Influence of pinealectomy on the amygdala kindling development in rats.
A considerable number of studies have demonstrated the anticonvulsant effect of melatonin. The present study examines the influence of pinealectomy on the amygdala kindling development in rats. Animals were divided into three groups: Pinealectomized rats (PNT) Sham rats (SHAM) and Control rats (CTL). The mean number of stimulations and the afterdischarge (AD) duration for each stage of kindling were similar among CTL and SHAM animals. Conversely, PNT animals showed particular characteristics during kindling development. They did not present stage 1 and spent a shorter time in stage 2 in relation to the CTL and SHAM animals. Consequently, the number of stimulations required to reach stage 5 was lower for the PNT group when compared to the CTL and SHAM groups. Besides, a longer AD duration during stage 5 in the PNT group was also observed. The present findings indicate that the pineal gland removal exert a significant influence on amygdala kindling development suggesting that melatonin holds potential interest in experimental therapy for epilepsy.


Comparison of ultrasound and MRI informativeness for detection and treatment monitoring of cervical cancer metastases in the vagina.
To assess ultrasound (US) method informativeness in the recurrence detection and treatment monitoring of patients with cervical cancer metastases in the vagina via comparing the US and magnetic resonance imaging (MRI) data. 42 patients with recurrence of cervical cancer were examined by transvaginal US and MRI. Data on radiation diagnostics of cervical cancer metastasis in the vagina were compared with pathomorphological data. US and MRI data on the metastatic tumors size were compared. The diagnostic efficiency of US and MRI for recurrence detection was determined. The sensitivity, specificity and accuracy of US were 92.8; 93.3 and 93.3%, respectively, and of MRI - 95.2; 96.6 and 95.8%, respectively. The informativeness of MRI was higher than US in cervical cancer recurrences detection, but the difference was not significant (p > 0.05). US can provide data as informative as MRI for estimation of metastases sizes in the vagina. The mean difference between MRI measurements and US measurements of the metastases volume was 0.79 mm (95% CI 0.62-0.95 cm3). US as a cheaper and simpler method could be an alternative for metastases detecting and treatment monitoring, especially if there are contraindications to MRI.


The Spraguea Parasitism in Anglerfishes of the Genus Lophius.
To follow the development of the microsporidian Spraguea americanus within the nervous tissue of Lophius. An attempt to determine when and how the infection begins. Acquiring different age groups of Lophius and recovering the infected sites, particularly the supramedullary neuron fibers and preparing them for microscopy. The youngest juvenile Lophius recovered were 140 mm long with established infections. These infections consisted of meronts and sporoblasts but no spores. The evidence indicates these infections began a month or so earlier. Early stages of S. americanus development occur only in juvenile Lophius and not present in older fish. The prediction is infections of all Spraguea species begin early in the life of benthic juvenile Lophius. The high incidence of infection among these fish is an indicator that the location where the infection begins is likely rich in infective spores.


General principles and intraventricular neuroendoscopy: endoscopic techniques.
To term and describe neuroendoscopic techniques. A classification into three major groups of endoscopic techniques is presented. 1) Endoscopic neurosurgery ("channel" endoscopy) is mainly used in ventricular endoscopy. The surgical instruments are introduced via working channels that are located within the endoscope. 2) Endoscope-controlled microneurosurgery means that the endoscope is the only visualization tool and microsurgical instruments are used along the endoscope. Major applications are endonasal endoscopic skull base surgery, endoport surgery, and endoscopic transcranial surgery. 3) Endoscope-assisted microneurosurgery means that the microscope and the endoscope are used in the same surgery. The endoscopes are applied when hidden structures to be inspected are not visible in straight line with the microscope. Endoscopic techniques are a valuable addition to the neurosurgeon's armamentarium. Endoscopes are especially beneficial in deep and narrow surgical approaches and when "looking around a corner" is required.


Postnatal alteration in hematocrit and viscosity in normal and polycythemic infants.
This study was done to document postnatal alterations in hematocrit and viscosity in the first 18 hours of life in 99 full-term infants, to better understand the age-dependent variations in these measurements that may have a bearing on the diagnosis of neonatal polycythemia. The peripheral venous Hct was highest at 2 hours of age, and dropped to cord blood levels by 18 hours. The whole blood viscosity of peripheral venous samples did not change significantly with age. In infants with peripheral venous Hct greater than or equal to 64%, and therefore considered to have polycythemia, a similar postnatal variation in Hct level was seen. Only 38% of infants with Hct greater than or equal to 64% at 2 hours of age continued to have a high level beyond 12 hours of age. The viscosity level in these infants tended to follow that of the Hct. The mean +/- 2 SD viscosity values obtained from peripheral venous samples was much higher than the upper limits of viscosity used in previous studies in which cord blood viscosity was used as the norm. Cord blood Hct correlated better with peripheral venous Hct than with capillary hematocrit, and provided a noninvasive method for screening. These findings suggest that the postnatal variations in Hct should be taken into consideration in the diagnosis of neonatal polycythemia.


Loneliness is associated with mentalizing and emotion recognition abilities in schizophrenia, but only in a cluster of patients with social cognitive deficits.
Loneliness is a concern for patients with schizophrenia. However, the correlates of loneliness in patients with schizophrenia are unclear; thus, the aim of the study is to investigate neuro- and social cognitive mechanisms associated with loneliness in individuals with schizophrenia. Data from clinical, neurocognitive, and social cognitive assessments were pooled from two cross-national samples (Poland/USA) to examine potential predictors of loneliness in 147 patients with schizophrenia and 103 healthy controls overall. Furthermore, the relationship between social cognition and loneliness was explored in clusters of patients with schizophrenia differing in social cognitive capacity. Patients reported higher levels of loneliness than healthy controls. Loneliness was linked to increased negative and affective symptoms in patients. A negative association between loneliness and mentalizing and emotion recognition abilities was found in the patients with social-cognitive impairments, but not in those who performed at normative levels. We have elucidated a novel mechanism which may explain previous inconsistent findings regarding the correlates of loneliness in individuals with schizophrenia.


Production and recovery of polyhydroxyalkanoates (PHA) from waste streams - A review.
Polyhydroxyalkanoates (PHA) are the more attractive sustainable green plastic, and it has the potential to replace petroleum-based plastics (PBP) in the global market. Recently, most of the developed and developing countries have banned the use of traditional PBP. This increases the demand for green plastic production and positively impacts the global market. Producing green plastic from various waste streams such as whey, animal, and crude glycerol will be eco-friendly and cost-effective. However, the factors influencing the environmental sustainability of PHA production from different waste streams are still unclear. This review could be reinforced concrete to researchers to gather deep knowledge on techno-economic analysis, life-cycle assessment, environmental and ecological risks caused during PHA production from different waste streams.


A comparison of phosphorus and nitrogen transfer between plants of different phosphorus status.
This study has two objections: (1) to compare transfers of phosphorus (32P) with nitrogen (15N) from undefoliated and defoliated mycorrhizal P-rich plants to an adjacent mycorrhizal plant and (2) to determine whether the improved nutrient status of a plant growing with a nutrient-rich plant is due primarily to movement of nutrients from roots of its nutrient-rich neighbor (= nutrient transfer) or to reduced nutrient uptake by its nutrient-rich neighbor (=shift in competition). Two plants of Plantago lanceolata were grown in a three-pot unit in which each of their root systems were split, with part in the central shared pot and part by themselves in an outside pot. There were three treatments: (1) no added P; (2) P added in the outer pot to only plant, termed the "donor" plant, since it might provide P to the companion plant, acting as a "receiver"; and (3) as in the previous treatment but the P-fertilized donor plant was also clipped. To encourage the formation of hyphal links between roots of the different plants, transfers were determined when root length densities were high (90 to 130 cm cm-3 soil) and when 56 to 85% of the root length was infected with vesicular-arbuscular mycorrhizae. Phosphorus fertilization enhanced P but not N movement within donor plants. Regardless of treatment, N transfer from donor to receiver plants was an order of magnitude greater than P transfer and in amounts that could potentially affect plant nutrition in very infertile soils. Phosphorus transfer was very small in any of the treatments. Although P fertilization and clipping improved P status of receiver plants, P transfer was not indicated as the main reason for the improved nutrition. A shift in competition between donor and receiver plants was likely the major factor in the shift in nutrition of the receiver plants.


Differential response to right unilateral ECT in depressed patients: impact of comorbidity and severity of illness [ISRCTN39974945].
Recent electroconvulsive therapy (ECT) efficacy studies of right unilateral (RUL) ECT may not apply to real life clinics with a wide range of patients with major depressive episodes. The study included two groups of patients. In addition to a homogeneous group of patients with major depression according to DSM-IV criteria with severity of the major depressive episode > 16 scores on 17-item Hamilton Rating Scale for Depression (HDRS) (Group 1, n = 16), we included a heterogeneous group of patients with less severe major depressive episodes or with a variety of comorbid conditions (Group 2, n = 24). We randomly assigned the patients to an RUL ECT treatment dosed at 5 or 2.5 times seizure threshold with an intent-to-treat design. The outcomes measured blindly were HDRS, number of treatments, and Mini-Mental State Examination (MMSE). The patients were considered to have responded to treatment if the improvement in HDRS score was at least 60% and they had a total score of less than ten. The Group 2 patients responded poorer (8% vs. 63%), and had more often simultaneous worsening in their MMSE scores than Group 1 patients. The differences in the outcomes between the two different doses of RUL ECT treatment were not statistically significant. ECT effectiveness seems to be lower in real-life heterogeneous patient groups than in homogeneous patient samples used in experimental efficacy trials.


Adult philopatry and dispersal in the field vol Microtus agrestis.
Using mark-recapture data, we related the movements of adult field voles to population density, sex ratio and population growth. Dispersal movements (defined as distances larger than 1 home range diameter) were few in both sexes; 4 out of 197 (2.0%) in males and 8 of 316 (2.5%) in females. The distance moved between sequential trapping periods was similar for males and females; the mean being 10.2 m and 9.0 m respectively. Both males and females moved larger distances during the breeding season than during the nonbreeding period. The distance moved between sequential trapping periods showed a strong negative relation to density, i.e. both sexes moved shorter distances at higher densities, but there were no differences between periods of increasing and declining population densities. These results contradict the dispersal predictions of all major hypotheses proposed to explain population fluctuations in small mammals. The dispersal patterns fit a geometric distribution, suggesting that competition is the primary factor determining the dispersal characteristics of this population.


A serological study on primary hepatocellular carcinoma in Zambia.
The enzyme linked immunosorbent assay (ELISA) was used to measure alpha-foetoprotein (AFP) levels and to detect Hepatitis B surface antigen (HBsAg) and antibody to Hepatitis B surface antigen (anti-HBs) in patients with primary hepatocellular carcinoma and in controls free of the disease in Zambia. Virtually all the patients with primary hepatocellular carcinoma had grossly elevated AFP levels and about two thirds of them were positive for HBsAg. All the controls had much lower AFP levels and one sixth were positive for HBsAg.


Cervical Cancer Screening in Average-Risk Women: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians.
The purpose of this best practice advice article is to describe the indications for screening for cervical cancer in asymptomatic, average-risk women aged 21 years or older. The evidence reviewed in this work is a distillation of relevant publications (including systematic reviews) used to support current guidelines. Clinicians should not screen average-risk women younger than 21 years for cervical cancer. Clinicians should start screening average-risk women for cervical cancer at age 21 years once every 3 years with cytology (cytologic tests without human papillomavirus [HPV] tests). Clinicians should not screen average-risk women for cervical cancer with cytology more often than once every 3 years. Clinicians may use a combination of cytology and HPV testing once every 5 years in average-risk women aged 30 years or older who prefer screening less often than every 3 years. Clinicians should not perform HPV testing in average-risk women younger than 30 years. Clinicians should stop screening average-risk women older than 65 years for cervical cancer if they have had 3 consecutive negative cytology results or 2 consecutive negative cytology plus HPV test results within 10 years, with the most recent test performed within 5 years. Clinicians should not screen average-risk women of any age for cervical cancer if they have had a hysterectomy with removal of the cervix.


Exopolyphosphatases PPX1 and PPX2 from Mycobacterium tuberculosis regulate dormancy response and pathogenesis.
Stress adaptation and virulence of various bacterial pathogens require stringent response pathways involving guanosine pentaphosphate and inorganic polyphosphate (PolyP). In M. tuberculosis, intracellular PolyP levels are maintained by the activities of polyphosphate kinase (PPK-1, PPK-2) and exopolyphosphatases (PPX-1, PPX-2). We demonstrate that these exopolyphosphatases cumulatively contribute to biofilm formation and survival of M. tuberculosis in nutrient limiting, low oxygen growth conditions and in macrophages. Characterization of single (Δppx2) and double knock out strain (dkppx) of M. tuberculosis demonstrated that these exopolyphosphatases are essential for establishing infection in guinea pigs and mice. Transcriptional profiling revealed that relative to the parental strain the expression of genes belonging to DosR regulon were significantly reduced in mid-log phase cultures of dkppx strain. We also show that PolyP inhibited the autophosphorylation activities associated with DosT and DosS sensor kinases. Host RNA-seq analysis revealed that transcripts involved in various antimicrobial pathways such as apoptosis, autophagy, macrophage activation, calcium signalling, innate and T-cell response were differentially expressed in lung tissues of dkppx strain infected mice. Taken together, we demonstrate that enzymes involved in PolyP homeostasis play a critical role in physiology and virulence of M. tuberculosis. These enzymes are attractive targets for developing novel interventions that might be active against drug-sensitive and drug-resistant M. tuberculosis.


Twenty-year observational study of paediatric tonsillitis and tonsillectomy.
Tonsillectomy is now only indicated in the UK when specific criteria are met, as outlined by the Scottish Intercollegiate Guidelines Network (SIGN) and The National Institute for Health and Care Excellence (NICE). As a result, fewer numbers of tonsillectomy are being performed. Tonsillectomy is the primary treatment for recurrent tonsillitis; therefore, we hypothesise that acute admissions to hospital with tonsillitis and infective complications will have risen since criteria were introduced. Our aim was to assess the rates of acute hospital admissions with tonsillitis in children and the factors associated with this. Data were provided by Information Service Division for all under 16s in Scotland between 1996/1997 and 2016/2017. Socioeconomic background was determined from the Scottish Index of Multiple Deprivation (SIMD) score. Poisson regression analysis was used to model predictors of surgery and correlation analysis to study the relationship between tonsillitis and other factors. 60 456 tonsillectomies were performed. The number of tonsillectomies dropped significantly following the introduction of SIGN guidelines, and the rates of tonsillitis increased; however, admissions with tonsillitis were already on an upward trajectory. Children from the most deprived areas were 72.0% (95% CI 60% to 85%, p<0.001) more likely to receive tonsillectomy and were also more likely to be admitted with tonsillitis than the least deprived areas. Tonsillectomy and tonsillitis rates are highest in the most deprived; postulated reasons include antibiotic stewardship and difficulty accessing primary care. Current guidelines on tonsillectomy may be disproportionately harmful in children from deprived households.


Treatment of a cat with presumed Bartonella henselae-associated immune-mediated hemolytic anemia, fever, and lymphadenitis.
A 2.5-year-old castrated male cat presented with fever and marked generalized lymphadenopathy of 4-months duration, despite treatment with amoxicillin-clavulanate/marbofloxacin. Abnormalities were not detected on complete blood count, serum chemistry, and FIV/FeLV test apart from a borderline, non-regenerative anemia. Peripheral lymph node fine needle aspirations revealed a marked increase in the percentage of intermediate- and lymphoblastic-lymphocytes in addition to reactive macrophages. Three weeks after presentation, the cat developed a severe, regenerative, immune-mediated hemolytic anemia (IMHA) which responded to immunosuppressive therapy. Fever and lymphadenopathy persisted. Peripheral lymph nodes tested positive for Bartonella henselae DNA in real-time PCR assay and sequencing. Treatment with pradofloxacin and doxycycline resulted in resolution of clinical signs, and negative PCR tests. Despite its reported low pathogenicity, B. henselae infection should also be considered in cats with protracted unexplained fever, lymphadenitis, and IMHA. Furthermore, a combination of pradofloxacin and doxycycline might be considered in cats with bartonellosis given its apparent clinical efficacy.


Using the Ugi multicomponent condensation reaction to prepare families of chromophore appended azamacrocycles and their complexes.
The Ugi reaction offers an effective method for preparing chromophore-appended DOTA-monoamide ligands, which can readily be elaborated to their lanthanide complexes.


The medial gastrocnemius muscle attenuates force fluctuations during plantar flexion.
Force fluctuations during steady contractions of multiple agonist muscles may be influenced by the relative contribution of force by each muscle. The purpose of the study was to compare force fluctuations during steady contractions performed with the plantar flexor muscles in different knee positions. Nine men (25.8+/-5.1 years) performed steady contractions of the plantar flexor muscles in the knee-flexed and knee-extended (greater involvement of the gastrocnemii muscles) positions. The maximal voluntary contraction (MVC) force was 32% greater in the knee-extended position compared with the knee-flexed position. The target forces were 2.5-10% MVC force in the respective position. The amplitude of electromyogram in the medial gastrocnemius muscle was greater in the knee-extended position (10.50+/-9.80%) compared with the knee-flexed position (1.26+/-1.15%, P<0.01). The amplitude of electromyogram in the soleus muscle was not influenced by the knee position. The amplitude of electromyogram in the lateral gastrocnemius and tibialis anterior muscles was marginal and unaltered with knee position. At the same force (in Newtons), the standard deviation of force was lower in the knee-extended position compared with the knee-flexed position. These results indicate that force fluctuations during plantar flexion are attenuated with greater involvement of the medial gastrocnemius muscle.


Negative Thermal Expansion in Ba0.5Sr0.5Zn₂SiGeO₇.
Solid solutions with the composition Ba0.5Sr0.5Zn₂Si2-xGexO₇ and BaZn₂Si2-xGexO₇ were prepared with different values of x using a conventional mixed oxide route. Both compounds exhibit very different thermal expansion, which is due to the different crystal structures. Ba0.5Sr0.5Zn₂Si2-xGexO₇ solid solutions exhibit the structure of high-temperature BaZn₂Si₂O₇ and show negative thermal expansion, which was proven via high-temperature X-ray diffraction. Up to around x = 1, the crystal structure remains the same. Above this value, the low-temperature phase becomes stable. The Sr-free solid solutions have the crystal structure of low-temperature BaZn₂Si₂O₇ and show also a limited solubility of Ge. These Sr-free compositions show transitions of low- to high-temperature phases, which are shifted to higher temperatures with increasing Ge-concentration.


Synergism between androgens and protein kinase-C on androgen-regulated gene expression.
Androgen (R1881) induced transcriptional activity of the human androgen receptor, stably expressed in CHO cells, can be stimulated an extra 2-fold by the addition of the protein kinase C activator, 4 beta-phorbol 12-myristate 13-acetate (PMA). This extra stimulation is not observed when the protein kinase A activator bromoadenosine 3':5'-cyclic monophosphate (8-BrcAMP) is used. The transcriptional activity was measured using a reporter plasmid containing the MMTV-promoter, coupled to the luciferase gene. The effect of PMA on R1881-induced transcription was not due to a higher expression level of the androgen receptor. Also, no extra phosphorylation of the androgen receptor could be measured after incubation with PMA. When GRE-tk-LUC and PSA-LUC reporters were used, the synergistic effect of PMA could not be observed. The findings on the composite MMTV-LTR promoter can be explained by either a direct synergistic interaction between occupied AP-1 like responsive elements and the androgen receptor or via an unknown transcription factor activated by the PKC pathway and interacting with the androgen receptor.


Proximal end clavicle fracture from a parachute jumping injury.
Fractures of the medial end of the clavicle are the least common type of clavicle fracture. We report a 29-year-old military parachutist who presented with medial end clavicle fracture after a bad landing. He was first treated non-operatively in a tertiary center and was then referred to our center by his general practitioner. Surgery was indicated since the fracture was displaced and the patient needed anatomical reconstruction to promote rapid bone healing and a prompt return to work. The medial fragment being comminuted, K-wires were used for internal fixation instead of a plate. The two K-wires were bent 180° to avoid risk of migration and were removed 3 months after surgery when the patient had begun to perform all activities without pain. Aggressive treatment is recommended for medial end clavicle fracture in case of displacement and facilitates rapid functional recovery, notably in patients with considerable clavicular demand.


Effects of bunaftine on morphology, microfilament integrity, and mitotic activity in cultured human fibroblasts and HeLa cells.
Human fibroblasts and HeLa cells were treated with bunaftine (N-butyl-N-/2-(diethylamino)ethyl/-1-naphthalenecarboxamide ) in vitro. At concentrations of 0.5-2.0 mM, the drug caused contraction and rounding of the cells with loss of microvilli-like processes. Aggregates of dense, partly granular, partly fibrillar material formed in the cytoplasm and the rough endoplasmic reticulum became vesiculated. Immunofluorescence microscopy with DNase I and anti-DNase I demonstrated that bundles of actin filaments were disrupted, forming rings, coils, and granules. Filaments stained with antibodies to vimentin (fibroblasts) and prekeratin (HeLa cells) showed less characteristic rearrangements, probably related to the rounding up of the cells. 0.4 mM bunaftine increased and 0.8-1.0 mM markedly decreased the percentage of mitotic cells, without accumulation of cells in any particular stage of mitosis. The drug may arrest the cell cycle at some point before mitosis; it may have a critical concentration above which the arrest becomes permanent. These results suggest that bunaftine interferes with the integrity of microfilament bundles in a different manner from that of cytochalasins. It does not cause any depletion of cellular ATP, indicating that its effect is not a result of inhibition of cell metabolism. It is proposed that bunaftine may be used a complement to cytochalasins in studies of the microfilament system of the cell. The possible binding of bunaftine to actin or myosin and further details of its mechanism of action remain to be elucidated.


Serogenetic investigations of Tibetans and Himachalis from Himachal Pradesh, India: genetic relationship between Tibetans and certain selected mongoloid populations.
Twenty two serogenetic systems were investigated in 115 Tibetans and 128 Himachalis from the state of Himachal Pradesh, northwest India. For eight of the loci (ABO, Rh, MNSs, P, Fy, 6PGD, EsD, and AK) the two populations showed conclusive heterogeneity and their frequency distribution showed that the serogenetic differences between two populations are due to their different racial affiliations. The Tibetans were also analysed for their genetic relationship with certain selected populations from the Cis-Himalayan, far east and south Asian regions. The calculations of the Harpending's kinship matrix R and the genetic distances showed that the Tibetans are closer to the mongoloid populations of the Cis-Himalayan region and the differences in the present day population structure of the mongoloid groups of this region are more likely to be due to differential migration, admixture and racial affiliation although there is a slight possibility of disruptive selection for certain loci such as 6PGD and AK which showed an exceptionally high value of Canning (6PGD*C) and AK*1 genes.


Thrombin-induced degranulation of cultured bone marrow-derived mast cells.
This study was undertaken to determine if a plasma protease such as thrombin, a highly specific procoagulant enzyme that has numerous effects on platelets, endothelial cells, and smooth muscle cells, could mediate mast cell activation processes. Our results indicate that at near physiologic levels, thrombin can rapidly trigger mast cell degranulation without activating the 5-lipoxygenase system.


Positive effect of inaudible high-frequency components of sounds on glucose tolerance: a quasi-experimental crossover study.
Although stress significantly impacts on various metabolic syndromes, including diabetes mellitus, most stress management techniques are based on psychological and subjective approaches. This study examined how the presence or absence of the inaudible high-frequency component (HFC) of sounds, which activates deep-brain structures, affects glucose tolerance in healthy participants using the oral glucose tolerance test (OGTT). Sounds containing HFC suppressed the increase in glucose levels measured by incremental area under the curve in the OGTT compared with the otherwise same sounds without HFC. The suppression effect of HFC was more prominent in the older age group and the group with high HbA1c. This suggests that sounds with HFC are more effective in improving glucose tolerance in individuals at a higher risk of glucose intolerance.


The psychometric properties of 30-day versions of the DSM-5 dimensional severity scales for social anxiety disorder and panic disorder.
The current study aimed to investigate the psychometric properties of the DSM-5 dimensional severity scales for social anxiety disorder (SAD) and panic disorder (PD) using a past 30 day timeframe. Data were from a sample of 1,052 Australian community dwelling adults (aged 18 years or older) recruited using online advertisements. Respondents completed the DSM-5 severity scales for SAD and PD as well as a range of additional widely used self-administered scales for SAD and PD in the past 30 days prior to the survey. Both scales exhibited high internal consistency (alpha>=0.94) and a strong general factor that justified unidimensional item response analysis (OmegaH=0.96). There was no evidence of significant local dependence amongst item pairs after accounting for the single factor. Similarly, there was no evidence for meaningful differential item functioning of the scales across sex, age, education level, and residential location. There was high convergent validity (0.71 - 0.85) amongst conceptually related scale and moderate to high correlations (0.54 - 0.80) between conceptually unrelated scales. These findings provide support for the use of past month versions of the DSM-5 severity scales for SAD and PD by researchers and clinicians to inform and supplement diagnostic decisions.


Microglia in Human Postmortem Brain Samples: Quantitative Ultrastructural Analysis of Scanning Electron Microscopy Images.
In this protocol, we describe the specific steps required to prepare human postmortem brain samples for ultrastructural microglial analysis. A detailed procedure is provided to improve the ultrastructural quality of the samples, using aldehyde fixatives followed by immunoperoxidase staining of allograft inflammatory factor 1 (AIF1, also known as IBA1), a marker of myeloid cells, and cluster of differentiation 68 (CD68), a marker of phagolysosomal activity. Additionally, we describe an osmium-thiocarbohydrazide-osmium (OTO) post-fixation method that preserves and increases the contrast of cellular membranes in human postmortem brain samples, as well as the steps necessary to acquire scanning electron microscopy (SEM) images of microglial cell bodies. In the last section, we cover the quantitative analysis of various microglial cytoplasmic organelles and their interactions with other parenchymal elements.


A novel CDH1 germline missense mutation in a sporadic gastric cancer patient in north-east of Italy.
It is well documented that germline mutations in the E-cadherin (CDH1) gene are linked to hereditary diffuse gastric cancer (HDGC). Despite the known molecular genetic causes, most gastric cancers are sporadic and poorly investigated for susceptibility genes. We report the finding of a novel germline missense mutation in exon 6, c. 820 G > A (p.G274S) in one sporadic gastric cancer patient. This new variant does not affect cryptic splicing of CDH1 as demonstrated by molecular assay. Immunohistochemical analysis shows a mixed pattern of E-cadherin staining (membranous and cytoplasmic) in the intestinal component, while in the diffuse counterpart, the membranous staining was prevalent and a reduced membranous expression of ß-catenin was observed. In vitro assays suggest that the mutant G274S does not affect the E-cadherin protein function, its expression pattern or subcellular localization. This new variant is present in EC2 extracellular domain of the protein (p.G120S in mature protein). The molecular modelling shows that this point mutation is not dramatic for local structure. However, p.S120 is located on the surface of the protein close to the functional calcium sites and in the region of interaction with EC1 domain of another E-cadherin molecule involved in the formation of the intercellular junction. Moreover, p.S120 residue could be involved in posttranslational modifications, such as phosphorylation or glycosylation, with possible effects on stability and integrity of adhesive properties of E-cadherin. In conclusion, the pathogenicity of this mutation is unlikely; probably we found a new germline CDH1 missense mutation with potential impact, however, of uncertain significance.


Pseudomonas infections in Tohid Burn Center, Iran.
Burn injury is a major public health problem in many areas of the world. Pseudomonas aeruginosa is one of the most common causes of burn wound infection in burn patients. Septicemia due to this organism is a major cause of mortality among burn patients. This study analyzed P. aeruginosa infections in the Tohid Burn Center in Tehran during 1995-1997 in order to estimate their frequency, antibiotic susceptibility and their role in burn morbidity. Among 2122 patients who were admitted during this study period, 3365 bacterial strains were isolated and the frequency of P. aeruginosa was 73.9%. This was followed by Staphylococcus aureus (9.1%) and other organisms (17%) in frequency. The frequency of P. aeruginosa resistant to gentamicin, carbenicillin, co-trimoxazole, ceftizoxime and tetracycline was over 95% and resistance to amikacin which was 49% in 1995, increased to 90% in 1997. With the introduction of ciprofloxacin at our burn center, the frequency of P. aeruginosa resistance increased from 45% in 1995, to 82% in 1997. P. aeruginosa was found more frequently in the ICU than in the wards. These findings show that P. aeruginosa remains the leading cause of nosocomial infections in our burn center. It is necessary to introduce urgent measures for restriction of the spread of P. aeruginosa infections in our burn center.


Saturated fatty acid exposure induces androgen overproduction in bovine adrenal cells.
Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenemia, from ovarian and adrenal origin, and is characterized by insulin resistance (IR). Studies found that raising in vivo non-esterified fatty acid (NEFA) levels, which induces lipotoxicity, increases androgen levels and IR. The aim of this study was therefore to determine the effects of in vitro over-exposure to NEFA on androgen synthesis in a bovine adrenocortical cell model. Bovine fasciculata/reticularis cells were cultured for 2days in the absence or presence of ACTH (10nmol/L) or Forskolin (fsk, 10μmol/L), alone or in combination with the saturated fatty acid (FA) palmitate (100μmol/L). Steroid production was measured in medium and corrected for initial cell seeding count. CYP17 protein expression and ERK1/2 phosphorylation were assessed by Western blotting. Under unstimulated conditions, dehydroepiandrosterone (DHEA) levels were barely detected and no difference was observed after palmitate exposure, which was also the case for CYP17 expression and ERK1/2 phosphorylation. Under stimulation, palmitate exposure increased DHEA production by 38% and 69%, for ACTH and fsk, respectively, as compared to untreated conditions (Ps⩽0.05). In palmitate-treated vs untreated cells, fsk-stimulated ERK1/2 phosphorylation was reduced by 46% (P=0.0047), but stimulated CYP17 expression was not significantly affected. In a model of androgen-producing cells, under stimulated conditions, overexposure to saturated FAs significantly increases androgen production and reduces MEK/ERK activation. Therefore, this study is the first to demonstrate that lipotoxicity can directly trigger androgen overproduction in vitro, in addition to its well-described impact on IR, which strongly supports a central role of lipotoxicity in PCOS pathophysiology.


Measuring Physical Violence and Rape Against Somali Women Using the Neighborhood Method.
This study was conducted to estimate prevalence of gender-based violence (GBV) among female Somalis in Ethiopian refugee camps and host communities, compare prevalence in camps and communities, and compare prevalence in flight and in camp. Systematic random sampling was used to select households in Awbare camp (n = 85), Awbare town (n = 76), and Kebribeyah camp (n = 83). GBV was common and overwhelmingly domestic. Prevalence was higher in Awbare town than Kebribeyah camp. Women were at increased risk of GBV in camp compared with in flight. The domestic nature of GBV in humanitarian settings requires attention. Assumptions about violence in humanitarian settings should be further tested.


Reliability of self-monitoring of blood glucose by CSII-treated patients with type I diabetes.
The reliability of patient-generated data from self-monitoring of blood glucose (SMBG) was studied in 14 patients with type I (insulin-dependent) diabetes mellitus treated by continuous subcutaneous insulin infusion (CSII) (7 women, 7 men). The reflectance meters (Glucometer I, Ames, Elkhart, IN) used by the patients were replaced for a period of 21 days by memory-reflectance meters; patients were unaware of the memory capacity of the new meters and were instructed to continue their practice of recording the meter readings in their logbook. This study compares the data recorded in the memory-reflectance meters with those reported in the logbook. The number of SMBG measurements was different in 11 patients (differences ranging from 2 to 66). Mean glycemia was similar (8.23 +/- 0.36 mM in logbook vs. 8.49 +/- 0.48 mM in memory-reflectance meters), but both the M value and mean amplitude of glycemic excursions (MAGE) index were lower when calculated from logbook data (38 +/- 5 vs. 48 +/- 7 mM, P less than .05 and 6.91 +/- 0.43 vs. 7.72 +/- 0.52 mM, respectively; P less than .05). Overreporting (addition of phantom values in logbook) and underreporting (omission of SMBG measurements from logbook) indexes were 19 +/- 7 and 12 +/- 3%, respectively. Precision (percent of identical values in logbook and in memory-reflectance meters at the corresponding time) was 77 +/- 6.8%. The number of SMBG measurements recorded in the memory-reflectance meter was negatively correlated with glycosylated hemoglobin [HbA1c; (r = -.85, P less than .001)], whereas overreporting was positively correlated with HbA1c (r = .76, P less than .01).


Specific bradycardic agents, a new therapeutic modality for anesthesiology: hemodynamic effects of UL-FS 49 and propranolol in conscious and isoflurane-anesthetized dogs.
A "specific bradycardic agent" has direct negative chronotropic actions without producing other systemic or coronary hemodynamic alterations. UL-FS 49, a recently synthesized structural analog of verapamil without classical slow channel calcium blocking activity, is proposed as such an agent. The purpose of this investigation was to characterize the hemodynamic and electrocardiographic actions of UL-FS 49 (0.25, 0.50, and 1.0 mg/kg) and compare its effects with those of propranolol (0.25, 0.50, and 1.0 mg/kg) in conscious or isoflurane-anesthetized (with and without neuromuscular blockade by pancuronium) chronically instrumented dogs. In six groups, comprising 52 experiments, UL-FS 49 was found to be more efficacious than propranolol in reducing heart rate, although this agent did not block the hemodynamic response to isoproterenol. UL-FS 49 produced 45-50% reductions in heart rate in dogs with isoflurane-induced tachycardia as compared to 15 and 30% reductions following propranolol. Furthermore, few other hemodynamic alterations were produced by UL-FS 49 indicating the remarkable specificity of this drug for reducing heart rate. A "specific bradycardic agent" such as UL-FS 49 may be useful clinically during the perioperative period. Such a drug may be especially advantageous for patients with documented or suspected ischemic heart disease, those who cannot tolerate the side effects of beta adrenergic blockade, as well as patients requiring a greater reduction in heart rate than can be obtained with beta adrenergic receptor antagonists.


Nerveless and gutsy: intestinal nutrient sensing from invertebrates to humans.
The increasingly recognized role of gastrointestinal signals in the regulation of food intake, insulin production and peripheral nutrient storage has prompted a surge of interest in studying how the gastrointestinal tract senses and responds to nutritional information. Identification of metabolically important intestinal nutrient sensors could provide potential new drug targets for the treatment of diabetes, obesity and gastrointestinal disorders. From a more fundamental perspective, the study of intestinal chemosensation is revealing novel, non-neuronal modes of communication involving differentiated epithelial cells. It is also identifying signalling mechanisms downstream of not only canonical receptors but also nutrient transporters, thereby supporting a chemosensory role for "transceptors" in the intestine. This review describes known and proposed mechanisms of intestinal carbohydrate, protein and lipid sensing, best characterized in mammalian systems. It also highlights the potential of invertebrate model systems such as C. elegans and Drosophila melanogaster by summarizing known examples of molecular evolutionary conservation. Recently developed genetic tools in Drosophila, an emerging model system for the study of physiology and metabolism, allow the temporal, spatial and high-throughput manipulation of putative intestinal sensors. Hence, fruit flies may prove particularly suited to the study of the link between intestinal nutrient sensing and metabolic homeostasis.


Plant dispersal by the Aldabran giant tortoise, Geochelone gigantea (Schweigger).
A total of 28 species of grasses, herbs, and woody plants germinated from faeces of Aldabran giant tortoises. It seems likely that all members of the land flora can be ingested by tortoises and so may be dispersed by them over short distances.The tortoises are thought to have derived from a Madagascan stock and reached Aldabra from time to time by transmarine migration until the extermination of the Madagascan tortoises about 1100 years ago. The time taken by a tortoise to void its last meal is much longer than that required to float, at present current speeds, from Madagascar to Aldabra. If neither of these parameters have changed since the tortoise migrations to Aldabra, the tortoises may have been responsible for the introduction of plant species to Aldabra.


Effects of mitomycin-C on tear film, corneal biomechanics, and surface irregularity in mild to moderate myopic surface ablation: preliminary results.
To assess the effect of mitomycin-C (MMC) on the tear film, corneal biomechanics, and surface irregularity in surface ablation (photorefractive keratectomy [PRK]) for low to moderate myopia. Refractive Surgery Unit, Farabi Eye Hospital, Tehran, Iran. Double-masked randomized clinical trial. In patients with spherical equivalent myopia of -0.75 to -3.87 diopters (D) and astigmatism up to -1.75 D, the first eye was randomly assigned to the application of MMC 0.02% or a balanced salt solution for 15 seconds. The fellow eye received the alternate in a masked fashion after excimer photoablation. The study enrolled 60 patients. In fellow eyes, the changes in the tear-film index were comparable 1 month and 6 months postoperatively. There was no significant difference in changes in total higher-order aberrations, spherical aberration, coma, or Q values (Pentacam HR) between fellow eyes at 1 month and 6 months. There was a trend toward a higher asymmetry index at 1 month; however, a statistically significant drop was observed at 6 months in the MMC group (P<.01). It was hypothesized that stromal remodeling was delayed, but better, in MMC-treated eyes. No haze was recorded at 6 months in either group. Use of MMC in PRK did not appear to contribute significantly to surface irregularity, transient tear-film dysfunction, or biomechanical weakening of the cornea compared with PRK without MMC. No author has a financial or proprietary interest in any material or method mentioned.


Acute pseudomonas infection of the external ear (malignant external otitis).
Pseudomonas aeruginosa commonly causes low-grade infections of the external auditory canal. If these infections are inadequately treated, they can progress into a severe form of external otitis called malignant external otitis (MEO). MEO usually occurs in elderly diabetic patients and demands immediate diagnosis and medical therapy in order to prevent systemic invasion, neurologic sequelae, and even death. We present two cases of acute pseudomonas infections of the ear, neither of which progressed to MEO due to early implementation of antibiotic therapy.


Maternal preeclampsia and risk of bronchopulmonary dysplasia in preterm infants.
To better understand whether preeclampsia (PE) increases the risk of bronchopulmonary dysplasia (BPD). Of 753 infants alive at 36 wks, 138 (18.3%) were exposed to PE. BPD was not significantly related to exposure to PE either before (odds ratio (OR) 0.73; 95% confidence interval (CI) 0.50, 1.06) or after adjustment for confounding variables (adjusted OR 1.14; 95% CI 0.71, 1.81). If infants were selected by gestational age alone, there was no association (OR 1.05; 95% CI 0.63, 1.75). In contrast, selecting by birth weight alone, PE was associated with a significant reduction in BPD (OR 0.61, 95% CI 0.41, 0.91). However, this effect disappeared after adjustment for confounding variables. Conclusions were unchanged when data from other studies were included in a pooled analysis. PE does not significantly affect the risk of BPD in extremely preterm (EP) or extremely-low-birth-weight (ELBW) subjects. We examined data on EP (<28 wks gestation) or ELBW (<1,000 g) infants live born in Victoria, Australia, in three eras: 1991-1992, 1997, and 2005. We compared the incidence of BPD (oxygen requirement at 36 wks' postmenstrual age) in the PE group (infants exposed to PE) with that in the remainder (nonexposed infants). We also contrasted results with comparable reported studies.


The Frequency of Specific KRAS Mutations, and Their Impact on Treatment Choice and Survival, in Patients With Metastatic Colorectal Cancer.
Patients with metastatic colorectal cancer (mCRC) and KRAS mutations have a poor prognosis, seemingly dependent on the location of the mutation. This multicenter, retrospective, cohort study assessed the frequency and prognostic value of specific KRAS mutation codon locations in mCRC patients, and survival outcomes in relation to treatment. Data from mCRC patients treated in 10 Spanish hospitals between January 2011 and December 2015 were analyzed. The main objective was to investigate (1) the impact of KRAS mutation location on overall survival (OS), and (2) the effect of targeted treatment plus metastasectomy and primary tumor location on OS in patients with KRAS mutations. The KRAS mutation location was known for 337/2002 patients. Of these, 177 patients received chemotherapy only, 155 received bevacizumab plus chemotherapy, and 5 received anti-epidermal growth factor receptor therapy plus chemotherapy; 94 patients underwent surgery. The most frequent KRAS mutation locations were G12A (33.8%), G12D (21.4%), and G12V (21.4%). Compared with other locations, patients with a G12S mutation had the shortest median OS (10.3 [95% CI, 2.5-18.0] months). OS was longer in patients who underwent surgery versus those who did not, with a trend toward prolonged survival with bevacizumab (median OS 26.7 [95% CI, 21.8-31.7] months) versus chemotherapy alone (median OS 23.2 [95% CI, 19.4-27.0] months). These findings confirm that KRAS mutation location may predict survival outcomes in patients with mCRC, and suggest that pre-/post-operative bevacizumab plus metastasectomy provides survival benefits in patients with KRAS mutations.


Metal concentrations in lime stabilised, thermally dried and anaerobically digested sewage sludges.
Cognisant of the negative debate and public sentiment about the land application of treated sewage sludges ('biosolids'), it is important to characterise such wastes beyond current regulated parameters. Concerns may be warranted, as many priority metal pollutants may be present in biosolids. This study represents the first time that extensive use was made of a handheld X-ray fluorescence (XRF) analyser to characterise metals in sludges, having undergone treatment by thermal drying, lime stabilisation, or anaerobic digestion, in 16 wastewater treatment plants (WWTPs) in Ireland. The concentrations of metals, expressed as mgkg(-1) dry solids (DS), which are currently regulated in the European Union, ranged from 11 (cadmium, anaerobically digested (AD) biosolids) to 1273mgkg(-1) (zinc, AD biosolids), and with the exception of lead in one WWTP (which had a concentration of 3696mgkg(-1)), all metals were within EU regulatory limits. Two potentially hazardous metals, antimony (Sb) and tin (Sn), for which no legislation currently exists, were much higher than their baseline concentrations in soils (17-20mgSbkg(-1) and 23-55mgSnkg(-1)), meaning that potentially large amounts of these elements may be applied to the soil without regulation. This study recommends that the regulations governing the values for metal concentrations in sludges for reuse in agriculture are extended to include Sb and Sn.


Association of brain-derived neurotrophic factor and tyrosine kinase B receptor in pregnancy.
Abnormal brain development in a compromised prenatal and/or early postnatal environment is thought to be a risk factor for several neurobehavioural disorders. However, the mechanisms underlying these are not well understood. We have earlier reported reduced placental docosahexaenoic acid (DHA) levels in preterm deliveries. We have hypothesized that increased oxidative stress and reduced DHA levels may lead to changes in the circulating levels of maternal and cord brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) levels. A total number of 96 women delivering preterm and 95 women delivering at term were recruited. Plasma BDNF levels were measured in both mother and cord blood plasma using the BDNF Immuno Assay kit. Placental TrkB levels were analysed using sandwich enzyme-linked immunosorbent assay (ELISA). Maternal plasma BDNF levels and placental TrkB levels were higher (p<0.05) while cord plasma BDNF levels were lower (p<0.01) in women delivering preterm as compared to term. There was a negative association between levels of placental TrkB and DHA (p=0.034). A negative association between maternal plasma BDNF levels and placental weight (p=0.001) was observed while a positive association was seen between cord plasma BDNF levels and gestation (p=0.025). The reduction in cord BDNF levels may have implications for altered neurodevelopment in childhood and later life. Studies need to be undertaken to follow up children born preterm for risk of neurobehavioural disorders like attention deficit hyperactivity disorder (ADHD) to understand the effect of altered BDNF at birth on neurodevelopment.


Bioaccumulation, maternal transfer and effects of dietary 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) exposure on medaka fish (Oryzias latipes) offspring.
A previous study conducted in our laboratory with growing medaka (Oryzias latipes) showed the capacity of BDE-47 (10-1000ng/g) to bioaccumulate during a 40-day oral exposure. However, the results did not provide evidence for effects during or after the exposure period. In this study, breeding medakas were fed a diet for 40days that contained 1000ng of BDE-47/g. At predefined time points, females (time points 10, 20, 30 and 40), males (time points 30 and 40) and pools of laid eggs (time points 10, 20, 30 and 40) were sampled and collected for: 1) the BDE-47 quantitative analysis in adults in the <24-h-old post-fertilization (hpf) embryos, and in the <24-h-old post-hatch (hph) eleutheroembryos; 2) the evaluation of fecundity, fertility and hatching. Additional pools of embryos collected at time point 40 were evaluated for: 1) the active swimming behavior of the 48hph offspring in the eleutheroembryonic stage; 2) the BDE-47 quantification in the 240hph resultant larvae. BDE-47 accumulated in parents rapidly, and concentrations remained constant at higher levels in males (values within the 50-60ng/g wet weight -w.w.- range) compared with females (70ng/g w.w. range). The BDE-47 concentrations detected in embryos and eleutheroembryos ranged from 200 to 500ng/g w.w. for time points 10-40. Reproductive capacity, hatching and ensuing swim bladder inflation were not affected by parental BDE-47 dietary exposure, nor was the active swimming behavior in eleutheroembryos. The BDE-47 concentration in the 240hph larvae lowered to levels close to those detected in parents. Despite the efficient BDE-47 maternal transfer, these results offered no evidence for BDE-47 effects on fish reproduction or in the early life stages of offspring.


Tumor-associated macrophages: Potential therapeutic targets and diagnostic markers in cancer.
Macrophages are plastic and functionally diverse, present in all tissues, and play a key role in organisms from development, homeostasis and repair, to immune responses to pathogens. They are central to many disease states and have emerged as important therapeutic targets for many diseases. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and are key factors influencing cancer progression, metastasis and tumor recurrence. TAMs can be derived from different sources and exert different pro- or anti-tumor effects based on the type, stage and immune composition of the tumor. TAMs are highly heterogeneous and diverse, and have multiple functional phenotypes. There is still a great deal of controversy regarding the relationship between TAMs and prognosis of cancer patients. In this review, we summarize the characteristics of common markers of TAMs as well as explore the prognostic role of TAMs in different cancers including lung, breast, gastric, colorectal, esophageal and ovarian cancers.


Evaluation of efficacy and indications of surgical fixation for multiple rib fractures: a propensity-score matched analysis.
The purpose of this study was to assess the effects of recent surgical rib fixation and establish its indications not only for flail chest but also for multiple rib fractures. Between 2007 and 2015, 187 patients were diagnosed as having multiple rib fractures in our institution. After the propensity score matching was performed, ten patients who had performed surgical rib fixation and ten patients who had treated with non-operative management were included. Categorical variables were analyzed with Fischer's exact test and non-parametric numerical data were compared using the Mann-Whitney U test. Wilcoxon signed-rank test was performed for comparison of pre- and postoperative variables. All statistical data are presented as median (25-75 % interquartile range [IQR]) or number. The surgically treated patients extubated significantly earlier than non-operative management patients (5.5 [1-8] vs 9 [7-12] days: p = 0.019). The duration of continuous intravenous narcotic agents infusion days (4.5 [3-6] vs 12 [9-14] days: p = 0.002) and the duration of intensive care unit stay (6.5 [3-9] vs 12 [8-14] days: p = 0.008) were also significantly shorter in surgically treated patients. Under the same ventilating conditions, the postoperative values of tidal volume and respiratory rate improved significantly compared to those values measured just before the surgery. The incidence of pneumonia as a complication was significantly higher in non-operative management group (p = 0.05). From the viewpoints of early respiratory stabilization and intensive care unit disposition without any complications, surgical rib fixation is a sufficiently acceptable procedure not only for flail chest but also for repair of severe multiple rib fractures.


Chemokine expression predicts T cell-inflammation and improved survival with checkpoint inhibition across solid cancers.
Immune checkpoint inhibitors (ICI) are highly effective in specific cancers where canonical markers of antitumor immunity are used for patient selection. Improved predictors of T cell-inflammation are needed to identify ICI-responsive tumor subsets in additional cancer types. We investigated associations of a 4-chemokine expression signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) with metrics of antitumor immunity across tumor types. Across cancer entities from The Cancer Genome Atlas, subgroups of tumors displayed high expression of the c-Score (c-Scorehi) with increased expression of immune checkpoint (IC) genes and transcriptional hallmarks of the cancer-immunity cycle. There was an incomplete association of the c-Score with high tumor mutation burden (TMB), with only 15% of c-Scorehi tumors displaying ≥10 mutations per megabase. In a heterogeneous pan-cancer cohort of 82 patients, with advanced and previously treated solid cancers, c-Scorehi tumors had a longer median time to progression (103 versus 72 days, P = 0.012) and overall survival (382 versus 196 days, P = 0.038) following ICI therapy initiation, compared to patients with low c-Score expression. We also found c-Score stratification to outperform TMB assignment for overall survival prediction (HR = 0.42 [0.22-0.79], P = 0.008 versus HR = 0.60 [0.29-1.27], P = 0.18, respectively). Assessment of the c-Score using the TIDE and PredictIO databases, which include ICI treatment outcomes from 10 tumor types, provided further support for the c-Score as a predictive ICI therapeutic biomarker. In summary, the c-Score identifies patients with hallmarks of T cell-inflammation and potential response to ICI treatment across cancer types, which is missed by TMB assignment.


Chronic stress and executive functioning: A specification-curve analysis.
To investigate the association between chronic stress and executive functioning (EF), we assessed 514 young to middle-aged adults in three EF tasks (i.e., Number-Letter, 2-Back, Go/Nogo) that assessed shifting, updating, and inhibition. Chronic stress was assessed by various self-report measures and hair cortisol concentrations as indicators of subjective and objective chronic stress, respectively. In order to test the association between chronic stress and EF, we fit a structural equation model with a latent common EF factor predicted by subjective and objective chronic stress on Kaplan-Meier estimates of response times. Controlling for participants' sex, age household income and the delay between cognitive testing and hair sample collection, neither subjective nor objective chronic stress showed a meaningful association with common EF. Exploratory analyses suggested a moderation effect of income on the association between subjective chronic stress and common EF, with a smaller association for high-income participants. Additionally, we conducted a specification-curve analysis on the association between chronic stress and EF to assess the influence of different analysis choices on results in our dataset. This analysis confirmed the absence of a coherent association between chronic stress and EF by showing that the majority of analytical choices produced null effects and only a small number of analytical choices produced meaningful associations (negative or positive). Taken together, our findings suggest that common EF likely remains preserved under the influence of chronic stress. Our specification-curve analysis, however, also shows that chronic stress may also have either a positive or a negative effect on EF, depending on the choice of covariates and measures of chronic stress and EF. Consequently, more research on the role of these factors for the association between chronic stress and EF is needed to avoid the interpretation of non-replicable stress-EF associations caused by analytical choices or selection bias.


An update on calcium carbonate nanoparticles as cancer drug/gene delivery system.
In recent years, the applications of calcium carbonate (CaCO3) nanoparticles (NPs) have gained extensive interest as targeted drug/gene delivery systems to cancerous tissues and cells due to their accessibility, low cost, safety, biocompatibility, pH-sensitivity, and slow biodegradability. Drug-loaded CaCO3 NPs (CCNPs) have been reviewed. An updated search on the current state of CCNPs as cancer drug/gene delivery systems with a focus on their special properties including pH-sensitivity, biodegradability, and sustained release performance has been also assessed. Based on the reviewed literature, CCNPs, because of their superior features, will have a great aiding role in safe and efficient cancer treatment in the near future.


Compression of ureter caused by a retained reservoir of penile prosthesis.
Routine removal of the reservoir in explanting a malfunctioning three-piece penile implant raises debates because that the retained reservoir has little risk of erosion and it often needs a second incision to remove the reservoir. We reported a case whose retained reservoir resulted in nonbacterial inflammation around it and caused an ipsilateral hydronephrosis.


Effect of low-dose oral contraceptives on metabolic risk factors in African-American women.
The effect of oral contraceptive pill (OCP) use on cardiovascular risk in African-American women is unknown. Our objective was to examine in African-American women the effect of OCP use on insulin resistance, glucose intolerance, and triglycerides (TGs). This was a cross-sectional study. The study was conducted at the National Institutes of Health Clinical Research Center. A total of 104 healthy nondiabetic African-American women [21 OCP users, 83 controls, age mean +/- sd, 34.7 +/- 7.6 yr, body mass index (BMI) 31 +/- 8.4 kg/m(2)] was included in the study. Subjects had oral glucose tolerance tests, insulin-modified frequently sampled iv glucose tolerance tests, and fasting lipid profiles. Insulin resistance was determined by the insulin sensitivity index (S(I)). Insulin resistance, glucose tolerance status, and TG levels were determined. Fasting glucose did not differ between OCP users and controls (P = 0.27). In contrast, compared with controls, 2-h glucose (135 +/- 23 vs.120 +/- 25 mg/dl; P = 0.01) and fasting TGs (73 +/- 31 vs.57 +/- 27 mg/dl; P = 0.02) were higher in OCP users. OCP users tended to be more insulin resistant than controls (S(I): 2.51 +/- 2.01 vs. 3.46 +/- 2.09; P = 0.09). Multiple regression analysis revealed that BMI, age, and OCP use were significant determinants of 2-h glucose (adjusted R(2) = 0.37; P < 0.001) and TG levels (adjusted R(2) = 0.21; P < 0.001). As BMI was a determinant of both 2-h glucose and TGs, participants were divided into nonobese and obese groups, and the analyses repeated. Among the nonobese women, the OCP users were more insulin resistant (S(I): 2.91 +/- 1.58 vs. 4.35 +/- 1.88; P = 0.03) and had a higher prevalence of glucose intolerance than controls (odds ratio 5.7; 95% confidence interval 1.4-24; P = 0.01). In African-American women, OCP use is associated with an increase in markers of cardiovascular risk manifested by increased insulin resistance, glucose intolerance, and elevated TGs.


Is it true that injecting palmar finger skin hurts more than dorsal skin? New level 1 evidence.
Since the first texts on local anesthesia were written in the early 1900s, it has been widely quoted and believed that dorsal finger skin is less sensitive to needlestick pain than volar finger skin. The result is that the most commonly used finger block for local anesthesia is the dorsal two injection technique. In this study, the needlestick discomfort associated with dorsal and volar finger skin was compared in a group of 78 volunteers who had the long finger of both hands poked with a 25 G needle; one in the midline of the volar side and the other in the lateral web space of the dorsal side. Volunteers then completed a pain scale for each needlestick and ranked which technique they would prefer for future injections. We found that there was no significant difference in needlestick pain or preference of future needle location between the dorsal and volar aspects of the finger. We provide level 1 evidence that the needlestick of the SIMPLE block which has one needlestick on the volar side of the finger is not more painful than the needlestick of the dorsal finger block.


The process of practice redesign in delirium care for hospitalised older people: a participatory action research study.
In 2007 three researchers completed a 6-month study in one 32-bed acute care medical ward in a large hospital in New South Wales, Australia. The problem drawn to the attention of researchers was that approximately 60% of older people were delirious on arrival or develop incident delirium during their hospital stay. Lack of recognition, underreporting and inadequate care responses to delirium in hospitalised older people signalled a major practice problem. To collaboratively explore ways in which clinical practice could be improved. We selected Participatory Action Research (PAR) as the methodology to involve health practitioners in practice redesign. PAR is a process in which 'we', researchers and participants, systematically work together in cycles of 'looking, thinking and acting'. Delirium and the high percentage of older people who succumb to this condition was the main practice problem requiring a response. Eight volunteer clinicians and three researchers met weekly as a group for 13 sessions over 6 months. Clinicians set the agenda for redesign of practice. Raising awareness about delirium and its prevention were the selected action strategies. A delirium alert protocol was developed for implementation by the clinicians and later evaluation as a separate study. There was evidence that practice had changed. Physical and chemical restraints had not been used for 3 months subsequent to the study's completion. The nurse manager reported that early detection strategies had prevented episodes of acute hyperactive delirium. Whilst there continued to be older people admitted with a diagnosis of delirium, there were fewer incidences of delirium developing on the ward and there was less disruption to other patients, especially at night. The strategy of raising the awareness of delirium in older people was successful. We are confident that working collaboratively with practitioners is the way to bring evidence to practice in delirium care for older people in acute care settings.


Quantification of Citrullinated Histone H3 Bound DNA for Detection of Neutrophil Extracellular Traps.
Formation of neutrophil extracellular traps (NETs) has been associated with multiple pathologies including cancer. While the visualization of NETs by microscopy is a routine technique, their quantification presents a number of challenges. Commonly, as citrullination of histone H3 is required for NET formation, the presence of this modified histone along with DNA is considered to be a hallmark of NETs. Here, we describe and validate a novel assay for the quantification of NETs based on the detection of citrullinated histone H3 bound to DNA (CitH3DNA binding assay). Using this assay, we investigated the effect of phorbol 12-myristate 13-acetate (PMA) on NET formation by neutrophils isolated from the bone marrow of control and myeloma-bearing mice. We found that PMA induced citrullination of histone H3, an increase in the level of CitH3DNA, and NET formation in neutrophils from both tumor-free and myeloma-bearing mice. The levels of CitH3DNA in the NET fractions, as measured by our assay, directly correlated with the citrullination of histone H3 in neutrophils, as detected by Western blotting, and were significantly higher in PMA-stimulated compared to unstimulated neutrophils. Neutrophils from tumor-bearing mice produced more NETs than those from tumor-free counterparts following stimulation with PMA. The increase in NET production correlated with significantly higher histone H3 citrullination levels and increased measurements of CitH3DNA. Thus, our data indicate that bone marrow neutrophils from myeloma-bearing hosts are prone to NET formation.


Anti-angiogenesis therapy based on the bone marrow-derived stromal cells genetically engineered to express sFlt-1 in mouse tumor model.
Bone marrow-derived stromal cells (BMSCs) are important for development, tissue cell replenishment, and wound healing in physiological and pathological conditions. BMSCs were found to preferably reach sites undergoing the process of cell proliferation, such as wound and tumor, suggesting that BMSCs may be used as a vehicle for gene therapy of tumor. Mouse BMSCs were loaded with recombinant adenoviruses which express soluble Vascular Endothelial Growth Factor Receptor-1 (sFlt-1). The anti-angiogenesis of sFlt-1 in BMSCs was determined using endothelial cells proliferation inhibition assay and alginate encapsulation assay. The anti-tumor effects of BMSCs expressing sFlt-1 through tail-vein infusion were evaluated in two mouse tumor metastases models. BMSCs genetically modified with Adv-GFP-sFlt-1 could effectively express and secret sFlt-1. BMSCs loaded with sFlt-1 gene could preferentially home to tumor loci and decrease lung metastases and prolong lifespan in mouse tumor model through inducing anti-angiogenesis and apoptosis in tumors. We demonstrated that BMSCs might be employed as a promising vehicle for tumor gene therapy which can effectively not only improve the concentration of anticancer therapeutics in tumors, but also modify the tumor microenvironment.


Self-induced versus reactive triggering of synchronous movements in a deafferented patient and control subjects.
The present study investigates the contribution of tactile-kinesthetic information to the timing of movements. The relative timing of simultaneous tapping movements of finger and foot (hand-foot asynchrony) was examined in a simple reaction time task and in discrete self-initiated taps (Experiment 1), and in externally triggered synchronization tapping (Experiment 2). We compared the performance of a deafferented participant (IW) to the performance of two control groups of different ages. The pattern of results in control groups replicates previous findings: Whereas positive hand-foot asynchronies (hand precedes foot) are observed in a simultaneous reaction to an auditory stimulus, hand-foot asynchronies are negative with discrete self-initiated as well as auditorily paced sequences of synchronized finger and foot taps. In the first case, results are explained by a simultaneous triggering of motor commands. In contrast, self-initiated and auditorily paced movements are assumed to be controlled in terms of their afferent consequences, as provided by tactile-kinesthetic information. The performance of the deafferented participant differed from that of healthy participants in some aspects. As expected on the basis of unaffected motor functions, the participant was able to generate finger and foot movements in reaction to an external signal. In spite of the lack of movement-contingent sensory feedback, the deafferented participant showed comparable timing errors in self-initiated and regularly paced tapping as observed in control participants. However, in discrete self-initiated taps IW's hand-foot asynchronies were considerably larger than in control participants, while performance did not differ from that of controls in continuous movement generation. These findings are discussed in terms of an internal generation of the movement's sensory consequences (forward-modeling).


Individual differences in tolerance to shift work--a systematic review.
Shift work tolerance is a term describing the ability to adapt to shift work without adverse consequences. In this paper we systematically review literature published investigating the relation between individual differences such as age, gender, personality, morningness/eveningness as well as biological variables and different measures of shift work tolerance from 1998 till 2009. A total of 60 articles were included in this review, of which ten studies were classified as longitudinal, while the rest were classified as cross-sectional. Overall, the studies indicate that young age, male gender, low scores on morningness, high scores on flexibility and low scores on languidity, low scores on neuroticism, high scores on extraversion and internal locus of control and some genetic dispositions are related to higher shift work tolerance. More longitudinal studies, especially concerning personality, are needed to make conclusions about the predictive power of individual differences for shift work tolerance.


Adolescent Defense Style as Correlate of Problem Behavior.
Adolescent problem behaviors are often the visible results of intrapsychic distress. Defensive reactions are the unconscious means of managing intrapsychic distress. This cross-sectional study examines the strength of defensive style as measured by self-report on the Response Evaluation Measure (REM-71) relative to age, sex, and SES, as a correlate of internalizing and externalizing problem behaviors, as assessed by the Youth Self Report (YSR). A sample of 1,487 students from two suburban high schools completed self-report measures of defense style, self-esteem, and internalizing and externalizing problem behaviors. Demographic variables (age, sex, and SES) were included as covariates. Mature and immature defense style correlated as expected with problem behaviors. Demographic variables contributed minimally to the variance in the outcome variable. Defense style, as assessed by the REM-71, is a significant correlate of clinically elevated internalizing and externalizing problem behaviors in youth as in adults. This study adds to the convergent validity of the REM-71.


Hysteroscopic management of uterine diverticulum after myomectomy: a case report.
A uterine diverticulum is defined as the presence of a niche within the inner contour of the uterine myometrial wall. Although secondary uterine diverticula can occur after hysterotomy such as cesarean section, reports of diverticula after myomectomy are extremely rare. A 45-year-old nulliparous woman undergoing infertility treatment was referred to our hospital because of abnormal postmenstrual bleeding after myomectomy. Transvaginal sonography and magnetic resonance imaging revealed a diverticulum in the isthmus. Fat-saturated T1 image showed a blood reservoir in the diverticulum. Hysteroscopic surgery was performed to remove the lowed edge of the defect and coagulate the hypervascularized area. Two months after surgery, the abnormal postmenstrual bleeding and chronic endometritis improved. This report highlights the similarities of the patient's diverticulum to cesarean scar defects in terms of symptoms and pathophysiology. First, this patient developed a diverticulum with hypervascularity after myomectomy and persistent abnormal bleeding. Second, after hysteroscopic surgery, the symptoms of irregular bleeding disappeared. Third, endometrial glands were identified within the resected scar tissue. Fourth, preoperatively identified CD138-positive cells in endometrial tissue spontaneously disappeared after hysteroscopic resection. To the best of our knowledge, this is the first report of symptomatic improvement following hysteroscopic surgery in a patient with an iatrogenic uterine diverticulum with persistent irregular bleeding after myomectomy.


Study on bone density at various skeletal sites for the diagnosis of primary osteoporosis.
The objective of this study was to evaluate the diagnostic value of bone density changes in lumbar vertebrae and femoral necks in patients with primary osteoporosis (OP) at various ages. Dual-energy X-ray absorptiometry (DXA) scans were performed on patients who had their primary visits between March 2008 and February 2009. The bone mineral density (BMD) of the lumbar vertebrae 1-4 (L1-L4) in anteroposterior projection and the proximal femoral neck in lateral projection were measured. If the BMD values (T score) of any site is -2.5 or less (T ≤ -2.5), the patients were diagnosed as primary OP, and the T scores were statistically analyzed. The 81 patients who had lumbar vertebrae with a T ≤ -2.5 led to a positive rate of 80.1 % in the diagnosis of primary OP; the 47 patients who had femoral neck with a T ≤ -2.5 gave a positive rate of 47.0 %. The patients with type I or type II primary OP were divided into two age groups of ≤70 and ≥71 years old. The comparison of lumbar spine T score values did not show significant statistical difference (P > 0.05) between the age groups, while the result of the femoral necks revealed significant difference between the two groups (P < 0.001). In diagnosis of primary OP, anteroposterior lumbar spine offers a significantly higher detection rate than that of the femoral neck, but to the patients older than 70, the measurement of femoral neck may generate higher detection rate. It is more sensitive to measure lumbar trabecular bone, especially to the patients in early postmenopausal period. BMD in elderly patients may falsely increase with age, attention should be paid to the determination of the hip bone mass.


Effects of Cognitive Behavioral Therapy for Reducing Anxiety in Children with High Functioning ASD: A Systematic Review and Meta-Analysis.
Children with autism spectrum disorder (ASD) are at greater risk for experiencing high levels of anxiety symptoms. Recent evidence suggests Cognitive behavioral therapy (CBT) may also be effective for anxiety reduction in some presentations of ASD. This meta-analysis evaluated twenty-three studies. Results yielded a moderate effect size (g = - 0.66) for the reduction of anxiety symptoms. Moderators indicated larger effects for studies were achieved with parental involvement (g = - 0.85, p < .05) than with child-only treatments (g = - 0.34, p < .05). Short-term interventions generated a smaller effect (g = - 0.37 p < .05) than either standard-term (g = - 1.02, p < .05) or long-term interventions (g = - 0.69, p < .05).Implications for children with ASD are discussed.


A homoleptic alkynyl-protected [Ag9Cu6( t BuC[triple bond, length as m-dash]C)12]+ superatom with free electrons: synthesis, structure analysis, and different properties compared with the Au7Ag8 cluster in the M15 + series.
We report the first homoleptic alkynyl-protected AgCu superatomic nanocluster [Ag9Cu6( t BuC[triple bond, length as m-dash]C)12]+ (NC 1, also Ag9Cu6 in short), which has a body-centered-cubic structure with a Ag1@Ag8@Cu6 metal core. Such a configuration is reminiscent of the reported AuAg bimetallic nanocluster [Au1@Ag8@Au6( t BuC[triple bond, length as m-dash]C)12]+ (NC 2, also Au7Ag8 in short), which is also synthesized by an anti-galvanic reaction (AGR) approach with a very high yield for the first time in this study. Despite a similar Ag8 cube for both NCs, structural anatomy reveals that there are some subtle differences between NCs 1 and 2. Such differences, plus the different M1 kernel and M6 octahedron, lead to significantly different optical absorbance features for NCs 1 and 2. Density functional theory calculations revealed the LUMO and HOMO energy levels of NCs 1 and 2, where the characteristic absorbance peaks can be correlated with the discrete molecular orbital transitions. Finally, the stability of NCs 1 and 2 at different temperatures, in the presence of an oxidant or Lewis base, was investigated. This study not only enriches the M15 + series, but also sets an example for correlating the structure-property relationship in alkynyl-protected bimetallic superatomic clusters.


Visualising fat reserves in an insect: A method using X-ray micro-computerised tomography of the Common Wasp (Vespula vulgaris).
The Common Wasp, Vespula vulgaris (Hymenoptera: Vespidae), has an annual nest cycle with new colonies initiated by over-wintered queens. Survival of adult queen wasps through winter dormancy is enabled through the deposition of substantial quantities of triglycerides in fat bodies. Worker (and male) wasps lack these fat reserves. By comparing micro-CT scans of workers, pre-hibernation queens and post-hibernation queens, we demonstrate that it is possible to semi-quantitatively measure fat reserves using arbitrary X-ray attenuation ranges. Venom in the venom gland of the queen wasps, has a significantly lower X-ray attenuation value than the triglyceride-rich fat bodies. This may be due to its content of low molecular weight volatile pheromones in addition to its other known constituents. We also demonstrate the utility of micro-CT for visualising a range of physiological and anatomical features of insects. This non-destructive method for measuring fat reserves can be used on appropriately preserved or freshly collected insect specimens.


Brain cooling maintenance with cooling cap following induction with intracarotid cold saline infusion: a quantitative model.
Intracarotid cold saline infusion (ICSI) is potentially much faster than whole-body cooling and more effective than cooling caps in inducing therapeutic brain cooling. One drawback of ICSI is hemodilution and volume loading. We hypothesized that cooling caps could enhance brain cooling with ICSI and minimize hemodilution and volume loading. Six-hour-long simulations were performed in a 3D mathematical brain model. The Pennes bioheat equation was used to propagate brain temperature. Convective heat transfer through jugular venous return and the circle of Willis was simulated. Hemodilution and volume loading were modeled using a two-compartment saline infusion model. A feedback method of local brain temperature control was developed where ICSI flow rate was varied based on the rate of temperature change and the deviation of temperature to a target (32 degrees C) within a voxel in the treated region of brain. The simulations confirmed the inability of cooling caps alone to induce hypothermia. In the ICSI and the combination models (ICSI and cap), the control algorithm guided ICSI to quickly achieve and maintain the target temperature. The combination model had lower ICSI flow rates than the ICSI model resulting in a 55% reduction of infusion volume over a 6h period and higher hematocrit values compared to the ICSI model. Moreover, in the combination model, the ICSI flow rate decreased to zero after 4h, and hypothermia was subsequently maintained solely by the cooling cap. This is the first study supporting a role of cooling caps in therapeutic hypothermia in adults.


Medication-focused approach to total pain: poor symptom control, polypharmacy, and adverse reactions.
Neuropathic pain, known to have poor opioid response, can be difficult to control. Although several classes of adjuvant medications are believed to be of benefit in managing neuropathic pain, they have potential side effects that occasionally outweigh their benefits. The psychospiritual suffering of patients with advanced cancer may heighten the distress associated with physical symptoms. If undiagnosed, this may lead to increases in dose and the number of medications administered in the hope of better symptom control. This case report describes the successful interdisciplinary management of an advanced cancer patient whose multiple drug therapy had added to rather than alleviated his distress by causing more side effects than symptom relief.


Seizures following carotid endarterectomy in patients with severely compromised cerebral circulation.
To determine the incidence of postoperative neurological complications following carotid endarterectomy in patients with severely compromised cerebral circulation. Prospective open clinical study. Department of Vascular Surgery, University Hospital. We determined the incidence of postendarterectomy seizures related to haemodynamic impairment in terms of intraoperatively measured perfusion pressure in 151 patients undergoing 153 carotid endarterectomies. Cerebral perfusion pressure index (ICA/CCA pressure ratio) was significantly reduced (25% or more) in 47% (55/118) of patients with 70-99% stenosis compared to 6% (2/35) of patients with 30-69% stenosis (p < 0.00005). Among the 57 haemodynamically compromised patients five developed seizures considered due to cerebral hyperperfusion five to seven days after surgery. The seizures were associated with headache in two, focal neurological deficits in four and hypertensive episodes in all cases. The symptoms remitted within 2 weeks and no patients suffered cerebral haemorrhage. Seizures following correction of high grade stenoses causing severe pressure reduction may be more common than previously assumed. Patients at risk should be identified and postoperative blood pressure controlled meticulously.


Guanidinoacetate decreases antioxidant defenses and total protein sulfhydryl content in striatum of rats.
Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited neurometabolic disorder biochemically characterized by tissue accumulation of guanidinoacetate (GAA) and depletion of creatine. Affected patients present epilepsy and mental retardation whose pathogeny is unclear. In the present study we investigated the in vitro and in vivo (intrastriatal administration) effects of GAA on some oxidative stress parameters in rat striatum. Sixty-day-old rats were used for intrastriatal infusion of GAA. For the in vitro studies, 60-day-old Wistar rats were killed by decapitation and the striatum was pre-incubated for 1 h at 37 degrees C in the presence of GAA at final concentrations ranging from 10 to 100 microM. Parameters of oxidative stress such as total radical-trapping antioxidant potential (TRAP), antioxidant enzymes (SOD, GPx, and CAT), protein carbonyl and thiol contents were measured. DNA damage was also evaluated. Results showed that GAA administration (in vivo studies) or the addition of 100 microM GAA to assays (in vitro studies) significantly decreased TRAP, SOD activity, and total thiol levels in rat striatum. In contrast, this guanidino compound did not alter protein carbonyl content and the activities of CAT and GPx. DNA damage was not found after intrastriatal administration of GAA. The data indicate that the metabolite accumulating in GAMT deficiency decreases antioxidant capacity and total thiol content in the striatum. It is therefore presumed that this pathomechanism may contribute at least in part to the pathophysiology of the brain injury observed in patients affected by GAMT deficiency.


Pseudotumor cerebri in a boy with 11-beta-hydroxylase deficiency--a possible relation to rapid steroid withdrawal.
A boy who was known to suffer from adrenogenital syndrome due to 11-beta-hydroxylase deficiency was treated with appropriate steroid replacement, which fully compensated for the deficiency. An intercurrent febrile illness with anorexia and vomiting necessitated an abrupt discontinuation of steroids. He presented with classic signs of pseudotumor cerebri 3 days following steroid withdrawal. Our studies imply that a combination of steroid withdrawal and dehydration with increased sodium urinary excretion, caused rapid fluid shifts within the brain, resulting in intracranial hypertension. At present, when a considerable number of children are on long-term steroids for various reasons, pseudotumor cerebri should be considered in the list of complications during abrupt steroid withdrawal.


In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate.
We previously developed 2 etomidate analogs that retain etomidate's favorable hemodynamic properties but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl (MOC)-etomidate is rapidly metabolized and ultrashort acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11β-hydroxylase. We hypothesized that MOC-etomidate's labile ester could be incorporated into carboetomidate to produce a new agent that possesses favorable properties individually found in each agent. We describe the synthesis and pharmacology of MOC-(R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (MOC-carboetomidate), a "soft" analog of carboetomidate. MOC-carboetomidate's octanol:water partition coefficient was determined chromatographically and compared with those of etomidate, carboetomidate, and MOC-etomidate. MOC-carboetomidate's 50% effective concentration (EC(50)) and 50% effective dose for loss of righting reflexes (LORR) were measured in tadpoles and rats, respectively. Its effect on γ-aminobutyric acid A (GABA(A)) receptor function was assessed using 2-microelectrode voltage clamp electrophysiological techniques and its metabolic stability was determined in pooled rat blood using high performance liquid chromatography. Its duration of action and effects on arterial blood pressure and adrenocortical function were assessed in rats. MOC-carboetomidate's octanol:water partition coefficient was 3300 ± 280, whereas those for etomidate, carboetomidate, and MOC-etomidate were 800 ± 180, 15,000 ± 3700, and 190 ± 25, respectively. MOC-carboetomidate's EC(50) for LORR in tadpoles was 9 ± 1 μM and its EC(50) for LORR in rats was 13 ± 5 mg/kg. At 13 μM, MOC-carboetomidate enhanced GABA(A) receptor currents by 400% ± 100%. Its metabolic half-life in pooled rat blood was 1.3 min. The slope of a plot of the duration of LORR in rats versus the logarithm of the hypnotic dose was significantly shallower for MOC-carboetomidate than for carboetomidate (4 ± 1 vs 15 ± 3, respectively; P = 0.0004123). At hypnotic doses, the effects of MOC-carboetomidate on arterial blood pressure and adrenocortical function were not significantly different from those of vehicle alone. MOC-carboetomidate is a GABA(A) receptor modulator with potent hypnotic activity that is more rapidly metabolized and cleared from the brain than carboetomidate, maintains hemodynamic stability similar to carboetomidate, and does not suppress adrenocortical function.


Coupled sodium-chloride influx across brush border of flounder intestine.
Measurements of the unidirectional influxes of Na and Cl from the mucosal solution into the epithelium (Jme) of flounder intestine under short-circuit conditions reveal the presence of a coupled NaCl influx process at the brush border membrane which appears to be essential for the absorption of these ions. JClme and JName were inhibited by replacing Na or Cl, respectively, in the bathing media with non-transported ions which also reduced the short-circuit current (Isc) to near-zero values. Addition of furosemide to the mucosal solution alone inhibited the Isc and reduced JClme and JName under control conditions, but not in the absence of Na or Cl, respectively. The reductions in JClme and JName elicited by ion replacement or furosemide were approximately equal, suggesting that the coupled influx mechanism mediates a one-for-one entry of these ions into the cell from the mucosal solution. Furosemide inhibited Cl absorption by reducing the unidirectional Cl flux from mucosa to serosa, consistent with its inhibition of the influx process. As in other epithelia, coupled NaCl influx is inhibited by cyclic AMP, which accounts for the decrease in Cl absorption elicited by cyclic nucleotides. These results support the notion that transcellular NaCl transport is a neutrla process and that the serosa-negative transepithelial electrical potential difference and preponderance of Cl over Na absorption under short-circuit conditions result from dissimilar permeabilities of the paracellular pathway to Na and Cl.


Metabolic studies on rabbit bladder smooth muscle and mucosa.
Recent studies indicate that the mucosa of the urinary bladder may play a major role in the maintenance of normal bladder function. The mucosal surface of the urinary bladder serves as a protective layer against the irritative solutes found in the urine. The integrity of this barrier can be broken by overdistension, anoxia, detergents, alcohols, bacterial infection and by contact with agents to which the mucosa has been sensitized. In view that both anoxia and ischemia can mediate a breakdown in the role of the mucosal layer as a permeability barrier, it is reasonable to assume that this function is dependent on cellular metabolism. As an initial investigation we have compared a variety of biochemical and metabolic parameters between the mucosal layer (consisting of the lamina propria, urothelium, and any connective tissue and vascular tissue within this layer); and the muscularis layer. The results of these studies demonstrated that the rate of glucose metabolism to lactic acid (LA) of the mucosa was more than three-fold greater than that of the smooth muscle. The rate of CO2 production of the mucosa was 60% greater than that of the unstimulated smooth muscle. The maximal activity of the mitochondrial enzyme citrate synthase was significantly greater in the mucosa than in the smooth muscle, however, the activity of malate dehydrogenase was similar for both tissues. The maximal activity of the cytosolic enzyme creatine kinase was more than two-fold greater in the bladder smooth muscle than in the mucosa; although the affinities of the creatine kinase isoforms of the mucosa were significantly greater than those of the muscle.(ABSTRACT TRUNCATED AT 250 WORDS)


[Carfilzomib-induced haemolytic and uremic syndrome: Favorable outcome with eculizumab].
Thrombotic microangiopathies are rare diseases characterized by an initial endothelial injury and the formation of thrombi in the microcirculation. Several types of thrombotic microangiopathies can be distinguished: the thrombotic thrombocytopenic purpura; the hemolytic and uremic syndrome, mainly "typical" following a shiga toxin-producing Escherichia coli infection or "atypical" due to a dysregulation of the alternative complement pathway; and "secondary" thrombotic microangiopathies. The use of drug treatments is reported as a frequent cause in this last category and requires stopping the offending drug. We report the case of a patient who developed "secondary" hemolytic and uremic syndrome associated with carfilzomib, a proteasome inhibitor which is used in case of multiple myeloma relapses. Besides stopping the treatment, the patient still showed signs of hemolysis and renal failure with anuria requiring hemodialysis. An eculizumab treatment was therefore initiated. The overall evolution was favorable and an improvement of the renal function promptly allowed the discontinuation of hemodialysis. We discuss the mechanisms that may activate the alternative complement pathway and the potential interest of a transient use of eculizumab in case of carfilzomib-induced hemolytic and uremic syndrome.


A two-phase pathogenesis of graft-versus-host disease in mice.
Activation of donor T cells is required for the development of graft-versus-host disease (GVHD), a major complication of bone marrow transplantation. We investigated a murine model of GVHD across major and minor histocompatibility barriers. BALB/c recipients were lethally irradiated and transplanted with 10(7) bone marrow and 5 x 10(6) spleen cells from C57BL/6 donors. There were two separate phases of clinical disease. The first phase was most severe on day 7 after transplant. Weight and condition improved until day 12 and then a second phase of clinical GVHD commenced, which persisted until euthanasia. IL-2 mRNA expression, as a measure of T cell activation, was determined by quantitative PCR. The two phases of clinical GVHD were preceded by two separate peaks of IL-2 mRNA in the spleen. Host MHC class II(+) cells became undetectable by flow cytometry 7 days after transplantation, whereas donor MHC class II(+) cells increased during the first 9 days after transplantation. Removal of donor MHC class II(+) cells from the graft had no effect on the first phase. Possible roles for host and donor antigen-presenting cells (APC) in the two phases of the disease are discussed.


Are We Floating Yet? Duration of Fixed Exchange Rate Regimes.
This study examines the duration of fixed exchange rate regimes to determine the factors that impact the probability of an exit from a peg. Using de facto exchange rate regime classification, we find that duration of a peg is non-monotonic. The results of the semi-parametric proportional hazard model highlight that GDP growth and openness decrease the probability of an exit from a peg, while growing unemployment and increasing claims on government increase the likelihood of abandoning a peg. The negative impact of economic growth on the hazard rate is robust when we use marginal risk analysis and net foreign assets and inflation are found to influence the pegged regime duration.