[A case of neonatal meningitis due to Flavobacterium meningosepticum successfully treated with cefmetazole and cefotaxime].
A 3-day-old male infant, weighing 3,413 g and a gestational age of 38 weeks developed neonatal meningitis due to Flavobacterium meningosepticum. Treatment with cefmetazole and cefotaxime led him to a complete recovery without neurologic deficit. Of 82 previously published cases under 1 year old, 41 cases died and 16 of survivors developed hydrocephalus because the organism was resistant to many antibiotics. Therapy of meningitis due to the organism has not been standardized but the early laboratory identification and the choice of effective and safe antibiotics determined by antimicrobial sensitivity test improve the outcome.


Contact allergic reactions on the eyes and eyelids.
To determine the most important causes of contact allergic reactions on the eyes and eyelids. This retrospective study provides an analysis of patch-test results obtained in a population of 1554 patients suffering from conjunctivitis and/or dermatitis on the eyelids, out of a total population of 9035 patients investigated for contact allergy between January 1990 and October 2003. If indicated, also prick testing with a latex extract was performed. 864 (56%) of the patients with eye- and/or eyelid-involvement presented with a positive reaction to at least one of the contact allergens tested. The main sensitisation sources were topical pharmaceutical products (antibiotics, corticosteroids), cosmetics (fragrance components, preservatives, emulsifiers, hair-care and nail products), metals (nickel), rubber derivatives, resins (e.g. epoxy resin), and plants. Also latex-allergy (immediate-type sensitivity presenting as a contact-urticaria syndrome) was a frequent finding in such patients. Contact allergy is a common cause of eyelid dermatitis in particular and the allergens may reach the skin in many different ways.


Multiple versus single arterial grafting in the elderly: a meta-analysis of randomized controlled trials and propensity score studies.
The benefit of adding a second arterial conduit is still controversial, mainly in specific subgroups. We conducted a meta-analysis of randomized controlled trials (RCTs) and propensity score (PS) studies comparing survival and early results in elderly patients who underwent coronary artery bypass grafting (CABG) with multiple (MAG) versus single arterial grafting (SAG). MEDLINE, Web of Science and Cochrane Library were used to find relevant literature (1960-April 2020). Survival at a ≥1-year follow-up and early outcomes were evaluated. Outcomes were collected from matched samples or PS adjusted analysis: hazard ratio (HR) along with their variance, frequencies or odds ratios. Random effect models were used to compute combined statistical measures and 95% confidence intervals (CI) through generic inverse variance method (time-to-event) or Mantel-Haenszel method (binary events). Eleven PS cohorts and 1 RCT comprising >18,800 patients older than 70 (>6200 MAG and >12,500 SAG) were included in this meta-analysis. MAG was associated with lower long-term mortality (pooled HR: 0.81, 95% CI: 0.72-0.91, P<0.01, I2=64%) in the absence of higher risk of early mortality (pooled OR: 0.74, 95% CI: 0.44 to 1.25, P=0.27, I2=0%). In a meta-regression, MAG survival advantage was more pronounced in studies with a higher MAG usage rate (β=-0.0052, P=0.021). Current evidence suggests that advanced age should not limit MAG's use considering its benefits in long-term survival. Of note, an individualized patient selection for this approach is warranted.


Local delivery of growth factors using coated suture material.
The optimization of healing processes in a wide range of tissues represents a central point for surgical research. One approach is to stimulate healing processes with growth factors. These substances have a short half-life and therefore it seems useful to administer these substances locally rather than systemically. One possible method of local delivery is to incorporate growth factors into a bioabsorbable poly (D, L-lactide) suspension (PDLLA) and coat suture material. The aim of the present study was to establish a procedure for the local delivery of growth factors using coated suture material. Sutures coated with growth factors were tested in an animal model. Anastomoses of the colon were created in a rat model using monofilament sutures. These were either untreated or coated with PDLLA coating alone or coated with PDLLA incorporating insulin-like growth factor-I (IGF-I). The anastomoses were subjected to biomechanical, histological, and immunohistochemical examination. After 3 days the treated groups showed a significantly greater capacity to withstand biomechanical stress than the control groups. This finding was supported by the results of the histomorphometric. The results of the study indicate that it is possible to deliver bioactive growth factors locally using PDLLA coated suture material. Healing processes can thus be stimulated locally without subjecting the whole organism to potentially damaging high systemic doses.


Transesophageal echocardiography and contrast-TCD in the detection of a patent foramen ovale: experiences with 111 patients.
Patent foramen ovale (PFO) is increasingly recognized in association with cryptogenic stroke. Using transesophageal echocardiography (TEE) and transcranial Doppler sonography with ultrasonic contrast medium (contrast-TCD), we evaluated the frequency of a PFO as the fundamental condition of paradoxical embolism in 111 patients after cerebral ischemia. There was a right-left shunt in 50 patients (45%) with TEE. In 31 of 40 patients with stroke of unknown etiology, a PFO was the only detectable finding associated with cerebral ischemia. Using TEE as the "gold standard," the sensitivity of contrast-TCD was 91.3%, specificity 93.8%, and the overall accuracy 92.8%. Contrast-TCD failed to detect a right-left shunt in four patients, but there were four other patients with negative TEE and positive contrast-TCD. We conclude that contrast-TCD is a highly sensitive method for detecting a right-left shunt. Its advantages are low cost, its ability to detect single contrast-medium embolism, and control of the Valsalva maneuver by observing the decrease of cerebral blood flow. Evidence of PFO in cryptogenic stroke should prompt a search for a subclinical venous thrombosis as the embolic source.


Correction of a malpositioned endosseous implant by a segmental osteotomy: a case report.
A mandibular overdenture supported by 2 or 4 endosseous implants has been proven to be a reliable treatment modality for patients suffering from conventional denture problems. However, fabrication of an implant-retained mesostructure to support an overdenture is not possible in all cases. Malpositioning of implants is a common cause of failure in such cases. A case is presented in which a ball attachment caused pain and severe swelling of the floor of the mouth because of the lingual inclination of an endosseous implant. The lingual inclination of the implant was corrected by a segmental osteotomy. Six weeks later, prosthodontic treatment began, and the resultant overdenture supported by a Dolder bar was quite acceptable for the patient.


Recognising Bipolar Disorders in Primary Care.
Bipolar disorder, previously called 'Manic-depression', is a complex group of conditions characterised by recurrent changes in mood and energy. Crucially, the intensity and duration of these changes go beyond normal fluctuations and personality traits. Bipolar Disorder is a mental health disorder, but physical health manifestations (Smith 2013, Westman 2013, Fagiolini 2008, Young 2013) and complications are just as important. GPs have a key role in the recognition and management, in conjunction with secondary care colleagues. Diagnosis is often difficult and may take several years (Smith 2011, Angst 2005, Manning 2010), because patients usually seek help for anxiety, depression or fatigue, not hypomania/mania, which they may not recognise. Individuals with a first episode of mania are more likely to present directly to secondary care, sometimes via a third party alerting the emergency services. There is also debate around the classification, diagnosis and treatment of individuals with brief and milder mood changes ('bipolar spectrum disorder') (Faravelli 2009, Spence 2011). In the UK, the recent NICE Guidelines (2014) 1 only included Bipolar I and Bipolar II for these reasons. A particular challenge for GPs is that whilst most people who have Bipolar Disorder (and especially Bipolar II) are depressed, most people with depression within a Primary Care setting do not have Bipolar Disorder. Thus, a brief pragmatic screen is recommended in Primary care: ask about a family history of Bipolar Disorder and screen for a history of mania/hypomania in individuals with anxiety, depression or irritability, especially if there are recurrent episodes, suicidal thoughts or a previous suicide attempt. For suspected cases, formal diagnosis should not be made within Primary Care but individuals should be referred for Psychiatric assessment, ideally to a Mood Disorders specialist.


Multiple pathways to compliance: mothers' willingness to cooperate and knowledge of their children's reactions to discipline.
Mothers of 59 children with ages from 6 to 9 years were assessed for their general willingness to cooperate with their children's desires and their accurate predictions of their children's evaluations of different discipline strategies. Mothers asked their children to clean up a playroom in their absence, with some children protesting and others not protesting. Results showed that maternal willing cooperation predicted children's compliance in the absence but not in the presence of protest. Conversely, maternal accuracy concerning their children's evaluations of discipline facilitated children's compliance in dyads in which children expressed initial resistance but not if children indicated no opposition. Mothers' responsive reactions to protest mediated between maternal accuracy and children's ultimate compliance. Results indicate that specific features of parenting facilitate compliance in specific situations.


Wall accumulation of bacteria with different motility patterns.
We systematically investigate the role of different swimming patterns on the concentration distribution of bacterial suspensions confined between two flat walls, by considering wild-type motility Escherichia coli and Pseudomonas aeruginosa, which perform Run and Tumble and Run and Reverse patterns, respectively. The experiments count motile bacteria at different distances from the bottom wall. In agreement with previous studies, an accumulation of motile bacteria close to the walls is observed. Different wall separations, ranging from 100 to 250μm, are tested. The concentration profiles result to be independent on the motility pattern and on the walls' separation. These results are confirmed by numerical simulations, based on a collection of self-propelled dumbbells-like particles interacting only through steric interactions. The good agreement with the simulations suggests that the behavior of the investigated bacterial suspensions is determined mainly by steric collisions and self-propulsion, as well as hydrodynamic interactions.


Cognitive Therapy for Dementia Patients: A Systematic Review.
Cognitive therapy is a well-established intervention for treating elderly suffering from dementia. In particular, reality orientation and skills training seem to be effective interventions for reversing cognitive impairment among elderly, although findings are inconclusive. Therefore, a systematic update of the existing evidence of cognitive therapy for people suffering from dementia is needed. To review existing scientific evidence regarding the efficacy of cognitive therapies for elderly suffering from dementia. Studies were retrieved from several bibliographic databases (January 2009 to December 2017) with prespecified selection criteria, data extraction, and methodological quality assessment. In total, 10 reality orientation, 25 skills training, and 12 mixed trials were identified as meeting the inclusion criteria and were systematically reviewed. Results from reality orientation trials showed minor effects for cognitive assessments, while skills training trials and mixed trials showed contradicting effects on cognition. Effects on other outcomes (e.g., daily functioning, depression, language) were limited or not found. Skills training trials and mixed trials seem to affect cognitive impairment in a positive way, although the results are inconclusive. Comparison between studies was difficult due to differences in form of intervention. Because findings are inconclusive, more structuralized and comparable randomized controlled trials are needed.


Biofilm formation and Candida albicans morphology on the surface of denture base materials.
Fungal biofilms may contribute to the occurrence of denture stomatitis. The objective of the study was to investigate the biofilm formation and morphology of Candida albicans in biofilms on the surface of denture base materials. Specimens were prepared from different denture base materials. After determination of surface properties and salivary pellicle formation, mono- and multispecies biofilm formation including Candida albicans ATCC 10231 was initiated. Relative amounts of adherent cells were determined after 20, 44, 68 and 188 h; C. albicans morphology was analysed employing selective fluorescence microscopic analysis. Significant differences were identified in the relative amount of cells adherent to the denture base materials. Highest blastospore/hyphae index suggesting an increased percentage of hyphae was observed in mono- and multispecies biofilms on the soft denture liner, which did not necessarily respond to the highest relative amount of adherent cells. For both biofilm models, lowest relative amount of adherent cells was identified on the methacrylate-based denture base material, which did not necessarily relate to a significantly lower blastospore/hyphae index. The results indicate that there are significant differences in both biofilm formation as well as the morphology of C. albicans cells in biofilms on the surface of different denture base materials.


Promoting parent-infant responsiveness in families experiencing homelessness.
My Baby's First Teacher is an intervention designed specifically for parents with infants staying in emergency homeless shelters. Infants are overrepresented in shelter populations and face considerable risk to their development, including mental health. We utilized a randomized controlled design across three family shelters to evaluate the program's effectiveness with 24 dyads assigned to the intervention compared to 21 dyads in care-as-usual. Dyads were randomized by round at each site to account for shelter effects. We used path analysis to illustrate change over time and in relation to intervention assignment.


A phase II trial of neoadjuvant chemoradiation and local excision for T2N0 rectal cancer: preliminary results of the ACOSOG Z6041 trial.
We designed American College of Surgeons Oncology Group (ACOSOG) Z6041, a prospective, multicenter, single-arm, phase II trial to assess the efficacy and safety of neoadjuvant chemoradiation (CRT) and local excision (LE) for T2N0 rectal cancer. Here, we report tumor response, CRT-related toxicity, and perioperative complications (PCs). Clinically staged T2N0 rectal cancer patients were treated with capecitabine and oxaliplatin during radiation followed by LE. Because of toxicity, capecitabine and radiation doses were reduced. LE was performed 6 weeks after CRT. Patients were evaluated for clinical and pathologic response. CRT-related complications and PCs were recorded. Ninety patients were accrued; 6 received nonprotocol treatment. The remaining 84 were 65% male; median age 63 years; 83% Eastern Cooperative Oncology Group performance score 0; 92% white; mean tumor size 2.9 cm; and average distance from anal verge 5.1 cm. Five patients were considered ineligible. Therapy was completed per protocol in 79 patients, but two patients did not undergo LE. Among 77 eligible patients who underwent LE, 34 patients achieved a pathologic complete response (44%) and 49 (64%) tumors were downstaged (ypT0-1), but 4 patients (5%) had ypT3 tumors. Five LE specimens contained lymph nodes; one T3 tumor had a positive node. All but one patient had negative margins. Thirty-three (39%) of 84 patients developed CRT-related grade ≥3 complications. Rectal pain was the most common PC. CRT before LE for T2N0 tumors results in a high pathologic complete response rate and negative resection margins. However, complications during CRT and after LE are high. The true efficacy of this approach will ultimately be assessed by the long-term oncologic outcomes.


Solid state coordination chemistry: structural consequences of variations in tether length in the oxovanadium-copper-bisterpy-[O3P(CH2)nPO3]4- system, n= 1-6 (bisterpy = 2,2':4',4'':2'',2'''-quarterpyridyl-6',6''-di-2-pyridine).
Hydrothermal reactions of Na3VO4, an appropriate Cu(II) source, bisterpy and an organodiphosphonate, H2O3P(CH2)nPO3H2 (n = 1-6) yielded a family of materials of the type [Cu2(bisterpy)]4+/VxOy(n-)/[O3P(CH2)nPO3]4-. This family of bimetallic oxides is characterized by an unusual structural diversity. The oxides [[Cu2(bisterpy)]V2O4[O3PCH2PO3H]2] (1), [[Cu2(bisterpy)(H2O)]VO2[O3P(CH2)3PO3][HO3P(CH2)3PO3H2]] (4) and [[Cu2(bisterpy)]V2O4[O3P(CH2)6PO3H]2].2H2O (7.2H2O) are one-dimensional, while [[Cu2(bisterpy)(H2O)2]V2O4[O3P(CH2)2PO3][HO3P(CH2)2PO3H]2] (2), [[Cu2(bisterpy)]V4O8[O3P(CH23PO3]2].4H2O (3.4H2O) and [[Cu2(bisterpy)]V2O4(OH)2[O3P(CH2)4PO3]].4H2O (5.4H2O) are two-dimensional. The V(IV) oxide [[Cu2(bisterpy)]V4O4[O3P(CH2)5PO3H]4].7.3H2O (6.7.3H2O) provides a relatively unusual example of a three-dimensional bimetallic oxide phosphonate. The structures reveal a variety of V/P/O substructures as building blocks.


Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry.
To determine the incidence and relative risk (RR) of cancer in children with Beckwith-Wiedemann syndrome (BWS), children with BWS were followed up from birth until death, diagnosis of cancer, fourth birthday, or last day of follow-up. A total of 183 children with BWS were followed up for 482 person-years. The end points were incidence of cancer, RR of cancer, and RR associated with specific BWS phenotypic features. Thirteen children were identified with cancers before the fourth year of life in comparison with fewer than one cancer expected in this group on the basis of general population rates over the same period. The average annual incidence of cancer in the first 4 years of life was 0.027 cancer per person-year. The RR of Wilms tumor (RR = 816; 95% confidence interval [CI], 359-1156), neuroblastoma (RR = 197; 95% CI, 22-711), and hepatoblastoma (RR = 2280; 95% CI, 928-11,656) were statistically significant. Asymmetry of the limbs (hemihypertrophy) was the only clinical feature associated with an increased RR of cancer (RR = 4.6; 95% CI, 1.5-14.2). Given the high incidence of cancer in infancy and early childhood of patients with BWS, a prospective study is warranted to address the utility of screening for cancer.


The 3' UTRs of Brain-Derived Neurotrophic Factor Transcripts Differentially Regulate the Dendritic Arbor.
The patterning of dendrites is regulated by many factors, such as brain-derived neurotrophic factor (BDNF), which our laboratory has previously shown alters the dendritic arbor uniquely depending on the mode of extracellular application. In the current work, we examine how BDNF affects dendritogenesis in hippocampal neurons when it is overexpressed intracellularly by transcripts previously reported to be transported to distinct cellular compartments. The BDNF gene is processed at two different polyadenylation sites, leading to mRNA transcription with two different length 3' untranslated regions (UTRs), and therefore, different mRNA localization preferences. We found that overexpression of BDNF mRNA with or without 3' UTRs significantly alters dendritic branching compared to branching in control neurons as analyzed by Sholl distribution curves. Unexpectedly, we found that the overexpression of the shorter BDNF mRNA (reported to be preferentially targeted to the cell body) results in similar changes to Sholl curves compared to overexpression of the longer BDNF mRNA (reported to be preferentially targeted to both the cell body and dendrites). We also investigated whether the BDNF receptor TrkB mediates these changes and found that inhibiting TrkB blocks increases in Sholl curves, although at different distances depending on the transcript's UTR. Finally, although it is not found in nature, we also examined the effects of overexpressing BDNF mRNA with the unique portion of the longer 3' UTR since it was previously shown to be necessary for dendritic targeting of mRNA. We found that its overexpression increases Sholl curves at distances close to the cell body and that these changes also depend on TrkB activity. This work illustrates how the mRNA spatial code affects how BDNF alters local dendritogenesis and how TrkB may mediate these effects. Finally, our findings emphasize the importance of intracellular transport of BDNF mRNAs in the regulation of dendrite morphology.


Supporting adults to support youth: An evaluation of two social justice trainings.
The current research examined pre- and post survey data in two social justice trainings for adults who support youth, including staff and volunteers (Study 1, N = 44) at youth-serving organizations and adults who mentor young Black men and boys (Study 2, N = 72). We investigate whether training participants' self-report scores of cultural competences (studies 1 and 2), self-efficacy for race equity (Study 1) and racial self-efficacy to support mentee (Study 2) changed between the beginning of the training and after the training. Furthermore, we examine whether the changes depend upon whether training participants share cultural background with the youth with whom they work. In Study 1, findings indicated that training participants reported significantly increased scores of cultural sensitivity and self-efficacy for race equity. Individuals who were not first-generation college students saw higher increases in sociopolitical awareness. In Study 2, participants reported significantly higher scores of cultural sensitivity and racial self-efficacy to support their mentees. Furthermore, non-Black and women participants showed greater increases in self-efficacy than Black and male participants. These results fill a gap in the literature on the potential role of social justice trainings to increase cultural competencies among adults who work with diverse youth.


Prefrontal cortex acetylcholine release, EEG slow waves, and spindles are modulated by M2 autoreceptors in C57BL/6J mouse.
Recent evidence suggests that muscarinic cholinergic receptors of the M2 subtype serve as autoreceptors modulating acetylcholine (ACh) release in prefrontal cortex. The potential contribution of M2 autoreceptors to excitability control of prefrontal cortex has not been investigated. The present study tested the hypothesis that M2 autoreceptors contribute to activation of the cortical electroencephalogram (EEG) in C57BL/6J (B6) mouse. This hypothesis was evaluated using microdialysis delivery of the muscarinic antagonist AF-DX116 (3 nM) while simultaneously quantifying ACh release in prefrontal cortex, number of 7- to 14-Hz EEG spindles, and EEG power spectral density. Mean ACh release in prefrontal cortex was significantly increased (P < 0.0002) by AF-DX116. The number of 7- to 14-Hz EEG spindles caused by halothane anesthesia was significantly decreased (P < 0.0001) by dialysis delivery of AF-DX116 to prefrontal cortex. The cholinergically induced cortical activation was characterized by a significant (P < 0.05) decrease in slow-wave EEG power. Together, these neurochemical and EEG data support the conclusion that M2 autoreceptor enhancement of ACh release in prefrontal cortex activates EEG in contralateral prefrontal cortex of B6 mouse. EEG slow-wave activity varies across mouse strains, and the results encourage comparative phenotyping of cortical ACh release and EEG in additional mouse models.


An evaluation of the levels of 25-hydroxyvitamin D3 and bone turnover markers in professional football players and in physically inactive men.
Vitamin D is synthesised in the skin during exposure to sunlight and its fundamental roles are the regulation of calcium and phosphate metabolism and bone mineralisation. The aim of our study was to evaluate serum levels of 25-hydroxyvitamin D3, PTH and bone turnover markers (P1NP, OC, beta-CTx, OC/beta-CTx) and the intake of calcium and vitamin D in Polish Professional Football League (Ekstraklasa) players and in young men with a low level of physical activity. Fifty healthy men aged 19 to 34 years were included in the study. We showed that 25(OH)D3 and P1NP levels and OC/beta-CTx were higher in the group of professional football players than in the group of physically inactive men. The daily vitamin D and calcium intake in the group of professional football players was also higher. We showed a significant relationship between 25(OH)D3 levels and body mass, body cell mass, total body water, fat-free mass, muscle mass, vitamin D and calcium intake. Optimum 25(OH)D3 levels were observed in a mere 16.7% of the football players and vitamin D deficiency was observed in the physically inactive men. The level of physical activity, body composition, calcium and vitamin D intake and the duration of exposure to sunlight may significantly affect serum levels of 25(OH)D3.


PANet: Patch-Aware Network for Light Field Salient Object Detection.
Most existing light field saliency detection methods have achieved great success by exploiting unique light field data-focus information in focal slices. However, they process light field data in a slicewise way, leading to suboptimal results because the relative contribution of different regions in focal slices is ignored. How we can comprehensively explore and integrate focused saliency regions that would positively contribute to accurate saliency detection. Answering this question inspires us to develop a new insight. In this article, we propose a patch-aware network to explore light field data in a regionwise way. First, we excavate focused salient regions with a proposed multisource learning module (MSLM), which generates a filtering strategy for integration followed by three guidances based on saliency, boundary, and position. Second, we design a sharpness recognition module (SRM) to refine and update this strategy and perform feature integration. With our proposed MSLM and SRM, we can obtain more accurate and complete saliency maps. Comprehensive experiments on three benchmark datasets prove that our proposed method achieves competitive performance over 2-D, 3-D, and 4-D salient object detection methods. The code and results of our method are available at https://github.com/OIPLab-DUT/IEEE-TCYB-PANet.


Choline Molecular Imaging with Small-animal PET for Monitoring Tumor Cellular Response to Photodynamic Therapy of Cancer.
We are developing and evaluating choline molecular imaging with positron emission tomography (PET) for monitoring tumor response to photodynamic therapy (PDT) in animal models. Human prostate cancer (PC-3) was studied in athymic nude mice. A second-generation photosensitizer Pc 4 was used for PDT in tumor-bearing mice. MicroPET images with (11)C-choline were acquired before PDT and 48 h after PDT. Time-activity curves of (11)C-choline uptake were analyzed before and after PDT. For treated tumors, normalized choline uptake decreased significantly 48 h after PDT, compared to the same tumors pre-PDT (p < 0.001). However, for the control tumors, normalized choline uptake increased significantly (p < 0.001). PET imaging with (11)C-choline is sensitive to detect early tumor response to PDT in the animal model of human prostate cancer.


Targeting Autophagic Pathways by Plant Natural Compounds in Cancer Treatment.
Nowadays, natural compounds of plant origin with anticancer effects have gained more attention because of their clinical safety and broad efficacy profiles. Autophagy is a multistep lysosomal degradation pathway that may have a unique potential for clinical benefit in the setting of cancer treatment. To retrieve articles related to the study, the databases of Google Scholar, Web of sciences, Medline and Scopus, using the following keywords: Autophagic pathways; herbal medicine, oncogenic autophagic pathways, tumor-suppressive autophagic pathways, and cancer were searched. Although natural plant compounds such as resveratrol, curcumin, oridonin, gossypol, and paclitaxel have proven anticancer potential via autophagic signaling pathways, there is still a great need to find new natural compounds and investigate the underlying mechanisms, to facilitate their clinical use as potential anticancer agents through autophagic induction.


The effect of pargyline and other monoamine oxidase inhibitors on blood acetaldehyde levels in ethanol-intoxicated mice.
Pargyline (100 mg/kg i.p.) administered to Swiss-Webster mice prior to the injection of ethanol (4 g/kg i.p.) elevated blood acetaldehyde levels to a mean of 20 mug/ml, compared to less than 1 mug/ml in control mice treated with ethanol alone. Elevated blood acetaldehyde was observed when ethanol was given at 15 minutes, 2 or 5 hours after pargyline; the action of pargyline had largely disappeared after 18 hours. The magnitude of the increase in blood acetaldehyde levels was dependent upon the dose of pargyline between 20 and 100 mg/kg; however, the elevation was relatively independent of the ethanol dose between 1 and 6 g/kg. Of the other monoamine oxidase inhibitors tested, Lilly 51641 showed a strong elevation in acetaldehyde (mean 13.3 mug/ml), whereas deprenyl and clorgyline gave modest elevations (2.9 and 2.6 mug/ml, respectively), and nialamide and tranylcypromine were only weakly active (1.4 and 1.2 mug/ml, respectively). Blood acetaldehyde levels in mice treated with pargyline and ethanol were strongly depressed (85%) by pyrazole, an inhibitor of alcohol dehydrogenase, and moderately to strongly depressed (49-71%) by pretreatment with phenobarbital, an inducer of liver aldehyde dehydrogenase.


Modulation of human BCRP (ABCG2) activity by anti-HIV drugs.
The safety and effectiveness of highly active antiretroviral therapy (HAART) is challenged by viral resistance to antiretrovirals and the frequent occurrence of drug interactions which may limit the access of these drugs to the target sites. In particular, drug distribution and elimination may be modified by active efflux transporters. While P-glycoprotein is well evaluated in this regard, the interaction of antiretrovirals with the ABC transporter BCRP (ABCG2) is far from being elucidated. The aim of this study was therefore to investigate the influence of all important anti-HIV drugs on BCRP activity in vitro in one assay to allow unrestricted comparison of the results. BCRP inhibition was assessed by an increase in pheophorbide A accumulation in MDCKII-BCRP cells and compared with the corresponding parental cell line MDCKII lacking human BCRP. According to the IC(50) estimation, the rank order for BCRP inhibition was lopinavir > nelfinavir > delavirdine > efavirenz > saquinavir > atazanavir > amprenavir > abacavir. Whereas nevirapine and zidovudine exerted weak inhibition, the inhibitory potency for ritonavir and tipranavir could not be estimated due to their low solubility and all other tested compounds (indinavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zalcitabine) were devoid of an effect. Taken together, our study demonstrates significant inhibition of BCRP by many anti-HIV drugs. These results suggest that inhibition of BCRP might contribute to drug-drug interactions observed during HAART in vivo and possibly also the superior effectiveness of combination antiretroviral therapy.


Acidovorax antarcticus sp. nov., isolated from a soil sample of Collins Glacier front, Antarctica.
A Gram-stain-negative, rod-shaped, and aerobic bacterium, strain 16-35-5T, was isolated from Collins Glacier front soil from the Fildes Peninsula, Antarctica. The bacterium grew optimally at 28 °C, pH 7.0 and in the presence of 0-4.0 % (w/v) NaCl. On the basis of the results of 16S rRNA gene sequence phylogenetic analyses, it was concluded that 16-35-5T represented a member of the genus Acidovorax and had the highest sequence similarities with Acidovorax anthurii CFBP 3232T (96.48 %). The genome of 16-35-5T is 4.2 Mb long with a DNA G+C content of 66.3 mol%. Average nucleotide identity (ANI) value between the genomes of 16-35-5T and Acidovorax wautersii DSM 27981T, was 85.29 %. Strain 16-35-5T had ubiquinone-8 (Q-8) as the respiratory ubiquinone. The polar lipids of 16-35-5T were consisted of phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. The main fatty acids were summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c, 25.2 %), summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c, 12.9 %), C16 : 0 (35.2 %), and C17 : 0 cyclo (19.0 %). On the basis of the evidence presented in this study, 16-35-5T should be classified as representing a novel species of the genus Acidovorax, for which the name Acidovorax antarcticus sp. nov., is proposed, with the type strain 16-35-5T (=CCTCC AB 2019325T=KCTC 72915T).


[Echography and hysteroscopy. 2 diagnostic technics compared in the identification of endometrial lesions in the postmenopause].
In this study we compared ultrasonographic scanning of the endometrium and the hysteroscopic view with histology obtained by endometrial biopsy. Forty six postmenopausal women were studied, 25 symptomatic and 21 asymptomatic. In 24 cases endometrial thickness was > 5 mm, it was considered abnormal, and in 12 cases was < 5 mm. Hysteroscopy detects the presence of 7 atrophic endometrium, 19 polyps, 8 myomas, 4 cancer, 5 synechiae. Echography had a sensitivity of 90.9%, specificity of 72% and positive predictive value of 90.9%. Hysteroscopy showed a sensitivity of 96.7%, a specificity of 92.8% and a positive predictive value of 96.8%. In conclusion we may suggest that TV scanning allows detection of endometrial pathology with a high sensitivity so it may be used as the first diagnostic step in the screening of postmenopausal women, but it should be completed by hysteroscopic evaluation when endometrial thickness is > 5 mm also in asymptomatic women in order to detect cancer in a early stage.


Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in healthy postmenopausal women.
We have performed a phase I study of the effect of a single dose of CGS 20267, an oral nonsteroidal aromatase inhibitor, in 12 healthy volunteer postmenopausal women. Each subject received 2 single doses of CGS 20267 (0.1, 0.5, or 2.5 mg) or placebo separated by a washout period of at least 6 weeks. There was statistically significant suppression of serum estrone and estradiol at all three doses of CGS 20267 tested. Serum estrone and estradiol concentrations were maximally suppressed by 76% and 79% from baseline levels, respectively. Urinary excretion of estrone and estradiol was also suppressed, although this did not reach statistical significance. Serum concentrations of aldosterone, cortisol, 17 alpha-hydroxyprogesterone, androstenedione, testosterone, FSH, LH, and TSH were unaffected by CGS 20267. The drug was well tolerated, with no significant side-effects. This study has shown CGS 20267 to be a potent and specific aromatase inhibitor, and further studies are now needed to assess its clinical efficacy.


Protective Efficacy Evaluation of Four Inactivated Commercial Vaccines Against Low Pathogenic Avian Influenza H9N2 Virus Under Experimental Conditions in Broiler Chickens.
Avian influenza vaccines are commonly used in the poultry industry. The objective of this study was to compare, under experimental conditions, the protective efficacy of four imported commercial inactivated H9N2 vaccines (A, B, C, and D) in broiler chickens. A total of 150 one-day-old chicks were divided into six groups: four experimental groups, each containing 30 chicks, received one of the vaccines (A, B, C, or D) delivered in a 0.3-ml dose subcutaneously at 1 day of age, whereas the control, Group T, was not vaccinated but challenged and Group E was kept unvaccinated and unchallenged. At 21 days postvaccination, Groups A, B, C, D, and T were challenged with 107 embryo infective dose 50% of A/Chicken/Morocco/01/2016 (H9N2). All chicks were observed daily for clinical signs during the 12 days postchallenge (dpc). At 5 and 12 dpc, chicks were euthanatized for necropsy examination. Blood samples were collected weekly for serologic analysis and oropharyngeal swabs were collected for virus detection by real-time RT-PCR. Respiratory signs started at 48 hr pc and maximum severity was observed on 9 dpc. Chiefly, the birds vaccinated with vaccine B showed significantly more respiratory signs than did their counterparts. Serologic analysis revealed that the sera of Groups A and D birds showed a decrease in antibody (Ab) levels up to day 26; then a slight increase of Ab level was observed until day 31, while Group B and C birds showed a stabilization of the titers from day 21 until the end of the experiment. The viral shedding rate was significantly lower in Groups C and A (40%-50% of the birds shed virus for <7 days) compared with other challenged groups (60%-75% of the birds shed virus for ≥9 days). This experiment illustrated that vaccination applied on the first day in the hatchery with the four vaccines tested did not provide an acceptable protection against H9N2 in comparison with the controls that did not receive any vaccine. However, at first glance, we might favor vaccines A and C for their ability to reduce and shorten viral shedding as compared with vaccines B and D.


Fast and repetitive in-capillary production of [18F]FDG.
The increasing demand for radiopharmaceuticals to be provided reproducibly and flexibly with high frequency for clinical application and animal imaging would be better met by improved or even new strategies for automated tracer production. Radiosynthesis in microfluidic systems, i.e. narrow tubing with a diameter of approximately 50-500 microm, holds promise for providing the means for repetitive multidose and multitracer production. In this study, the performance of a conceptually simple microfluidic device integrated into a fully automated synthesis procedure for in-capillary radiosynthesis (ICR) of clinical grade [(18)F]FDG was evaluated. The instrumental set-up consisted of pumps for reagent and solvent delivery into small mixing chambers, micro-fluidic capillaries, in-process radioactivity monitoring, solid-phase extraction and on-column deprotection of the (18)F-labelled intermediate followed by on-line formulation of [(18)F]FDG. In-capillary(18)F-fluorination of 2.1 micromol 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulphonyl-beta-D-mannopyranose (TATM; precursor for [(18)F]FDG) in acetonitrile (MeCN) at a flow rate of 0.3 ml/min within 40 s and subsequent on-line hydrolysis of the intermediate by treatment with 0.3 M NaOH for 1 min at 40 degrees C resulted in a radiochemical yield of 88 +/- 4% within <7 min. Reproducibility, robustness and suitability as a fast and efficient radiopharmaceutical research tool for (18)F-fluorination was demonstrated by eight independent, sequentially performed ICRs which provided identical tracer quality (radiochemical purity >97%, MeCN <5 microg/ml) and similar absolute yields (approximately 1.4 GBq). The described ICR process is a simple and efficient alternative to classic radiotracer production systems and provides a comparatively cheap instrumental methodology for the repetitive production of [(18)F]FDG with remarkably high efficiency and high yield under fully automated conditions. Although the results concerning the levels of activity need to be confirmed after installation of the equipment in a suitable GMP hot-cell environment, we expect the instrumental design to allow up-scaling without major difficulties or fundamental restrictions. Furthermore, we are convinced that similar or nearly identical procedures, and thus instrumentation, will allow ICR of other (18)F-labelled radiopharmaceuticals.


Oligo(ethylene glycol)-sidechain microgels prepared in absence of cross-linking agent: Polymerization, characterization and variation of particle deformability.
We present a systematic study of self-cross-linked microgels formed by precipitation polymerization of oligo ethylene glycol methacrylates. The cross-linking density of these microgels and, thus, the network flexibility can be easily tuned through the modulation of the reaction temperature during polymerization. Microgels prepared in absence of any difunctional monomer, i.e. cross-linker, show enhanced deformability and particle spreading on solid surfaces as compared to microgels cross-linked with varying amounts of poly(ethylene glycol diacrylate) (PEG-DA) in addition to self-crosslinking. Particles prepared at low reaction temperatures exhibit the highest degree of spreading due to the lightly cross-linked and flexible polymer network. Moreover, AFM force spectroscopy studies suggest that cross-linker-free microgels constitute of a more homogeneous polymer network than PEG-DA cross-linked particles and have elastic moduli at the particle apex that are ~5 times smaller than the moduli of 5 mol-% PEG-DA cross-linked microgels. Resistive pulse sensing experiments demonstrate that microgels prepared at 75 and 80°C without PEG-DA are able to deform significantly to pass through nanopores that are smaller than the microgel size. Additionally, we found that polymer network flexibility of microgels is a useful tool to control the formation of particle dewetting patterns. This offers a promising new avenue for build-up of 2D self-assembled particle structures with patterned chemical and mechanical properties.


Optimizing antiretroviral therapy for children living with HIV: Experience from an observational cohort in Lesotho.
We describe transition of HIV-positive children from efavirenz- or nevirapine-based antiretroviral therapy (ART) to optimal dolutegravir (DTG) or lopinavir/ritonavir (LPV/r) (solid formulation)-based ART in Lesotho. We followed a cohort of children less than 15 years of age who were initiated on ART on or after January 1, 2018 from 21 selected health facilities in Lesotho. From March 2020 to May 2022, we collected data retrospectively through chart abstraction and prospectively through caregiver interviews to cover a period of 24 months following treatment initiation. We used a structured questionnaire to collect data on demographics, ART regimen, drug formulations and switches, viral suppression, retention, and drug administration challenges. Data were summarized as frequencies and percentages, using SAS ver.9.4. Of 310 children enrolled in the study, 169 (54.5%) were female, and median age at ART initiation was 5.9 years (IQR 1.1-11.1). During follow-up, 19 (6.1%) children died, 41 (13.2%) were lost to follow-up and 74 (23.9%) transferred to non-study sites. At baseline, 144 (46.4%) children were receiving efavirenz-based ART regimen, 133 (42.9%) LPV/r, 27 (8.7%) DTG, 5 (1.6%) nevirapine; 1 child had incomplete records. By study end, 143 (46.1%) children were receiving LPV/r-based ART regimen, 109 (35.2%) DTG, and 58 (18.7%) were on efavirenz or nevirapine-based regimen. Of 116 children with viral load results after six months or more on a consistent regimen, viral suppression was seen in 35/53 (66.0%) children on LPV/r, 36/38 (94.7%) children on DTG and 19/24 (79.2%) children on efavirenz. Following optimal ART introduction in Lesotho, most children in the cohort were transitioned and many attained or maintained viral suppression after transition; however, we recommend more robust viral load monitoring and patient tracking to reduce losses and improve outcomes after ART transition.


Driving after drinking in Canada: findings from the Canadian Addiction Survey.
Despite substantial decreases in the magnitude of the alcohol-crash problem over the past 25 years, many Canadians continue to drive under the influence of alcohol, causing thousands of serious injuries and deaths every year. Data from the 2004 Canadian Addiction Survey (CAS) were used to determine the prevalence of self-reported driving after drinking and the characteristics of those who engage in the behaviour. Overall, 11.6% of licensed drivers in Canada reported operating a vehicle within an hour of consuming two or more drinks containing alcohol. Less than 5% of licensed drivers accounted for 86% of the more than 20 million (estimated) past-year drinking and driving occurrences. Drinking Drivers reported more extensive and problematic use of alcohol, and were more likely to report illegal drug use relative to Non-drinking Drivers. Driving after drinking remains a common behaviour among Canadian drivers. Those who persist in driving after drinking can be distinguished from other drivers on the basis of their greater use of alcohol and drugs. Those who drive after drinking frequently consume even greater quantities of alcohol on more frequent occasions and are more likely to experience problems as a result of their drinking. These findings suggest that countermeasure efforts need to be continued on all levels and expanded to specifically target high-risk heavy drinkers.


Participation of proteasomes in Xenopus embryogenesis.
We examined the effects of various protease substrates on Xenopus laevis embryogenesis. Thirty-three peptidyl-MCA substrates were added to the culture medium in which Xenopus embryos were developing. Five of the 33 substrates were found to inhibit embryogenesis at the early gastrula stage or much earlier ones. These results suggest that proteases that hydrolyze these substrates are involved in embryonic development. We found that the developmental stage of embryos is crucial for these substrates to inhibit their development. We purified a protease that hydrolyzes Pyr-Arg-Thr-Lys-Arg-MCA, a substrate that inhibits embryogenesis, from Xenopus embryos. This protease turned out to be a component of proteasomes. We found that 4 of the 5 substrates that inhibit embryogenesis are among the proteasome substrates. Thus, we concluded that proteasomes play a crucial role in the development of Xenopus embryos. Possibly, various catalytic subunits in proteasomes function independently, in stage-specific manners.


The Role of Glyoxalase in Glycation and Carbonyl Stress Induced Metabolic Disorders.
Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation of irreversibly bound products known as advanced glycation end products (AGEs). AGEs are synthesized in high amounts both in pathological conditions, such as diabetes and under physiological conditions resulting in aging. The body's anti-glycation defense mechanisms play a critical role in removing glycated products. However, if this defense system fails, AGEs start accumulating, which results in pathological conditions. Studies have been shown that increased accumulation of AGEs acts as key mediators in multiple diseases, such as diabetes, obesity, arthritis, cancer, atherosclerosis, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, aging, and Alzheimer's disease. Furthermore, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), causes potential damage to the genome, proteome, and lipidome. Glyoxalase-1 (GLO-1) acts as a part of the anti-glycation defense system by carrying out detoxification of GO and MGO. It has been demonstrated that GLO-1 protects dicarbonyl modifications of the proteome and lipidome, thereby impeding the cell signaling and affecting age-related diseases. Its relationship with detoxification and anti-glycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide evidence for the rationale that the functional modulation of the GLO pathway could be used as a potential therapeutic target. In the present review, we summarized the newly emerged literature on the GLO pathway, including enzymes regulating the process. In addition, we described small bioactive molecules with the potential to modulate the GLO pathway, thereby providing a basis for the development of new treatment strategies against age-related complications.


Stress-Induced Mutagenesis.
Early research on the origins and mechanisms of mutation led to the establishment of the dogma that, in the absence of external forces, spontaneous mutation rates are constant. However, recent results from a variety of experimental systems suggest that mutation rates can increase in response to selective pressures. This chapter summarizes data demonstrating that,under stressful conditions, Escherichia coli and Salmonella can increase the likelihood of beneficial mutations by modulating their potential for genetic change.Several experimental systems used to study stress-induced mutagenesis are discussed, with special emphasison the Foster-Cairns system for "adaptive mutation" in E. coli and Salmonella. Examples from other model systems are given to illustrate that stress-induced mutagenesis is a natural and general phenomenon that is not confined to enteric bacteria. Finally, some of the controversy in the field of stress-induced mutagenesis is summarized and discussed, and a perspective on the current state of the field is provided.


Antibody-targeted photolysis: in vitro studies with Sn(IV) chlorin e6 covalently bound to monoclonal antibodies using a modified dextran carrier.
A monoclonal antibody-dextran-Sn(IV) chlorin e6 immunoconjugate was prepared by a technique involving the site-specific covalent modification of the monoclonal antibody oligosaccharide moiety. Dextran carriers were synthesized with a single chain-terminal hydrazide group, which was used as the coupling point between the carrier and the monoclonal antibody carbohydrate. Selective in vitro photolysis of SK-MEL-2 human malignant melanoma cells was accomplished using several conjugates prepared from anti-melanoma 2.1 (chromophore:antibody molar ratios, 6.8 and 11.2). Phototoxicity, as measured by clonogenic assay, was dependent on the delivered dose of 634-nm light and was observed only for conjugates that bound SK-MEL-2 cells. As judged by competitive inhibition radioimmunoassay, conjugates prepared in this fashion showed excellent retention of antigen binding activity relative to the unmodified antibody.


Splicing-related genes are alternatively spliced upon changes in ambient temperatures in plants.
Plants adjust their development and architecture to small variations in ambient temperature. In a time in which temperatures are rising world-wide, the mechanism by which plants are able to sense temperature fluctuations and adapt to it, is becoming of special interest. By performing RNA-sequencing on two Arabidopsis accession and one Brassica species exposed to temperature alterations, we showed that alternative splicing is an important mechanism in ambient temperature sensing and adaptation. We found that amongst the differentially alternatively spliced genes, splicing related genes are enriched, suggesting that the splicing machinery itself is targeted for alternative splicing when temperature changes. Moreover, we showed that many different components of the splicing machinery are targeted for ambient temperature regulated alternative splicing. Mutant analysis of a splicing related gene that was differentially spliced in two of the genotypes showed an altered flowering time response to different temperatures. We propose a two-step mechanism where temperature directly influences alternative splicing of the splicing machinery genes, followed by a second step where the altered splicing machinery affects splicing of downstream genes involved in the adaptation to altered temperatures.


Analytic results for the three- and four-particle correlation functions of the fluid of hard disks.
Analytic expressions for the three- and four-particle correlation functions of the hard disk fluid in terms of geometric functionals have been derived using the combined geometric/thermodynamic idea of Boublik [Fluid Phase Equilib. 316, 1 (2012)]. To assess the approximate result, extensive Monte Carlo simulations were performed to obtain the triplet correlation function, g3, over a wide range of densities. We then focussed on the rolling contact configurations that are required in the second-order thermodynamic perturbation theory of patchy colloid models. The analytic approximation is shown to perform very well, and the simulation data have therefore been parametrized using Boublik's functional form for their subsequent use.


Spatial regularization of SVM for the detection of diffusion alterations associated with stroke outcome.
In this paper, we propose a new method to detect differences at the group level in brain images based on spatially regularized support vector machines (SVM). We propose to spatially regularize the SVM using a graph Laplacian. This provides a flexible approach to model different types of proximity between voxels. We propose a proximity graph which accounts for tissue types. An efficient computation of the Gram matrix is provided. Then, significant differences between two populations are detected using statistical tests on the outputs of the SVM. The method was first tested on synthetic examples. It was then applied to 72 stroke patients to detect brain areas associated with motor outcome at 90 days, based on diffusion-weighted images acquired at the acute stage (median delay one day). The proposed method showed that poor motor outcome is associated to changes in the corticospinal bundle and white matter tracts originating from the premotor cortex. Standard mass univariate analyses failed to detect any difference on the same population.


11C-methionine PET/CT after inconclusive 99mTc-MIBI-SPECT/CT for localisation of parathyroid adenomas in primary hyperparathyroidism.
To investigate the efficacy of PET/CT with 11C-methionine for localizing parathyroid adenomas in patients with suspected primary hyperparathyroidism and inconclusive results of cervical ultrasonography and 99mTc-MIBI-SPECT/CT. Retrospective analysis of imaging data of 18 patients and correlation with clinical outcome, in particular intraoperative findings and histopathology of excised tissue. 12 of 18 patients received surgery. In 10 patients single parathyroid adenomas were found (diameter: 5-20 mm), 2 patients presented parathyroid hyperplasia (5 excised hyperplastic glands (diameter: 2-12 mm). PET/CT correctly localized all adenomas and 1 of 5 hyperplastic glands. The sensitivity per patient was 91.7% (11 of 12), the sensitivity per lesion 73.3% (11 of 15). All lesions missed by PET/CT had a size smaller than 9 mm and a volume of less than 0.2 ml. In 6 patients no surgery was performed. Five of them had a negative or atypical PET/CT. Further follow-up indicated familial hypocalciuric hypercalcemia in 3 of them (thus, PET/CT true negative), in the remaining 2 patients no validation is available. One patient with 2 highly suggestive lesions rejected surgery so far. PET/CT with 11C-methionine is a very sensitive method for the detection of parathyroid adenomas, even if they are too small to be visualized by 99mTc-MIBI-SPECT/CT.


[Evaluation of the usefulness of the agglutination test with Mangifera indica extract for the identification of pathogenic Yersinia enterocolitica strains].
The study was performed on 137 Y. enterocolitica strains belonging to various serological groups, including 75 03 group strains isolated form human clinical material. The agglutination test on slides was carried out on this strains using Mangifera indica extract of own production. Agglutinating preparation obtained from the seeds of M. indica agglutinated Y. enterocolitica organisms possessing the pVY plasmid and CRMOX+ phenotype in dilutions to 1.56 micrograms/ml. In identification tests conducted parallelly agglutination solution was used in concentrations of 100 and 10 micrograms/ml. All clones of Y. enterocolitica from O3 group from cultures at 37 degrees C and with CRMOX+ phenotype possessing the pVY plasmid were agglutinated by the extract. Agglutination failed to develop in the cultures of these clones incubated at 25 degrees C. Yersinia clones not containing the pVY plasmid with CRMOX- phenotype were resistant to agglutination. The virulence plasmid was found in 44 out of 75 strains of Y. enterocolitica O3 and was identified by restriction analysis after plasmid DNA digestion with Eco RI enzyme. The obtained results agreed with those of Wauters et al. in 1995 and confirmed the opinion of these authors on the usefulness of the test with M. indica agglutinin for the identification of virulent Y. enterocolitica strains.


Staurosporine Induces Filamentation in the Human Fungal Pathogen Candida albicans via Signaling through Cyr1 and Protein Kinase A.
Protein kinases are key regulators of signal transduction pathways that participate in diverse cellular processes. In fungal pathogens, kinases regulate signaling pathways that govern drug resistance, stress adaptation, and pathogenesis. The impact of kinases on the fungal regulatory circuitry has recently garnered considerable attention in the opportunistic fungal pathogen Candida albicans, which is a leading cause of human morbidity and mortality. Complex regulatory circuitry governs the C. albicans morphogenetic transition between yeast and filamentous growth, which is a key virulence trait. Here, we report that staurosporine, a promiscuous kinase inhibitor that abrogates fungal drug resistance, also influences C. albicans morphogenesis by inducing filamentation in the absence of any other inducing cue. We further establish that staurosporine exerts its effect via the adenylyl cyclase Cyr1 and the cyclic AMP (cAMP)-dependent protein kinase A (PKA). Strikingly, filamentation induced by staurosporine does not require the known upstream regulators of Cyr1, Ras1 or Pkc1, or effectors downstream of PKA, including Efg1. We further demonstrate that Cyr1 is capable of activating PKA to enable filamentation in response to staurosporine through a mechanism that does not require degradation of the transcriptional repressor Nrg1. We establish that staurosporine-induced filamentation is accompanied by a defect in septin ring formation, implicating cell cycle kinases as potential staurosporine targets underpinning this cellular response. Thus, we establish staurosporine as a chemical probe to elucidate the architecture of cellular signaling governing fungal morphogenesis and highlight the existence of novel circuitry through which the Cyr1 and PKA govern a key virulence trait. IMPORTANCE The impact of fungal pathogens on human health is devastating. One of the most pervasive fungal pathogens is Candida albicans, which kills ~40% of people suffering from bloodstream infections. Treatment of these infections is extremely difficult, as fungi are closely related to humans, and there are limited drugs that kill the fungus without host toxicity. The capacity of C. albicans to transition between yeast and filamentous forms is a key virulence trait. Thus, understanding the genetic pathways that regulate morphogenesis could provide novel therapeutic targets to treat C. albicans infections. Here, we establish the small molecule staurosporine as an inducer of filamentous growth. We unveil distinct regulatory circuitry required for staurosporine-induced filamentation that appears to be unique to this filament-inducing cue. Thus, this work highlights the fact that small molecules, such as staurosporine, can improve our understanding of the pathways required for key virulence programs, which may lead to the development of novel therapeutics.


Outcomes for elderly patients with mental illness following relocation from a stand-alone psychiatric hospital to community-based extended care units.
To assess the outcomes for a group of elderly patients with mental illness following their discharge from a stand-alone psychiatric facility to seven extended care units (ECUs). All patients (n=60) who were relocated to the ECUs were assessed using a number of standardized clinical and general functioning instruments at 6 months and 6 weeks pre-move, and again at 6 weeks, 6 months and 18 months post-move. By 18 months post-discharge, 13 of the 60 patients (21.7%) had died and seven others had been transferred to nursing homes. Those who died were older and had significantly higher levels of physical ill health when compared to those who did not die. Changes on measures of clinical and behavioural functioning in those who remained in the study did not reach statistical significance by 18 months post-move. However, participants did demonstrate improvements in quality of life with significantly higher scores on measures of social contact and community access. The mortality observed in the follow-up period is likely to be related to physical ill health and old age rather than the trauma associated with relocation. While overall functioning did not improve following relocation, patients had more independence and greater access to community-based activities.


Acute myocardial infarction with patent coronary artery after a long-distance flight--a case report.
Acute myocardial infarction is unusual in a young woman, especially with normal coronary arteriography. There are several mechanisms hypothesized, including coronary artery embolism, coronary spasm, illegal drug abuse and toxic condition. However, the etiology could be detected in only one third of these patients. Although air travel is known to precipitate deep vein thrombosis and pulmonary embolism, it is unclear whether it also causes myocardial infarction. We report a 37 year-old woman who had no risk factor for coronary artery disease, who suffered from acute myocardial infarction complicated with ventricular fibrillation after a long-distance flight across the Pacific Ocean from the United States to Taiwan. The coronary arteriogram disclosed patent coronary artery with slight intraluminal haziness in the proximal left anterior descending artery. The left ventriculogram demonstrated akinesia of anterolateral and apical segments with apical thrombus formation. We reviewed the related literature and considered the myocardial infarction in this patient was related to coronary thrombus formation after long-distance air travel.


Determinants of the decision-to-delivery interval and the effect on perinatal outcome after emergency caesarean delivery: a cross-sectional study.
Preventing prolongation of the decision-to-delivery interval (DDI) for emergency caesarean delivery (CD) remains central to improving perinatal health. This study evaluated the effects of the DDI on perinatal outcome following emergency CD. A prospective cross-sectional study involving 205 consenting women who had emergency CD at a tertiary hospital in Nigeria was conducted. The time-motion documentation of events from decision to delivery was documented; the outcome measures were perinatal morbidity (neonatal resuscitation, 5-minute Apgar score, neonatal intensive admission) and mortality. Data analysis was performed with IBM SPSS Statistics version 20.0, and P<0.05 was considered significant. The overall mean DDI was 233.99±132.61 minutes (range 44-725 minutes); the mean DDI was shortest for cord prolapse (86.25±86.25 minutes) and was shorter for booked participants compared with unbooked participants (207.19±13.88 minutes vs 249.25±12.05 minutes; P=0.030) and for general anaesthesia compared with spinal anaesthesia (219.48±128.60 minutes vs 236.19±133.42 minutes; P=0.543). All neonatal parameters were significantly worse for unbooked women compared with booked women, including perinatal mortality (10.8% vs 1.3%; P=0.012). Neonatal morbidity increased with DDI for clinical indications, UK National Institute of Health and Care Excellence (NICE) and Robson classification for CDs; perinatal mortality was 73.2 per 1000 live births, all were category 1 CDs and all except one occurred with DDI greater than 90 minutes. Severe preeclampsia/eclampsia, obstructed labour and placenta praevia tolerated DDI greater than 90 minutes compared with abruptio placentae and umbilical cord prolapse. However, logistic regression showed no statistical correlation between the DDI and neonatal outcomes. Perinatal morbidity and mortality increased with DDI relative to the clinical urgency but perinatal deaths were increased with DDI greater than 90 minutes. For no category of emergency CD should the DDI exceed 90 minutes, while patient and institutional factors should be addressed to reduce the DDI.


[Spatiotemporal variations of crop radiation use efficiency and harvest index: research progress].
The radiation use efficiency (RUE) model suggested by Monteith in 1972 is one of the most widely applied approaches for modeling net primary production and crop yield, especially by means of remote sensing techniques. To use this approach, RUE and harvest index (HI) are the two key parameters that need to be defined, besides the absorbed photosynthetically active radiation. However, there exist some problems in the studies and applications of RUE and HI. This paper reviewed the research progress on RUE and HI, summarized the current methods and procedures for defining RUE and HI values when using the RUE approach for predicting crop yield by remote sensing, and proposed that in order to maximize the effective application of RUE and HI in remote sensing crop yield and crop production management, future researches should seek proper procedures to determine the spatial heterogeneities of RUE and HI at regional scale based on field experiments.


Novel Method Based on Ion Mobility Spectrometry Combined with Machine Learning for the Discrimination of Fruit Juices.
Fruit juices are one of the most widely consumed beverages worldwide, and their production is subject to strict regulations. Therefore, this study presents a methodology based on the use of headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) in combination with machine-learning algorithms for the characterization juices of different raw material (orange, pineapple, or apple and grape). For this purpose, the ion mobility sum spectrum (IMSS) was used. First, an optimization of the most important conditions in generating the HS was carried out using a Box-Behnken design coupled with a response surface methodology. The following factors were studied: temperature, time, and sample volume. The optimum values were 46.3 °C, 5 min, and 750 µL, respectively. Once the conditions were optimized, 76 samples of the different types of juices were analyzed and the IMSS was combined with different machine-learning algorithms for its characterization. The exploratory analysis by hierarchical cluster analysis (HCA) and principal component analysis (PCA) revealed a clear tendency to group the samples according to the type of fruit juice and, to a lesser extent, the commercial brand. The combination of IMSS with supervised classification techniques reported an excellent result with 100% accuracy on the test set for support vector machines (SVM) and random forest (RF) models regarding the specific fruit used. Nevertheless, all the models have proven to be an effective alternative for characterizing and classifying the different types of juices.


Comparing the fragmentation reactions of protonated cyclic indolyl α-amino esters in quadrupole/orbitrap and quadrupole time-of-flight mass spectrometers.
The comparative study of higher-energy collisional dissociation (HCD) and collision-induced dissociation (CID) mechanisms for protonated cyclic indolyl α-amino esters in quadrupole/orbitrap (Q/Orbitrap) and quadrupole time-of-flight (QTOF) mass spectrometers, respectively, is helpful to study the structures and properties of biologically active indole derivatives using tandem mass spectrometry (MS/MS) technology. HCD and CID experiments were carried out using electrospray ionization Q/Orbitrap MS and QTOFMS in positive ion mode, respectively. Only the labile hydrogens were exchanged with deuterium in hydrogen/deuterium exchange (HDX) experiments and only the aromatic indole C-H hydrogens were substituted with deuterium in regiospecific hydrogen-deuterium labeling experiments. Theoretical calculations were carried out using the density functional theory (DFT) method at the B3LYP level with the 6-311G(d,p) basis set in the Gaussian 03 package of programs. In Q/Orbitrap MS/MS, when the added proton on the N8 position of protonated cyclic indolyl α-amino esters migrated in a stepwise fashion to the C3 position via two sequential 1,4-H shifts, an ion-neutral complex INC1 of [protonated cyclic N-sulfonyl ketimino esters/indoles] was formed by a charge-directed heterolytic cleavage of the C3 -C10 bond, while an ion-neutral complex INC3 of [cyclic N-sulfonyl ketimino esters/protonated indoles] was formed when another labile hydrogen on the N8 position successively migrated to the C4 position. Direct decomposition of INC1 and INC3 resulted in protonated cyclic N-sulfonyl ketimino esters and protonated indoles, respectively, while proton transfer led to protonated indoles and protonated cyclic N-sulfonyl ketimino esters. The HDX reaction with residual water in the HCD cell was also observed. In QTOF-MS/MS, protonated cyclic N-sulfonyl ketimino esters and protonated indoles resulted from direct decomposition of INC1 and INC3 , respectively, rather than proton transfer. Due to the specific construction of the Q/Orbitrap and QTOF mass spectrometers, different fragmentation mechanisms medicated by ion-neutral complexes of protonated cyclic indolyl α-amino esters were proposed. This study is desirable for qualitative and quantitive investigation of indole derivatives using MS/MS technology.


[Use of Plaferon LB for cardiac preconditioning during experimental ischemia/reperfusion injury in rabbits].
The main goal of research was to study potential of Plaferon LB for cardiac preconditioning during experimental ischemia/reperfusion injury in rabbits. 30 rabbits (2.5-3.0 kg) were used in experiment. They were divided in 3 groups and 6 subgroups (n=5). In I group experimental design of m/i was performed by proximal ligation of left coronary artery (LCA) (2-6 hours). In II group on the 2 and 6 hour ligature was removed - reperfusion during 1 hour. In III group before ligation of LCA animals was administered Plaferon LB (0.2 mg/kg). The animals were under electrocardiographic monitoring. Troponin I was measured in blood. In II group after 1 hour of reperfusion Troponin I concentration was higher than in I group after 2 and 6 hours. In II group electrocardiographic data was worsened (rhythm and heart rate). In III group these changes were less marked. Obtained data confirm enhancement of myocardial injury during the reperfusion. Cardiac preconditioning by Plaferon LB significantly decreased pathologic indices.


[Evaluation of vasculogenic erectile impotence using DICC (dynamic infusion cavernosometry & cevernosography) with intracavernous injection of papaverine].
Dynamic infusion cavernosometry and cavernosography (DICC) with intracevernous injection of papaverine was performed in 28 men. The change of the corporal body pressure after injection of papaverine and the intracavernous pressure decrease within the first 30 seconds after discontinuation of saline infusion were observed. Four different patterns of cavernometric findings can be identified on the basis of the intracavernous pressure behavior in response to injection of papaverine, infusion of saline and discontinuation of infusion: pattern A represents no vasculogenic insufficiency, pattern B represents pure arterial insufficiency, pattern C clearly represents venous leak and pattern D represents venous leak and arterial insufficiency. Cavernosography has found out effectively the sites of venous leakage in most our cases.


PhosphoLipid transfer protein (PLTP) exerts a direct pro-inflammatory effect on rheumatoid arthritis (RA) fibroblasts-like-synoviocytes (FLS) independently of its lipid transfer activity.
Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with modification of lipids profile and an increased risk of cardiovascular events related to inflammation. Plasma phospholipid transfer protein (PLTP) exerts a lipid transfer activity through its active form. PLTP can also bind to receptors such as ATP-binding cassette transporter A1 (ABCA1). In addition to its role in lipoprotein metabolism and atherosclerosis, the latest advances came in support of a complex role of PLTP in the regulation of the inflammatory response, both with pro-inflammatory or anti-inflammatory properties. The aim of the present study was to decipher the role of PLTP in joint inflammation and to assess its relevance in the context of RA. PLTP expression was examined by western-blot and by immunochemistry. ABCA1 expression was analyzed by flow cytometry. Lipid transfer activity of PLTP and pro-inflammatory cytokines were measured in sera and synovial fluid (SF) from RA patients and controls (healthy subjects or osteoarthritis patients [OA]). FLS were treated with both lipid-transfer active form and inactive form of recombinant human PLTP. IL-8, IL-6, VEGF and MMP3 produced by FLS were assessed by ELISA, and proliferation by measuring 3H-Thymidine incorporation. RA synovial tissues showed higher PLTP staining than OA and PLTP protein levels were also significantly higher in RA-FLS. In addition, RA, unlike OA patients, displayed elevated levels of PLTP activity in SF, which correlated with pro-inflammatory cytokines. Both lipid-transfer active and inactive forms of PLTP significantly increased the production of cytokines and proliferation of FLS. ABCA1 was expressed on RAFLS and PLTP activated STAT3 pathway. To conclude, PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation and FLS proliferation, independently of its lipid transfer activity. These results suggest a pro-inflammatory role for PLTP in RA.


Pre-Exercise Glucose Ingestion May Improve Endurance Capacity in East Asian Student Athletes with Lower Blood Glucose Response.
The main purpose of this study was to investigate the influence of pre-exercise glucose ingestion after a 2.5-h fast on the endurance capacity and blood glucose response in East Asian athletes who is expected to have genetically low insulin response. A total of 8 Japanese student athletes ingested 1.5 g/kg body mass of glucose (G trial) or 0.5 g/kg body mass of artificial sweetener dissolved in water (P trial) 30 min before exercise test after consuming a standardized breakfast. The exercise test comprised 40 min cycling exercise at 50% maximal oxygen uptake (VO2max), immediately followed by cycling to exhaustion at 70% VO2max. Before analyzing the data, we grouped the subjects into two groups depending on whether they showed rapid increase in blood glucose at the onset of exercise (increase rate in LOW group is <20% and HIGH group is ≥20%) to evaluate subject's insulin response to glucose feeding. No subjects developed rebound hypoglycemia (<70 mg/dL) in the G trial of both group. Significantly higher blood glucose during exercise was recognized only in the G trial of LOW group. Although no significant difference was observed between the two trials of both group, cycling time to exhaustion in the LOW group tended to increase because of glucose ingestion. These results suggest that pre-exercise ingestion of glucose in East Asian student athletes does not induce rebound hypoglycemia regardless of difference in individual insulin responses. Furthermore, individuals with low insulin responses seem to improve endurance performance with glucose ingestion before exercise.


Pooled sputum to optimise the efficiency and utility of rapid, point-of-care molecular SARS-CoV-2 testing.
As SARS-CoV-2 testing expands, particularly to widespread asymptomatic testing, high sensitivity point-of-care PCR platforms may optimise potential benefits from pooling multiple patients' samples. We tested patients and asymptomatic citizens for SARS-CoV-2, exploring the efficiency and utility of CovidNudge (i) for detection in individuals' sputum (compared to nasopharyngeal swabs), (ii) for detection in pooled sputum samples, and (iii) by modelling roll out scenarios for pooled sputum testing. Across 295 paired samples, we find no difference (p = 0.1236) in signal strength for sputum (mean amplified replicates (MAR) 25.2, standard deviation (SD) 14.2, range 0-60) compared to nasopharyngeal swabs (MAR 27.8, SD 12.4, range 6-56). At 10-sample pool size we find some drop in absolute strength of signal (individual sputum MAR 42.1, SD 11.8, range 13-60 vs. pooled sputum MAR 25.3, SD 14.6, range 1-54; p < 0.0001), but only marginal drop in sensitivity (51/53,96%). We determine a limit of detection of 250 copies/ml for an individual test, rising only four-fold to 1000copies/ml for a 10-sample pool. We find optimal pooled testing efficiency to be a 12-3-1-sample model, yet as prevalence increases, pool size should decrease; at 5% prevalence to maintain a 75% probability of negative first test, 5-sample pools are optimal. We describe for the first time the use of sequentially dipped sputum samples for rapid pooled point of care SARS-CoV-2 PCR testing. The potential to screen asymptomatic cohorts rapidly, at the point-of-care, with PCR, offers the potential to quickly identify and isolate positive individuals within a population "bubble".


Phosphatidic acid binding proteins display differential binding as a function of membrane curvature stress and chemical properties.
Phosphatidic acid (PA) is a crucial membrane phospholipid involved in de novo lipid synthesis and numerous intracellular signaling cascades. The signaling function of PA is mediated by peripheral membrane proteins that specifically recognize PA. While numerous PA-binding proteins are known, much less is known about what drives specificity of PA-protein binding. Previously, we have described the ionization properties of PA, summarized in the electrostatic-hydrogen bond switch, as one aspect that drives the specific binding of PA by PA-binding proteins. Here we focus on membrane curvature stress induced by phosphatidylethanolamine and show that many PA-binding proteins display enhanced binding as a function of negative curvature stress. This result is corroborated by the observation that positive curvature stress, induced by lyso phosphatidylcholine, abolishes PA binding of target proteins. We show, for the first time, that a novel plant PA-binding protein, Arabidopsis Epsin-like Clathrin Adaptor 1 (ECA1) displays curvature-dependence in its binding to PA. Other established PA targets examined in this study include, the plant proteins TGD2, and PDK1, the yeast proteins Opi1 and Spo20, and, the mammalian protein Raf-1 kinase and the C2 domain of the mammalian phosphatidylserine binding protein Lact as control. Based on our observations, we propose that liposome binding assays are the preferred method to investigate lipid binding compared to the popular lipid overlay assays where membrane environment is lost. The use of complex lipid mixtures is important to elucidate further aspects of PA binding proteins.


The perfusion of cisplatin and cisplatin structural analogues through the isolated rat heart: The effects on coronary flow and cardiodynamic parameters.
The therapeutic use of cisplatin for the treatment of solid tumours is associated with organ toxicity. Amongst those, the cardiotoxicity is an occasional but very serious and severe side effect. To prevent or reduce these negative effects, many cisplatin analogues have been synthesized and evaluated in terms of being a less toxic and more effective agent. In present study, we examined the effects of cisplatin and its three analogues in the isolated rat heart to determine whether changes in the structure of the platinum complexes (changing of carrier ligands - ethylenediamine; 1,2-diaminocyclohexane; 2,2':6',2''-terpyridine) can influence their cardiotoxic effects. The results of our research indicate that the introduction of aromatic rings in the structure of the platinum complexes has a negative influence on the heart function. Conversely, the other two examined complexes had less negative effects on heart function compared to cisplatin. Our findings may be of interest for a possible synthetic strategy of introducing a carrier ligand that will exert a less cardiotoxic effect.


Spatially resolved high resolution x-ray spectroscopy for magnetically confined fusion plasmas (invited).
The use of high resolution x-ray crystal spectrometers to diagnose fusion plasmas has been limited by the poor spatial localization associated with chord integrated measurements. Taking advantage of a new x-ray imaging spectrometer concept [M. Bitter et al., Rev. Sci. Instrum. 75, 3660 (2004)], and improvements in x-ray detector technology [Ch. Broennimann et al., J. Synchrotron Radiat. 13, 120 (2006)], a spatially resolving high resolution x-ray spectrometer has been built and installed on the Alcator C-Mod tokamak. This instrument utilizes a spherically bent quartz crystal and a set of two dimensional x-ray detectors arranged in the Johann configuration [H. H. Johann, Z. Phys. 69, 185 (1931)] to image the entire plasma cross section with a spatial resolution of about 1 cm. The spectrometer was designed to measure line emission from H-like and He-like argon in the wavelength range 3.7 and 4.0 A with a resolving power of approximately 10,000 at frame rates up to 200 Hz. Using spectral tomographic techniques [I. Condrea, Phys. Plasmas 11, 2427 (2004)] the line integrated spectra can be inverted to infer profiles of impurity emissivity, velocity, and temperature. From these quantities it is then possible to calculate impurity density and electron temperature profiles. An overview of the instrument, analysis techniques, and example profiles are presented.


Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility.
Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Cav) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Cav genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Cav3.2 channel, in ASD probands from two different families. Thus, to clarify the role of these CACNA1H variants on calcium channel activity we performed electrophysiological analysis using whole-cell patch clamp technology. Three out of four tested variants were shown to mildly affect Cav3.2 channel current density and activation properties, possibly leading to a dysregulation of intracellular Ca2+ ions homeostasis, thus altering calcium-dependent neuronal processes and contributing to ASD etiology in these families. Our results provide further support for the role of CACNA1H in neurodevelopmental disorders and suggest that rare CACNA1H variants may be involved in ASD development, providing a high-risk genetic background.


Natural history of diabetes mellitus with special reference to age of onset and vascular complications.
Age and sex distribution of diabetics, seasonal incidence of diabetes, grade of hyperglycemia, frequency of vascular complications and daily living conditions were studied of 2771 diabetic patients experienced at five clinics. The cases consisted of 1587 male and 1184 female diabetics. The distribution of age of diabetes onset revealed that males predominate among diabetics but females predominate among child diabetics, and that the precentage of child was extremely low. This pattern was emphasized as characteristic of Japanese diabetic population. Distribution of fasting blood sugar at the diagnosis of diabetes was compared among the age groups of diabetes-onset and the results showed that percentage of the value exceeding 300 mg/100 ml was highest in the under 10 year-onset cases and decreased with age. The frequency of diabetic retinopathy and of ischemic ECG changes was analysed from the view point of age of diabetes onset and also the duration of the disease. The frequency of the retinopathy at the diabetes-onset was zero in the under 10 year-onset cases, 4.2% in the 10s-onset cases and increased with age. The longer the duration of the disease the higher the frequency of the retinopathy was. This increase along with the duration was most remarkable in the 10s- and 20s-onset cases and less remarkable in the 30s-onset cases. The retinopathy was significantly more frequent in female diabetics. Daily of the patients were studied by a questionnaire and the analysis of 1022 cases with diabetes of more than three years revealed that cases of patients working uneventfully and/or feeling fit were most frequent among the 30s- or 40s-onset cases and that cases of bed-disability were frequent among the cases whose diabetes was found in their twenties or younger. This study showed that the prognosis of the patients is quite different according to whether their diabetes occurred before of after 30 years of age.


National Survey of Prison Health Care: Selected Findings.
This report presents selected findings on the provision of health care services in U.S. state prisons. Findings on admissions testing for infectious disease, cardiovascular risk factors, and mental health conditions, as well as the location of the provision of care and utilization of telemedicine are all included.


Skeletal muscle enzyme alterations after sprint and endurance training.
Specifically designed programs of sprint and endurance running were used to determine how different types of training affect enzyme activities in selected energy metabolism pathways. Three types of rat skeletal muscle were studied. After 8 wk of training, small but significant decreases in lactate dehydrogenase activity (15%) were found in the soleus and white vastus lateralis muscles of the sprint animals. Decreased levels of phosphoglucomutase and lactate dehydrogenase (approx. 20%) of the white vastus lateralis muscles of the endurance group were observed at the same time. By 16 wk of training, fumarase activity increased approximately twofold in the white vastus muscles and 45% in the soleus and plantaris muscles of the endurance group. Similarly, increased fumarase activity (42%) was seen in the soleus muscles of the sprint group. In all muscles, phosphoglucomutase and lactate dehydrogenase activities generally were lower in the endurance animals than in the control animals. No significant differences were found between the sprint and endurance groups at either or sixteen weeks of training. These results suggest that similar enzyme adaptations occur over time with both types of training.


[Infection with "enteritis salmonella" at non-intestinal sites (author's transl)].
So-called "enteritis Salmonella" was isolated in five cases from extra-intestinal specimens (about 3% of all primary Salmonella isolations in one year). The organisms were: S. typhimurium, S. enteritidis, S. java, S. panama, and S. infantis. In four of the five cases the clinical picture was not that of a Salmonella infection. Focal manifestations were a knee-joint empyema after long-term treatment with glucocorticoids, pleuritis in Hodgkin's disease, osteomyelitis of the head of the tibia, and meningitis in a child. In a 72-year-old man, acute renal failure occurred after enteritis, following which the Salmonella was isolated from the respiratory tract for many weeks.


Specialist neurocritical care and outcome from head injury.
To document the effect of neurocritical care, delivered by specialist staff and based on protocol-driven therapy aimed at intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targets, on outcome in acute head injury. Retrospective record review to compare presentation, therapy and outcome in patients with head injury referred to a regional neurosurgical centre, before and after establishment of protocol-driven therapy. Neurosciences Critical Care Unit (NCCU). Two hundred and eighty-five patients aged 18-65 years with at least one reactive pupil, referred with a diagnosis of head injury, requiring tracheal intubation and mechanical ventilation. Measurement of Glasgow Outcome Scale 6 months after injury. Patients from the two epochs were well matched for admission Glasgow Coma Scale and extracranial injuries. When all referred patients were considered, institution of protocol-driven therapy was not associated with a statistically significant increase in favourable outcomes (56.0% vs. 66.4%). However, we observed a significant increase in favourable outcomes in the severely head injured patients studied (40.4% vs. 59.6%). The proportion of favourable outcomes was also high (66.6%) in those presenting with evidence of raised ICP in the absence of a mass lesion and (60.0%) in those that required complex interventions to optimise ICP/CPP. Specialist neurocritical care with protocol-driven therapy is associated with a significant improvement in outcome for all patients with severe head injury. Such management may also benefit patients requiring no surgical therapy, some of whom may need complex therapeutic interventions. We found it impossible to predict need for such interventions from clinical features at presentation. These data suggest that specialist critical care with ICP/CPP guided therapy may benefit patients with severe head injury.


Surface Segregation Methods toward Molecular Separation Membranes.
As a highly promising approach to solving the issues of energy and environment, membrane technology has gained increasing attention in various fields including water treatment, liquid separations, and gas separations, owing to its high energy efficiency and eco-friendliness. Surface segregation, a phenomenon widely found in nature, exhibits irreplaceable advantages in membrane fabrication since it is an in situ method for synchronous modification of membrane and pore surfaces during the membrane forming process. Meanwhile, combined with the development of synthesis chemistry and nanomaterial, the group has developed surface segregation as a versatile membrane fabrication method using diverse surface segregation agents. In this review, the recent breakthroughs in surface segregation methods and their applications in membrane fabrication are first briefly introduced. Then, the surface segregation phenomena and the classification of surface segregation agents are discussed. As the major part of this review, the authors focus on surface segregation methods including free surface segregation, forced surface segregation, synergistic surface segregation, and reaction-enhanced surface segregation. The strategies for regulating the physical and chemical microenvironments of membrane and pore surfaces through the surface segregation method are emphasized. The representative applications of surface segregation membranes are presented. Finally, the current challenges and future perspectives are highlighted.


Large-scale road safety programmes in low- and middle-income countries: an opportunity to generate evidence.
The growing burden of road traffic injuries, which kill over 1.2 million people yearly, falls mostly on low- and middle-income countries (LMICs). Despite this, evidence generation on the effectiveness of road safety interventions in LMIC settings remains scarce. This paper explores a scientific approach for evaluating road safety programmes in LMICs and introduces such a road safety multi-country initiative, the Road Safety in 10 Countries Project (RS-10). By building on existing evaluation frameworks, we develop a scientific approach for evaluating large-scale road safety programmes in LMIC settings. This also draws on '13 lessons' of large-scale programme evaluation: defining the evaluation scope; selecting study sites; maintaining objectivity; developing an impact model; utilising multiple data sources; using multiple analytic techniques; maximising external validity; ensuring an appropriate time frame; the importance of flexibility and a stepwise approach; continuous monitoring; providing feedback to implementers, policy-makers; promoting the uptake of evaluation results; and understanding evaluation costs. The use of relatively new approaches for evaluation of real-world programmes allows for the production of relevant knowledge. The RS-10 project affords an important opportunity to scientifically test these approaches for a real-world, large-scale road safety evaluation and generate new knowledge for the field of road safety.


Myrcene hydroxylases do not determine enantiomeric composition of pheromonal ipsdienol in Ips spp.
Myrcene (7-methyl-3-methylene-1,6-octadiene) hydroxylation is likely one of the final reactions involved in the production of the Ips spp. (Coleoptera: Scolytidae) aggregation pheromone components, ipsdienol (2-methyl-6-methylene-2,7-octadien-4-ol) and ipsenol (2-methyl-6-methylene-7-octen-4-ol). To gain insight into the evolution of pheromone production, we isolated a full-length cDNA from the pinyon ips, Ips confusus (LeConte), that encodes a pheromone-biosynthetic cytochrome P450, I. confusus CYP9T1 (IcCYP9T1). The recovered cDNA is 1.70 kb, and the open reading frame encodes a 532 amino acid protein. IcCYP9T1 is 94% identical to the pine engraver, Ips pini (Say), CYP9T2 ortholog that hydroxylates myrcene. Quantitative real-time PCR experiments showed that IcCYP9T1, as does CYP9T2, has an expression pattern similar to other pheromone-biosynthetic genes in I. pini. Basal expression levels were higher in males than females, and expression was significantly induced in male, but not in female, anterior midguts by feeding on host phloem. Microsomes, prepared from Sf9 cells co-expressing baculoviral-mediated recombinant IcCYP9T1 and house fly (Musca domestica) NADPH-cytochrome P450 reductase, converted myrcene to ~85%-(R)-(-)-ipsdienol. These results are consistent with IcCYP9T1 encoding a myrcene hydroxylase that functions near the end of the pheromone-biosynthetic pathway. Since the I. confusus pheromone blend contains >90%-(S)-(+)-ipsdienol, these results confirm further that Ips spp. myrcene hydroxylases do not control the final ipsdienol enantiomeric blend. Other enzymes are required following myrcene hydroxylation to achieve the critical quantity and enantiomeric composition of pheromonal ipsenol and ipsdienol used by different Ips spp.


Inhibitors of metabolic reactions. Scope and limitation of acyl-CoA-analogue CoA-thioethers.
Substrate and intermediate analogue inhibitors of enzymes were prepared in which the thioester oxygen of acyl-CoA substrates is replaced by hydrogen with formation of CoA-thioethers. Experiments performed with ATP citrate lyase and S-(3,4-dicarboxy-3-hydroxybutyl)-CoA are consistent with citryl-CoA but not with citryl-enzyme being the direct precursor of the products acetyl-CoA and oxaloacetate. Consistent with these results, a previously described isotopic exchange between acetyl-CoA and [3H]CoASH, indicating the formation of an acetyl-enzyme in the reaction pathway, could not be confirmed. Substrate analogue CoA-thioethers of malate synthase are inhibitors endowed with the affinity of the substrates. Acetyl carboxylase and fatty acid synthetase are not inhibited by the substrate analogue S-ethyl-CoA; S-carboxyethyl-CoA, which could substitute for malonyl-CoA, is likewise not inhibitory. An explanation is proposed. Previously suggested roles of S-carboxymethyl-CoA, an acetyl-CoA-related inhibitor of citrate synthase, are discussed in the light of new experimental data. S-Acetyl, S-propionyl and S-carboxymethyl derivatives of 1,N6-etheno-CoA loose the high affinity of their CoA-counterparts to citrate synthase, probably because the ethylene group prevents proper binding to the enzyme.


Tailoring a bacteriochlorin building block with cationic, amphipathic, or lipophilic substituents.
Bacteriochlorins are attractive candidates for photodynamic therapy (PDT) of diverse medical indications owing to their strong absorption in the near-infrared (NIR) region, but their use has been stymied by lack of access to stable, synthetically malleable molecules. To overcome these limitations, a synthetic free base 3,13-dibromobacteriochlorin (BC-Br(3)Br(13)) has been exploited as a building block in the synthesis of diverse bacteriochlorins via Pd-mediated coupling reactions (Sonogashira, Suzuki, and reductive carbonylation). Each bacteriochlorin is stable to adventitious dehydrogenation by virtue of the presence of a geminal dimethyl group in each pyrroline ring. The target bacteriochlorins bear cationic, lipophilic, or amphipathic substituents at the 3- and 13- (beta-pyrrolic) positions. A dicarboxybacteriochlorin was converted to amide derivatives via the intermediate diacid chloride. A diformylbacteriochlorin was subjected to reductive amination to give aminomethyl derivatives. A set of 3,5-disubstituted aryl groups bearing lipophilic or amphipathic groups was introduced via Suzuki coupling. Altogether 22 free base bacteriochlorins have been prepared. Eight aminoalkylbacteriochlorins were quaternized with methyl iodide at two or four amine sites per molecule, which resulted in water solubility. Each bacteriochlorin exhibits a Q(y) absorption band in the range of 720-772 nm. The ability to introduce a wide variety of peripheral functional groups makes these bacteriochlorins attractive candidates for diverse applications in photomedicine including PDT in the NIR region.