Open aortic valve replacement in a patient with Glanzmann's thrombasthenia: a multidisciplinary strategy to minimize perioperative bleeding.
Glanzmann thrombasthenia (GT) is an autosomal recessive disorder in which the platelet (PLT) glycoprotein IIb/IIIa complex is either deficient or dysfunctional. In its most severe form, GT may result in spontaneous bleeding, although most cases are first detected in the setting of an invasive procedure. A 59-year-old male with Type I GT and a history of transfusion reactions to PLT infusions developed severe aortic stenosis secondary to bicuspid valve disease. He successfully underwent open aortic valve replacement with cardiopulmonary bypass without perioperative bleeding complications. A multidisciplinary team (anesthesia, hematology, cardiac surgery, and transfusion medicine) was established to optimize perioperative hematologic management. Bleeding risk was assessed given the patient's prior history and a dosing timeline for administration of blood products and recombinant clotting factors was established. Successful management was achieved during the operation by prophylactic administration of HLA-matched PLTs and Factor VIIa. Prophylactic PLT administration was continued through the immediate postoperative period and no bleeding complications occurred. Thromboelastograms (TEGs) were used in conjunction with traditional hematologic laboratory analysis to optimize clinical management. Patients with GT requiring cardiac surgical procedures are at high risk for perioperative bleeding complications. This case report illustrates the importance of multidisciplinary planning, TEG analysis, and the judicious use of recombinant factors to minimize operative bleeding risk.


Bioactivity of CaSiO3/poly-lactic acid (PLA) composites prepared by various surface loading methods of CaSiO3 powder.
Mixing bioactive ceramic powders with polymers is an effective method for generating bioactivity to the polymer-matrix composites but it is necessary to incorporate up to 40 vol% of bioactive ceramic powder. However, such a high mixing ratio offsets the advantages of the flexibility and formability of polymer matrix and it would be highly advantageous to lower the mixing ratio. Since surface loading of ceramic powders in the polymer is thought to be an effective way of reducing the mixing ratio of the ceramic powder while maintaining bioactive activity, CaSiO(3)/poly-lactic acid (PLA) composites were prepared by three methods; (1) casting, (2) spin coating and (3) hot pressing. In methods (1) and (2), a suspension was prepared by dissolving PLA in chloroform and dispersing CaSiO(3) powder in it. The suspension was cast and dried to form a film in the case of method (1) while it was spin-coated on a PLA substrate in method (2). In method (3), CaSiO(3) powder was surface loaded on to a PLA substrate by hot pressing. The bioactivity of these samples was investigated in vitro using simulated body fluid (SBF). Apatite formation was not observed in the samples prepared by method (1) but some apatite formation was achieved by mixing polyethylene glycol (PEG) with the PLA, producing a porous polymer matrix. In method (2), apatite was clearly observed after soaking for 7 days. Enhanced apatite formation was observed in method (3), the thickness of the resulting apatite layers becoming about 20 microm after soaking for 14 days. Since the amount of CaSiO(3) powder used in these samples was only <or=0.4 vol%, it is concluded that this preparation method is very effective in generating bioactivity in polymer-matrix composites by loading with only very small amounts of ceramic powder.


Necrotizing pneumonia and pleuritis associated with extraintestinal pathogenic Escherichia coli in a tiger (Panthera tigris) cub.
Extraintestinal pathogenic Escherichia coli (ExPEC) cause diseases in humans and animals, affecting organs outside the alimentary canal. In recent years, ExPEC have been reported as a cause of fatal pneumonia in dogs, cats, and in a horse. In the current report, a fatal case of pneumonia and pleuritis is described in a 4-week-old tiger (Panthera tigris) cub associated with ExPEC. The cub was presented with a sudden-onset respiratory illness and died after a few hours. Postmortem examination of the cub revealed an acute necrotizing pneumonia. The alveolar spaces were filled with large numbers of inflammatory cells (predominantly macrophages), edema, fibrin strands, and short bacillary bacteria. Escherichia coli O6:H31 was isolated in pure culture from the affected lung. It carried virulence genes cnf-1, sfa, fim, hlyD, and papG allele III, which are known to be associated with ExPEC strains. No evidence of infection by any other agent was detected. This is the first report, to the authors' knowledge, in which ExPEC has been associated with pneumonia in tigers.


Quantifying the semantics of search behavior before stock market moves.
Technology is becoming deeply interwoven into the fabric of society. The Internet has become a central source of information for many people when making day-to-day decisions. Here, we present a method to mine the vast data Internet users create when searching for information online, to identify topics of interest before stock market moves. In an analysis of historic data from 2004 until 2012, we draw on records from the search engine Google and online encyclopedia Wikipedia as well as judgments from the service Amazon Mechanical Turk. We find evidence of links between Internet searches relating to politics or business and subsequent stock market moves. In particular, we find that an increase in search volume for these topics tends to precede stock market falls. We suggest that extensions of these analyses could offer insight into large-scale information flow before a range of real-world events.


Sensory gating deficits in schizophrenia: new results.
It has been widely hypothesized that sensory gating failures and sensory overload occur in schizophrenic patients compared to normal subjects. The authors of this study sought to confirm and extend results of earlier studies that showed specific sensory gating deficits in schizophrenic patients. Age- and sex-matched schizophrenic patients (N = 20) and normal subjects (N = 20) were tested using electrophysiologically recorded P50 event-related potentials to assess the overall competence of the subjects' central sensory inhibitory capacity by measuring sensory filtering or gating. P50 area responses to two 75-dB (conditioning and test) click stimuli of 0.04-msec duration, averaged over 60 trials, were recorded for each subject. Normally, the first (conditioning) click stimulus induces gating mechanisms that result in diminished or gated P50 event-related potentials in response to the second click stimulus. The schizophrenic subjects manifested a significant sensory gating deficit at frontal, central, and parietal electrode placement sites, with a nonsignificant tendency for the deficit to be most prominent in the frontal areas of the brain. These data reflect a regionally diffuse loss of normal sensory gating in schizophrenic patients.


A unique symbiosis in the gut of tropical herbivorous surgeonfish (acanthuridae: teleostei) from the red sea.
Herbivorous surgeonfish (Acanthurus species) in the Red Sea harbor gut symbionts that include bacteria, trichomonadid flagellates, and a peculiar putative protist that attains densities of 20,000 to 100,000 cells per milliliter of gut contents. The structure, mode of reproduction, and within-gut distribution of the latter are described. This may be the first report of an organism of this type and the first evidence of a consistent endosymbiosis in the gut of a herbivorous marine fish.


EXPERIMENTS ON THE RELATION OF THE INHIBITORY TO THE ACCELERATOR NERVES OF THE HEART.
The experiments described in Part IV of this paper show that in whatever manner the problem of the relation of the vagus to the accelerators is approached, whether the accelerators are stimulated during a stimulation of the vagus, or the vagus during a stimulation of the accelerators, or both are stimulated simultaneously, either for a short or for a longer period, the result is the same, viz., the effect upon the rate of the heart is determined entirely by the relative strength of the stimuli applied to the two nerves. If the stimuli are of approximately the same strength, as judged by the effect of stimulating the nerves separately, the rate of the heart is but slightly affected; if the stimulus applied to the vagus is the stronger, the heart is slowed; if it is weaker, the heart is accelerated. In all cases the result of stimulating the two nerves simultaneously is approximately the algebraic sum of the results of stimulating them separately; sometimes the inhibitory effect slightly predominates, but not more frequently than does the accelerator effect. Moreover, the two nerves may be stimulated simultaneously for a considerable period of time without either completely overcoming the effect of the other. Thus as far as their effect upon the rate of the ventricular beat is concerned, the vagus and accelerator nerves seem to be purely antagonistic; the statement that a minimal stimulation of the one can completely overcome a maximal stimulation of the other is undoubtedly incorrect, and the hypotheses as to the mode of action of these nerves upon the heart, based upon this statement, lose their chief support.


Acute, Low-Dose Neutron Exposures Adversely Impact Central Nervous System Function.
A recognized risk of long-duration space travel arises from the elevated exposure astronauts face from galactic cosmic radiation (GCR), which is composed of a diverse array of energetic particles. There is now abundant evidence that exposures to many different charged particle GCR components within acute time frames are sufficient to induce central nervous system deficits that span from the molecular to the whole animal behavioral scale. Enhanced spacecraft shielding can lessen exposures to charged particle GCR components, but may conversely elevate neutron radiation levels. We previously observed that space-relevant neutron radiation doses, chronically delivered at dose-rates expected during planned human exploratory missions, can disrupt hippocampal neuronal excitability, perturb network long-term potentiation and negatively impact cognitive behavior. We have now determined that acute exposures to similar low doses (18 cGy) of neutron radiation can also lead to suppressed hippocampal synaptic signaling, as well as decreased learning and memory performance in male mice. Our results demonstrate that similar nervous system hazards arise from neutron irradiation regardless of the exposure time course. While not always in an identical manner, neutron irradiation disrupts many of the same central nervous system elements as acute charged particle GCR exposures. The risks arising from neutron irradiation are therefore important to consider when determining the overall hazards astronauts will face from the space radiation environment.


Single and multiple pyogenic liver abscesses: clinical course, etiology, and results of treatment.
A total of 483 patients with pyogenic liver abscess during the years 1986 to June 1995 were studied at Chang Gung Memorial Hospital in Kaohsiung: 343 were a single abscess and 140 were multiple abscesses. Males were predominantly affected by this disease. Abdominal pain was more frequent with the single abscess than with multiple abscesses, and jaundice was more frequent with multiple abscesses. Blood levels of alkaline phosphatase, bilirubin, and creatinine and the white blood cell count were significantly higher in patients with multiple abscesses than in those with a single abscess; and the hemoglobin level was higher with single abscesses. The single abscess was usually larger than 5 cm, and the multiple abscesses were usually smaller than 5 cm. The single abscess was always located on the right side (72%) and the multiple abscesses always on the right or both sides. Single abscesses mainly had a cryptogenic origin (58.9%) and multiple abscesses a biliary origin (45.0%). Liver aspirates revealed Klebsiella pneumoniae, Escherichia coli, Streptococcus, Bacteroides, Enterococcus, among others. K. pneumoniae was more often found in a single abscess and E. coli more often in multiple abscesses. Percutaneous catheter drainage and aspiration comprised the main treatment initially, and the failure rate with multiple abscesses was higher than that with single abscesses. Surgical intervention should be considered for multiple abscesses because of the underlying disease. The overall mortality with multiple abscesses (22.1%) was higher than that with a single abscess (12.8%). Partial hepatectomy produced a low mortality rate for both single and multiple abscesses and should be considered in the presence of severe hepatic destruction by an abscess or a stone.


Comparison of Intravenous Dexmedetomidine with Midazolam in Prolonging Spinal Anaesthesia with Ropivacaine.
Midazolam and dexmedetomidine both being sedatives, but the latter with additional analgesic properties is expected to prolong the duration of sensory and motor block obtained with spinal anaesthesia. To compare intravenous dexmedetomidine with midazolam and placebo with respect to sensory and motor block duration, analgesia, and sedation in patients undergoing lower limb and lower abdominal surgeries with intrathecal ropivacaine anaesthesia. In this single blind placebo controlled trial, 60 patients, classified as American Society of Anaesthesiologists' (ASA) physical status I-II, were randomized into three groups (n=20 per group). All patients were administered ropivacaine (15 mg) for spinal anaesthesia. Intravenous dexmedetomidine was administered in Group D (1 μg/kg loading dose over 10 minutes, followed by a continuous infusion (0.5 μg/kg/hr), intravenous midazolam was administered in Group M (0.05 mg/kg) loading dose, followed by a continuous infusion (0.02 mg/kg/hr) and normal saline was infused in Group C. Intraoperative haemodynamic changes, onset, level and duration of sensory block, onset and duration of motor block, level of sedation, postoperative analgesia and side effects were recorded. Heart rate was seen to fall significantly in Group D patients for the first 15 minutes. Measurements of mean blood pressure revealed significant decrease in Group D after 40 minutes, whereas the fall in Group C occurred after 15 minutes. Duration of sensory block was significantly longer in Group D patients (208±19.358 mins) as compared to Group M and C where the duration was (177±15.252 mins) and (177±17.800 mins) respectively. Higher levels of sedation were achieved in Group D and M where sedation score was 3 (fully asleep but arousable), 90% cases in Group D and 100% cases in Group M. The time at which first analgesic was given to patients (VAS score 4) was (271.50±21.831) in Group D and (202±25.047) in M and (218.50±38.013) in Group C. Dexmedetomidine significantly prolongs duration of analgesia providing pain relief in intraoperative and postoperative period. Injection of diclofenac sodium 75 mg intramuscular was used as rescue analgesic. The VAS score reached a value of 4 earlier in the midazolam and saline group than dexmedetomidine group. Intravenous dexmedetomidine prolonged spinal anaesthesia, though midazolam did not. It also provided sedation and additional analgesia. Therefore, dexmedetomidine is appropriate during spinal anaesthesia, although heart rate needs to be monitored cautiously.


Fluorescent probes for nucleic Acid visualization in fixed and live cells.
This review analyses the literature concerning non-fluorescent and fluorescent probes for nucleic acid imaging in fixed and living cells from the point of view of their suitability for imaging intracellular native RNA and DNA. Attention is mainly paid to fluorescent probes for fluorescence microscopy imaging. Requirements for the target-binding part and the fluorophore making up the probe are formulated. In the case of native double-stranded DNA, structure-specific and sequence-specific probes are discussed. Among the latest, three classes of dsDNA-targeting molecules are described: (i) sequence-specific peptides and proteins; (ii) triplex-forming oligonucleotides and (iii) polyamide oligo(N-methylpyrrole/N-methylimidazole) minor groove binders. Polyamides seem to be the most promising targeting agents for fluorescent probe design, however, some technical problems remain to be solved, such as the relatively low sequence specificity and the high background fluorescence inside the cells. Several examples of fluorescent probe applications for DNA imaging in fixed and living cells are cited. In the case of intracellular RNA, only modified oligonucleotides can provide such sequence-specific imaging. Several approaches for designing fluorescent probes are considered: linear fluorescent probes based on modified oligonucleotide analogs, molecular beacons, binary fluorescent probes and template-directed reactions with fluorescence probe formation, FRET donor-acceptor pairs, pyrene excimers, aptamers and others. The suitability of all these methods for living cell applications is discussed.


Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer's Disease.
The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer's disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. We recruited 78 individuals with AD from the Paisa genetic isolate in Antioquia, Colombia. These individuals belong to the world largest multigenerational and extended pedigree segregating AD as a consequence of a dominant fully penetrant mutation in the PSEN1 gene and exhibit an AOO ranging from the early 1930s to the late 1970s. To shed light on the genetic underpinning that could explain the large spread of the age of onset (AOO) of AD, 64 single nucleotide polymorphisms (SNP) associated with neuroanatomical, cardiovascular, and cognitive measures in AD were genotyped. Standard quality control and filtering procedures were applied, and single- and multi-locus linear mixed-effects models were used to identify AOO-associated SNPs. A full two-locus interaction model was fitted to define how identified SNPs interact to modulate AOO. We identified two key epistatic interactions between the APOE*E2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~ 8 years (95% CI 3.2-12.7, P = 1.83 × 10-3) and ~ 7.6 years (95% CI 3.3-11.8, P = 8.69 × 10-4), respectively, and validated our previous finding indicating that APOE*E2 delays AOO of AD in PSEN1 E280 mutation carriers. This new evidence involving APOE*E2 as an AOO delayer could be used for developing precision medicine approaches and predictive genomics models to potentially determine AOO in individuals genetically predisposed to AD.


The IASLC Mesothelioma Staging Project: Proposals for Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma.
The current T component for malignant pleural mesothelioma (MPM) has been predominantly informed by surgical data sets and consensus. The International Association for the Study of Lung Cancer undertook revision of the seventh edition of the staging system for MPM with the goal of developing recommendations for the eighth edition. Data elements including detailed T descriptors were developed by consensus. Tumor thickness at three pleural levels was also recorded. An electronic data capture system was established to facilitate data submission. A total of 3519 cases were submitted to the database. Of those eligible for T-component analysis, 509 cases had only clinical staging, 836 cases had only surgical staging, and 642 cases had both available. Survival was examined for T categories according to the current seventh edition staging system. There was clear separation between all clinically staged categories except T1a versus T1b (hazard ratio = 0.99, p = 0.95) and T3 versus T4 (hazard ratio = 1.22, p = 0.09), although the numbers of T4 cases were small. Pathological staging failed to demonstrate a survival difference between adjacent categories with the exception of T3 versus T4. Performance improved with collapse of T1a and T1b into a single T1 category; no current descriptors were shifted or eliminated. Tumor thickness and nodular or rindlike morphology were significantly associated with survival. A recommendation to collapse both clinical and pathological T1a and T1b into a T1 classification will be made for the eighth edition staging system. Simple measurement of pleural thickness has prognostic significance and should be examined further with a view to incorporation into future staging.


Examining Referral Patterns between Otolaryngology and Gastroenterology: A Window into Potential Inter-Specialty Knowledge Gaps.
The objective of this study was to examine referral patterns between otolaryngology and gastroenterology in order to delineate areas of clinical overlap, as well as to identify areas that might benefit from improved inter-specialty communication and collaboration. Montefiore's Clinical Looking Glass tool was used to define parameters for electronic medical record data extraction from 2015 to 2018. Two cohorts were generated, one representing referrals placed by gastroenterology to otolaryngology and a second representing referrals placed by otolaryngology to gastroenterology. The ICD-10 codes in both cohorts were reviewed and 13 distinct "reason for referral" categories were defined. The rates of referral for each category were then calculated for each of the referral cohorts. Otolaryngology referred to gastroenterology at a greater rate than gastroenterology referred to otolaryngology, despite seeing fewer total patients than gastroenterology. For referrals from gastroenterology to otolaryngology, the three most frequent referral reasons were oral cavity/oropharyngeal pathology (28.3%), dysphagia (28.3%), and gastroesophageal reflux disease/laryngopharyngeal reflux disease (GERD/LPRD) (11.3%). For referrals from otolaryngology to gastroenterology, the three most frequent referral reasons were GERD/LPRD (61.7%), dysphagia (18.6%), and esophageal pathology (5.3%). GERD/LPRD was more frequently referred out by otolaryngology than it was by gastroenterology, suggesting the need for further characterization of the discrepancy in management of a disease commonly treated by both specialties. The discrepant rates of referral for dysphagia also suggest a need to better understand what factors contribute to the differences in management of another clinical condition commonly assessed by both specialties. 4.


Malignant brain tumor with rhabdoid features in an adult.
Rhabdoid tumor (RT) of the central nervous system is an uncommon and aggressive neoplasm that usually affects pediatric patients. Currently, these tumors are classified as malignant RT or atypical teratoid/RT. Another entity of intraparenchymal brain tumor with a rhabdoid component is the extremely rare rhabdoid glioblastoma. A 23-year-old woman presented with a malignant RT in the right thalamus. The tumor was adjacent to the right lateral ventricle and was partially resected. Histological examination revealed prominent proliferation of rhabdoid cells, which is consistent with a diagnosis of malignant RT; the typical features of glioblastoma were not observed. The tumor cells stained positively for integrase interactor-1 and glial fibrillary acidic protein. Therefore, the tumor may have originated from glial components. Genetic analysis using comparative genomic hybridization showed a deoxyribonucleic acid copy-number gain on chromosome 7 but not on chromosome 22. The tumor did not respond to chemotherapy or radiotherapy, and the patient survived for only 4 months after surgery. The present case of malignant RTs shows certain similarities with those of rhabdoid glioblastoma. Further accumulation and analysis of data, including data from genetic analyses, may lead to the identification of a new type of malignant RT.


The Shifting Sands of Nursing Informatics Education: From Content to Connectivity.
This chapter considers the development of nurse education over the past 50 years and ventures a view towards 2020. A link will be made to the introduction of informatics to nursing curricula. It is clear when looking over the recent history of nurse education that it has moved from a medical model and content driven apprentice mode to that of a reflective agile professional mode where autonomous practice allows for collaboration in care and connectivity between health professionals. Parallel to these pedagogical changes are the introduction of informatics across healthcare, starting with computer skills and moving through information management to decision support. The chapter will conclude with some thoughts around the next possible steps forward for nursing informatics education.


IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+) Th17 cells.
Although very high levels of interleukin (IL)-1β are present in the intestines of patients suffering from inflammatory bowel diseases (IBD), little is known about the contribution of IL-1β to intestinal pathology. Here, we used two complementary models of chronic intestinal inflammation to address the role of IL-1β in driving innate and adaptive pathology in the intestine. We show that IL-1β promotes innate immune pathology in Helicobacter hepaticus-triggered intestinal inflammation by augmenting the recruitment of granulocytes and the accumulation and activation of innate lymphoid cells (ILCs). Using a T cell transfer colitis model, we demonstrate a key role for T cell-specific IL-1 receptor (IL-1R) signals in the accumulation and survival of pathogenic CD4(+) T cells in the colon. Furthermore, we show that IL-1β promotes Th17 responses from CD4(+) T cells and ILCs in the intestine, and we describe synergistic interactions between IL-1β and IL-23 signals that sustain innate and adaptive inflammatory responses in the gut. These data identify multiple mechanisms through which IL-1β promotes intestinal pathology and suggest that targeting IL-1β may represent a useful therapeutic approach in IBD.


How does the environment influence consumers' perceptions of safety in acute mental health units? A qualitative study.
To explore how the physical and social environment of acute mental health units influences consumers' perception and experience of safety. Acute mental health units are places in which consumers should feel safe. Not all consumers, however, feel safe in this environment. Little is known about what contributes to consumers' feelings of safety in this setting. The study used a qualitative descriptive design, influenced by naturalistic enquiry. Data were analysed using thematic analysis and are reported according to the COREQ checklist. Fifteen people who had experienced admission to an acute mental health unit were individually interviewed. Having a supportive environment enhanced consumers' perception and experience of safety. A supportive environment was experienced when consumers had privacy, felt safe from other consumers and had meaningful activities to participate in within the acute mental health unit. In contrast, having their privacy breached by other consumers made participants feel unsafe. Many participants were fearful of other consumers, and felt unsafe and unable to protect themselves. Lack of meaningful activities led to boredom and contributed to consumers feeling unsafe. Personal spaces should address consumers' privacy needs without compromising staff access. Staff presence enhances consumers' feelings of safety, but this need can be heightened when consumers are unable to alert staff when they feel unsafe. Meaningful activities link consumers to their lives outside of the hospital and can enhance recovery. Understanding how the acute unit environment is perceived by consumers can assist nurses and managers to promote feelings of safety among consumers. Feeling safe can, in turn, optimise recovery.


Early activation of vascular endothelium in nonobese, nondiabetic essential hypertensive patients with multiple metabolic abnormalities.
Circulating soluble E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) concentrations were evaluated in 93 nonobese essential hypertensive patients, of whom 16 had impaired glucose tolerance and hyperlipidemia (group I); 25 had impaired glucose tolerance (group II); 28 had hyperlipidemia (group III); and 24 had no metabolic abnormalities (group IV). A group of 22 healthy volunteers served as a control group. All groups were without clinical or ultrasound evidence of vascular lesion and were matched for age, sex, and BMI. Endothelial soluble adhesion molecules were measured at baseline, during an oral glucose tolerance test, and after 12 weeks of either enalapril or placebo treatments. Plasma soluble E-selectin, ICAM-1, and VCAM-1 were higher (P < 0.05) in group I and II than in the other groups (group I: E-selectin, 96.1+/-27.1; ICAM-1, 304.0+/-102.1; VCAM-1, 626.1+/-156.2 microg/l. Group II: E-selectin, 88.0+/-18.0; ICAM-1, 268.0+/-84.1; VCAM-1, 594.1+/-140.9 microg/I. Group III: E-selectin, 70.1+/-18.1; ICAM-1, 195.1+/-68.0; VCAM-1, 495.9+/-110.1 microg/l. Group IV: E-selectin, 65.1+/-16.1; ICAM-1, 168.1+/-64.0; VCAM-1, 472.1+/-108.2 microg/l). Soluble adhesins levels were not higher than normal in groups III and IV. Plasma soluble ICAM-1 concentrations increased in group I after glucose administration and were directly correlated with 2-h insulin levels (r=0.648, P=0.007). Compared with placebo, 12 weeks of enalapril treatment significantly (P < 0.0001) reduced soluble E-selectin, ICAM-1, and VCAM-1. Decrements of soluble adhesins were not dependent on enalapril-related blood pressure changes. Therefore, an early endothelial activation was present in essential hypertensive patients with impaired glucose tolerance, regardless of the presence of hyperlipidemia. ACE inhibition counteracted such endothelial activation.


Lake Erie College of Osteopathic Medicine's preclinical problem-based learning pathway program: an alternative medical school curriculum design.
In 1999, the American Osteopathic Association approved plans for "substantive change" to the medical curriculum at Lake Erie College of Osteopathic Medicine (LECOM) in Erie, Pa. In addition to the school's traditional, lecture-based curriculum, LECOM sought to create alternative--but distinct--learning pathways: independent study (described elsewhere) and problem-based learning (PBL). After selecting a long-standing, successful PBL program to guide our efforts and after a 1-year period of planning, developing, piloting, and refining the program, we introduced PBL in the 2000-2001 academic year. This learning pathway consists of carefully constructed cases that allow for progressive disclosure across group-tutorial sessions, from patient presentation to diagnosis and management. With more than 5 years of data on student performance and evaluations, LECOM can investigate the merits of its three basic science learning pathways. The description of LECOM's longitudinal database will allow program evaluators to assess and compare each of the three basic science learning pathways.


Multiple-image encryption using polarized light encoding and the optical interference principle in the Fresnel-transform domain.
We propose a multiple-image encryption scheme, based on polarized light encoding and the interference principle of phase-only masks (POMs), in the Fresnel-transform (FrT) domain. In this scheme, each secret image is converted into an intensity image by polarized light encoding, where a random key image and a pixilated polarizer with random angles are employed as keys. The intensity encrypted images produced by different secret images are convolved together and then inverse Fresnel-transformed. Phase and amplitude truncations are used to generate the asymmetric decryption keys. The phase-truncated inverse FrT spectrum is sent into an interference-based encryption (IBE) system to analytically obtain two POMs. To reduce the transmission and storage load on the keys, the chaotic mapping method is employed to generate random distributions of keys for encryption and decryption. One can recover all secret images successfully only if the corresponding decryption keys, the mechanism of FrTs, and correct chaotic conditions are known. The inherent silhouette problem can be thoroughly resolved by polarized light encoding in this proposal, without using any time-consuming iterative methods. The entire encryption and decryption process can be realized digitally, or in combination with optical means. Numerical simulation results are presented to verify the effectiveness and performance of the proposed scheme.


N1-acetyl-N2-formyl-5-methoxykynuramine, a biogenic amine and melatonin metabolite, functions as a potent antioxidant.
The biogenic amine The biogenic amine N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) was investigated for its potential antioxidative capacity. AFMK is a metabolite generated through either an enzymatic or a chemical reaction pathway from melatonin. The physiological function of AFMK remains unknown. To our knowledge, this report is the first to document the potent antioxidant action of this biogenic amine. Cyclic voltammetry (CV) shows that AFMK donates two electrons at potentials of 456 mV and 668 mV, and therefore it functions as a reductive force. This function contrasts with all other physiological antioxidants that donate a single electron only when they neutralize free radicals. AFMK reduced 8-hydroxydeoxyguanosine formation induced by the incubation of DNA with oxidants significantly. Lipid peroxidation resulting from free radical damage to rat liver homogenates was also prevented by the addition of AFMK. The inhibitory effects of AFMK on both DNA and lipid damage appear to be dose-response related. In cell culture, AFMK efficiently reduced hippocampal neuronal death induced by either hydrogen peroxide, glutamate, or amyloid b25-35 peptide. AFMK is a naturally occurring molecule with potent free radical scavenging capacity (donating two electrons/molecule) and thus may be a valuable new antioxidant for preventing and treating free radical-related disorders.


Beneficial effects of a Cannabis sativa extract treatment on diabetes-induced neuropathy and oxidative stress.
Neuropathy is the most common complication of diabetes and it is still considered to be relatively refractory to most of the analgesics. The aim of the present study was to explore the antinociceptive effect of a controlled cannabis extract (eCBD) in attenuating diabetic neuropathic pain. Repeated treatment with cannabis extract significantly relieved mechanical allodynia and restored the physiological thermal pain perception in streptozotocin (STZ)-induced diabetic rats without affecting hyperglycemia. In addition, the results showed that eCBD increased the reduced glutathione (GSH) content in the liver leading to a restoration of the defence mechanism and significantly decreased the liver lipid peroxidation suggesting that eCBD provides protection against oxidative damage in STZ-induced diabetes that also strongly contributes to the development of neuropathy. Finally, the nerve growth factor content in the sciatic nerve of diabetic rats was restored to normal following the repeated treatment with eCBD, suggesting that the extract was able to prevent the nerve damage caused by the reduced support of this neurotrophin. These findings highlighted the beneficial effects of cannabis extract treatment in attenuating diabetic neuropathic pain, possibly through a strong antioxidant activity and a specific action upon nerve growth factor.


The interaction in vitro between human polymorphonuclear leukocytes and Neisseria gonorrhoeae cultivated in the chick embryo.
Cultivation of Neisseria gonorrhoeae in the allantoic cavity of 10-day chick embryos ensured the following necessary properties for subsequent quantitive in vitro phagocytosis studies of viable gonococci: log phase of growth, resistance to the cidal effect of fresh human serum, maintenance of colonial type, and absence of clumping. Employing a modification of the Maaloe technique, phagocytosis of log-phase type 1 and 2 gonococci by human PMN leukocytes did not occur in the presence or absence of serum. These findings indicate that log-phase type 1 and 2 gonococci possess antiphagocytic surface factors Stationary-phase organisms of the same colonial type were ingested and rapidly killed by human PMN leukocytes under similar experimental conditions, thus emphasizing the necessity to employ log-phase gonococci in the study of phagocytosis and antiphagocytic surface factors. Log-phase type 4 gonococci were ingested and rapidly killed by human PMN leukocytes in the presence of fresh human serum but not heat-inactivated serum or in the absence of serum. Morphologic studies demonstrated that log-phase viable gonococci attach to the surface membrane of human PMN leukocytes. Interiorization of avirulent but not virulent organisms was observed in the presence of fresh human serum. Gonococci-human PMN leukocyte interactions thus provide a model for the investigation of the nonimmunologic and immunologic parameters associated with the attachment and ingestion stages of phagocytosis.


Spirituality and mood pathology in severe skin conditions: a prospective observational study.
Although the association between spirituality and parameters of psychological health and disease has been investigated extensively, little evidence is available for its potential role in dermatology. In a single-centre observational prospective study, 149 outpatients (107 women) with systemic sclerosis (SSc; n = 44), lupus erythematosus (LE; n = 48), or early stage malignant melanoma (MM; n = 57) were investigated using the multidimensional inventory for religious/spiritual well-being together with the Brief Symptom Inventory for psychiatric symptoms (BSI-18). SSc patients reported the highest amount of Somatization in comparison with LE and MM patients (p < 0.05). Furthermore, in line with the previous research, spiritual dimensions, such as Hope for a better future (p < 0.01) or Hope for a better afterlife (p < 0.01), proved to be especially negatively predictive for the global amount of psychiatric symptom burden in these dermatological patient groups. Our findings suggest that greater attention should be given to spiritual issues, such as encouraging patients, imbuing them with optimism, and offering interventions that address spiritual well-being.


Physical mapping of temporally regulated, overlapping transcripts in the region of the 10K protein gene in Autographa californica nuclear polyhedrosis virus.
We investigated transcriptional activity in the region of a gene for a major late protein (10 kilodaltons) of Autographa californica nuclear polyhedrosis virus. This 10K protein gene spans an HindIII cleavage site, with the 5' end of the gene located in the HindIII-Q fragment and the 3' end in the HindIII-P fragment. Northern blot analysis showed that there were at least four transcripts mapping in this region, two that are present maximally at 12 h (1,500 and 1,100 bases in length) and two that are present at 24 h (750 and 2,500 bases in length). Northern blot analysis also suggested that these transcripts overlap. S1 mapping identified the precise positions of the transcripts and confirmed the overlap. The 1,500- and 1,100-base transcripts share a common 5' end, about 1,056 bases upstream from the HindIII-P-Q boundary; the 750- and 2,500-base transcripts share a common 5' end, about 303 bases upstream from the HindIII-P-Q boundary. The 1,100-base transcript terminates in the Q fragment, about 234 bases from the HindIII-P-Q boundary. The other three transcripts all end in the P fragment. Both the 1,500- and the 750-base transcripts terminate approximately 240 bases from the HindIII-P-Q boundary. The 2,500-base transcript exhibits 3'-end heterogeneity, ending around 2,046 bases from the HindIII-P-Q boundary. Therefore, three different transcripts (1,500, 750, and 2,500 bases in length) contain the complete 10K protein coding region. A fourth transcript (1,100 bases in length) overlaps the 750-base 10K protein gene transcript by 70 bases.


Forest malaria and prospects for anti-malarial chemoprophylaxis among forest goers: findings from a qualitative study in Thailand.
Across the Greater Mekong Subregion, malaria remains a dangerous infectious disease, particularly for people who visit forested areas where residual transmission continues. Because vector control measures offer incomplete protection to forest goers, chemoprophylaxis has been suggested as a potential supplementary measure for malaria prevention and control. To implement prophylaxis effectively, additional information is needed to understand forest goers' activities and their willingness to use malaria prevention measures, including prophylaxis, and how it could be delivered in communities. Drawing on in-depth interviews with forest goers and stakeholders, this article examines the potential acceptability and implementation challenges of malaria prophylaxis for forest goers in northeast Thailand. In-depth interviews were conducted with forest goers (n = 11) and stakeholders (n = 16) including healthcare workers, community leaders, and policymakers. Interviews were audio-recorded, transcribed and coded using NVivo, employing an inductive and deductive approach, for thematic analysis. Forest goers were well aware of their (elevated) malaria risk and reported seeking care for malaria from local health care providers. Forest goers and community members have a close relationship with the forest but are not a homogenous group: their place and time-at-risk varied according to their activities and length of stay in the forest. Among stakeholders, the choice and cost of anti-malarial prophylactic regimen-its efficacy, length and complexity, number of tablets, potential side effects, and long-term impact on users-were key considerations for its feasibility. They also expressed concern about adherence to the preventive therapy and potential difficulty treating malaria patients with the same regimen. Prophylaxis was considered a low priority in areas with perceived accessible health system and approaching malaria elimination. In the context of multi-drug resistance, there are several considerations for implementing malaria prophylaxis: the need to target forest goers who are at-risk with a clear period of exposure, to ensure continued use of vector control measures and adherence to prophylactic anti-malarials, and to adopt an evidence-based approach to determine an appropriate regimen. Beyond addressing current intervention challenges and managing malaria incidence in low-transmission setting, it is crucial to keep malaria services available and accessible at the village level especially in areas home to highly mobile populations.


Workshops of the Fifth International Brain-Computer Interface Meeting: Defining the Future.
The Fifth International Brain-Computer Interface (BCI) Meeting met June 3-7th, 2013 at the Asilomar Conference Grounds, Pacific Grove, California. The conference included 19 workshops covering topics in brain-computer interface and brain-machine interface research. Topics included translation of BCIs into clinical use, standardization and certification, types of brain activity to use for BCI, recording methods, the effects of plasticity, special interest topics in BCIs applications, and future BCI directions. BCI research is well established and transitioning to practical use to benefit people with physical impairments. At the same time, new applications are being explored, both for people with physical impairments and beyond. Here we provide summaries of each workshop, illustrating the breadth and depth of BCI research and high-lighting important issues for future research and development.


Thiopurine S-methyltransferase alleles, TPMT(*)2, (*)3B and (*)3C, and genotype frequencies in an Indian population.
Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds including thiopurine drugs such as 6-mercaptopurine, 6-thioguanine and azathioprine. TPMT activity exhibits genetic variation and shows tri-modal distribution with 89-94% of individuals possessing high activity, 6-11% intermediate activity and approximately 0.3% low activity. Patients with intermediate or deficient TPMT activity exposed to thiopurine drugs show severe hematopoietic toxicity. Three single nucleotide polymorphisms (SNPs) in TPMT (NM_000367.2:c.238G>C, NM_000367.2:c.460G>A and NM_000367.2:c.719A>G) define the most prevalent mutant alleles associated with loss of catalytic activity reported in several populations. The present study investigated, for the first time, the frequency distribution of these three SNPs of TPMT, their alleles and genotypes in a Southern Indian population. Peripheral blood was obtained from 326 individuals of a Southern Indian population, and genomic DNA was isolated from total peripheral white blood cells. The genotypes at the polymorphic loci were determined by allele-specific polymerase chain reaction, restriction fragment length polymorphism and confirmatory DNA sequencing. The estimated genotype frequency for homozygous TPMT(*)1/(*)1 was 97.24%, for heterozygous TPMT(*)1/(*)2 and TPMT(*)1/(*)3B, 0.61% each, and for heterozygous TPMT(*)1/(*)3C, 1.53%. The frequency of heterozygous mutants in the studied Indian population was 2.76%. This study demonstrated significant variations in TPMT gene polymorphisms in an Indian population in relation to other human populations and may help to predict both clinical efficacy and drug toxicity of thiopurine drugs.


Convergence of the 26S proteasome and the REVOLUTA pathways in regulating inflorescence and floral meristem functions in Arabidopsis.
The 26S proteasome is a large multisubunit proteolytic complex, regulating growth and development in eukaryotes by selective removal of short-lived regulatory proteins. Here, it is shown that the 26S proteasome and the transcription factor gene REVOLUTA (REV) act together in maintaining inflorescence and floral meristem (IM and FM) functions. The characterization of a newly identified Arabidopsis mutant, designated ae4 (asymmetric leaves1/2 enhancer4), which carries a mutation in the gene encoding the 26S proteasome subunit, RPN2a, is reported. ae4 and rev have minor defects in phyllotaxy structure and meristem initiation, respectively, whereas ae4 rev demonstrated strong developmental defects. Compared with the rev single mutant, an increased percentage of ae4 rev plants exhibited abnormal vegetative shoot apical and axillary meristems. After flowering, ae4 rev first gave rise to a few normal-looking flowers, and then flowers with reduced numbers of all types of floral organs. In late reproductive development, instead of flowers, the ae4 rev IM produced numerous filamentous structures, which contained cells seen only in the floral organs, and then carpelloid organs. In situ hybridization revealed that expression of the WUSCHEL and CLAVATA3 genes was severely down-regulated or absent in the late appearing ae4 rev primordia, but the genes were strongly expressed in top-layer cells of inflorescence tips. Double mutant plants combining rev with other 26S proteasome subunit mutants, rpn1a and rpn9a, resembled ae4 rev, suggesting that the 26S proteasome might act as a whole in regulating IM and FM functions.


Predictors of perceived benefit among patients committed by court order in the Netherlands: one-year follow-up.
This study identified predictors of perceived benefit resulting from court-ordered hospitalization in the Netherlands. This prospective study included 174 psychiatric inpatients committed under court order. Logistic regression was used to examine the relationship between predictor variables and perceived benefit. At one year, 52% of patients evaluated their involuntary hospitalization as beneficial. These patients were more likely to be homeless (odds ratio [OR]=4.13, 95% confidence interval [CI]=1.33-12.84), to have been previously hospitalized voluntarily (OR=2.30, CI=1.18-4.48), and to have high service engagement (OR=2.79, CI=1.19-6.53) or more illness insight (OR=2.78, 95% CI=1.13-6.89). Having a psychotic disorder or higher severity of symptoms at baseline was correlated with an improved perception of benefit. Perceived benefits were predicted by living condition, hospitalization history, service engagement, and illness insight. Clinical characteristics were associated with improvement in perceived benefit. Additional research should focus on causality of associations before effective intervention programs can be developed.


Anti-inflammatory tetraquinane diterpenoids from a Crinipellis species.
The small pro-inflammatory 10kDa chemokine CXCL10 (Interferon-inducible protein 10, IP-10) plays an important role in mediating immune responses through the activation and recruitment of leukocytes such as T cells, eosinophils, monocytes and NK cells to the sites of inflammation. Elevated levels of CXCL10 have been associated with chronic inflammatory and infectious diseases and therefore CXCL10 represents an attractive target for the development of new anti-inflammatory drugs. In a search for anti-inflammatory compounds from fungi inhibiting the inducible CXCL10 promoter activity, four new tetraquinane diterpenoids, crinipellin E (1), crinipellin F (2), crinipellin G (3) and crinipellin H (4) were isolated from fermentations of a Crinipellis species. The structures of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy and mass spectrometry. Compounds 1, 2, and 3 inhibited the LPS/IFN-γ induced CXCL10 promoter activity in transiently transfected human MonoMac6 cells in a dose-dependent manner with IC50 values of 15μM, 1.5μM, and 3.15μM respectively, whereas compound 4 was devoid of any biological activity. Moreover, compounds 1, 2 and 3 reduced mRNA levels and synthesis of pro-inflammatory mediators such as cytokines and chemokines in LPS/IFN-γ stimulated MonoMac6 cells.


FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway.
To better understand the signaling properties of oncogenic FGFR3, we performed phospho-proteomics studies to identify potential downstream signaling effectors that are tyrosine phosphorylated in hematopoietic cells expressing constitutively activated leukemogenic FGFR3 mutants. We found that FGFR3 directly tyrosine phosphorylates the serine/threonine kinase p90RSK2 at Y529, which consequently regulates RSK2 activation by facilitating inactive ERK binding to RSK2 that is required for ERK-dependent phosphorylation and activation of RSK2. Moreover, inhibition of RSK2 by siRNA or a specific RSK inhibitor fmk effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells. Our findings suggest that FGFR3 mediates hematopoietic transformation by activating RSK2 in a two-step fashion, promoting both the ERK-RSK2 interaction and subsequent phosphorylation of RSK2 by ERK.


The Caenorhabditis elegans Excretory System: A Model for Tubulogenesis, Cell Fate Specification, and Plasticity.
The excretory system of the nematode Caenorhabditis elegans is a superb model of tubular organogenesis involving a minimum of cells. The system consists of just three unicellular tubes (canal, duct, and pore), a secretory gland, and two associated neurons. Just as in more complex organs, cells of the excretory system must first adopt specific identities and then coordinate diverse processes to form tubes of appropriate topology, shape, connectivity, and physiological function. The unicellular topology of excretory tubes, their varied and sometimes complex shapes, and the dynamic reprogramming of cell identity and remodeling of tube connectivity that occur during larval development are particularly fascinating features of this organ. The physiological roles of the excretory system in osmoregulation and other aspects of the animal's life cycle are only beginning to be explored. The cellular mechanisms and molecular pathways used to build and shape excretory tubes appear similar to those used in both unicellular and multicellular tubes in more complex organs, such as the vertebrate vascular system and kidney, making this simple organ system a useful model for understanding disease processes.


Factor Xa as an interface between coagulation and inflammation. Molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo.
Coagulation proteases were tested in a rat model of acute inflammation. Subplantar injection of Factor Xa (10-30 microg) produced a time- and dose-dependent edema in the rat paw, and potentiated carrageenin-induced edema. In contrast, the homologous protease Factor IXa was ineffective. This inflammatory response was recapitulated by the Factor Xa sequence L83FTRKL88(G), which mediates ligand binding to effector cell protease receptor-1 (EPR-1), while a control scrambled peptide did not induce edema in vivo. Conversely, injection of the EPR-1-derived peptide S123PGKPGNQNSKNEPP137 (corresponding to the receptor binding site for Factor Xa) inhibited carrageenin-induced rat paw edema, while the adjacent EPR-1 sequence P136PKKRERERSSHCYP150 was without effect. EPR-1-Factor Xa-induced inflammation was characterized by fast onset and prominent perivascular accumulation of activated and degranulated mast cells, was inhibited by the histamine/serotonin antagonists cyproheptadine and methysergide, but was unaffected by the thrombin-specific inhibitor, Hirulog. These findings suggest that through its interaction with EPR-1, Factor Xa may function as a mediator of acute inflammation in vivo. This pathway may amplify both coagulation and inflammatory cascades, thus contributing to the pathogenesis of tissue injury in vivo.


Subclinical ketosis: prevalence and associations with production and disease.
Cows in 32 southern Ontario Holstein herds were monitored for subclinical ketosis for a period of two and one half years. Milk samples were routinely collected and the level of milk ketone bodies determined by the use of a commercial nitroprusside based test powder (reactions scored as negative, +1 or +2). Approximately 92% of positive reactions were observed in the first 65 days of lactation and for that time period the prevalence of ketosis was 12.1%. Based on this prevalence, the minimum possible duration of subclinical ketosis would be 7.9 days and the minimum possible lactational incidence rate would be 12.1%. The prevalence during the first 65 days of lactation in individual herds ranged from 0 to 33.9%. Subclinical ketosis was more likely to be found in cows experiencing metritis than in unaffected cows. Detection of elevated levels of milk ketones also indicated that the cow had a significantly higher risk of having clinical ketosis, metritis or cystic ovaries diagnosed within the following four days. Milk ketone scores of +1 and +2 were found to be associated with a reduction in daily milk production of 1.0 and 1.4 kg of milk respectively.


Reaction mechanism and product branching ratios of the CH + C3H4 reactions: a theoretical study.
Two ground-state CH radical reactions with the C3H4 isomers allene and methylacetylene occurring along the C4H5 potential energy surface (PES) were studied to probe the reaction mechanisms and final product distributions. The calculations were performed using a CCSD(T)-F12//B2PLYPD3 PES in combination with the 1-D chemical master equation. The reaction between the CH radical and allene was found to lead to exclusive "funneling" of the energized C4H5 intermediates into linear C4H5 configurations before reaching the exit channels, regardless of the specific nature of the initial bimolecular reactive encounter. In the case of the CH radical reaction with methylacetylene, energized C4H5 three-membered ring structures underwent H loss in significant amounts resulting in the production of a cyclic C4H4 methylenecyclopropene product, in accordance with experiments. The theoretical product distribution at room temperature for methylacetylene + CH was ∼35% methylenecyclopropene, ∼36% vinylacetylene, and ∼28% 1,2,3-butatriene, which is in agreement with the available experimental data. The distribution for allene + CH was ∼93% vinylacetylene, ∼4% 1,2,3-butatriene and ∼3% acetylene + vinyl, which overestimates the experimental yield of vinylacetylene and underestimates that of 1,2,3-butatriene by ∼10%. The possible reasons for this slight quantitative deviation of the theoretical results obtained within statistical treatment from the experiment are discussed.


Logistic, ethical, and political dimensions of stepped wedge trials: critical review and case studies.
Three arguments are usually invoked in favour of stepped wedge cluster randomised controlled trials: the logistic convenience of implementing an intervention in phases, the ethical benefit of providing the intervention to all clusters, and the potential to enhance the social acceptability of cluster randomised controlled trials. Are these alleged benefits real? We explored the logistic, ethical, and political dimensions of stepped wedge trials using case studies of six recent evaluations. We identified completed or ongoing stepped wedge evaluations using two systematic reviews. We then purposively selected six with a focus on public health in high, middle, and low-income settings. We interviewed their authors about the logistic, ethical, and social issues faced by their teams. Two authors reviewed interview transcripts, identified emerging issues through qualitative thematic analysis, reflected upon them in the context of the literature, and invited all participants to co-author the manuscript. Our analysis raises three main points. First, the phased implementation of interventions can alleviate problems linked to simultaneous roll-out, but also brings new challenges. Issues to consider include the feasibility of organising intervention activities according to a randomised sequence, estimating time lags in implementation and effects, and accommodating policy changes during the trial period. Second, stepped wedge trials, like parallel cluster trials, require equipoise: without it, randomising participants to a control condition, even for a short time, remains problematic. In stepped wedge trials, equipoise is likely to lie in the degree of effect, effectiveness in a specific operational milieu, and the balance of benefit and harm, including the social value of better evaluation. Third, the strongest arguments for a stepped wedge design are logistic and political rather than ethical. The design is advantageous when simultaneous roll-out is impractical and when it increases the acceptability of using counterfactuals. The logistic convenience of phased implementation is context-dependent, and may be vitiated by the additional requirements of phasing. The potential for stepped wedge trials to enhance the social acceptability of cluster randomised trials is real, but their ethical legitimacy still rests on demonstrating equipoise and its configuration for each research question and setting.


Factors influencing Rickettsia tsutsugamushi infection of cultured cells.
Several factors which influence Rickettsia tsutsugamushi infectivity of, and replication in, cultured cells have been investigated in order to establish standard laboratory conditions for reliable quantitation and maximization of rickettsial yield and to begin to explore the nature of the relationship between the rickettsia and its host cell. The extent of scrub typhus rickettsial association with host cells was dependent on the rickettsial and target cell concentrations and on the medium in which the infection took place. Brain heart infusion broth, a standard rickettsial diluent for infectivity, was markedly inhibitory. Both rickettsial and host cell replication were dependent on a component(s) supplied by serum to the tissue culture medium; rickettsial multiplication was less affected by small temperature variation (optimum 34 to 37 degrees C) than was host cell growth (optimum 37 degrees C). The antibiotic daunomycin was very useful in selectively inhibiting host cell replication and permitting attainment of somewhat greater rickettsial yields than in uninhibited cells. These findings have underscored the close relationship between parasite and infected cell and have led to more predictable, higher yields of rickettsiae in vitro.


Towards 5G communication systems: Are there health implications?
The spread of radiofrequency electromagnetic fields (RF-EMF) is rising and health effects are still under investigation. RF-EMF promote oxidative stress, a condition involved in cancer onset, in several acute and chronic diseases and in vascular homeostasis. Although some evidences are still controversial, the WHO IARC classified RF-EMF as "possible carcinogenic to humans", and more recent studies suggested reproductive, metabolic and neurologic effects of RF-EMF, which are also able to alter bacterial antibiotic resistance. In this evolving scenario, although the biological effects of 5G communication systems are very scarcely investigated, an international action plan for the development of 5G networks has started, with a forthcoming increment in devices and density of small cells, and with the future use of millimeter waves (MMW). Preliminary observations showed that MMW increase skin temperature, alter gene expression, promote cellular proliferation and synthesis of proteins linked with oxidative stress, inflammatory and metabolic processes, could generate ocular damages, affect neuro-muscular dynamics. Further studies are needed to better and independently explore the health effects of RF-EMF in general and of MMW in particular. However, available findings seem sufficient to demonstrate the existence of biomedical effects, to invoke the precautionary principle, to define exposed subjects as potentially vulnerable and to revise existing limits. An adequate knowledge of pathophysiological mechanisms linking RF-EMF exposure to health risk should also be useful in the current clinical practice, in particular in consideration of evidences pointing to extrinsic factors as heavy contributors to cancer risk and to the progressive epidemiological growth of noncommunicable diseases.


Safety of primary anastomosis following emergency left sided colorectal resection: an international, multi-centre prospective audit.
Some evidence suggests that primary anastomosis following left sided colorectal resection in the emergency setting may be safe in selected patients, and confer favourable outcomes to permanent enterostomy. The aim of this study was to compare the major postoperative complication rate in patients undergoing end stoma vs primary anastomosis following emergency left sided colorectal resection. A pre-planned analysis of the European Society of Coloproctology 2017 audit. Adult patients (> 16 years) who underwent emergency (unplanned, within 24 h of hospital admission) left sided colonic or rectal resection were included. The primary endpoint was the 30-day major complication rate (Clavien-Dindo grade 3 to 5). From 591 patients, 455 (77%) received an end stoma, 103 a primary anastomosis (17%) and 33 primary anastomosis with defunctioning stoma (6%). In multivariable models, anastomosis was associated with a similar major complication rate to end stoma (adjusted odds ratio for end stoma 1.52, 95%CI 0.83-2.79, P = 0.173). Although a defunctioning stoma was not associated with reduced anastomotic leak (12% defunctioned [4/33] vs 13% not defunctioned [13/97], adjusted odds ratio 2.19, 95%CI 0.43-11.02, P = 0.343), it was associated with less severe complications (75% [3/4] with defunctioning stoma, 86.7% anastomosis only [13/15]), a lower mortality rate (0% [0/4] vs 20% [3/15]), and fewer reoperations (50% [2/4] vs 73% [11/15]) when a leak did occur. Primary anastomosis in selected patients appears safe after left sided emergency colorectal resection. A defunctioning stoma might mitigate against risk of subsequent complications.


A school outbreak of Norwalk-like virus: evidence for airborne transmission.
An outbreak of gastroenteritis affected a school attended by children aged 4-11 years. Epidemiological features suggested this was due to Norwalk-like virus (NLV) and this was confirmed by polymerase chain reaction (PCR). Nucleotide sequence analysis of the PCR amplicons revealed identical strains in all five positive stool samples. Pupils were significantly more likely to become ill following an episode of vomiting within their classroom (adjusted odds ratio 4.1, 95% CI 1.8-9.3). The times from exposure to illness were consistent with direct infection from aerosolized viral particles where exposure to vomiting was high. Cleaning with quaternary ammonium preparations made no impact on the course of the outbreak. However, the outbreak stopped after the school closed for 4 days and was cleaned using chlorine-based agents. This study confirms the importance of vomiting in the transmission of NLV and provides evidence that direct infection with aerosolized viral particles occurs.


Antiproliferative effects of delta opioids on highly purified CD4+ and CD8+ murine T cells.
Numerous studies have shown that opioids modulate the proliferative response of mixed splenocytes to T cell mitogens. To identify the T cell subpopulations affected by opioids, splenocytes from C57BL/6 and CD1 mice were separated using a fluorescent activated cell sorter (FACS) to obtain 98 to 99% pure populations of either CD4+ or CD8+ T cells. Cells were stimulated to proliferate in serum-free medium by cross-linking the T cell receptor using plate-coated anti-CD3-epsilon, then 3H-thymidine uptake and cell number were measured at 48 and 72 hr. [D-Ala2]-deltorphin 1 (deltorphin) dose-dependently inhibited the proliferation of C57BL/6 CD4+ T cells by approximately 50%. This effect was maximal when cells were preincubated with deltorphin 60 min before activation, whereas deltorphin was ineffective when added at the time of activation. Similarly, [D-Ala2]-Met-Enkephalinamide (DAME) 10(-11) to 10(-7) M inhibited CD4+ T cell proliferation. Naltrindole 10(-12) M abolished the antiproliferative effect of 10(-7) M deltorphin on CD4+ T cells. Proliferation of CD8+ T cells from C57BL/6 mice also was dose-dependently inhibited by deltorphin. At all concentrations to deltorphin, the antiproliferative effects were greater after 48 compared to 72 hr in culture. The effect of deltorphin and DAME on secretion of the T cell growth factor, IL-2, was determined by ELISA analysis of supernatants obtained from CD4+ T cells after 48-hr culture. Deltorphin showed a biphasic effect: 10(-11) M enhanced IL-2 secretion, whereas higher concentrations (10(-9)-10(-7) M) were inhibitory.(ABSTRACT TRUNCATED AT 250 WORDS)


Vinyl-triphenylamine dyes, a new family of switchable fluorescent probes for targeted two-photon cellular imaging: from DNA to protein labeling.
On the basis of our previous work on vinyl-triphenylamine derived DNA fluorophores we explored the structure space around this core by coupling it to diverse cationic, anionic and zwitterionic groups in the aim of targeting different classes of biomolecules. In parallel core modifications were performed to optimize the photophysical properties (quantum yield, two-photon absorption). The resulting water soluble π-conjugated molecules are called TP dyes and display an exceptional combination of optical properties: high two-photon absorption cross-section, high photostability, no self-quenching, and switchable fluorescence emission when bound to a biopolymer matrix. The linear and nonlinear optical properties of the TP dyes were studied in vitro in presence of DNA and in presence of a model protein (human serum albumin) using complementary absorption and fluorescence spectroscopy characterization tools. Structure modifications enabled to switch from DNA probes (cationic TP-pyridinium series) to protein probes (anionic TP-rhodanine series) without affecting the optical properties. Finally most TP compounds appear cell-permeant and show an intracellular localization consistent with their in vitro target specificity.


Role of surface energy and nano-roughness in the removal efficiency of bacterial contamination by nonwoven wipes from frequently touched surfaces.
Healthcare associated infections (HCAIs) are responsible for substantial patient morbidity, mortality and economic cost. Infection control strategies for reducing rates of transmission include the use of nonwoven wipes to remove pathogenic bacteria from frequently touched surfaces. Wiping is a dynamic process that involves physicochemical mechanisms to detach and transfer bacteria to fibre surfaces within the wipe. The purpose of this study was to determine the extent to which systematic changes in fibre surface energy and nano-roughness influence removal of bacteria from an abiotic polymer surface in dry wiping conditions, without liquid detergents or disinfectants. Nonwoven wipe substrates composed of two commonly used fibre types, lyocell (cellulosic) and polypropylene, with different surface energies and nano-roughnesses, were manufactured using pilot-scale nonwoven facilities to produce samples of comparable structure and dimensional properties. The surface energy and nano-roughness of some lyocell substrates were further adjusted by either oxygen (O2) or hexafluoroethane (C2F6) gas plasma treatment. Static adpression wiping of an inoculated surface under dry conditions produced removal efficiencies of between 9.4% and 15.7%, with no significant difference (p < 0.05) in the relative removal efficiencies of Escherichia coli, Staphylococcus aureus or Enterococcus faecalis. However, dynamic wiping markedly increased peak wiping efficiencies to over 50%, with a minimum increase in removal efficiency of 12.5% and a maximum increase in removal efficiency of 37.9% (all significant at p < 0.05) compared with static wiping, depending on fibre type and bacterium. In dry, dynamic wiping conditions, nonwoven wipe substrates with a surface energy closest to that of the contaminated surface produced the highest E. coli removal efficiency, while the associated increase in fibre nano-roughness abrogated this trend with S. aureus and E. faecalis.


Role of the 5'-untranslated regions in post-transcriptional regulation of the human glucocorticoid receptor.
GR transcripts display a remarkable heterogeneity in their 5' untranslated regions (5'UTRs). These variable 5'UTRs are encoded by a series of alternative 1st exons, and together with their associated promoters they maintain tissue-specific GR expression levels. In this study we over-expressed GR transcripts containing individual 1st exons, and assessed their effect on RNA stability, 3'-splicing, translation initiation and protein isoform production. We showed that these alternative 5'UTRs influence the predicted mRNA structure and free energy, and were associated with differential levels of functional spliced mRNA. However, the 5'UTR had little influence on the relative levels of the two principal 3' splice transcripts, GR-α and -β. The overall mRNA length, the free energy of the transcript and the translational efficiency directly influenced total GR levels. However, individual N-terminal protein isoform levels appeared to depend upon elements within the 5'UTR. Membrane-GR specific labelling suggested that the mGR originates from transcripts containing exon 1D and possibly 1H, although the specific trafficking sequences or structures within these transcripts remain unidentified. The role of the alternative first exons and their associated 5'UTRs has now been expanded to translational control, influencing total GR levels, individual constituent isoform levels, as well as trafficking to the cell surface.


Reviewing the role of healthy volunteer studies in drug development.
With the exception of genotoxic oncology drugs, first-in-human, Phase 1 clinical studies of investigational drugs have traditionally been conducted in healthy volunteers (HVs). The primary goal of these studies is to investigate the pharmacokinetics and pharmacodynamics of a novel drug candidate, determine appropriate dosing, and document safety and tolerability. When tailored to specific study objectives, HV studies are beneficial to manufacturers and patients alike and can be applied to both non-oncology and oncology drug development. Enrollment of HVs not only increases study accrual rates for dose-escalation studies but also alleviates the ethical concern of enrolling patients with disease in a short-term study at subtherapeutic doses when other studies (e.g. Phase 2 or Phase 3 studies) may be more appropriate for the patient. The use of HVs in non-oncology Phase 1 clinical trials is relatively safe but nonetheless poses ethical challenges because of the potential risks to which HVs are exposed. In general, most adverse events associated with non-oncology drugs are mild in severity, and serious adverse events are rare, but examples of severe toxicity have been reported. The use of HVs in the clinical development of oncology drugs is more limited but is nonetheless useful for evaluating clinical pharmacology and establishing an appropriate starting dose for studies in cancer patients. During the development of oncology drugs, clinical pharmacology studies in HVs have been used to assess pharmacokinetics, drug metabolism, food effects, potential drug-drug interactions, effects of hepatic and renal impairment, and other pharmacologic parameters vital for clinical decision-making in oncology. Studies in HVs are also being used to evaluate biosimilars versus established anticancer biologic agents. A thorough assessment of toxicity and pharmacology throughout the drug development process is critical to ensure the safety of HVs. With the appropriate safeguards, HVs will continue to play an important role in future drug development.


Long-Term Urban Market Dynamics Reveal Increased Bushmeat Carcass Volume despite Economic Growth and Proactive Environmental Legislation on Bioko Island, Equatorial Guinea.
Bushmeat hunting is extensive in west and central Africa as both a means for subsistence and for commercial gain. Commercial hunting represents one of the primary threats to wildlife in the region, and confounding factors have made it challenging to examine how external factors influence the commercial bushmeat trade. Bioko Island, Equatorial Guinea is a small island with large tracts of intact forest that support sizeable populations of commercially valuable vertebrates, especially endemic primates. The island also has a low human population and has experienced dramatic economic growth and rapid development since the mid-1990's. From October 1997 - September 2010, we monitored the largest bushmeat market on Bioko in Malabo, recording over 197,000 carcasses for sale. We used these data to analyze the dynamics of the market in relation to political events, environmental legislation, and rapid economic growth. Our findings suggest that bushmeat hunting and availability increased in parallel with the growth of Equatorial Guinea's GDP and disposable income of its citizens. During this 13-year study, the predominant mode of capture shifted from trapping to shotguns. Consequently, carcass volume and rates of taxa typically captured with shotguns increased significantly, most notably including intensified hunting of Bioko's unique and endangered monkey fauna. Attempts to limit bushmeat sales, including a 2007 ban on primate hunting and trade, were only transiently effective. The hunting ban was not enforced, and was quickly followed by a marked increase in bushmeat hunting compared to hunting rates prior to the ban. Our results emphasize the negative impact that rapid development and unenforced legislation have had on Bioko's wildlife, and demonstrate the need for strong governmental support if conservation strategies are to be successful at preventing extinctions of tropical wildlife.


The Dual Amylin and Calcitonin Receptor Agonist, KBP-066, Induces an Equally Potent Weight Loss Across a Broad Dose Range While Higher Doses May Further Improve Insulin Action.
Pharmacological treatment with dual amylin and calcitonin receptor agonists (DACRAs) cause significant weight loss and improvement of glucose homeostasis. In this study, the maximally efficacious dose of the novel DACRA, KeyBiosciencePeptide (KBP)-066, was investigated. Two different rat models were used: high-fat diet (HFD)-fed male Sprague-Dawley rats and male Zucker diabetic fatty (ZDF, fa/fa) rats to determine the maximum weight loss and glucose homeostatic effect, respectively. One acute study and one chronic study was performed in HFD rats. Two chronic studies were performed in ZDF rats: a preventive and an interventive. All studies covered a dose range of 5, 50, and 500 µg/kg KBP-066 delivered by subcutaneous injection. Treatment with KBP-066 resulted in a significant weight reduction of 13%-16% and improved glucose tolerance in HFD rats, which was independent of dose concentration. Dosing with 50 and 500 µg/kg led to a transient but significant increase in blood glucose, both in the acute and the chronic study in HFD rats. All doses of KBP-066 significantly improved glucose homeostasis in ZDF rats, both in the preventive and interventive study. Moreover, dosing with 50 and 500 µg/kg preserved insulin secretion to a greater extent than 5 µg/kg when compared with ZDF vehicle rats. Taken together, these results show that maximum weight loss is achieved with 5 µg/kg, which is within the range of previously reported DACRA dosing, whereas increasing dosing concentration to 50 and 500 µg/kg may further improve preservation of insulin secretion compared with 5 µg/kg in diabetic ZDF rats. SIGNIFICANCE STATEMENT: Here we show that KeyBiosciencePeptide (KBP)-066 induces an equally potent body weight loss across a broad dose range in obese rats. However, higher dosing of KBP-066 may improve insulin action in diabetic rats both as preventive and interventive treatment.


Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding.
There is conflicting evidence regarding the clinical efficacy of proton pump inhibitors (PPI) initiated before endoscopy for upper gastrointestinal bleeding. To systematically review evidence from randomised controlled trials (RCTs) of PPI treatment initiated before endoscopy for upper gastrointestinal bleeding. We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE and CINAHL databases and major conference proceedings to September 2005, using the Cochrane Upper Gastrointestinal and Pancreatic Diseases model. Searches were re-run in February 2006 and October 2008. We selected randomised controlled trials (RCTs), of hospitalised participants with unselected upper gastrointestinal bleeding, undergoing active treatment with a proton pump inhibitor PPI (oral or intravenous) and control treatment with either placebo, histamine-2 receptor antagonist (H2RA) or no treatment prior to endoscopy. Outcomes were assessed at 30 days and included mortality, rebleeding and surgery. Also assessed were stigmata of recent haemorrhage (SRH; active bleeding, non bleeding visible vessel or adherent clot) at index endoscopy, length of hospital stay, blood transfusion requirements and requirement for endoscopic therapy at index endoscopy. At least two review authors assessed eligibility criteria and extracted data regarding outcomes and factors affecting methodological quality. Six RCTs comprising 2223 participants were included. There was no statistical heterogeneity among trials for dichotomous outcomes. There were no statistically significant differences in mortality, rebleeding or surgery between PPI and control treatment. Unweighted pooled mortality rates were 6.1% and 5.5% respectively (odds ratio (OR)1.12; 95% CI 0.72 to 1.73). Unweighted pooled rebleeding rates were 13.9% and 16.6% respectively (OR 0.81; 95%CI 0.61 to 1.09). Pooled rates for surgery were 9.9% and 10.2% respectively (OR 0.96 95% CI 0.68 to 1.35). PPI treatment compared to control significantly reduced the proportion of participants with SRH at index endoscopy; unweighted pooled rates were 37.2% and 46.5% respectively (OR 0.67; 95% CI 0.54 to 0.84). However, this result was not robust to sensitivity analysis. PPI treatment compared to control significantly reduced endoscopic therapy at index endoscopy; unweighted pooled rates were 8.6% and 11.7% respectively (OR 0.68; 95% CI 0.50 to 0.93). For continuous outcomes (length of hospital stay and blood transfusion requirements), quantitative analysis could not be performed. PPI treatment initiated before endoscopy for upper gastrointestinal bleeding might reduce the proportion of participants with SRH at index endoscopy and significantly reduces requirement for endoscopic therapy during index endoscopy. However, there is no evidence that PPI treatment affects clinically important outcomes, namely mortality, rebleeding or need for surgery.


Dendritic cells utilize the evolutionarily conserved WASH and retromer complexes to promote MHCII recycling and helper T cell priming.
Immature dendritic cells (DCs) maintain a highly dynamic pool of recycling MHCII that promotes sampling of environmental antigens for presentation to T helper cells. However, the molecular basis of MHCII recycling and the cellular machinery that orchestrates MHCII trafficking are incompletely understood. Using a mouse model we show that WASH, an actin regulatory protein that facilitates retromer function, is essential for MHCII recycling and efficient priming of T helper cells. We further demonstrate that WASH deficiency results in impaired MHCII surface levels, recycling, and an accumulation of polyubiquitinated MHCII complexes, which are subsequently slated for premature lysosomal degradation. Consequently, conditional deletion of the Wash gene in DCs impairs priming of both conventional and autoimmune T helper cells in vivo and attenuates disease progression in a model of experimental autoimmune encephalitis (EAE). Thus, we identify a novel mechanism in which DCs employ the evolutionarily conserved WASH and retromer complex for MHCII recycling in order to regulate T helper cell priming.


Effects of mobile phone radiation on serum testosterone in Wistar albino rats.
To investigate the effects of electromagnetic field radiation generated by mobile phones on serum testosterone levels in Wistar albino rats. This experimental interventional control study was conducted in the Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia during the period December 2006 to April 2008. A total of 34 male Albino rats [Wistar strain], 2 months of age, weighing 150-160 gm were used for the experiment. These animals were divided into 3 groups. The first group containing 6 rats was assigned as a control group. The second group containing 14 rats was exposed to mobile phone radiation for 30 minutes daily and the third group containing 14 rats was exposed to mobile phone radiation for 60 minutes daily for the total period of 3 months. At the end of experimental period, blood was collected into the container, and serum testosterone was analyzed using double-antibody radioimmunoassay method by Coat-A-Count. Exposure to mobile phone radiation for 60 minutes/day for the total period of 3 months significantly decrease the serum testosterone level [p=0.028] in Wistar Albino rats compared to their matched control. Long-term exposure to mobile phone radiation leads to reduction in serum testosterone levels. Testosterone is a primary male gender hormone and any change in the normal levels may be devastating for reproductive and general health.


Virus-based piezoelectric energy generation.
Piezoelectric materials can convert mechanical energy into electrical energy, and piezoelectric devices made of a variety of inorganic materials and organic polymers have been demonstrated. However, synthesizing such materials often requires toxic starting compounds, harsh conditions and/or complex procedures. Previously, it was shown that hierarchically organized natural materials such as bones, collagen fibrils and peptide nanotubes can display piezoelectric properties. Here, we demonstrate that the piezoelectric and liquid-crystalline properties of M13 bacteriophage (phage) can be used to generate electrical energy. Using piezoresponse force microscopy, we characterize the structure-dependent piezoelectric properties of the phage at the molecular level. We then show that self-assembled thin films of phage can exhibit piezoelectric strengths of up to 7.8 pm V(-1). We also demonstrate that it is possible to modulate the dipole strength of the phage, hence tuning the piezoelectric response, by genetically engineering the major coat proteins of the phage. Finally, we develop a phage-based piezoelectric generator that produces up to 6 nA of current and 400 mV of potential and use it to operate a liquid-crystal display. Because biotechnology techniques enable large-scale production of genetically modified phages, phage-based piezoelectric materials potentially offer a simple and environmentally friendly approach to piezoelectric energy generation.


Ultrafocused Electromagnetic Field Pulses with a Hollow Cylindrical Waveguide.
We theoretically show that a dipole externally driven by a pulse with a lower-bounded temporal width, and placed inside a cylindrical hollow waveguide, can generate a train of arbitrarily short and focused electromagnetic pulses. The waveguide encloses vacuum with perfect electric conducting walls. A dipole driven by a single short pulse, which is properly engineered to exploit the linear spectral filtering of the cylindrical hollow waveguide, excites longitudinal waveguide modes that are coherently refocused at some particular instances of time, thereby producing arbitrarily short and focused electromagnetic pulses. We numerically show that such ultrafocused pulses persist outside the cylindrical waveguide at distances comparable to its radius.


Transport and Deposition of Welding Fume Agglomerates in a Realistic Human Nasal Airway.
Welding fume is a complex mixture containing ultra-fine particles in the nanometer range. Rather than being in the form of a singular sphere, due to the high particle concentration, welding fume particles agglomerate into long straight chains, branches, or other forms of compact shapes. Understanding the transport and deposition of these nano-agglomerates in human respiratory systems is of great interest as welding fumes are a known health hazard. The neurotoxin manganese (Mn) is a common element in welding fumes. Particulate Mn, either as soluble salts or oxides, that has deposited on the olfactory mucosa in human nasal airway is transported along the olfactory nerve to the olfactory bulb within the brain. If this Mn is further transported to the basal ganglia of the brain, it could accumulate at the part of the brain that is the focal point of its neurotoxicity. Accounting for various dynamic shape factors due to particle agglomeration, the current computational study is focused on the exposure route, the deposition pattern, and the deposition efficiency of the inhaled welding fume particles in a realistic human nasal cavity. Particular attention is given to the deposition pattern and deposition efficiency of inhaled welding fume agglomerates in the nasal olfactory region. For particles in the nanoscale, molecular diffusion is the dominant transport mechanism. Therefore, Brownian diffusion, hydrodynamic drag, Saffman lift force, and gravitational force are included in the model study. The deposition efficiencies for single spherical particles, two kinds of agglomerates of primary particles, two-dimensional planar and straight chains, are investigated for a range of primary particle sizes and a range of number of primary particles per agglomerate. A small fraction of the inhaled welding fume agglomerates is deposited on the olfactory mucosa, approximately in the range 0.1-1%, and depends on particle size and morphology. The strong size dependence of the deposition in olfactory mucosa on particle size implies that the occupation deposition of welding fume manganese can be expected to vary with welding method.


Do we monitor enough? We don't monitor enough.
The choice of which intraoperative monitors to use for routine cases is difficult, because a multitude of monitors is available today. Monitoring is deemed necessary to avoid problems, although there is little hard evidence that a specific monitor will improve outcome. The risk associated with modern noninvasive monitors, however, is negligible, and they should be considered for routine use in all patients. Although errors in the variables displayed or misuse of correct information can cause difficulties, these result from a lack of education and are not a valid reason to abandon a particular monitoring modality. Regular use of such monitoring tools as the electroencephalogram would allow clinicians to become familiar with how to interpret it in normal and crisis situations. The cost of a disaster during anesthesia (such as unrecognized hypoxia) is high. The dollars spent to cover a single major malpractice award could buy a tremendous number of monitors. The state of the art in the mid-1980s demands traditional anesthesia monitors plus continuous capnography and measurement of peripheral oxygenation. Other negligible-risk monitors should also be used when feasible. Improvement in monitoring design, particularly in output formats and in integration of monitored data, will be essential in the next few years, as will training in the proper use of monitors.


Expression of transient receptor potential C6 channels in human lung macrophages.
Chronic obstructive pulmonary disease (COPD) is associated with pulmonary inflammation with increased numbers of macrophages located in the parenchyma. These macrophages have the capacity to mediate the underlying pathophysiology of COPD; therefore, a better understanding of their function in chronic inflammation associated with this disease is vital. Ion channels regulate many cellular functions; however, their role in macrophages is unclear. This study examined the expression and function of transient receptor potential (TRP) channels in human macrophages. Human alveolar macrophages and lung tissue macrophages expressed increased mRNA and protein for TRPC6 when compared with monocytes and monocyte-derived macrophages. Moreover, TRPC6 mRNA expression was significantly elevated in alveolar macrophages from patients with COPD compared with control subjects. There were no differences in mRNA for TRPC3 or TRPC7. Although mRNA for TRPM2 and TRPV1 was detected in these cells, protein expression could not be determined. Fractionation of lung-derived macrophages demonstrated that TRPC6 protein was more highly expressed by smaller macrophages compared with larger macrophages. Using whole-cell patch clamp electrophysiology, TRPC6-like currents were measured in both macrophage subpopulations with appropriate biophysical and basic pharmacological profiles. These currents were active under basal conditions in the small macrophages. These data suggest that TRPC6-like channels are functional on human lung macrophages, and may be associated with COPD.


Effects of proctolin on contractions, membrane resistance, and non-voltage-dependent sarcolemmal ion channels in crustacean muscle fibers.
The neuropeptide proctolin in nanomolar concentrations enhances the contraction of crustacean muscle fibers manyfold. The cellular mechanisms underlying this potentiation were investigated in single, isolated, fast-contracting abdominal extensor muscle fibers of a small crustacean, the marine isopod Idotea baltica. Force measurements and current-clamp experiments revealed two actions of proctolin on the muscle fibers. In half of the preparations, proctolin (10(-9)-10(-6) M) increased the fiber's input resistance by up to 25%. In about one-fourth of the preparations, proctolin induced all-or-none action potentials in response to depolarizing current pulses in muscle fibers that showed graded electric responses under control conditions. In both cases, proctolin potentiated the peak force of muscle contractions (between 1.5- and 18-fold for 5 x 10(-9) M proctolin). Proctolin affected neither the membrane resting potential nor the threshold for excitation-contraction coupling. Using cell-attached patches on the sarcolemmal membrane, we identified non-voltage-dependent ion channels which contribute to the passive membrane properties of the muscle fibers. A 53 +/- 6 pS channel had its reversal potential near rest and carried outward current at depolarized potentials with physiological saline in the recording pipette. With isotonic K+ saline in the patch pipette, the reversal potential was +85 +/- 12 mV depolarized from the resting potential and single-channel conductances ranged from 36 to 166 pS. Proctolin modulated the activity of all these putative K+ channels by reducing the number of functionally active channels. The effects of proctolin on force of contraction, input resistance, and single-channel activity were mimicked by a membrane-permeating analog of cAMP. Conversely, a monothio analog of cAMP (Rp-cAMPS), a blocker of protein kinase A activity, substantially decreased the membrane input resistance of the muscle fibers. The results suggest that activation of the cAMP signal pathway and phosphorylation of non-voltage-dependent K+ channels by protein kinase A are involved in the potentiation of contractions by proctolin in the muscle fibers of this crustacean.


Self-isolation: A significant contributor to cannabis use during the COVID-19 pandemic.
Emerging research suggests the COVID-19 pandemic has resulted in a significant increase in self-reported isolation and loneliness in a large proportion of the population. This is particularly concerning given that isolation and loneliness are associated with increased cannabis use, as well as using cannabis to cope with negative affect. Objective: We investigated whether self-isolation due to COVID-19 and using cannabis to cope with depression were unique and/or interactive predictors of cannabis use during the pandemic, after controlling for pre-pandemic levels of cannabis use. Method: A sample of 70 emerging adults (mean age = 23.03; 34.3% male) who used both alcohol and cannabis pre-pandemic completed measures of cannabis use (i.e., quantity x frequency) and a novel COVID-19 questionnaire between March 23 and June 15, 2020. Pre-pandemic cannabis use levels had been collected four months earlier. Results: Linear regressions indicated self-isolation and coping with depression motives for cannabis use during the pandemic were significant predictors of pandemic cannabis use levels after accounting for pre-pandemic use levels. There was no interaction between coping with depression motives and self-isolation on cannabis use during the pandemic. Conclusions: Those who engaged in self-isolation were found to use 20% more cannabis during the pandemic than those who did not. Our results suggest that self-isolation is a unique risk factor for escalating cannabis use levels during the pandemic. Thus, self-isolation may inadvertently lead to adverse public health consequences in the form of increased cannabis use.


Transcranial sonography reveals cerebellar, nigral, and forebrain abnormalities in Friedreich's ataxia.
Friedreich's ataxia (FA) is essentially characterized by degeneration of the dorsal root ganglia, the dorsal nuclei of Clarke, and the long spinal fiber tracts, yet there is accumulating evidence that neurodegeneration extends beyond these predilection sites. Transcranial sonography (TCS) has evolved as a valuable complementary neuroimaging tool in the assessment of neurodegenerative diseases due to its capacity to well depict structural changes and the accumulation of heavy metals. Its use for assessing cerebellar neurodegeneration, however, has not yet been investigated.Here we investigated whether TCS allows to assess particular features of cerebellar as well as midbrain and forebrain abnormalities in FA. Comprehensive TCS imaging of 34 FA patients and 34 age-matched healthy controls. Hyperechogenicity of the dentate nucleus was very frequent in FA patients (85%) and could even be observed in patients with short disease duration, suggesting that dentate alterations are a common and probably early feature of FA. Substantia nigra was significantly hypoechogenic, possibly indicating regional changes in subcellular brain iron regulation. FA patients showed significantly enlarged 4th, 3rd, and lateral ventricles, thus corroborating earlier MRI and postmortem findings of substantial cerebellar and forebrain atrophy in FA. TCS provides a quick-to-apply and inexpensive in vivo assessment of both cerebellar and noncerebellar abnormalities in FA, in particular highlighting dentate hyperechogenicity as a core feature. It might serve as a promising tool for imaging aspects of cerebellar neurodegeneration also in other neurodegenerative disorders.