Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Clinical Practice Guideline.
To provide resource-stratified, evidence-based recommendations on the secondary prevention of cervical cancer globally. ASCO convened a multidisciplinary, multinational panel of oncology, primary care, epidemiology, health economic, cancer control, public health, and patient advocacy experts to produce recommendations reflecting four resource-tiered settings. A review of existing guidelines, a formal consensus-based process, and a modified ADAPTE process to adapt existing guidelines were conducted. Other experts participated in formal consensus. Seven existing guidelines were identified and reviewed, and adapted recommendations form the evidence base. Four systematic reviews plus cost-effectiveness analyses provided indirect evidence to inform consensus, which resulted in ≥ 75% agreement. Human papillomavirus (HPV) DNA testing is recommended in all resource settings; visual inspection with acetic acid may be used in basic settings. Recommended age ranges and frequencies by setting are as follows: maximal: ages 25 to 65, every 5 years; enhanced: ages 30 to 65, if two consecutive negative tests at 5-year intervals, then every 10 years; limited: ages 30 to 49, every 10 years; and basic: ages 30 to 49, one to three times per lifetime. For basic settings, visual assessment is recommended as triage; in other settings, genotyping and/or cytology are recommended. For basic settings, treatment is recommended if abnormal triage results are present; in other settings, colposcopy is recommended for abnormal triage results. For basic settings, treatment options are cryotherapy or loop electrosurgical excision procedure; for other settings, loop electrosurgical excision procedure (or ablation) is recommended. Twelve-month post-treatment follow-up is recommended in all settings. Women who are HIV positive should be screened with HPV testing after diagnosis and screened twice as many times per lifetime as the general population. Screening is recommended at 6 weeks postpartum in basic settings; in other settings, screening is recommended at 6 months. In basic settings without mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed.Additional information can be found at www.asco.org/rs-cervical-cancer-secondary-prev-guideline and www.asco.org/guidelineswiki.It is the view of of ASCO that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement, but not replace, local guidelines.


Development of a Plasmodium vivax biobank for functional ex vivo assays.
Plasmodium vivax is the second most prevalent cause of malaria yet remains challenging to study due to the lack of a continuous in vitro culture system, highlighting the need to establish a biobank of clinical isolates with multiple freezes per sample for use in functional assays. Different methods for cryopreserving parasite isolates were compared and subsequently the most promising one was validated. Enrichment of early- and late-stage parasites and parasite maturation were quantified to facilitate assay planning. In order to compare cryopreservation protocols, nine clinical P. vivax isolates were frozen with four glycerolyte-based mixtures. Parasite recovery post thaw, post KCl-Percoll enrichment and in short-term in vitro culture was measured via slide microscopy. Enrichment of late-stage parasites by magnetic activated cell sorting (MACS) was measured. Short and long-term storage of parasites at either - 80 °C or liquid nitrogen were also compared. Of the four cryopreservation mixtures, one mixture (glycerolyte:serum:RBC at a 2.5:1.5:1 ratio) resulted in improved parasite recovery and statistically significant (P < 0.05) enhancement in parasite survival in short-term in vitro culture. A parasite biobank was subsequently generated using this protocol resulting in a collection of 106 clinical isolates, each with 8 vials. The quality of the biobank was validated by measuring several factors from 47 thaws: the average reduction in parasitaemia post-thaw (25.3%); the average fold enrichment post KCl-Percoll (6.65-fold); and the average percent recovery of parasites (22.0%, measured from 30 isolates). During short-term in vitro culture, robust maturation of ring stage parasites to later stages (> 20% trophozoites, schizonts and gametocytes) was observed in 60.0% of isolates by 48 h. Enrichment of mature parasite stages via MACS showed good reproducibility, with an average of 30.0% post-MACS parasitaemia and an average of 5.30 × 105 parasites/vial. Finally, the effect of storage temperature was tested, and no large impacts from short-term (7 days) or long-term (7-10 years) storage at - 80 °C on parasite recovery, enrichment or viability was observed. Here, an optimized freezing method for P. vivax clinical isolates is demonstrated as a template for the generation and validation of a parasite biobank for use in functional assays.


Local and systemic hemostatics in trauma: a review.
Hemorrhage is the leading cause of trauma-related deaths. The early identification and surgical control of this hemorrhage is the crucial first step in the management of the injured patient; however, this objective remains challenging in the most critically ill trauma patients. As an adjunct to traditional methods of surgical hemorrhage control, several advanced hemostatic agents are currently available. Oxidized cellulose, fibrin glue and synthetic adhesives constitute the first-line of local hemostatic agents. Materials such as Zeolite and Chitosan comprise the newest generation of local hemostatics and the efficacy and safety of these agents are currently under investigation. Recombinant factor VIIa has emerged recently as a promising systemic hemostatic adjunct for the treatment of intractable surgical bleeding; however, until completion of the ongoing multinational randomized control trial, the indications for its use in trauma patients and its safety profile are unclear. This article reviews the role of commercially available local and systemic hemostatic products in the trauma patient population; it also addresses the unique set of characteristics, indications, limitations and rationale for their use.


Widespread distribution of PLTP in human CNS: evidence for PLTP synthesis by glia and neurons, and increased levels in Alzheimer's disease.
Plasma phospholipid transfer protein (PLTP) is one of the key proteins in lipid and lipoprotein metabolism. We examined PLTP distribution in human brain using PLTP mRNA dot-blot, Northern blot, immunohistochemistry (IHC), Western blot, and phospholipid transfer activity assay analyses. PLTP mRNA of 1.8 kb was widely distributed in all the examined regions of the central nervous system at either comparable or slightly lower levels than in the other major organs, depending on the region. Cerebrospinal fluid phospholipid transfer activity represented 15% of the plasma activity, indicating active PLTP synthesis in the brain. Western blot and phosholipid transfer activity assay demonstrated secretion of active PLTP by neurons, microglia, and astrocytes in culture. IHC demonstrated PLTP presence in neurons, astrocytes, microglia, and oligodendroglia. Some neuronal groups, such as nucleus hypoglossus and CA2 neurons in hippocampus, ependymal layer, and choroid plexus were particularly strongly stained, with substantial glial and neuropil immunostaining throughout the brain. Comparison between brain tissues from patients with Alzheimer's disease (AD) and nonAD subjects revealed a significant increase (P = 0.02) in PLTP levels in brain tissue homogenates and increased PLTP immunostaining in AD.


Invasion and Extinction Dynamics of Mating Types Under Facultative Sexual Reproduction.
In sexually reproducing isogamous species, syngamy between gametes is generally not indiscriminate, but rather restricted to occurring between complementary self-incompatible mating types. A longstanding question regards the evolutionary pressures that control the number of mating types observed in natural populations, which ranges from two to many thousands. Here, we describe a population genetic null model of this reproductive system, and derive expressions for the stationary probability distribution of the number of mating types, the establishment probability of a newly arising mating type, and the mean time to extinction of a resident type. Our results yield that the average rate of sexual reproduction in a population correlates positively with the expected number of mating types observed. We further show that the low number of mating types predicted in the rare-sex regime is primarily driven by low invasion probabilities of new mating type alleles, with established resident alleles being very stable over long evolutionary periods. Moreover, our model naturally exhibits varying selection strength dependent on the number of resident mating types. This results in higher extinction and lower invasion rates for an increasing number of residents.


The 2018 AANS Presidential Address. The privilege of service.
The theme of the 2018 American Association of Neurological Surgeons Annual Meeting was "The Privilege of Service." In the current climate of rapid change in healthcare delivery and increasing pressure on physicians, this theme was chosen to remind us of our true priorities and of the amazing opportunities that we have as neurosurgeons. In parallel to the classic triple-threat practitioner who excels in teaching, research, and clinical care, future neurosurgeons will need to acquire mastery in three areas of service, which have been summarized as the three A's: administration, advocacy, and altruism. The blessings that we enjoy afford us a platform from which we can take advantage of the many opportunities to experience the privilege of serving others.


Fiber type populations and Ca2+-activation properties of single fibers in soleus muscles from SHR and WKY rats.
Electrophoretic analyses of muscle proteins in whole muscle homogenates and single muscle fiber segments were used to examine myosin heavy chain (MHC) and myosin light chain 2 (MLC2) isoform composition and fiber type populations in soleus muscles from spontaneously hypertensive rats (SHRs) and their age-matched normotensive controls [Wistar-Kyoto (WKY) rats], at three stages in the development of high blood pressure (4 wk, 16 wk, and 24 wk of age). Demembranated (chemically skinned with 2% Triton X-100), single fiber preparations were used to determine the maximum Ca2+-activated force per cross-sectional area, calcium sensitivity, and degree of cooperativity of the contractile apparatus and Ca2+-regulatory system with respect to Ca2+. The results show that, at all ages examined, 1) SHR soleus contained a lower proportion of MHCI and MLC2 slow (MLC2s) and a higher proportion of MHCIIa, MHCIId/x, and MLC2 fast (MLC2f ) isoforms than the age-matched controls; 2) random dissection of single fibers from SHR and WKY soleus produced four populations of fibers: type I (expressing MHCI), type IIA (expressing MHCIIa), hybrid type I+IIA (coexpressing MHCI and MHCIIa), and hybrid type IIA+IID (coexpressing MHCIIa and MHCIId/x); and 3) single fiber dissection from SHR soleus yielded a lower proportion of type I fibers, a higher proportion of fast-twitch fibers (types IIA and IIA+IID), and a higher proportion of hybrid fibers (types I+IIA and IIA+IID) than the homologous muscles from the age-matched WKY rats. Because the presence of hybrid fibers is viewed as a marker of muscle transformation, these data suggest that SHR soleus undergoes transformation well into adulthood. Our data show also that, for a given fiber type, there are no significant differences between SHR and WKY soleus muscles with respect to any of the Ca2+-activation properties examined. This finding indicates that the lower specific tensions reported in the literature for SHR soleus muscles are not due to strain- or hypertension-related differences in the function of the contractile apparatus or regulatory system.


Achievement of longitudinally polarized focusing with long focal depth by amplitude modulation.
The longitudinal component of a focused beam is split into two parts along the optical axis to obtain a longitudinally polarized long focal depth using amplitude filtering based on Euler transformation and a radially polarized Bessel-Gaussian beam. Numerical results indicate that long focal depth and FWHM can be easily achieved with 9λ and 0.8λ, respectively. A radially polarized beam can be converted into a longitudinally polarized beam with a conversion efficiency of 51.0%. It can therefore be believed that the proposed scheme can be widely used to generate a longitudinally polarized beam for particle acceleration, laser cutting, and optical trapping.


Fuel partitioning and food intake.
Fuel metabolism generates signals that the brain uses to control food intake. Because the influence of metabolism on eating behavior depends on where and in what way metabolic fuels are utilized, the partitioning of fuels among different tissues and between metabolic pathways has significant effects on food intake. There is substantial evidence that shifts in fat fuel partitioning between oxidation and storage influence food intake, and data indicate that this may also be the case for carbohydrates. Carbohydrate and fat fuel interactions appear to affect eating behavior, and may play a role in the overconsumption of high-fat diets. A mechanism for the control of eating behavior that is sensitive to a stimulus generated at the level of oxidative phosphorylation and ATP production may underlie changes in food intake associated with shifts in fuel partitioning. A model based on such a mechanism provides a framework for understanding changes in food intake under a variety of conditions associated with alterations in energy storage and expenditure, including obesity and cachexia.


Cleavage of protein S by a platelet membrane protease.
Protein S is a vitamin K-dependent glycoprotein cofactor to the serine protease, activated protein C. In this study we demonstrate that 125I-protein S bound to unstimulated platelets in a time- and calcium-dependent saturable reaction. Half-maximal binding occurred at a protein S concentration of 10 nM, with approximately 1,100 binding sites per platelet. The binding of protein S to platelets was followed by rapid cleavage of the protein mediated by a protease confined to the platelet membrane. The membrane protease was Ca++-dependent, inhibited by high concentrations of diisopropyl fluorophosphate, but was resistant to a variety of other protease inhibitors. Functional studies demonstrated that the cleavage of protein S was associated with complete loss of cofactor anticoagulant activity. We conclude that protein S binds to platelets and is inactivated by a novel Ca++-dependent membrane protease. This may represent a physiological reaction that regulates the activity of protein S.


Impact of cigarette smoking on coronary plaque composition.
Cigarette smoking is associated with atherosclerosis and is an important risk factor for cardiovascular disease. We evaluated the impact of cigarette smoking on coronary plaque composition using integrated backscatter intravascular ultrasound (IB-IVUS). A total of 143 consecutive patients undergoing percutaneous coronary intervention were enrolled. A history of illness, as well as smoking habits, was obtained by interview. Participants were asked to report whether they were current smokers, had quit smoking, or had never smoked. According to interview results, patients were divided into the following three groups: current, former, and never smokers. Conventional and IB-IVUS tissue characterization analyses were carried out. Three-dimensional analyses were carried out to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcified). IB-IVUS analysis indicated that the patients in the current smoker group had significantly increased percent lipid volume and significantly decreased percent fibrous volume (P=0.01 and 0.03). Logistic regression analysis showed that the current smoking state (odds ratio 3.51, 95% confidence interval 1.02-12.10, P=0.04) was independently associated with the presence of lipid-rich plaques, which was defined as the upper 75th percentile of the study population. Smoking is independently associated with lipid-rich plaques, contributing to the increasing risk for plaque vulnerability.


Music therapy's relevance in a cancer hospital researched through a constructivist lens.
The constructivist research paradigm informed a research investigation on the relevance of music therapy in a cancer hospital, that is, what did the music therapy do and did it help? Over 3 months, criterion sampling was used to elicit interpretations in 5 studies from 5 sources: 128 patients who participated, 27 patients who overheard or witnessed music therapy, 41 visitors, 61 staff, and the music therapist-researcher. Fifty-seven percent of the patients who participated had advanced or end stage cancer. The music therapist's interpretations were recorded in a reflexive clinical journal and the respondents' interpretations were written on anonymous open-ended questionnaires. Thematic and content analyses were performed on the 5 groups of data with the support of qualitative data management software. Findings from the 5 data groups were contrasted and compared. Many patients', visitors' and staff members' affective, contemplative, and imagined moments in music therapy affirmed their "aliveness," resonating with an expanded consciousness, in a context where life's vulnerability is constantly apparent. Philosophical depictions about the relevance of music in human life, including theories by Addis and Winnicott, substantiated the therapeutic reactions.


Plasma-membrane-associated immunoglobulins and other polypeptides of pig mesenteric node lymphocytes.
Plasma membranes from pig mesenteric lymph-node lymphocytes contain a large number of polypeptide chains ranging in molecular weight from 20,000 to greater than 470,000, with a major component of 46,000. There are approx. 12-15 glycoproteins. The membranes contain immunoglobulin G, which comprises 0.6% of the total protein. Immunoglobulin M is also detected, but has not been accurately quantified for technical reasons. Possible origins of the membrane-associated immunoglobulin are briefly discussed. It is concluded that the immunoglobulin is probably associated with the plasma membrane in the intact cell.


Subtyping of Parkinson's Disease - Where Are We Up To?
Heterogenous clinical presentations of Parkinson's disease have aroused several attempts in its subtyping for the purpose of strategic implementation of treatment in order to maximise therapeutic effects. Apart from a priori classifications based purely on motor features, cluster analysis studies have achieved little success in receiving widespread adoption. A priori classifications demonstrate that their chosen factors, whether it be age or certain motor symptoms, do have an influence on subtypes. However, the cluster analysis approach is able to integrate these factors and other clinical features to produce subtypes. Differences in inclusion criteria from datasets, in variable selection and in methodology between cluster analysis studies have made it difficult to compare the subtypes. This has impeded such subtypes from clinical applications. This review analysed existing subtypes of Parkinson's disease, and suggested that future research should aim to discover subtypes that are robustly replicable across multiple datasets rather than focussing on one dataset at a time. Hopefully, through clinical applicable subtyping of Parkinson's disease would lead to translation of these subtypes into research and clinical use.


ERAP1 polymorphisms and haplotypes are associated with ankylosing spondylitis susceptibility and functional severity in a Spanish population.
The aim of this study was to assess the involvement of the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene in AS susceptibility and functional severity in a Spanish population. Eight single nucleotide polymorphisms (SNPs) spanning the ERAP1 gene were genotyped by allele-specific fluorescent PCR in 300 AS Spanish patients and 300 spondylarthritis-free controls. The influence of the ERAP1 SNPs on the functional severity of AS was analysed with the BASFI corrected for disease duration. Association analyses with AS susceptibility and functional severity were performed. Significant ERAP1 single marker association with AS susceptibility was found for five SNPs, namely rs30187 (allele T: P = 0.035), rs17482078 (allele C: P = 0.030), rs2287987 (allele T: P = 0.028), rs26653 (allele C: P = 0.041) and rs10050860 (allele C: P = 0.018). Three of the associated SNPs (rs17482078, rs2287987 and rs10050860) were in strong linkage disequilibrium. After imputing genotypes with the HapMap CEU data as reference, the strongest association was with rs41135 (P = 0.0046) in the 5'-upstream region of ERAP1. In addition, the SNP rs17481856 was found to be a risk factor for functional severity in AS and a borderline trend was observed for rs27044. These results suggest that the ERAP1 gene is associated with genetic predisposition to AS and influences the functional severity of the disease in a Spanish population.


Two G-proteins act in series to control stimulus-secretion coupling in mast cells: use of neomycin to distinguish between G-proteins controlling polyphosphoinositide phosphodiesterase and exocytosis.
Provision of GTP (or other nucleotides capable of acting as ligands for activation of G-proteins) together with Ca2+ (at micromolar concentrations) is both necessary and sufficient to stimulate exocytotic secretion from mast cells permeabilized with streptolysin-O. GTP and its analogues, through their interactions with Gp, also activate polyphosphoinositide-phosphodiesterase (PPI-pde generating inositol 1,4,5-trisphosphate and diglyceride [DG]). We have used mast cells labeled with [3H]inositol to test whether the requirement for GTP in exocytosis is an expression of Gp activity through the generation of DG and consequent activation of protein kinase C, or whether GTP is required at a later stage in the stimulus secretion sequence. Neomycin (0.3 mM) inhibits activation of PPI-pde, but maximal secretion due to optimal concentrations of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) can still be evoked in its presence. When ATP is also provided the concentration requirement for GTP-gamma-S in support of exocytosis is reduced. This sparing effect of ATP is nullified when the PPI-pde reaction is inhibited by neomycin. We argue that the sparing effect of ATP occurs as a result of enhancement of DG production and through its action as a phosphoryl donor in the reactions catalyzed by protein kinase C.


Prefrontal cortex reactivity underlies trait vulnerability to chronic social defeat stress.
Psychological stress contributes to the onset and exacerbation of nearly all neuropsychiatric disorders. Individual differences in stress-regulatory circuits can therefore dramatically affect vulnerability to these illnesses. Here we identify neural circuit mechanisms underlying individual differences in vulnerability to stress using a murine model of chronic social defeat stress. In chronically stressed mice, we find that the degree of prefrontal cortex (PFC) control of amygdala activity predicts stress susceptibility in individual mice. Critically, we also find that individual differences in PFC activation (that is, reactivity) during exposure to an aggressor mouse predict the emergence stress-induced behavioural deficits in stress-naïve mice. Finally, we show that naturally occurring differences in PFC reactivity directly correspond to the intrinsic firing rate of PFC neurons. This demonstrates that naturally occurring differences in PFC function underlie individual differences in vulnerability to stress, raising the hypothesis that PFC modulation may prevent stress-induced psychiatric disorders.


Electronic survey investigating UK veterinarians' perceptions of the potential for veterinary prescription medication misuse or abuse.
To investigate veterinarians' experience and perception of the risk of veterinary prescription medication (VPM) misuse and abuse by the public and veterinary professionals and to determine the clinical context in which respondent veterinarians prescribed certain VPMs. Anonymous online voluntary survey. A total of 361 of 7126 veterinarians registered as practicing in the UK, who provided e-mail contact details to the Royal College of Veterinary Surgeons Knowledge for participation in research. Respondents included general practitioners, with or without further qualifications, and European specialists, covering charity, private or academic small, large or mixed animal practice. The anonymous online survey, open from September to December 2021, posed 27 questions regarding personal experience and perception of VPM misuse or abuse, including which VPMs were considered most at risk of abuse by clients or veterinary staff. Thematic analysis was performed on free-text sections. The participation rate was 5% (361/7126), and the completion rate 60% (216/361 respondents). Of these, 88% of respondents somewhat agreed, agreed or strongly agreed that some VPMs were at risk of abuse. A third (29.9%; 107/358) had suspected an owner of taking VPMs, and one fifth (20.1%; 72/358) had suspected veterinary staff. Perceptions regarding the likelihood of public VPM abuse ranged from not suspecting a problem to having first-hand experience. Drugs considered most at risk of owner abuse were opioids, benzodiazepines and gabapentin, and those for veterinary staff were opioids, benzodiazepines and ketamine. Numerous 'red flags' prompting suspicion of VPM abuse were identified alongside ways of mitigating risk. Veterinarians in the UK reported varied experiences with, awareness of, and attitudes towards VPM abuse by the public and veterinary staff. Although not quantified, the UK veterinary industry could be a source of abusable drugs.


Host granulomatous response in schistosomiasis mansoni. Antibody and cell-mediated damage of parasite eggs in vitro.
In chronic schistosomiasis mansoni the major pathologic lesions are granulomas surrounding eggs deposited in host tissues. Parasite ova release antigenic material that sensitize the host, resulting in the development of delayed-type hypersensitivity granulomas. The objectives of the present study were to assess the ability of components of the host granulomatous response to induce biochemical and biologic alterations in eggs in vitro, and to correlate these with the capacity of ova to induce granulomas in vivo. An assay of egg tricarboxylic acid cycle activity was developed by use of 2-[14C]acetate as substrate and measurement of accumulation of released 14CO2. Addition of human granulocytes (96% neutrophils, 4% eosinophils) to eggs (cell/egg ratio 1,000:1) and heat-inactivated normal human serum reduced predicted egg 14CO2 generation by 15.6 +/- 3.0%. This effect was greater in the presence of sera of subjects with schistosomiasis (25.6 +/- 2.8% reduction) or when complement was present (24.4 +/- 4.0%). Autologous eosinophils and neutrophils were equally effective in decreasing egg 2-[14C]acetate metabolism (25.6 and 21.4% reductions, respectively). Since the biological role of schistosome eggs relates to their ability to hatch and produce miracidia, we evaluated the effect of granulocytes and sera on this function. The hatching rate of eggs incubated with normal serum was 52.8 +/- 3.3 miracidia/100 eggs; this value decreased to 37.0 +/- 2.6 when granulocytes were added (P less than 0.01). Granulocytes plus antibody- or complement-containing sera led to hatching rates of 23 and 20 miracidia/100 eggs. When ova were pre-incubated with granulocytes and various sera and injected into mice, the areas of egg-induced pulmonary granulomas measured 8 d later were reduced 32 to 45% as compared with lesions elicited by parasite eggs not exposed to granulocytes. Exposure of antigen-coated Sepharose beads to granulocytes and immune serum before injection into mice also led to a reduction in granuloma formation as compared with beads pre-incubated with serum alone. These data indicate that granulocytes in conjunction with antibodies and complement inflict biologically relevant toxic effects on eggs that are manifest in vivo by a decreased ability to elicit granulomas.


Predictors of chronic kidney disease in obstructive sleep apnea patients.
Obstructive sleep apnea (OSA) is a common condition in patients with chronic kidney disease (CKD). It may worsen renal function in CKD patients and is associated with uncontrolled blood pressure. Although OSA is found in up to 80% of CKD patients, there are limited data available on its clinical features in patients with and without CKD. This study aimed to identifying the differences in the clinical characteristics of OSA between CKD and non-CKD OSA patients and determine the clinical predictors for CKD in OSA patients. This was a retrospective study conducted at Khon Kaen University's Srinagarind Hospital in Thailand between July and December 2018. The inclusion criteria were diagnosis with OSA via polysomnography and having undergone laboratory tests for CKD. Obstructive sleep apnea is diagnosed according to the apnea-hypopnea index (AHI) as experiencing ≥5 events/hour, while CKD diagnosed based on the KDOQI guidelines. Eligible patients were divided into two groups: OSA with CKD and OSA without CKD. Predictors of CKD in OSA patients were analyzed using multivariate logistic regression analysis. During the study period, there were 178 OSA patients who met the study criteria, 88 (49.44%) of whom were in the OSA with CKD group. Both age and body mass index were comparable between OSA patients with CKD and those without (age: 59 and 57 years, respectively; body mass index: 30 and 29 kg/m2, respectively. There were three significant factors that differed between those with and without CKD group including systolic blood pressure (147 vs 135 mmHg), proportion of patients with diabetes (55% vs 34%), and proportion of patients with Mallampati scores of 3-4 (73% vs 39%). There were three independent predictors for OSA in patients with CKD: female sex, high systolic blood pressure, and Mallampati score of 3 or 4, with adjusted odds ratios (95% confidence interval) of 4.624 (1.554, 13.750), 1.060 (1.020, 1.101), and 2.816 (1.356, 5.849), respectively. The Hosmer-Lemeshow chi-square statistic of the predictive model was 6.06 (p 0.640). Systolic blood pressure of more than 130 and 150 mmHg resulted in sensitivity of 84.21% and specificity of 81.40%, respectively. Female sex, high systolic blood pressure, and Mallampati score of 3-4 were suggestive of OSA with CKD. Obstructive sleep apnea patients with one or more of these predictors may have a high risk of CKD.


[Surgical treatment of hepatic echinococcosis and its complications].
Over 11 years 280 patients underwent surgery for hepatic echinococcosis. A complicated form of the disease was revealed in 151 (54%) patients. Suppuration of cyst was in 88 (31.4%) patients, perforation of cyst into biliary tract--in 87 (31.1%), compression of bile ducts by cyst with mechanical jaundice--in 5 (1.8%), perforation into abdominal cavity--in 2 (0.7%) and cyst's calcification--in 9 (3.2%). The diagnosis was based on clinical, objective and instrumental examinations. The most informative methods in diagnosis of hepatic echinococcosis were US (96.7%) and CT (100%). Radical operations were performed in 26 patients: pericystectomy--6, "ideal" echinococcectomy--11, resection of the liver--9. In true bursting of parasite's elements into biliary tract with mechanical jaundice and cholangitis, the correction of biliary tract's passability was carried out. Postoperative complications were revealed in 33.2% patients, in the most cases they were non-specific. Lethality was 1.7% (3 patients).


Haploinsufficiency in the prometastasis Kiss1 receptor Gpr54 delays breast tumor initiation, progression, and lung metastasis.
Activation of KISS1 receptor (KISS1R or GPR54) by its ligands (Kisspeptins) regulates a diverse function both in normal physiology and pathophysiology. In cancer, KISS1R has been implicated in tumor angiogenesis and metastasis, but a broader evaluation of KISS1R in tumorigenesis and tumor progression is yet to be conducted. In this study, we used mouse models of Kiss1r gene knockout and mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT)-induced breast cancer to conduct such an evaluation. Kiss1r heterozygosity in MMTV-PyMT mice was sufficient to attenuate breast cancer initiation, growth, latency, multiplicity, and lung metastasis. To confirm these effects and assess possible contributions of endogenous ligands, we isolated primary tumor cells from PyMT/Kiss1r(+/+) and PyMT/Kiss1r(+/-) mice and compared their phenotypes by in vitro and in vivo assays. Kiss1r loss attenuated in vitro tumorigenic properties as well as tumor growth in vivo in immunocompromised NOD.SCID/NCr mice. Kiss1r activation in these cells, resulting from the addition of its ligand Kisspeptin-10, resulted in RhoA activation and RhoA-dependent gene expression through the Gαq-p63RhoGEF signaling pathway. Anchorage-independent growth was tightly linked to dose-dependent regulation of RhoA by Kiss1r. In support of these results, siRNA-mediated knockdown of KISS1R or inactivation of RhoA in human MCF10A breast epithelial cells overexpressing H-RasV12 was sufficient to reduce Ras-induced anchorage-independent growth. In summary, we concluded that Kiss1r attenuation was sufficient to delay breast tumor initiation, progression, and metastasis through inhibitory effects on the downstream Gαq-p63RhoGEF-RhoA signaling pathway.


Intervention of cGAS‒STING signaling in sterile inflammatory diseases.
Sterile inflammation characterized by unresolved chronic inflammation is well established to promote the progression of multiple autoimmune diseases, metabolic disorders, neurodegenerative diseases, and cardiovascular diseases, collectively termed 'sterile inflammatory diseases'. By recognizing host-derived DNA, cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) activates endoplasmic reticulum-associated stimulator of interferon genes (STING), which leads to the induction of type I interferons and inflammatory cytokines or immunogenic cell death that promotes sterile inflammation. Additionally, the DNA/cGAS-independent mode of STING activation has also been characterized in the progression of several sterile inflammatory diseases. This review focuses on the molecular mechanism of cGAS-dependent and cGAS-independent STING signaling under various disease conditions, particularly highlighting the diverse initiators upon this signaling pathway. We also summarize recent advances in the discovery of antagonists targeting cGAS and STING and the evaluation of their efficiencies in preclinical models. Finally, we discuss potential differences in the clinical applications of the specific antagonists, which may shed light on the precision therapeutic interventions.


A longitudinal 6-year study of the molecular epidemiology of clinical campylobacter isolates in Oxfordshire, United kingdom.
Temporal and seasonal trends in Campylobacter genotypes causing human gastroenteritis were investigated in a 6-year study of 3,300 recent isolates from Oxfordshire, United Kingdom. Genotypes (sequence types [ST]) were defined using multilocus sequence typing and assigned to a clonal complex (a cluster of related strains that share four or more identical alleles with a previously defined central genotype). A previously undescribed clonal complex (ST-464) was identified which, together with ST-42, ST-45, and ST-52 complexes, showed increasing incidence. Concurrently, the incidence of ST-574, ST-607, and ST-658 complexes declined. The relative frequencies of three clonal complexes (ST-45, ST-283, and ST-42) peaked during summer and those of two (ST-353 and ST-403) peaked during winter. Nine clonal complexes (ST-22, ST-45, ST-48, ST-61, ST-257, ST-283, ST-403, ST-658, and ST-677) were significantly associated with ciprofloxacin sensitivity (P < 0.05). Seven clonal complexes (ST-49, ST-206, ST-354, ST-446, ST-460, ST-464, and ST-607) were associated with ciprofloxacin resistance (P < 0.05). Clonal complexes exhibited changing incidence and differences in seasonality and antibiotic resistance phenotype. These data also demonstrated that detailed surveillance at a single site captures information which reflects that observed nationally.


Fibronectins are essential for heart and blood vessel morphogenesis but are dispensable for initial specification of precursor cells.
The underlying mechanisms of lethal cardiovascular defects associated with the fibronectin-null (FN.null) mutation in mouse embryos were investigated by lineage analysis of myocardial, endocardial, and endothelial cells. A wide variation in phenotype was observed on two genetic backgrounds. In the less severe class (C57/BL6 background), FN.null embryos display a defective heart. Myocardial cells express the specific marker MF-20 and are correctly localized in the anterior trunk region, but myocardial organization is disrupted, resulting in a bulbous heart tube. Endocardial cells express the specific marker platelet-endothelial cell adhesion molecule-1 (PECAM-1) and are localized within the myocardium, but the endocardium appears collapsed. Endothelial cells of two vascular beds are specified, but the aortae are distended and lack contact with the surrounding mesenchyme, while no vessels form in the yolk sac. Defects in the more severe class suggest that FNs are essential earlier in development on the 129/Sv background. Myocardial and endocardial cells are specified, but morphogenesis of the myocardium and endocardium does not occur. Aortic endothelial cells are specified and localized normally, but remain scattered. Yolk sac endothelial cells resemble those of the less severe class. We conclude that FNs are essential for organization of heart and blood vessels, but are dispensable for cellular specification in the appropriate regions within the embryo.


Synthesis of the protected 6-16 segment of zervamicin 11-2, an application of the azirine/oxazolone method.
The protected 11 amino acid segment (6-16) of the peptaibol zervamicin II-2 was synthesized by using the 'azirine/oxazolone method' for the introduction of all Aib residues. Whereas a 2,2-dimethyl-2H-azirin-3-amine was used as the building block for Aib(7), methyl 2,2-dimethyl-2H-azirine-3-prolinate and -3-(3-hydroxyprolinate) proved to be ideally suited as dipeptide synthons for the introduction of Aib-Pro and Aib-Hyp, respectively. The coupling of Z-protected amino acids or peptide acids with the 2H-azirin-3-amines were performed in 75% to quantitative yield.


Prediction of infarct size and adverse cardiac outcomes by tissue tracking-cardiac magnetic resonance imaging in ST-segment elevation myocardial infarction.
We investigated whether quantification of global left ventricular (LV) strain by tissue tracking-CMR (TT-CMR) can estimate the infarct size and clinical outcomes in patients with acute myocardial infarction (MI). We retrospectively registered 247 consecutive patients (58 ± 12 years; male, 81%) who underwent 1.5-T CMR within 1 month after ST-segment elevation MI (median, 4 days; interquartile range, 3-6 days), and 20 age- and sex-matched controls (58 ± 11 years; male, 80%). TT-CMR analysis was applied to cine-images to measure global LV radial, circumferential and longitudinal peak strains (GRS, GCS and GLS, respectively). Adverse cardiac events were defined as cardiac death and hospitalization for heart failure. During the follow-up (median, 7.8 years), 20 patients (8.1%) experienced adverse events. LV myocardial deformation was significantly decreased in MI patients compared to controls and closely related to the infarct size. The GRS, GCS and GLS were all significant predictors of adverse cardiac events. In particular, a GLS > -14.1% was independently associated with a > 5-fold increased risk for adverse events, even after adjustment for the LV ejection fraction and infarct size. TT-CMR-derived LV strain is significantly related to the infarct size and adverse events. GLS measurement provides strong prognostic information in MI patients. • TT-CMR provides reliable quantification of LV strain in MI patients. • TT-CMR allows prediction of the infarct size and adverse events. • In particular, GLS by TT-CMR had independent prognostic value in MI patients.


The rehabilitation of children and adolescents with severe or medically complicated obesity: an ISPED expert opinion document.
Severe/medically complicated obesity in childhood, and particularly in adolescence, is a real disability that requires an intensive and continuous approach which should follow the procedures and schedule of rehabilitation medicine. Given the lack of a specific document focusing on children and adolescents, the Childhood Obesity Study Group set out to explore the available evidence for the treatment of severe or medically complicated obesity and to set standards tailored to the specific context of the Italian Health Service. Through a series of meetings and electronic communications, the writing committee (selected from members of the Study Group) selected the key issues, explored the literature and produced a draft document which was submitted to the other experts until the final synthesis was approved by the group. In brief, the following issues were involved: (1) definition and epidemiology; (2) identification of common goals designed to regain functional competence and limit the progression of metabolic and psychological complications; (3) a multi-professional team approach; (4) the care setting. This paper is an expert opinion document on the rehabilitation of severe and medically complicated obesity in children and adolescents produced by experts belonging to the Childhood Obesity Study Group of the Italian Society for Pediatric Endocrinology and Diabetology (ISPED).


Doubly resonant optical nanoantenna arrays for polarization resolved measurements of surface-enhanced Raman scattering.
We report that rhomb-shaped metal nanoantenna arrays support multiple plasmonic resonances, making them favorable bio-sensing substrates. Besides the two localized plasmonic dipole modes associated with the two principle axes of the rhombi, the sample supports an additional grating-induced surface plasmon polariton resonance. The plasmonic properties of all modes are carefully studied by far-field measurements together with numerical and analytical calculations. The sample is then applied to surface-enhanced Raman scattering measurements. It is shown to be highly efficient since two plasmonic resonances of the structure were simultaneously tuned to coincide with the excitation and the emission wavelength in the SERS experiment. The analysis is completed by measuring the impact of the polarization angle on the SERS signal.


Antigen interaction and heat inactivation expose new epitopes on human IgE.
It is well established that heat-denatured IgE is no longer capable of binding to FcepsilonRI. We have found an antibody that interacts with heat-denatured IgE. Interestingly, this antibody can also be used to detect some serum IgE, but not IgE synthesized de novo in vitro. However, native IgE can be transformed into an IgE that is recognized by this antibody, if antigen is added. Our data indicate that physiological mechanisms exist that biologically inactivate IgE which might still be mistaken for 'functional' IgE by assays based on polyclonal antibodies.


Transcriptomes analysis reveals novel insight into the molecular mechanisms of somatic embryogenesis in Hevea brasiliensis.
Somatic embryogenesis (SE) is a promising technology for plant vegetative propagation, which has an important role in tree breeding. Though rubber tree (Hevea brasiliensis Muell. Arg.) SE has been founded, few late SE-related genes have been identified and the molecular regulation mechanisms of late SE are still not well understood. In this study, the transcriptomes of embryogenic callus (EC), primary embryo (PE), cotyledonary embryo (CE), abnormal embryo (AE), mature cotyledonary embryo (MCE) and withered abnormal embryo (WAE) were analyzed. A total of 887,852,416 clean reads were generated, 85.92% of them were mapped to the rubber tree genome. The de novo assembly generated 36,937 unigenes. The differentially expressed genes (DEGs) were identified in the pairwise comparisons of CE vs. AE and MCE vs. WAE, respectively. The specific common DEGs were mainly involved in the phytohormones signaling pathway, biosynthesis of phenylpropanoid and starch and sucrose metabolism. Among them, hormone signal transduction related genes were significantly enriched, especially the auxin signaling factors (AUX-like1, GH3.1, SAUR32-like, IAA9-like, IAA14-like, IAA27-like, IAA28-like and ARF5-like). The transcription factors including WRKY40, WRKY70, MYBS3-like, MYB1R1-like, AIL6 and bHLH93-like were characterized as molecular markers for rubber tree late SE. CML13, CML36, CAM-7, SERK1 and LEAD-29-like were also related to rubber tree late SE. In addition, histone modification had crucial roles during rubber tree late SE. This study provides important information to elucidate the molecular regulation during rubber tree late SE.


Dependence of membrane potential on extracellular ionic concentrations in myotonic goats and rats.
Intracellular potassium concentration([K]i) and the resting sodium-to-potassium permeability ratio (alpha = PNa/PK) were determined by recording resting potentials at 25 degrees C in six solutions with variable potassium concentrations, constant [K+] + [Na+], and constant [K+] X [Cl-] product and fitting the results by nonlinear least squares to the Goldman-Hodgkin-Katz equation. Fits to models including chloride permeability terms suggest that chloride is in Donnan equilibrium in the muscles studied. External intercostal muscle was biopsied from anesthetized normal goats and goats with hereditary myotonia. In normal goat muscle, alpha was 0.012 +/- 0.001 (mean +/- SE, n = 11), and [K]i was 133 +/- 6 mM (n = 9); myotonic goat muscle did not differ from this. Extensor digitorum longus (EDL) muscle was removed from anesthetized male Wistar rats and from like rats pretreated with a single large dose of 20,25-diazacholesterol (DAC). In normal rat EDL, alpha was 0.019 +/- 0.002 (n = 12), and [K]i was 142 +/- 4 mM (n = 12). In the 16-day DAC-treated rats, alpha was significantly reduced (P < 0.002) to 0.010 +/- 0.002 (n = 8), and [K]i was slightly reduced by DAC. It is concluded that DAC reduced PNa in rat fibers. Tetrodotoxin at 5 microM did not affect either parameter in the rats.


Studies of the digestibility and retention of nitrogen and amino acids in rats fed raw or heated soy flour.
Apparent digestibility and absorption of nitrogen and amino acids from raw and heated soy flour were studied in rats. The apparent digestibility of all the amino acids from raw soybean was lower than from the heated flour. The net absorption was also significantly lower in the group fed raw soy flour for most of the amino acids, with the exception of cystine and methionine. The pattern of the amino acids along the digestive tract showed that while the levels of amino acids from heated soy flour started to decline in the jejunum and continued to decline in the ileum, in the group fed raw soy flour, the decline in levels of the amino acids did not begin until the ileum. The delay in the absorption might affect the overall absorption and utilization of the amino acids, and might explain the lower percentage retention of total nitrogen and amino acids in the carcasses of rats fed raw soy flour as compared with those fed heated soy flour. Possible reasons for the markedly lower cystine retention (relative to other amino acids) in the carcasses of the raw-soybean-fed rats are discussed.


Amide proton transfer magnetic resonance imaging in detecting intracranial hemorrhage at different stages: a comparative study with susceptibility weighted imaging.
Amide proton transfer (APT) imaging is a noninvasive molecular magnetic resonance imaging (MRI) technique based on the chemical exchange-dependent saturation transfer mechanism. The purpose of this study was to investigate the diagnostic performance of APT MRI in detecting intracranial hemorrhage (ICH) at hyperacute, acute and subacute stages by comparing with susceptibility weighted imaging (SWI). APT MRI and SWI were performed on 33 included patients with ICH by using a 3-T MRI unit. A two-sided Mann-Whitney U test was used to detect differences in APT-weighted (APTw) and SWI signal intensities of ICH at hyperacute, acute and subacute stages. Receiver operating characteristic analysis was used to assess the diagnostic utilities of APT MRI and SWI. Our results showed that APT MRI could detect ICH at hyperacute, acute and subacute stages. Therefore, APTw signal intensity may serve as a reliable, noninvasive imaging biomarker for detecting ICH at hyperacute, acute and subacute stages. Moreover, APT MRI could provide additional information for the ICH compared with SWI.


In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery.
Leber congenital amaurosis (LCA) is a severe disorder resulting in visual impairment usually starting in the first year of life. The most frequent genetic cause of LCA is an intronic mutation in CEP290 (c.2991 + 1655A > G) that creates a cryptic splice donor site resulting in the insertion of a pseudoexon (exon X) into CEP290 mRNA. Previously, we showed that naked antisense oligonucleotides (AONs) effectively restored normal CEP290 splicing in patient-derived lymphoblastoid cells. We here explore the therapeutic potential of naked and adeno-associated virus (AAV)-packaged AONs in vitro and in vivo In both cases, AON delivery fully restored CEP290 pre-mRNA splicing, significantly increased CEP290 protein levels and rescued a ciliary phenotype present in patient-derived fibroblast cells. Moreover, administration of naked and AAV-packaged AONs to the retina of a humanized mutant Cep290 mouse model, carrying the intronic mutation, showed a statistically significant reduction of exon X-containing Cep290 transcripts, without compromising the retinal structure. Together, our data highlight the tremendous therapeutic prospective of AONs for the treatment of not only CEP290-associated LCA but potentially many other subtypes of retinal dystrophy caused by splicing mutations.


Bone-conduction force values for the sensorineural acuity level (SAL) test.
The sensorineural acuity level (SAL) test has the advantages of eliminating the questions of when to mask and how much masking to use in audiometry, greater efficiency in assessing cochlear sensitivity than conventional bone-conduction (bc) testing, and fewer and less serious errors in measuring cochlear sensitivity. However, a major limitation of the SAL test is that norms are generally determined using the time-consuming real-ear calibration method. A more satisfactory procedure is to establish normative force levels using an artificial mastoid. Normal-hearing young adults (N:18) were tested with pure tones and with spondees, in the presence of bc white noise delivered to a Radioear B-70-AA vibrator and calibrated with a Bruel & Kjaer 4930 artificial mastoid. Force levels in db re 1 mu Newton found to produce a 30-db HTL in bc white noise were: 104, 94, 94, 94, and 100 for tones of .5, 1, 2, and 4 kc/s, and for spondees, in that order. Force levels for narrow bands of noise centered at .5, 1, 2, and 4 kc/s were 104, 84, 76, and 86 db in that order. Clinicians are cautioned to use these force values with reservation unless their bone vibrator, artificial mastoid, and noise spectra are similar to those used in the present study. If clinics choose to obtain their own baseline data, artificial mastoid measures can still serve as a convenient reference to monitor equipment stability. The use of the SAL is urged as part of a test battery for assessing the presence and degree of conductive pathology.


Usefulness of prolonged P-wave duration on signal averaged ECG in predicting atrial fibrillation in acute myocardial infarction patients.
Atrial fibrillation (AF) is a frequent complication of acute myocardial infarction (AMI), with a reported incidence of 7-18%. The incidence of congestive heart failure, in-hospital mortality, and long-term mortality is higher in AMI patients with AF than in those without. P-wave duration (PWD) on Signal-Averaged ECG is a non-invasive marker of intra-atrial conduction disturbances, which are believed to be the main electrophysiological cause of AF. In the present study we investigated whether PWD can predict development of AF in 130 AMI patients (100 men and 30 women, aged 56.9+/-12). PWD was recorded, along with clinical and hemodynamic characteristics. During the observation period (up to 21 days) 22 patients (16.9%) developed AF. In univariate analysis the variables associated with development of AF were age>65, Killip class III-IV, and PWD>125 ms. Stepwise logistic regression analysis showed that age>65 and PWD>125 ms were independently associated with AF. PWD measured in a very early period of AMI is a useful tool in predicting AF.


Judgement of risk in traumatized and nontraumatized emergency medical service personnel.
This study investigated the hypothesis that posttraumatic stress is associated with a judgement of risk bias, defined as an overestimation of the likelihood of the occurrence of adverse events, as proposed by information-processing theories of posttraumatic stress disorder. Emergency medical service personnel with high PTSD symptomatology (n =27) and without PTSD symptoms (n = 74) completed the PTSD Symptom Scale: Self-report version, the Work Experiences Questionnaire, the Beck Depression Inventory, and an Event Probability Questionnaire. Analysis showed that individuals with high PTSD symptomatology exhibited significantly more judgement of risk bias, that this cognitive bias was towards a wider range of threats than those involving only the threat of external harm, and that intrusion was its best predictor.


Prevalence and incidence of symptomatic pulmonary tuberculosis based on repeated population screening in a district in Ethiopia: a prospective cohort study.
In Ethiopia, one-third of the estimated tuberculosis cases are not detected or reported. Incidence estimates are inaccurate and rarely measured directly. Assessing the 'real' incidence under programme conditions is useful to understand the situation. This study aimed to measure the prevalence and incidence of symptomatic pulmonary tuberculosis (PTB) during 1 year in the adult population of Dale in Ethiopia. A prospective population-based cohort study. Every household in Dale was visited three times at 4-month intervals. Individuals aged ≥15 years. Microscopy smear positive PTB (PTB s+), bacteriologically confirmed PTB (PTB b+) by microscopy, GeneXpert, or culture and clinically diagnosed PTB (PTB c+). Among 136 181 individuals, 2052 had presumptive TB (persistent cough for 14 days or more with or without haemoptysis, weight loss, fever, night sweats, chest pain or difficulty breathing), in the first round of household visits including 93 with PTB s+, 98 with PTB b+ and 24 with PTB c+; adding those with PTB who were already on treatment, the total number of PTB was 201, and the prevalence was 147 (95% CI: 127 to 168)/100 000 population. Out of all patients with PTB, the proportion detected by symptom screening was in PTB s+ 65%, PTB b+ 67% and PTB c+44%. During 96 388 person-years follow-up, 1909 had presumptive TB, 320 had PTB and the total incidence of PTB was 332 (95% CI: 297 to 370)/100 000 person-years, while the incidence of PTB s+, PTB b+ and PTB c+ was 230 (95% CI: 201 to 262), 263 (95% CI: 232 to 297) and 68 (95% CI: 53 to 86)/100 000 person-years, respectively. The prevalence of symptomatic sputum smear-positive TB was still high, only one-third of prevalent PTB cases notified and the incidence rate highest in the age group 25-34 years, indicating ongoing transmission. Finding missing people with TB through repeated symptom screening can contribute to reducing transmission.


Thiamine Assays-Advances, Challenges, and Caveats.
Thiamine (vitamin B1) is essential to the health of all living organisms and deficiency has long been associated with diseases in animals such as fish, birds, alligators, and domesticated ruminant mammals. Thiamine is also implicated in several human diseases including Alzheimer's, diabetes, dementia, depression and, most notably, Wernicke-Korsakoff syndrome and Beriberi disease. Yet, highly sensitive and specific detection of thiamine remains an analytical challenge, as pM to nm levels of thiamine need to be detected in environmental and human samples, respectively, various phosphorylated variants need to be discriminated, and rapid on-site detection would be highly desirable. Furthermore, appropriate sample preparation is mandatory, owing to the complexity of the relevant sample matrices including fish tissues, ocean water, and body fluids. This Review has two objectives. First, it provides a thorough overview of analytical techniques published for thiamine detection over the last 15 years. Second, it describes the principles of analytical approaches that are based on biorecognition and may open up new avenues for rapid and high-throughput thiamine analysis. Most notably, periplasmic binding proteins, ribozymes, and aptamers are of particular interest, as they function as bioaffinity recognition elements that can fill an important assay technology gap, owing to the unavailability of thiamine-specific commercial antibodies. Finally, the authors provide brief evaluations of key outcomes of the major assay concepts and suggest how innovative techniques could help develop sensitive and specific thiamine analytical test systems.


Prolong the flushing and locking interval of TIVAD is feasible in COVID-19: An overview of systematic reviews.
The aim of the overview was to synthesize existing systematic reviews (SRs) of flushing interval for patients who inserted totally implanted venous catheter devices (TIVAD). Regular flushing is indispensable for catheter patency, the recommended flushing interval of TIVAD is 4 weeks, however, there is an argument for prolonging the maintenance interval, which has been proved by many SRs. However, the flushing interval range from 4-week to 3-month. The discrepancy in maintenance period could puzzle health professionals and hinder best practice into the clinic. So, we performed the overview by following the PRISMA statement. The PubMed, Ovid, Wan Fang database, Web of Science, CINAHL, CNKI, EMBASE, Cochrane Library were searched from inception to November 2021. The AMSTAR-2, the PRISMA statement, and ROBIS tool were used to assess SRs' method, report quality, and risk of bias, respectively. Then all results were synthesized, the quality of SRs' results was evaluated with GRADE. Finally, five SRs were included. However, non-randomized and small sample size of original studies result in the limitation of SRs. The evidence grade of conclusions is low, bias of mixed factors in included studies, further large sample sizes, RCTs need to be conducted in the future. Prolonged flushing interval was feasible based on the recent evidence, especially during the COVID-19 pandemic because the overwhelming healthcare system and inconvenience of transportation made maintenance not as easy as it used to be. There is no difference of complication between prolonged flushing interval (⩾4-week) and 4-week period, and it can also reduce healthcare cost with no harm to patients.


Paleoceanographic events and deep-sea ostracodes.
Eight recognized or theorized paleoceanographic events during the past 70 million years were tested against changes in the global deep-sea benthic ostracode fauna. Two events, the sudden Cretaceous-Tertiary boundary event at 66 million years ago and the more gradual 40-million-year event (formation of the psychrosphere), show up most dramatically. Before the 40-million-year event, ostracodes freely radiated into the deeper water regions but were provincial. The development of thermal stratification isolated these deep-water taxa, mostly the survivors of the Cretaceous-Tertiary boundary event, which adapted to a new, free-flowing but more frigid ecosystem and spread rapidly throughout the world.


Hepatic interferon-stimulated genes are differentially regulated in the liver of chronic hepatitis C patients with different interleukin-28B genotypes.
Pretreatment up-regulation of hepatic interferon (IFN)-stimulated genes (ISGs) has a stronger association with the treatment-resistant interleukin (IL)28B minor genotype (MI; TG/GG at rs8099917) than with the treatment-sensitive IL28B major genotype (MA; TT at rs8099917). We compared the expression of ISGs in the liver and blood of 146 patients with chronic hepatitis C who received pegylated IFN and ribavirin combination therapy. Gene expression profiles in the liver and blood of 85 patients were analyzed using an Affymetrix GeneChip (Affymetrix, Santa Clara, CA). ISG expression was correlated between the liver and blood of the MA patients, whereas no correlation was observed in the MI patients. This loss of correlation was the result of the impaired infiltration of immune cells into the liver lobules of MI patients, as demonstrated by regional gene expression analysis in liver lobules and portal areas using laser capture microdissection and immunohistochemical staining. Despite having lower levels of immune cells, hepatic ISGs were up-regulated in the liver of MI patients and they were found to be regulated by multiple factors, namely, IL28A/B, IFN-λ4, and wingless-related MMTV integration site 5A (WNT5A). Interestingly, WNT5A induced the expression of ISGs, but also increased hepatitis C virus replication by inducing the expression of the stress granule protein, GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1), in the Huh-7 cell line. In the liver, the expression of WNT5A and its receptor, frizzled family receptor 5, was significantly correlated with G3BP1. Immune cells were lost and induced the expression of other inflammatory mediators, such as WNT5A, in the liver of IL28B minor genotype patients. This might be related to the high level of hepatic ISG expression in these patients and the treatment-resistant phenotype of the IL28B minor genotype.


Serum thyroxine concentrations after radioactive iodine therapy in cats with hyperthyroidism.
Thirty-one cats with hyperthyroidism were given one dose of radioactive iodine (131I) IV. Serum thyroxine (T4) concentrations were measured before treatment in all cats, at 12-hour intervals after treatment in 10 cats, and at 48-hour intervals after treatment in 21 cats. Serum T4 concentrations also were measured one month after 131I therapy in 29 cats. Activity of 131I administered was 1.5 to 6.13 mCi, resulting in a dose of 20,000 rads to the thyroid. Serum T4 concentrations before 131I administration were 5.3 to 51.0 micrograms/dl, with a median T4 concentration of 11.0 micrograms/dl. Serum T4 decreased most rapidly during the first 3 to 6 days after treatment. Sixteen cats (55%) had normal serum thyroxine concentrations by day 4 after 131I administration, and 23 cats (74%) were euthyroxinemic by day 8 after treatment. One month after administration of 131I, the 29 cats evaluated were clinically improved, and 24 (83%) of the 29 cats evaluated had normal serum T4 concentrations, 3 cats (10%) remained hyperthyroxinemic, and 2 cats (7%) were hypothyroxinemic. Therefore, administration of 131I was a safe and effective method to quickly decrease serum T4 concentrations in hyperthyroid cats.


Preliminary experience with the enterprise stent for endovascular treatment of complex intracranial aneurysms: potential advantages and limiting characteristics.
Stent-assisted coiling is an accepted endovascular treatment (EVT) for complex intracranial aneurysms. The Enterprise self-expandable stent (Cordis, Miami Lakes, FL) is a new retractable stent that is delivered via a conventional coiling catheter to potentially circumvent the limitations of other stents. The aim of this study was to evaluate the use of this stent for EVT of complex aneurysms. Between January and May 2007, 14 patients with 15 unruptured wide-necked or fusiform aneurysms were treated. EVT consisted of stent placement and subsequent endosaccular coiling. Clinical outcome was assessed with the modified Glasgow Outcome Scale. EVT was successfully performed and led to an excellent outcome in all patients. The stent was easily navigated and precisely positioned in all cases. However, the stent's visibility was poor once it was delivered. Moreover, procedural complications occurred in three patients, including stent migration (n = 1) and coil protrusion between the stent and the vessel wall (n = 2). In these latter two cases, a remodeling balloon was required to assist in delivery of the coils. No clinical incidence of complications was observed when the parent artery had a diameter of more than 4 mm. Angiographic results consisted of eight complete occlusions, four neck remnants, and three incomplete occlusions. The Enterprise stent is very useful for EVT of complex intracranial aneurysms because it is easy to navigate and place precisely. However, the currently available stent has two relatively limiting characteristics: 1) it has poor visibility, and 2) it should only be used for aneurysms located on a parent artery with a maximal diameter of 4 mm.


Uptake of a web-based oncology protocol system: how do cancer clinicians use eviQ cancer treatments online?
The use of computerized systems to support evidence-based practice is commonplace in contemporary medicine. Despite the prolific use of electronic support systems there has been relatively little research on the uptake of web-based systems in the oncology setting. Our objective was to examine the uptake of a web-based oncology protocol system (http://www.eviq.org.au) by Australian cancer clinicians. We used web-logfiles and Google Analytics to examine the characteristics of eviQ registrants from October 2009-December 2011 and patterns of use by cancer clinicians during a typical month. As of December 2011, there were 16,037 registrants; 85% of whom were Australian health care professionals. During a typical month 87% of webhits occurred in standard clinical hours (08:00 to 18:00 weekdays). Raw webhits were proportional to the size of clinician groups: nurses (47% of Australian registrants), followed by doctors (20%), and pharmacists (14%). However, pharmacists had up to three times the webhit rate of other clinical groups. Clinicians spent five times longer viewing chemotherapy protocol pages than other content and the protocols viewed reflect the most common cancers: lung, breast and colorectal. Our results demonstrate eviQ is used by a range of health professionals involved in cancer treatment at the point-of-care. Continued monitoring of electronic decision support systems is vital to understanding how they are used in clinical practice and their impact on processes of care and patient outcomes.


Apocynum venetum leaf extract, an antihypertensive herb, inhibits rat aortic contraction induced by angiotensin II: a nitric oxide and superoxide connection.
The leaves extract of Apocynum venetum (AVLE), also known as "luobuma", have long been used in traditional Chinese medicine to treat hypertension and depression in parts of China and it has been shown to possess anti-oxidant and anti-lipid peroxidation effects. AVLE (10 μg/ml) has been reported to have a long-lasting endothelium-dependent relaxant effect and this effect has been proposed to be due to its nitric oxide(NO)-releasing and superoxide anion(SOA)-scavenging properties. The present study seeks to evaluate the differential actions of AVLE extract between Ang II- and PE-induced vasoconstriction and the involvement of superoxide anions. Single dose of Ang II (100 nM and 1 nM)- or PE (0.1 μM)-induced contraction were assessed in both endothelium-intact and -denuded aortic rings after pre-incubation of AVLE (10 μg/ml) for 15 min. The experiment was repeated in either the presence of NO synthase inhibitor, L-NAME (300 μM) or selective AT(1) receptor inhibitor, losartan (0.1 nM), or superoxide scavenger, tiron (1 mM) or a combination of L-NAME and AVLE. Superoxide production was measured by using enhanced-chemiluminescence assay. We have demonstrated that AVLE (10 μg/ml) effectively suppressed the Ang II-induced contraction (100 nM and 1 nM) of both endothelium-intact and -denuded rat aortic rings. In endothelium-intact rings, L-NAME, reversed AVLE-induced inhibition of Ang II-contraction. PE-induced contraction was significantly inhibited by AVLE in endothelium-intact rings, but not in endothelium-denuded rings. The inhibition by AVLE of PE-induced contraction was totally abolished in the presence of L-NAME. Ang II-induced SOA production concentration dependently with the optimal effect seen at 100 nM of Ang II, and AVLE (0.3, 1, 10 μg/ml) reduced this effect. SOA production in Ang II-stimulated rings was significantly higher than unstimulated control rings, while PE did not stimulate SOA production at all. SOA formation in the presence of Ang II was also inhibited in the presence of SOD (superoxide scavenger), DPI (NADPH inhibitor) and losartan (specific AT(1) receptor antagonist). These results collectively suggest that the ability of AVLE in inhibiting Ang II-induced contraction via its SOA scavenging properties and nitric oxide releasing effect may account for its usage as an antihypertensive treatment in traditional folk medicine.


[Examination of tear film by specular microscopy (author's transl)].
The examination of tear film by specular microscopy enables various phenomena to be observed in normal and irritated eyes. In cases of dry eye syndrome some differentiations are possible.


Differential induction of apoptosis in Swiss 3T3 cells by nitric oxide and the nitrosonium cation.
We have investigated the effect of nitric oxide (NO) on apoptosis in Swiss 3T3 fibroblasts and compared it to the effect of the nitrosonium cation (NO+). Both species induced apoptosis, confirmed by electron microscopy, propidium iodide staining, DNA laddering and activation of caspases. The kinetics of triggering apoptosis were different for the two redox species: NO+ required only a 2 hour exposure, whereas NO required 24 hours. Three sources of NO were used: aqueous solutions of NO and two NO donors, S-nitrosoglutathione and S-nitroso-N-acetylpenicillamine. The time course of apoptosis induced by these two S-nitrosothiols correlated with their rate of decomposition to NO. The apoptotic effect of NO was reduced in the presence of the NO scavenger oxyhaemoglobin, or the antioxidants N-acetylcysteine and ascorbic acid, whereas in the case of NO+ these antioxidants potentiated apoptosis. Glutathione also had a potentiating effect on the cytotoxicity of NO+. This suggests that cellular antioxidants may play a role in protecting the cell from NO-induced apoptosis while NO+ may trigger apoptosis independently of oxidative stress mechanisms.


Progesterone improves the maturation of male-induced preovulatory follicles in anoestrous ewes.
The first ovulation induced by male effect in sheep during seasonal anoestrus usually results in the development of a short cycle that can be avoided by progesterone priming before ram introduction. In elucidating the involvement of the hypothalamic-pituitary-gonadal axis in the occurrence of short cycles, the effects of progesterone and the time of anoestrus on the development of male-induced preovulatory follicles were investigated in anoestrous ewes using morphological, endocrine and molecular approaches. Ewes were primed with progesterone for 2 (CIDR2) or 12 days (CIDR12) and untreated ewes used as controls during early (April) and late (June) anoestrus. The duration of follicular growth and the lifespan of the male-induced preovulatory follicles were prolonged by ∼1.6 days in CIDR12 ewes compared with the controls. These changes were accompanied by a delay in the preovulatory LH and FSH surges and ovulation. Intra-follicular oestradiol concentration and mRNA levels of LHCGR and STAR in the granulosa and theca cells of the preovulatory follicles were higher in CIDR12 ewes than the control ewes. The expression of mRNA levels of CYP11A1 and CYP17A1 also increased in theca cells of CIDR12 ewes. CIDR2 ewes gave intermediate results. Moreover, ewes ovulated earlier in June than in April, without changes in the duration of follicular growth, but these effects were unrelated to the lifespan of corpus luteum. Our results give the first evidence supporting the positive effect of progesterone priming on the completion of growth and maturation of preovulatory follicles induced by male effect in seasonal anoestrous ewes, thereby preventing short cycles.


Ilyobacter insuetus sp. nov., a fermentative bacterium specialized in the degradation of hydroaromatic compounds.
The mesophilic, anaerobic bacterium strain VenChi2T was isolated with quinic acid (1,3,4,5-tetrahydroxy-cyclohexane-1-carboxylic acid) as the sole source of carbon and energy. Of more than 30 substrates tested, only quinic acid and shikimic acid (3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid) were utilized, yielding acetate, propionate, butyrate, H2 and CO2 as fermentation products. Sugars, alcohols, (di-)carboxylic acids, amino acids and aromatic compounds were not fermented and no external electron acceptors were used. Strain VenChi2T is a gram-negative, strictly anaerobic, coccoid rod; it does not employ the classical hydroaromatic pathway of aerobic bacteria for the degradation of hydroaromatic compounds (no aromatic intermediates involved). Comparative 16S and 23S rDNA sequence analyses placed strain VenChi2T in the fusobacteria phylum, with the closest relatives among species of the genera Ilyobacter and Propionigenium. The results indicate that, disregarding the taxonomically misplaced Ilyobacter delafieldii, which is a member of the clostridia, the validly described Ilyobacter and Propionigenium species are phylogenetically intermixed. Based on its phenotypic properties, strain VenChi2T (= DSM 6831T = ATCC BAA-291T) is assigned to the genus Ilyobacter as the type strain of a novel species, Ilyobacter insuetus sp. nov.


VHL-TGFBI signaling is involved in the synergy between 5-aza-2'-deoxycytidine and paclitaxel against human renal cell carcinoma.
To analyse the role of von Hippel-Lindau (VHL) and transforming growth factor β-induced (TGFBI) in synergistic mechanisms of 5-aza-2'-deoxycytidine (DAC) and paclitaxel (PTX) against renal cell carcinoma (RCC). To elucidate the role in the synergy between DAC and PTX against RCC cells, TGFBI expression was regulated using siRNA technology and an expression vector containing the full-length cDNA for TGFBI was also transfected into RCC cells. The proliferation of RCC cells was evaluated using the WST-1 assay and TGFBI expression was detected by real-time PCR (RT-PCR), and Western blot. The results indicated that the expression of TGFBI was significantly decreased by DAC or PTX alone in vitro and in vivo. Moreover, the combination of DAC and PTX caused a synergistic decrease in the expression of TGFBI in RCC cells. We also investigated the effect of VHL-TGFBI signaling on the synergy between DAC and PTX, although the synergy between the two medications was not abolished by interfering with VHL activity or TGFBI expression. RCC cells without VHL activity and RCC cells expressing high levels of TGFBI displayed an increased synergistic effect compared to control cells. Our study suggests that VHL-TGFBI signaling is involved in the synergy between DAC and PTX against RCC cells. In addition, the synergy between DAC and PTX is more effective in VHL inactive RCC cells.


Breed differences in return to estrus after PGF2 alpha-induced abortions in swine.
Fifty-seven Duroc, 41 Landrace and 38 Yorkshire purebred sows in d 10 to 53 of pregnancy were aborted to synchronize estrus by using prostaglandin F2 alpha (PGF2 alpha). Breed differences in time between injection of two 10-mg doses of PGF2 alpha and return to estrus were observed in these three breeds of pregnant sows during two breeding seasons. Duroc sows returned to estrus .9 d faster (P less than .01) than Yorkshire and 1.3 d faster (P less than .01) than Landrace sows. Seasonal differences were also observed. The mean days from injection to estrus were 1.8 d fewer (P less than .01) for the spring season than in the fall season. All sows expressed estrus 5 to 11 d after injection. Normal gestation, parturition and piglet survival were observed in the sows after the treatment. Genetic differences in response to induced abortion and return to estrus could have implications in planned breeding and farrowing systems.


Clinical Applications of Cerebrospinal Fluid Circulating Tumor DNA as a Liquid Biopsy for Central Nervous System Tumors.
Central nervous system (CNS) malignancies are associated with poor prognosis, as well as exceptional morbidity and mortality, likely as a result of low rates of early diagnosis and limited knowledge of the tumor growth and resistance mechanisms, dissemination, and evolution in the CNS. Monitoring patients with CNS malignancies for treatment response and tumor recurrence can be challenging because of the difficulty and risks of brain biopsies and the low specificity and sensitivity of the less invasive methodologies that are currently available. Therefore, there is an urgent need to detect and validate reliable and minimally invasive biomarkers for CNS tumors that can be used separately or in combination with current clinical practices. The circulating tumor DNA (ctDNA) of cerebrospinal fluid (CSF) samples can outline the genetic landscape of entire CNS tumors effectively and is a promising, suitable biomarker, though its role in managing CNS malignancies has not been studied extensively. This review summarizes recent studies that explore the diagnostic, prognostic, and predictive roles of CSF-ctDNA as a liquid biopsy with primary and metastatic CNS malignancies.


Deficiency of the effector mechanisms of the immune response and autoimmunity.
It has long been the conventional wisdom that most autoimmune responses represent a pathological aberration of the immune system and a great deal of effort has been devoted to investigating how such abnormal responses may be induced. It seems likely, however, particularly in the form of autoimmunity seen in diseases like systemic lupus erythematosus (LE) and associated with immune complex disease, that it is not the induction of the autoimmune response that is primarily abnormal, but its persistence, and that this abnormal persistence is a consequence of a failure of the proper functioning of the effector mechanisms of the immune response. The strongest reason for so believing is the striking incidence of these diseases in subjects with deficiencies of the early components of the classical complement pathway. Total, homozygous deficiencies are rare and account for only a small proportion of patients with systemic LE. However, partial, heterozygous deficiency of these components is much commoner and also carries an increased susceptibility to these diseases. An explanation for this association is given. In the presence of an adequately functioning complement system immune complexes remain soluble and of relatively small size. It is proposed that this is a result of the incorporation of C4 and C3 into the antigen-antibody lattice leading to a reduction in the effective valency of antigen and antibody. The Goldberg theory of immune precipitation predicts that a reduction in valency would inhibit precipitation and the formation of large complexes. In the absence of adequate complement function this mechanism will fail and large, potentially insoluble complexes with little C4 and C3 on them will be formed. These large immune complexes without sufficient C4 and C3 bound on them will also not be bound normally to erythrocyte CR1 and will therefore be transported in the (peripheral) plasma stream rather than in the (central) erythrocyte stream. It is proposed that this will result in the deposition of immune complexes in peripheral small blood vessels rather than in the sinusoids of the liver and spleen; and that this peripheral deposition gives rise to inflammation, with the release of autoantigens and the formation of further autoantibodies. The importance of CR1 in relation to these diseases is emphasized by the reduction in CR1 numbers that accompanies their active phase. This appears to be due to proteolysis of the receptor while the immune complex-bearing erythrocyte is sequestered in the reticuloendothelial system.


Murine cerebral malaria is associated with a vasospasm-like microcirculatory dysfunction, and survival upon rescue treatment is markedly increased by nimodipine.
Brain hemodynamics in cerebral malaria (CM) is poorly understood, with apparently conflicting data showing microcirculatory hypoperfusion and normal or even increased blood flow in large arteries. Using intravital microscopy to assess the pial microvasculature through a closed cranial window in the murine model of CM by Plasmodium berghei ANKA, we show that murine CM is associated with marked decreases (mean: 60%) of pial arteriolar blood flow attributable to vasoconstriction and decreased blood velocity. Leukocyte sequestration further decreased perfusion by narrowing luminal diameters in the affected vessels and blocking capillaries. Remarkably, vascular collapse at various degrees was observed in 44% of mice with CM, which also presented more severe vasoconstriction. Coadministration of artemether and nimodipine, a calcium channel blocker used to treat postsubarachnoid hemorrhage vasospasm, to mice presenting CM markedly increased survival compared with artemether plus vehicle only. Administration of nimodipine induced vasodilation and increased pial blood flow. We conclude that vasoconstriction and vascular collapse play a role in murine CM pathogenesis and nimodipine holds potential as adjunctive therapy for CM.


Assessing impact of differential symptom functioning on post-traumatic stress disorder (PTSD) diagnosis.
This article explores the generalizability of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for post-traumatic stress disorder (PTSD) to various subpopulations. Besides identifying the differential symptom functioning (also referred to as differential item functioning [DIF]) related to various background variables such as gender, marital status and educational level, this study emphasizes the importance of evaluating the impact of DIF on population inferences as made in health surveys and clinical trials, and on the diagnosis of individual patients. Using a sample from the National Comorbidity Study-Replication (NCS-R), four symptoms for gender, one symptom for marital status, and three symptoms for educational level were significantly flagged as DIF, but their impact on diagnosis was fairly small. We conclude that the DSM-IV diagnostic criteria for PTSD do not produce substantially biased results in the investigated subpopulations, and there should be few reservations regarding their use. Further, although the impact of DIF (i.e. the influence of differential symptom functioning on diagnostic results) was found to be quite small in the current study, we recommend that diagnosticians always perform a DIF analysis of various subpopulations using the methodology presented here to ensure the diagnostic criteria is valid in their own studies.


Phenotypic Variation in Mitochondria-Related Performance Traits Across New Zealand Snail Populations.
Mitochondrial function is critical for energy homeostasis and should shape how genetic variation in metabolism is transmitted through levels of biological organization to generate stability in organismal performance. Mitochondrial function is encoded by genes in two distinct and separately inherited genomes-the mitochondrial genome and the nuclear genome-and selection is expected to maintain functional mito-nuclear interactions. The documented high levels of polymorphism in genes involved in these mito-nuclear interactions and wide variation for mitochondrial function demands an explanation for how and why variability in such a fundamental trait is maintained. Potamopyrgus antipodarum is a New Zealand freshwater snail with coexisting sexual and asexual individuals and, accordingly, contrasting systems of separate vs. co-inheritance of nuclear and mitochondrial genomes. As such, this snail provides a powerful means to dissect the evolutionary and functional consequences of mito-nuclear variation. The lakes inhabited by P. antipodarum span wide environmental gradients, with substantial across-lake genetic structure and mito-nuclear discordance. This situation allows us to use comparisons across reproductive modes and lakes to partition variation in cellular respiration across genetic and environmental axes. Here, we integrated cellular, physiological, and behavioral approaches to quantify variation in mitochondrial function across a diverse set of wild P. antipodarum lineages. We found extensive across-lake variation in organismal oxygen consumption and behavioral response to heat stress and differences across sexes in mitochondrial membrane potential but few global effects of reproductive mode. Taken together, our data set the stage for applying this important model system for sexual reproduction and polyploidy to dissecting the complex relationships between mito-nuclear variation, performance, plasticity, and fitness in natural populations.


Statistical transformation and the interpretation of inpatient glucose control data from the intensive care unit.
Glucose control can be problematic in critically ill patients. We evaluated the impact of statistical transformation on interpretation of intensive care unit inpatient glucose control data. Point-of-care blood glucose (POC-BG) data derived from patients in the intensive care unit for 2011 was obtained. Box-Cox transformation of POC-BG measurements was performed, and distribution of data was determined before and after transformation. Different data subsets were used to establish statistical upper and lower control limits. Exponentially weighted moving average (EWMA) control charts constructed from April, October, and November data determined whether out-of-control events could be identified differently in transformed versus nontransformed data. A total of 8679 POC-BG values were analyzed. POC-BG distributions in nontransformed data were skewed but approached normality after transformation. EWMA control charts revealed differences in projected detection of out-of-control events. In April, an out-of-control process resulting in the lower control limit being exceeded was identified at sample 116 in nontransformed data but not in transformed data. October transformed data detected an out-of-control process exceeding the upper control limit at sample 27 that was not detected in nontransformed data. Nontransformed November results remained in control, but transformation identified an out-of-control event less than 10 samples into the observation period. Using statistical methods to assess population-based glucose control in the intensive care unit could alter conclusions about the effectiveness of care processes for managing hyperglycemia. Further study is required to determine whether transformed versus nontransformed data change clinical decisions about the interpretation of care or intervention results.


EEG topography recognition by neural networks.
Electroencephalography (EEG) pattern-recognition studies were carried out using EEG topography (readiness potential, or RP, spatiotemporal patterns) generated the moment before voluntary movements of muscles. RPs generated prior to pronouncing syllables and controlling a joystick were studied by experiments and simulation. The spatiotemporal patterns of RPs were measured by multichannel surface electrodes pasted on the subject's scalp. Backpropagation neural networks were used for RP pattern recognition. The results show that RPs generated prior to syllable pronouncement contain some information about those syllables, and that RPs generated prior to joy stick movements contain information on the direction of intended movement. They also show that neural networks can be used to recognize EEG information and so create a new type of man-machine interface for data input.


Design and characterization of a diode-pumped, single longitudinal and transverse mode, intracavity-doubled cw Nd:YAG laser.
We report on the experimental results of a diode-pumped, intracavity-doubled cw Nd:YAG laser, pumped by a 10-W fiber-coupled semiconductor laser at 808 nm and emitting as much as 600 mW in a stable single longitudinal mode and TEM(00) spatial mode. We discuss the main issues of the resonator design and the optimization of the intracavity second harmonic conversion by interpreting our results using simple models. Improvements for the current project are also discussed.


Minimally invasive procedure of acute acromioclavicular joint dislocation: one suture-button device versus two suture-button devices.
The purpose of this study was to assess the clinical results of patients treated with either one suture-button device or two suture-button devices for acute acromioclavicular (AC) joint dislocations. Eighty patients were randomized to operative stabilization either by one suture-button device (OSB, 40) or by two suture-button devices (TSB, 40). Postoperative complications, the Constant, VAS and SST scores, patient subjective satisfaction result were reviewed. The total incidence of complications was similar in both groups (16/40 vs. 17/40, P =0 .820). There were no significant differences in the length of hospitalization, the Constant, VAS and SST scores, and the ability to return to previous work between the two groups. However, the patients of TSB group had longer incision length, more blood loss, more operative and radiation time and more hospitalization costs (P < 0.01). The radiological evaluation showed no significant difference in the CC distance between the two groups (P = 0.557). Our results indicated that one suture-button device could achieve the same good radiological and clinical results as two suture-button devices did.


Melanocytes in conditional Rb-/- mice are normal in vivo but exhibit proliferation and pigmentation defects in vitro.
The function of the retinoblastoma tumour suppressor (Rb1), and the pocket protein family in general, has been implicated as an important focal point for deregulation in many of the molecular pathways mutated in melanoma. We have focused on the role of Rb1 in mouse melanocyte homeostasis using gene targeting and Cre/loxP mediated tissue-specific deletion. We show that constitutive Cre-mediated ablation of Rb1 exon 2 prevents the production of Rb1 and recapitulates the phenotype encountered in other Rb1 knockout mouse models. Mice with conditional melanocyte-specific ablation of Rb1 manifest overtly normal pigmentation and are bereft of melanocytic hyperproliferative defects or apoptosis-induced depigmentation. Histologically, these mice have melanocyte morphology and distribution comparable with control littermates. In contrast, Rb1-null melanocytes removed from their in vivo micro-environment and cultured in vitro display some of the characteristics associated with a transformed phenotype. They proliferate at a heightened rate when compared with control melanocytes and have a decreased requirement for mitogens. With progressive culture the cells depigment at relatively early passage and display a gross morphology which, whilst reminiscent of early passage melanocytes, is generally different to equivalent passage control cells. These results indicate that Rb1 is dispensable for in vivo melanocyte homeostasis when its ablation is targeted from the melanoblast stage onwards, however, when cultured in vitro, Rb1 loss increases melanocyte growth but the cells are not fully transformed.


Prevalence, Safety and Long-Term Retention Rates of Biologics in Hong Kong from 2001 to 2015.
Biologic agents were initially introduced as treatment for rheumatoid arthritis (RA) but have since been used for other medical conditions. As new biologics become increasingly widespread in treatment regimens, it is important to understand their safety and utilization in the post-marketing context. The aim of this study was to investigate long-term prescribing patterns and the safety of biologics in real clinical settings in Hong Kong. This was a population-based drug utilization study in Hong Kong using a territory-wide electronic medical database Clinical Data Analysis and Reporting System (CDARS). Patients who received biologic treatments from 2001 to 2015 were identified and their corresponding demographic and clinical details retrieved from CDARS. The annual prevalence of biologic prescriptions, the long-term retention rates and incidence rates of infections associated with biologic treatments were evaluated. A total of 30,298 patients (male: 44%) prescribed biologic treatments were identified from CDARS from 2001 to 2015. The annual prevalence of biologic prescriptions increased from 0.1 to 16.1 per 100 persons for both sexes. Infliximab had the highest first-year retention rate of 95.6% among all biologics and continuously attained the highest retention rate from second to fifth year. The overall incidence rate of serious infections was less than five per 100 person-years. Specifically, the incidence rates of tuberculosis, upper and lower respiratory infections and herpes zoster were 0.52, 3.24, 4.99 and 1.01 per 100 person-years, respectively. This population-based study revealed an increasing prevalence of biologic prescribing. Results from the study described the long-term retention rates and incidence rates of serious infections of biologic treatments for all indications, and confirmed the safety of biologic treatments. Since this study provides an overview of all biologic utilization, further studies on cost effectiveness, safety and compliance of treatment in different patient groups are still warranted.


The influence of glucocorticoid on the fibrinogen messenger RNA content of rat liver in vivo and in hepatocyte suspension culture.
The plasma concentration of fibrinogen, one of the major acute-phase proteins produced by the liver, increases during the acute-phase response as a result of enhanced synthesis in liver. Since adrenal-cortical hormones have been thought to have a key role in the regulation of the fibrinogen synthesis, fibrinogen-polypeptide mRNA sequences were determined in the present study, by using a specific complementary-DNA probe, in RNA fractions obtained from rat hepatocytes exposed to glucocorticoids in vitro (hepatocyte suspension cultures) and in vivo. Maximal induction of the fibrinogen-polypeptide mRNA (to 400% of the control value) was found in vitro at 0.1 microM-dexamethasone after 9 h of incubation. The same magnitude of induction was obtained with 20 microM-cortisol or 60 microM-corticosterone. In contrast with the findings in vitro, no induction of the fibrinogen-polypeptide mRNA was observed in the liver at various times after injection of different doses of glucocorticoids into rats. These results suggest that more complex regulatory mechanisms are involved and that glucocorticoids are not the sole regulatory factors in vivo in the enhanced synthesis of fibrinogen during the acute-phase response.


Depletion of 14-3-3 protein exacerbates cardiac oxidative stress, inflammation and remodeling process via modulation of MAPK/NF-ĸB signaling pathways after streptozotocin-induced diabetes mellitus.
Diabetic cardiomyopathy is associated with increased oxidative stress and inflammation. Mammalian 14-3-3 proteins are dimeric phosphoserine-binding proteins that participate in signal transduction and regulate several aspects of cellular biochemistry. The aim of the study presented here was to clarify the role of 14-3-3 protein in the mitogen activated protein kinase (MAPK) and nuclear factor-kB (NF-κB) signaling pathway after experimental diabetes by using transgenic mice with cardiac-specific expression of a dominant-negative 14-3-3 protein mutant (DN 14-3-3). Significant p-p38 MAPK activation in DN 14-3-3 mice compared to wild type mice (WT) after diabetes induction and with a corresponding up regulation of its downstream effectors, p-MAPK activated protein kinase 2 (MAPKAPK-2). Marked increases in cardiac hypertrophy, fibrosis and inflammation were observed with a corresponding up-regulation of atrial natriuretic peptide, osteopontin, connective tissue growth factor, tumor necrosis factor α, interleukin (IL)-1β, IL-6 and cellular adhesion molecules. Moreover, reactive oxygen species, left ventricular expression of NADPH oxidase subunits, p22 phox, p67 phox, and Nox4, and lipid peroxidation levels were significantly increased in diabetic DN 14-3-3mice compared to diabetic WT mice. Furthermore, myocardial NF-κB activation, inhibitor of kappa B-α degradation and mRNA expression of proinflammatory cytokines were significantly increased in DN 14-3-3 mice compared to WT mice after diabetes induction. In conclusion, our data suggests that depletion of 14-3-3 protein induces cardiac oxidative stress, inflammation and remodeling after experimental diabetes induction mediated through p38 MAPK, MAPKAPK-2 and NF-κB signaling.