MCT1 and is connected to lactate-LacRS2 signaling, leading to CM metabolic switching toward glycolysis/biosynthesis and CM de-differentiation before entering the cell-cycle. Our work sheds lights on the understanding CM regenerative mechanisms and opens therapeutic avenues for repairing the heart.


Identification of covalent fragment inhibitors for Plasmodium falciparum UCHL3 with anti-malarial efficacy.
Malaria continues to be a major burden on global health, responsible for 619,000 deaths in 2021. The causative agent of malaria is the eukaryotic parasite Plasmodium. Resistance to artemisinin-based combination therapies (ACTs), the current first-line treatment for malaria, has emerged in Asia, South America, and more recently Africa, where >90% of all malaria-related deaths occur. This has necessitated the identification and investigation of novel parasite proteins and pathways as antimalarial targets, including components of the ubiquitin proteasome system. Here, we investigate Plasmodium falciparum deubiquitinase ubiquitin C-terminal hydrolase L3 (PfUCHL3) as one such target. We carried out a high-throughput screen with covalent fragments and identified seven scaffolds that selectively inhibit the plasmodial UCHL3, but not human UCHL3 or the closely related human UCHL1. After assessing toxicity in human cells, we identified four promising hits and demonstrated their efficacy against asexual P. falciparum blood stages and P. berghei sporozoite stages.


Chronic exposure to morphine, cocaine or ethanol in rats produced different effects in brain cannabinoid CB(1) receptor binding and mRNA levels.
Recent evidence suggest that the endocannabinoid system might be a component of the brain reward system and, then, play a role, not only in cannabinoid tolerance/dependence, but also in dependence/withdrawal to other drugs of abuse. However, there are not many studies that compare the changes in endocannabinoid ligands and/or receptors in brain regions (particularly in those areas related to reinforcement processes) during dependence to opiates, cocaine or alcohol. The present study addressed this objective, by examining the changes in CB(1) receptor binding (measured by [3H]-CP55,940 autoradiography) and its mRNA levels (measured by in situ hybridization) in different brain regions of animals chronically exposed to morphine, cocaine or ethanol. The results showed that these three drugs produced different changes in CB(1) receptor binding and mRNA levels, a finding that precludes the existence of a common alteration of the endocannabinoid system during dependence states to these habit-forming drugs. Thus, chronic ethanol exposure was usually uneffective in altering both CB(1) receptor binding and mRNA levels in all regions examined. In contrast, chronic cocaine exposure produced significant changes only at the level of CB(1) receptor mRNA, with decreases of the transcript levels in the ventromedial hypothalamic nucleus and the superficial and deep layers of the cerebral cortex, but no changes in the hippocampal, motor and limbic structures. Finally, chronic morphine exposure increased the density of CB(1) receptors in the medial caudate-putamen, but decreased their mRNA levels in this region and also in the lateral caudate-putamen and the cerebellum. In limbic structures, chronic morphine exposure increased both binding and mRNA levels for CB(1) receptors in the septum nuclei. Binding was also increased in the nucleus accumbens, but reduced in the basolateral amygdala. In hippocampal structures, chronic morphine exposure reduced CB(1) receptor binding in the dentate gyrus, although mRNA levels were unaffected in this region, but increased in the CA2 subfield of the Ammon's horn. The results indicate that mechanisms of dependence for alcohol, cocaine and morphine are different in terms of their impact on the endocannabinoid system. Alcohol did not produce any effects on CB(1) receptor binding and mRNA levels, whereas cocaine only affected transcript levels in selected regions and morphine produced divergent and region-dependent effects.


Effects of dietary selenium on lipid peroxidation, mitochondrial function and protein profiles in the heart of the myopathic Syrian golden hamster (BIO 14.6).
Male, weanling myopathic Syrian Golden Hamsters (BIO 14.6 strain) were fed a selenium-adequate diet (controls) or this diet supplemented with 1.0 ppm selenium (treated) for 30 days. Se-treated animals exhibited a 50% reduction in lipid peroxidation in heart homogenates relative to controls and a 61% increase in mitochondrial glycerophosphate acyltransferase activity. Gel electrophoresis revealed no alterations in cardiac protein profiles from treated or control animals. These data suggest that the selenium prevents peroxidative injury and maintains mitochondrial function in the absence of alterations in cardiac proteins.


Electromechanical activity of the equine small intestine and its correlation with transit of fluid through Thiry-Vella loops.
Motility patterns in the equine small intestine were investigated in eight ponies. Muscular activity was assessed by means of extramural strain gauge transducers, bi-polar electrodes and in three of the animals, fitted with Thiry-Vella loops, the transit of fluid. Circular muscle contractions were preceded by spiking superimposed on the slow wave and fluid transit in the loops correlated with both these events.


Adding insult to injury: Ship groundings are associated with coral disease in a pristine reef.
In 2013, the remote Tubbataha Reef UNESCO World Heritage Site, in the western Philippines, experienced two ship groundings within four months: the USS Guardian (USSG), a US military vessel, and the Min Ping Yu (MPY), an illegal Chinese fishing vessel. Here, we present the results of coral disease assessments completed two years post-grounding and recovery patterns monitored annually within these grounding sites. Site assessments were undertaken in three distinct zones: 'ground zero', where reef was scoured to its limestone base by direct ship impact; the 'impact border', containing surviving upright but damaged, abraded and fragmented colonies injured during ship movement; and undamaged 'control' sites, remote from the ship groundings but located on the same atoll. Coral diseases were dominated by white syndromes, and prevalence was an order of magnitude higher within the impact border zones than within the other zones two years after the events. Hard coral cover has steadily increased at a mean rate of 3% per year within the scoured USSG site at a rate comparable to control sites. In contrast, recovery has been negligible within the rubble-dominated MPY site, suggesting that substrate quality strongly influenced recovery processes such as recruitment, as larvae do not survive well on unstable substrates. Long-term recovery trajectories from these two grounding events appeared strongly influenced by movement of the ship during and after each event, and site-specific wave-influenced persistence of rubble and debris. High prevalence of coral disease among damaged but surviving colonies two years post-grounding suggested long-term impacts which may be slowing recovery and creating localized pockets of higher persistent disease prevalence than that of the surrounding population.


Does gender predict performance of novices undergoing Fundamentals of Laparoscopic Surgery (FLS) training?
This study was performed to assess the hypothesis that performance levels for Fundamentals of Laparoscopic Surgery (FLS) tasks were not dependent on trainee gender. Initial and final task completion times for 4 FLS tasks performed by 132 novices (4th-year medical students and 1st-year residents) were collated by task type and compared by gender. All novices improved significantly with training (P > .001) on all tasks. Initial performance by men was better than by women but only reached significance for peg transfer and intracorporeal knot tying (P > .05). With training, women's performance became equivalent to that of men but showed a comparable or greater response to training. The gender-related differences noted in initial FLS task performance disappeared after training. Gender displayed no effect on FLS training outcomes. The use of initial FLS task performance levels, seemingly objective selection criteria, would introduce gender bias into the ranking process.


Impact of a multifaceted intervention on physicians' knowledge, attitudes and practices in relation to pharmaceutical incentivisation: protocol for a randomised control trial.
In settings where the private sector constitutes a larger part of the health system, profit-gathering can take primacy over patients' well-being. In their interactions with pharmaceutical companies, private general practitioners (GPs) can experience the conflict of interest (COI), a situation whereby the impartiality of GPs' professional decision making may be influenced by secondary interests such as financial gains from prescribing specific pharmaceutical brands. This study is a randomised controlled trial to assess the impact of a multifaceted intervention on GPs' medical practice. The study sample consists of 419 registered GPs who own/work in private clinics and will be randomly assigned to intervention and control groups. The intervention group GPs will be exposed to emotive and educational seminars on medical ethics, whereas control group GPs will be given seminars on general medical topics. The primary outcome measure will be GPs' prescribing practices, whereas the secondary outcome measures will be their knowledge and attitudes regarding COI that arises from pharmaceutical incentivisation. In addition to a novel standardised pharmaceutical representatives (SPSR) method, in which field researchers will simulate pharmaceutical marketing with GPs, presurvey and postsurvey, and qualitative interviewing will be performed to collect data on GPs' knowledge, attitudes and practices in relation to COI linked with pharmaceutical incentives. Univariate and multivariate statistical analyses will be performed to measure a change in GPs' knowledge, attitudes and practices, while qualitative analysis will add to our understanding of the quantitative SPSR data. Ethics approval has been obtained from the Pakistan National Bioethics Committee (# 4-87/NBC-582/21/1364), the Aga Khan University (# 2020-4759-1129) and the London School of Hygiene and Tropical Medicine (# 26506). We will release results within 6-9 months of the study's completion. ISRCTN12294839.


Survey of cause-of-death query criteria used by state vital statistics programs in the US and the efficacy of the criteria used by the Oregon Vital Statistics Program.
A survey of the 52 vital statistics registration areas in the United States revealed that at least 23 did not fulfill the minimum cause-of-death query guidelines recommended by the National Center for Health Statistics. The Oregon Center for Health Statistics is one of only a few that query certifying physicians at a comprehensive level. During August 1986-July 1987, a total of 2,453 of 23,238 death certificates were returned to the certifiers for additional information, not including those returned in a tobacco use study. More than one-half (56.1 per cent) resulted in new and more specific underlying cause-of-death data. Only 5.2 per cent of the queries were unanswered. One probable result of Oregon's program is that the state has the highest percentage of liver cirrhosis and disease deaths attributed to alcohol abuse in the United States. Nationally, 41.7 per cent of all liver disease and cirrhosis deaths in 1984 were listed as due to alcohol compared to 82.4 per cent in Oregon. The state's total liver cirrhosis and disease death rate (12.0 per 100,000 population) is only marginally higher than the United States rate (11.6). The query program also serves to locate maternal deaths that would otherwise not be reported, as well as to provide more accurate cause-of-death statistics in general.


A SEER-Medicare Based Quality Score for Patients With Metastatic Upper Tract Urothelial Carcinoma.
Population-based studies evaluating outcomes for metastatic upper tract urothelial carcinoma (mUTUC) are sparse and rarely capture both patients with de novo (synchronous) metastases and those who progress to metastatic disease (metachronous). Herein we evaluated the outcomes and costs associated with synchronous and metachronous mUTUC, utilizing a novel Methodology. Additionally, we created a guideline-based quality score to improve care in this space. We identified all patients with mUTUC aged 66 years and older included in the SEER-Medicare linked database between 2004 and 2012. Achievement of 3 quality criteria was assessed: (1) cancer-specific survival (CSS)>12 months; (2) receipt of systemic therapy; (3) receipt of hospice/palliative care. Total healthcare and out-of-pocket costs were evaluated. Regression analyses were performed to assess characteristics associated with quality criteria and total healthcare costs. Of the 1223 patients identified, at least one quality criterion was met in just 40.2% and only 54 patients (4.4%) received palliative care. In multivariable analysis, patients with synchronous mUTUC (OR:0.55, 95%CI:0.41-0.72), and at least 3 comorbidities (OR:0.68, 95%CI:0.47-0.98) were less likely to achieve at least 1 quality criterion. Meeting at least 1 quality criterion was associated with increased costs ($94,677, 95%CI:87,702-101,652 versus $63,575, 95%CI:59,598-67,552). Less than half of patients with mUTUC met at least 1 quality criterion. Quality score achievement was associated with a modest increase in total healthcare spending. These findings not only provide guidance for future study of rare diseases using secondary data, but also highlight inadequacies in the current management of mUTUC.


Parenting stress mediates the association between negative affectivity and harsh parenting: A longitudinal dyadic analysis.
The current study examined parenting stress (disaggregated into personal distress and child rearing stress) at 12 months postpartum as a mediator of the longitudinal association between parental negative affectivity at 6 months postpartum and harsh parenting at 3 years postpartum for first-time parents with a child transitioning from late toddlerhood to the early preschool years. Analyses were conducted using Mediation for Actor Partner Interdependence Modeling in a sample of 164 couples who participated in a randomized controlled trial of a universal, couple-based transition to parenthood program. There were indirect actor effects of negative affect on a parent's own harsh parenting through both dimensions of parenting stress, with a stronger mediating effect for personal distress than child rearing stress. There were also indirect partner effects of negative affect on one's partner's harsh parenting through the partner's parenting stress, with a stronger indirect partner effect from mothers' negative affect to fathers' harsh parenting than vice versa. Specifically, the mediating effect of personal distress was found for both mothers and fathers, whereas the mediating effect of child rearing stress was found from mothers' negative affect to fathers' harsh parenting only. Findings highlight the importance of a dyadic approach in examining the longitudinal association between negative affect and harsh parenting and suggest that reducing parenting stress in the first year postpartum may decrease the risk of future harsh parenting among couples in which one or both partners experience negative affectivity. (PsycINFO Database Record


Using machine learning to estimate health spillover effects.
We develop a nonparametric model to study health spillover effects of policy interventions. We use double/debiased machine learning to estimate the model using data from 74 hospitals in Rio de Janeiro, Brazil, and examine cross-patient spillover effects during the COVID-19 pandemic. The pandemic forced hospitals to develop new protocols to offer intensive care to both COVID and non-COVID patients. Our results show that the need to care for COVID patients affects health outcomes of non-COVID patients. Controlling for a number of confounders, we find that mortality rates and length of stay of non-COVID ICU patients increase when hospitals simultaneously offer intensive care to both types of patients. Policy simulations suggest that an increase in the number of ICU beds can counter morbidity spillover, but it is unlikely to be a feasible approach to counter mortality spillover.


Bacteriocin production by Enterococcus faecium RZS C5 is cell density limited and occurs in the very early growth phase.
Enterocins, bacteriocins produced by enterococci, are gaining interest because of their antilisterial activity. Enterococcus faecium RZS C5, a natural isolate from cheese, produces such a bacteriocin. Generally, bacteriocin production by lactic acid bacteria is a growth-associated process which ceases when cell growth starts to level off. Remarkably, enterocin production by Ent. faecium RZS C5 seems to be limited to the very early growth phase and is switched off at a well-defined cell density of 0.4 g cell dry mass (CDM) l(-1). However, at pH values higher than 6.5, enterocin production displays distinct kinetics. At such pH values, enterocin production is reduced but is maintained until the end of the active growth phase. The relation with cell concentration suggests that enterocin production is part of a severely regulated mechanism. A kinetic model is set up for the description of the early enterocin activity peak. Furthermore, the influence of pH and temperature on the kinetics of growth and bacteriocin production of Ent. faecium RZS C5 was investigated. At pH 6.5, high enterocin activity was obtained in the temperature range 20-35 degrees C. At 35 degrees C, enterocin activity could only be detected between pH 5.5 and 8.0.


The effect of medial preoptic area lesions on sexually stimulated hormone release in the male rat.
Male rats were subjected to bilateral electrolytic lesions in the medial preoptic area (mPOA). These lesions disrupted sexual behavior without affecting basal levels of luteinizing hormone (LH), prolactin (PRL), or testosterone (T). During exposure to an estrous female, intact and sham-operated rats mated; these rats showed elevations in LH, PRL, and T levels. Lesioned rats, which did not mate, showed elevations in LH but not PRL or T levels. These results demonstrate that the mPOA is not required for sexually stimulated LH release. The failure of lesioned rats to release PRL and T may be secondary to their failure to mate. Alternatively, the mPOA may participate in sexually stimulated PRL release, while T release may depend on prior elevations in both LH and PRL levels. LH release may be related to arousal, and PRL release to consummation, providing a hormonal analogy for the dual mechanism theory of sexual behavior.


Current evidence and future perspectives of omega-3 polyunsaturated fatty acids for the prevention of cardiovascular disease.
Omega-3 fatty acids have been traditionally used for the prevention of major cardiovascular events in patients with or without a history of cardiovascular disease. Their main mechanism of action is to lower triglyceride levels, but they also exert anti-arrythmic and anti-inflammatory properties, they reduce blood pressure levels and stabilize the atherosclerotic plaques. There is a vast amount of evidence derived from randomized studies that seems to question their benefit for the prevention of major cardiovascular events. Upcoming trials will help to better clarify their use in certain indications.


Ready-to-be-addressed oxo-clusters: individualized, periodically organized and separated from the substrate.
Clusters and oxo-clusters are drawing attention for their amazing physical properties, especially at the scale of the single molecule. However, chemical methods to organize them individually on a surface are still lacking. In this study we show that it is possible to periodically organize individual polyoxometalates thanks to their ordering by a new supramolecular assembly.


Stimulated single-fiber electromyography (sSFEMG) in Lambert-Eaton syndrome.
To report the clinical features and the neurophysiological approach of a patient with Lambert-Eaton myasthenic syndrome (LEMS), highlighting the diagnostic role of the stimulated single fiber electromyography (sSFEMG). A 60-year-old woman presenting with the LEMS triad (proximal and axial weakness, autonomic dysfunction and areflexia) was evaluated by neurophysiological tests (electroneuromyography, repetitive stimulation test (TSR), voluntary and stimulated SFEMG). We reported: 1) increase of compound muscle action potential (CMAP) amplitude (>60%) following brief isometric exercise compared to the rest (baseline); 2) decremental/incremental response of CMAP amplitude at low- (3 Hz) and high-frequency (30 Hz) repetitive stimulation test (RST), respectively; 3) increased neuromuscular jitter and blocking at voluntary single-fiber electromyography (vSFEMG); 4) stimulation rate-dependent reduction of the neuromuscular jitter and blocking at sSFEMG. Diagnosis was confirmed by serological demonstration of circulating voltage gated calcium channels (VGCC) antibodies. The present case highlights the role of the sSFEMG in the diagnosis of LEMS, underling the stimulation rate-dependency of both neuromuscular jitter and blocks.


Identification and Precise Mapping of Resistant QTLs of Cercospora Leaf Spot Resistance in Sugar Beet (Beta vulgaris L.).
The complex inheritance of resistance to Cercospora leaf spot (CLS), the most severe fungal foliar disease in sugar beet, was investigated by means of quantitative trait loci (QTL) analysis. Over a three year period, recombinant inbred lines (RILs) of sugar beet (Beta vulgaris L.), generated through a cross between lines resistant ('NK-310mm-O') and susceptible ('NK-184mm-O') to CLS, were field-tested for their resistance to the pathogen. Composite interval mapping (CIM) showed four QTL involved in CLS resistance to be consistently detected. Two resistant QTL (qcr1 on chromosome III, qcr4 on chromosome IX) bearing 'NK-310mm-O' derived alleles promoted resistance. Across 11 investigations, the qcr1 and qcr4 QTL explained approximately 10% and over 20%, respectively, of the variance in the resistance index. Two further QTL (qcr2 on chromosome IV, qcr3 on chromosome VI) bearing 'NK-184mm-O' derived alleles each explained about 10% of the variance. To identify the monogenic effect of the resistance, two QTL derived from 'NK-310mm-O' against the genetic background of 'NK-184mm-O', using molecular markers. The qcr1 and qcr4 were precisely mapped as single QTL, using progenies BC(5)F(1) and BC(2)F(1), respectively. The qcr1 that was located near e11m36-8 had CLS disease severity indices (DSI) about 15% lower than plants homozygous for the 'NK-184mm-O' genotype. As with qcr1, heterozygosis of the qcr4 that was located near e17m47-81 reduced DSI by about 45% compared to homozygosis. These two resistant QTL might be of particular value in marker-assisted selection (MAS) programs in CLS resistance progression.


Mass chemotherapy options to control lymphatic filariasis: a systematic review.
Understanding the efficacy of microfilaricidal drugs is important in guiding the global programme for the elimination of lymphatic filariasis as a public-health problem. We did a systematic review of the available literature to determine which currently available drug intervention most effectively decreases circulating Wuchereria bancrofti microfilaria in individuals and populations. 57 randomised studies of drug efficacy were identified. Data were combined and compared using weighted mean effect estimates taking into account the longitudinal nature of the data. Combined treatment with diethylcarbamazine plus ivermectin, diethylcarbamazine plus albendazole, and ivermectin plus albendazole resulted in average microfilarial intensity decreases that were 0.7%, 4.6%, and 12.7% of the pre-treatment values, respectively. Drug combinations containing diethylcarbamazine were the most effective against microfilarial prevalence and intensity relative to single drugs or other combinations. The relative efficacies of drug combinations have not been well documented from existing studies and therefore limit the application of evidenced-based recommendations for chemotherapy-based interventions to control lymphatic filariasis. These results provide valuable estimates of drug effect using existing data, but highlight the need for more comprehensive comparative drug studies.


Recoiling, regrouping, and recovering: first-person accounts of the role of spirituality in the course of serious mental illness.
Because many consumers view spirituality as important in their recovery, mental health professionals can benefit from a clearer understanding of the role of religion from the consumer's perspective.


Health Economic Research Assessing the Value of Early Detection of Cardiovascular Disease: A Systematic Review.
Cardiovascular disease (CVD) is the most prominent cause of death worldwide and has a major impact on healthcare budgets. While early detection strategies may reduce the overall CVD burden through earlier treatment, it is unclear which strategies are (most) efficient. This systematic review reports on the cost effectiveness of recent early detection strategies for CVD in adult populations at risk. PubMed and Scopus were searched to identify scientific articles published between January 2016 and May 2022. The first reviewer screened all articles, a second reviewer independently assessed a random 10% sample of the articles for validation. Discrepancies were solved through discussion, involving a third reviewer if necessary. All costs were converted to 2021 euros. Reporting quality of all studies was assessed using the CHEERS 2022 checklist. In total, 49 out of 5552 articles were included for data extraction and assessment of reporting quality, reporting on 48 unique early detection strategies. Early detection of atrial fibrillation in asymptomatic patients was most frequently studied (n = 15) followed by abdominal aortic aneurysm (n = 8), hypertension (n = 7) and predicted 10-year CVD risk (n = 5). Overall, 43 strategies (87.8%) were reported as cost effective and 11 (22.5%) CVD-related strategies reported cost reductions. Reporting quality ranged between 25 and 86%. Current evidence suggests that early CVD detection strategies are predominantly cost effective and may reduce CVD-related costs compared with no early detection. However, the lack of standardisation complicates the comparison of cost-effectiveness outcomes between studies. Real-world cost effectiveness of early CVD detection strategies will depend on the target country and local context. CRD42022321585 in International Prospective Registry of Ongoing Systematic Reviews (PROSPERO) submitted at 10 May 2022.


Cageside Ultrasonography in the Emergency Room and Intensive Care Unit.
Global Focused Assessment with Sonography for Trauma (FAST) and point-of-care ultrasonography carry the potential to screen for and monitor conditions rather than traditional means without ultrasonography. Advantages include being point of care, cageside, low impact, rapid, safe, and radiation sparing, and requiring no shaving and/or minimal patient restraint. Moreover, information is real time for free fluid and soft tissue abnormalities of the abdomen, heart, and lung, which are missed or only suspected by physical examination, basic blood and urine testing, and radiography. A standardized approach with recording of patient data is integral to a successful Global FAST program.


Woven Polymer Networks: From Crystalline to Elastomeric Materials.
Weaving technology has been extensively used for manufacturing macroscopic fabrics and satisfying the artistic demands of humans through the ages. Integrating woven geometries into molecular structures is a persistent pursuit, and yet a significant challenge to chemists, owing to the lack of effective methodologies to guide the regular mutual interlacing of molecular strands. In this Concept article, recent progress and related strategies in constructing woven polymer networks (WPNs) are summarized and discussed. An outlook is then given to highlight the future opportunities and challenges in the development of both molecularly woven structures and molecularly woven functional materials.


Regio- and stereoselective synthesis of enantiomerically pure [60]fullerene tris-adducts with an inherently chiral e,e,e addition pattern.
The synthesis and flash column chromatographic separation of enantiomerically pure tris-adducts of C60 with an e,e,e-addition pattern is achieved via cyclopropanation with chiral D3-symmetrical cyclo-tris(malonate) tethers.


Histamine H1-receptor in endothelial and smooth muscle cells of guinea-pig aorta.
The location of histamine H1-receptors in the thoracic aorta of guinea-pigs was studied with a [3H]mepyramine binding assay. [3H]Mepyramine binding studies of whole and rubbed aortas, and of cultured endothelial and smooth muscle cells showed that the Kd values were all in the range 0.53-0.76 nM, but that the Bmax values were 19.1, 10.1, 63.3 and 11.6 fmol/mg protein, respectively. Thus, the whole aorta contained more H1-receptors than the rubbed one (free of endothelium), and cultured endothelial cells contained more H1-receptors than smooth muscle cells. These results indicate that more histamine H1-receptors were concentrated in the endothelial cells than in the smooth muscle cells in guinea-pig aorta.


Does the extraction-site location in laparoscopic colorectal surgery have an impact on incisional hernia rates?
Incisional hernias are a common postoperative complication with abdominal surgery. The major risk factors for their development include wound infection, obesity, and age. This study aimed to evaluate the impact of extraction-site location and technique on incisional hernia rates in laparoscopic colorectal surgery. A prospective study of 208 consecutive patients who underwent laparoscopic colorectal surgery between March 2002 and July 2006 was performed. The study included only patients who had an extraction site on the abdominal wall. Patients were excluded if they were lost to follow-up evaluation or underwent conversion to open procedure. For the 166 patients included in the study, the mean follow-up period was 20.2 +/- 14.4 months. Extraction-site incisions were classified into two groups: midline or off-midline. Midline wounds involved sharp division of the linea alba and were closed with a single layer of no.1 Vicryl. Off-midline incisions involved sharp division of the anterior and posterior sheaths with blunt spreading of the muscular layers and were closed in two layers with no. 1 Vicryl. Risk factors including wound infection, body mass index (BMI), age, and diabetes were analyzed. The incisional hernia rate for the entire series was 7.8%. The incisional hernia rate was 17.6% for the midline group (n = 74) and 0% for the off-midline group (n = 92) (p = 0.0002, statistically significant). There was no statistically significant difference in age, BMI, diabetes, follow-up time, or wound infection rate between the two groups. In this series, the midline extraction site resulted in a significantly higher incisional hernia rate statistically than the off-midline extraction sites. The authors therefore have adopted an off-midline blunt muscle-splitting extraction site when performing laparoscopic colorectal surgery.


Aptamer-based fluorescence sensor for rapid detection of potassium ions in urine.
We unveil a new homogeneous assay-using OliGreen and an ATP-binding aptamer-for the highly selective and sensitive detection of potassium ions.


Identification of different species of Bacillus isolated from Nisargruna Biogas Plant by FTIR, UV-Vis and NIR spectroscopy.
Definitive identification of microorganisms, including pathogenic and non-pathogenic bacteria, is extremely important for a wide variety of applications including food safety, environmental studies, bio-terrorism threats, microbial forensics, criminal investigations and above all disease diagnosis. Although extremely powerful techniques such as those based on PCR and microarrays exist, they require sophisticated laboratory facilities along with elaborate sample preparation by trained researchers. Among different spectroscopic techniques, FTIR was used in the 1980s and 90s for bacterial identification. In the present study five species of Bacillus were isolated from the aerobic predigester chamber of Nisargruna Biogas Plant (NBP) and were identified to the species level by biochemical and molecular biological (16S ribosomal DNA sequence) methods. Those organisms were further checked by solid state spectroscopic absorbance measurements using a wide range of electromagnetic radiation (wavelength 200 nm to 25,000 nm) encompassing UV, visible, near Infrared and Infrared regions. UV-Vis and NIR spectroscopy was performed on dried bacterial cell suspension on silicon wafer in specular mode while FTIR was performed on KBr pellets containing the bacterial cells. Consistent and reproducible species specific spectra were obtained and sensitivity up to a level of 1000 cells was observed in FTIR with a DTGS detector. This clearly shows the potential of solid state spectroscopic techniques for simple, easy to implement, reliable and sensitive detection of bacteria from environmental samples.


Synthesis, characterization and application of ZnO-Ag as a nanophotocatalyst for organic compounds degradation, mechanism and economic study.
The current work deals with ZnO-Ag nanocomposites (in the wide range of x in the Zn1-xO-Agx chemical composition) synthesized using microwave assisted solution combustion method. The structural, morphological and optical properties of the samples were characterized by XRD (X-ray diffraction), FTIR (Fourier transform infrared spectrometry), SEM (scanning electron microscopy technique), EDX (energy dispersive X-ray spectrum), ICP (inductively coupled plasma technique), TEM (transmission electron microscopy), BET (Brunauer-Emmett-Teller method), UV-Vis (ultraviolet-visible spectrophotometer) and photoluminescence spectrophotometer. The photocatalytic activity of the ZnO-Ag was investigated by photo-degradation of Acid Blue 113 (AB 113) under UV illumination in a semi-batch reactor. This experiment showed that ZnO-Ag has much more excellent photocatalytic properties than ZnO synthesized by the same method. The enhanced photocatalytic activity was due to the decrease in recombination of photogenerated electron-holes. The results showed the improvement of ZnO photocatalytic activity and there is an optimum amount of Ag (3.5mol%) that needs to be doped with ZnO. The effect of operating parameters such as pH, catalyst dose and dye concentration were investigated. The reaction byproducts were identified by LC/MS (liquid chromatography/mass spectrometry) analysis and a pathway was proposed as well. Kinetic studies indicated that the decolorization process follows the first order kinetics. Also, the degradation percentage of AB 113 was determined using a total organic carbon (TOC) analyzer. Additionally, cost analysis of the process, the mechanism and the role of Ag were discussed.


Protoporphyrin biosynthesis in melanoma B16 cells stimulated by 5-aminolevulinic acid and chemical inducers: characterization of photodynamic inactivation.
The stimulation of protoporphyrin (PP) biosynthesis in B16 melanoma cells in order to facilitate photodynamic cell killing was studied. Biosynthesis and accumulation of PP in the melanoma cells was increased from 8 to 15 pmol/mg protein by the use of dimethyl-sulfoxide (DMSO), a differentiation-inducer. Treatment of the cells with the porphyrogenic agent allylisopropyl-acetamide (AIA) stimulated an additional PP increase. The most remarkable enhancement of intracellular PP was achieved by the supplementation of 5-aminolevulinic acid (5-ALA) to the growth medium following the addition of DMSO and AIA during the induction phase. The intracellular concentration of PP exceeded 21,950 pmol/mg protein following combined stimulation by DMSO/AIA and 5-ALA. The porphyrins produced in the incubated cells, in serum-depleted medium, consisted of 95% PP; 88% of it was recovered from the cells and only 7% was excreted into the medium. Photosensitization of the B16 melanoma cells containing high PP concentrations was effective even at low light doses. Potassium (K) efflux was the first measurable sign of cell damage determined by X-ray microanalysis (XRMA) following fast liquid-nitrogen fixation. During a 1 min interval, 70% of cellular K was lost. After 5 min illumination, complete cell destruction was detected by scanning electron microscopy (SEM) and XRMA. The photodamaged cells showed influx of Na, Cl and Ca ions accompanying the immediate K losses. Ultrastructural cell damage was manifested by disintegration of the outer membrane. Total cell death of B16 melanoma cells was achieved by chemical induction of endogenous PP and photosensitization.


A novel 3-phenylglutaric acid derivative (84-B10) alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial oxidative stress-mediated ferroptosis.
Cisplatin is one of the most effective chemotherapy drugs and is widely used for cancer treatment. However, its clinical use is limited by nephrotoxicity. Emerging findings suggested that both ferroptosis and mitochondrial dysfunction mediate cisplatin-induced nephrotoxicity. In the current study, a novel 3-phenylglutaric acid derivative 5-[[2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl]amino]-5-oxo-3-phenylpentanoic acid (referred to as 84-B10) was found to play a protective role in cisplatin-induced acute kidney injury with no tumor promoting effects. A genome-wide transcriptome analysis indicated that the protective effect of 84-B10 might be dependent on antagonizing ferroptosis. In accordance, lipid peroxide accumulation and downregulation of key ferroptosis suppressors were reversed using 84-B10 treatment both in vivo and in vitro. In addition, 84-B10 inhibited cisplatin-induced mitochondrial damage and mitochondrial reactive oxygen species (mtROS) production and restored superoxide dismutases (SODs). Furthermore, 84-B10 showed similar therapeutic effects to MnTBAP (a cell-permeable SOD mimetic) in eliminating mtROS, restoring mitochondrial homeostasis, and inhibiting ferroptosis under cisplatin challenge. Comparable effects of 84-B10 and liproxstatin-1 in ameliorating cisplatin-induced ferroptosis were observed. However, liproxstatin-1 failed to prevent mitochondrial dysfunction. These data indicated that mtROS might act upstream of cisplatin-induced tubular ferroptosis. Taken together, the novel 3-phenylglutaric acid derivative 84-B10 showed therapeutic potential against cisplatin-induced nephrotoxicity possibly by restoring mitochondria homeostasis and inhibiting mtROS-induced ferroptosis, which suggests the potential use of 84-B10 in preventing and treating cisplatin-nephrotoxicity.


Determining the effects of in ovo administration of monosodium glutamate on the embryonic development of brain in chickens.
Monosodium glutamate (MSG) is a popular flavor enhancer largely used in the food industry. Although numerous studies have reported the neurotoxic effects of MSG on humans and animals, there is limited information about how it affects embryonic brain development. Thus, this study aimed to determine the effects of in ovo administered MSG on embryonic brain development in chickens. For this purpose, 410 fertilized chicken eggs were divided into 5 groups as control, distilled water, 0.12, 0.6 and 1.2 mg/g egg MSG, and injections were performed via the egg yolk. On days 15, 18, and 21 of the incubation period, brain tissue samples were taken from all embryos and chicks. The mortality rates of MSG-treated groups were significantly higher than those of the control and distilled water groups. The MSG-treated groups showed embryonic growth retardation and various structural abnormalities such as abdominal hernia, unilateral anophthalmia, hemorrhage, brain malformation, and the curling of legs and fingers. The relative embryo and body weights of the MSG-treated groups were significantly lower than those of the control group on incubation days 18 and 21. Histopathological evaluations revealed that MSG caused histopathological changes such as necrosis, neuronophagia, and gliosis in brain on incubation days 15, 18, and 21. There was a significant increase in the number of necrotic neurons in the MSG-treated groups compared to the control and distilled water groups in the hyperpallium, optic tectum and hippocampus regions. Proliferating cell nuclear antigen (PCNA) positive cells in brain were found in the hyperpallium, optic tectum, and hippocampus regions; there were more PCNA(+) immunoreactive cells in MSG-treated groups than in control and distilled water groups. In conclusion, it was determined that in ovo MSG administered could adversely affect embryonic growth and development in addition to causing necrosis in the neurons in the developing brain.


4-Arylamino-6-nitroquinazolines: Synthesis and their activities against neglected disease leishmaniasis.
4-Arylamino-6-nitroquinazolines (2-25) were synthesized and evaluated for their leishmanicidal activities against Leishmania major promastigotes in vitro with IC50 values = 1.87-61.48 μM. Among the twenty four synthetic derivatives, 4-[4'-(methylsulfanyl)phenyl]amino-6-nitroquinazoline (21), and 4-(2'-methoxyphenyl)amino-6-nitroquinazoline (8) showed excellent antileishmanial activities with IC50 values 1.87 ± 0.31 and 4.37 ± 0.02 μM, respectively, more active than the standard drug, pentamidine (IC50 = 5.09 ± 0.09 μM). Compound 16 (IC50 = 6.53 ± 0.21 μM) displayed an activity comparable to the standard. Compounds 15 (IC50 = 9.04 ± 0.03 μM), 18 (IC50 = 12.28 ± 0.18 μM), 14 (IC50 = 19.87 ± 0.22 μM), and 5 (IC50 = 24.03 ± 2.71 μM) also showed good activities.