The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.

OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. METHODS: A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). RESULTS: Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. CONCLUSIONS: Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. TRIAL REGISTRATION NUMBER: NCT00976599.

Conservative management of preterm premature rupture of membranes beyond 32 weeks' gestation: is it worthwhile?

We aimed to investigate whether conservative management of preterm premature rupture of membranes (PPROM) at 32-34 weeks' gestation improves outcome. In this retrospective analysis of singleton pregnancies, the study group included patients with PPROM at 28-34 weeks' gestation and the control group included patients presented with spontaneous preterm delivery at 28-34 weeks' gestation. Both groups were subdivided according to gestational age - early (28-31 weeks' gestation) versus late (32-34 weeks' gestation). Adverse neonatal outcome included neonatal death, intraventricular haemorrhage grade 3/4, respiratory distress syndrome, periventricular leucomalacia and neonatal sepsis. The study and control groups included 94 and 86 women, respectively. The study group had a lower incidence of adverse neonatal outcome at the earlier weeks (28-31), compared with the control group at the same gestational age. In contrast, at 32-34 weeks' gestation no difference in the risk for adverse neonatal outcome was noticed. Additionally, within the study group, chorioamnionitis rate was significantly higher among those who delivered at 32-34 weeks' gestation (p < 0.01). No advantage for conservative management of PPROM was demonstrated beyond 31 weeks' gestation. Moreover, conservative management of PPROM at 32-34 weeks' gestation may expose both mother and neonate to infectious morbidity.

Mathematically aggregating experts' predictions of possible futures.

Structured protocols offer a transparent and systematic way to elicit and combine/aggregate, probabilistic predictions from multiple experts. These judgements can be aggregated behaviourally or mathematically to derive a final group prediction. Mathematical rules (e.g., weighted linear combinations of judgments) provide an objective approach to aggregation. The quality of this aggregation can be defined in terms of accuracy, calibration and informativeness. These measures can be used to compare different aggregation approaches and help decide on which aggregation produces the "best" final prediction. When experts' performance can be scored on similar questions ahead of time, these scores can be translated into performance-based weights, and a performance-based weighted aggregation can then be used. When this is not possible though, several other aggregation methods, informed by measurable proxies for good performance, can be formulated and compared. Here, we develop a suite of aggregation methods, informed by previous experience and the available literature. We differentially weight our experts' estimates by measures of reasoning, engagement, openness to changing their mind, informativeness, prior knowledge, and extremity, asymmetry or granularity of estimates. Next, we investigate the relative performance of these aggregation methods using three datasets. The main goal of this research is to explore how measures of knowledge and behaviour of individuals can be leveraged to produce a better performing combined group judgment. Although the accuracy, calibration, and informativeness of the majority of methods are very similar, a couple of the aggregation methods consistently distinguish themselves as among the best or worst. Moreover, the majority of methods outperform the usual benchmarks provided by the simple average or the median of estimates.

Listeriosis in pregnancy: under-diagnosis despite over-treatment.

OBJECTIVE: To compare the symptomatology of pregnant women with suspected listeriosis to culture confirmed listeriosis. STUDY DESIGN: All cases of suspected and culture confirmed pregnancy-associated listeriosis from a single center were retrospectively reviewed assessing demographics, clinical, laboratory and pathological findings, and maternal, fetal and neonatal outcomes. RESULTS: Listeriosis was identified in seven patients, none of whom belonged to the 117 women with suspected listeriosis. Women with confirmed infection were more likely to exhibit fever (P=0.01), flu-like symptoms (P=0.006), threatened preterm labor (P=0.05) and inflammatory markers (P=0.02), but less likely to exhibit gastrointestinal complaints (P=0.004) in comparison with suspected non-confirmed cases. Confirmed cases resulted in preterm delivery (n=5) and stillbirth (n=2). Neonatal complications included meningitis, respiratory disease and sepsis. Maternal outcomes were favorable. CONCLUSION: Although 'febrile gastroenteritis' is a poor predictor of listeriosis in pregnancy, fever, premature contractions and inflammatory markers are important risk indices prompting workup and adequate empiric treatment.

Evidence for the role of platelet-activating factor in immune complex vasculitis in the rat.

These studies were designed to determine the role of platelet-activating factor (PAF) in the pathogenesis of immune complex (IgG) induced dermal vasculitis in the rat. In vitro, very low (pM and nM) concentrations of PAF "primed" rat neutrophils for enhanced O2-. responses to IgG immune complexes while higher concentrations were directly stimulatory. The PAF receptor antagonist, L-652,731, blocked responses (O2-. production and enzyme release) of rat neutrophils stimulated with PAF but did not block responses triggered by immune complexes, formyl chemotactic peptide or opsonized zymosan particles. When L-652,731 was added to the antibody employed in the reversed passive Arthus reaction, the injury resulting from immune complex-induced vasculitis was significantly attenuated. In order to determine if in vivo protection provided by L-652,731 was related to neutrophils, we developed a new model in which rats are systemically depleted of neutrophils by cyclophosphamide and then locally reconstituted with intact neutrophils in a manner that allows restoration of immune complex-induced vascular injury. With this model, we demonstrated that the effects of neutrophil reconstitution are substantially diminished if the cells are pretreated with L-652,731 and then washed. By priming neutrophils with substimulatory concentrations of PAF, we have also provided in vivo evidence that neutrophil priming can increase the magnitude of vascular injury. These data provide evidence that vascular injury associated with immune complex dermal vasculitis is related to availability of PAF receptors on neutrophils, suggesting a mechanism through which PAF may function as a mediator in the pathogenesis of immune complex vasculitis.

The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the immunogenicity, safety, and efficacy of 50 mg/mL liquid etanercept. METHODS: In a multicenter, open-label study, adults with active rheumatoid arthritis (RA) received 50 mg/mL liquid etanercept subcutaneously once weekly for 24 weeks. Immunogenicity was assessed at baseline and weeks 24 and 28, safety at all study visits, and efficacy at baseline and weeks 12 and 24. RESULTS: Of 222 treated patients, 88% completed the study; 81% were women; 84% were white; mean age was 53 years; mean RA duration was 10 years. Antibodies to etanercept, all non-neutralizing, were detected in 12 of 214 patients; 7 of the 12 were borderline positive (antibody titers <1:50). The presence of non-neutralizing anti-etanercept antibodies did not appear to affect clinical safety or efficacy. Few patients reported serious adverse events (6.3%), serious infections (2.3%), or withdrew because of adverse events (4.5%). Most adverse events were mild or moderate. The most common event, injection site reaction, occurred in 29.3% patients. At week 24, 63% of patients achieved an ACR20 response, 36% an ACR50 response, and 14% an ACR70 response. Similar responses were apparent by week 12. Week 24 mean improvement in the Health Assessment Questionnaire disability index scores was 0.6 points; improvement in the Short Form-36 Physical Component Score was 10.0 points. CONCLUSION: The 50 mg/mL liquid etanercept formulation administered once weekly was well tolerated. The incidence of anti-etanercept antibodies, the nature and frequency of adverse events, and improvements in signs and symptoms of RA and patient physical function were similar to those in previous etanercept studies.

Decreased neonatal tibial bone ultrasound velocity in term infants born after breech presentation.

OBJECTIVE: Fetuses found to be in the breech presentation have limited motion of their lower limbs. The aim of this study was to test the hypothesis that bone speed of sound (SOS) would be lower in infants born after breech presentation than in those born after vertex presentation. STUDY DESIGN: We studied 127 singleton, appropriate for gestational age, term infants delivered by a scheduled cesarean delivery at approximately 38 weeks of gestation because of breech presentation or repeat elective cesarean section with vertex presentation. We used the Sunlight Omnisense 7000p device to measure axially transmitted SOS of the right tibia within the first 96 h of life. RESULT: Fifty-three infants studied (42%) were born by cesarean section after breech presentation compared to 74 vertex controls. Bone SOS was significantly lower in the breech presentation group, even after taking into account the effect of gender and parity (as well as gestational age at birth and birth weight). CONCLUSION: Bone SOS is lower in infants born after breech presentation than in those born after vertex presentation. We speculate that limited motion of lower limbs in fetuses found to be in the breech presentation leads to a decrease in bone mineralization and strength.

The effect of maternal habitus on macronutrient content of human milk colostrum.

OBJECTIVE: There is a paucity of studies on the impact of maternal body mass index (BMI) on macronutrient content of human milk colostrum (HMC). The objective of this study was to compare macronutrient content of HMC in healthy women of term infants in relation to their BMI. We hypothesized that mother habitus influences human milk colostrum content. METHOD: Colostrum was collected from 109 healthy mothers of hospitalized healthy term infants divided into four prepregnancy BMI groups: 12 underweight, 59 normal weight, 20 overweight, and 18 obese women between 24 and 72 h after birth. Macronutrient content was measured using mid-infrared spectroscopy. RESULTS: There were no significant differences in macronutrients between the BMI groups. We performed four separate stepwise backward multiple regression analyses taking into account fat, carbohydrate, protein or energy content as dependent variables and maternal BMI, parity, gestational age, infant gender, maternal age, maternal education, mode of delivery and time postdelivery. In these analyses, fat, carbohydrate and energy content were not related to maternal BMI, while protein content was significantly and positively correlated with BMI (P=0.008) and negatively correlated with gestational age (P=0.004) and time postdelivery (P<0.001). Colostrum carbohydrate content was positively correlated with parity. Colostrum fat and energy content were negatively correlated with maternal age and positively correlated with parity. CONCLUSION: Most macronutrient and energy content of colostrum are unaffected by prepregnancy maternal BMI, with the exception of protein content that is positively related to maternal BMI.

Use of Doppler ultrasound in the management of uteroplacental perfusion during cardiopulmonary bypass in pregnancy.

Cardiopulmonary bypass, the extreme of non-obstetric surgery during pregnancy, presents unique challenges to minimize maternal and fetal risk. We present our experience with a woman who was diagnosed with a left atrial myxoma following an ischemic cerebrovascular accident. We discuss clinical management specific to cardiopulmonary bypass during pregnancy and delivery in the context of a multidisciplinary team approach. We recommend using intermittent Doppler ultrasound as a non-invasive real-time assessment of uteroplacental perfusion during non-obstetric surgery in pregnancy. Monitoring of perfusion facilitates active feedback for appropriate in utero resuscitation in these cases.

The effect of between-breast differences on human milk macronutrients content.

OBJECTIVE: Little is known about the effect of maternal handedness and preferential side of breastfeeding upon macronutrients concentration in human milk (HM). We aimed to compare macronutrients content of HM from both breasts, taking into account the self-reported preferential feeding ('dominant') breast, breast size and handedness (right versus left). We tested the null hypothesis that macronutrients content of HM is not affected by breast dominancy, breast size or maternal handedness. STUDY DESIGN: Fifty-seven lactating mothers were recruited. HM macronutrients were measured after mid manual expression using infrared transmission spectroscopy. RESULTS: Out of the 57 mothers recruited, 12 were excluded from the analyses because they brought in insufficient samples. Among the 22 who reported a size difference, 16 (73%) had a larger left breast (P<0.001). Approximately a third of women reported no breastfeeding side dominance, a third reported a right dominance and another third reported a left dominance. Breastfeeding side dominance was unaffected by either handedness or breasts size. When size asymmetry was reported (n=22) the dominant side was also the larger breast in 16 (73%) women, the smaller breast in 2 (9%) women, whereas 4 (18%) additional women with asymmetry had no preferential breastfeeding side. There were no statistically significant differences in macronutrients between the right and the left breasts. In multiple stepwise backward regression analysis, fat, carbohydrate, protein and energy contents were unaffected by maternal handedness, breast side dominance or breast size asymmetry. CONCLUSIONS: Macronutrients content of mid expression HM is unaffected by maternal handedness, breast size or breast side dominance.

Breast milk fat content of mothers to small-for-gestational-age infants.

OBJECTIVE: Little is known about the composition of human milk (HM) expressed by mothers of asymmetrically growth-restricted infants. To test the null hypothesis that lactating mothers of small-for-gestational-age (SGA) infants produce milk with fat content similar to that of lactating mothers of infants whose growth is appropriate for gestational age (AGA). STUDY DESIGN: Fifty-six lactating mothers of newborns (26 SGA and 30 AGA) were recruited within the first 3 days of delivery. Creamatocrit (CMT) levels in HM were measured at 72 h, 7 days and 14 days postdelivery in capillary tubes after centrifugation at 9000 r.p.m. for 5 min. RESULT: The groups did not differ in terms of maternal age, body mass index, gestational age (GA), pregnancy weight gain and parity. They differed significantly in terms of infant's birth weight by design. The mean CMT levels at the three time points were similar for the two groups. This remained true when timing of the sample (colostrum, transitional, mature milk) was introduced as a confounder in the analysis of variance (general linear model). CONCLUSION: Fat content of HM is not affected by fetal growth status. We suggest that mothers of SGA infants may be reassured that their milk contains adequate amount of fat that is appropriate for the growth of their infants.

Role of O2- in neutrophil recruitment into sites of dermal and pulmonary vasculitis.

Using analogous models of acute dermal vasculitis and alveolitis in rats, we have examined the role of oxygen-derived metabolities in the tissue damage associated with neutrophil influx into sites of immune complex deposition. In the lung, as previously reported, catalase and deferoxamine are highly protective, while superoxide dismutase (SOD) has a transient protective effect. The xanthine oxidase inhibitors, allopurinol, and lodoxamide, are also protective. In the skin, neither catalase (which has been covalently linked to the antibody) nor deferoxamine is protective, suggesting that H2O2 and iron are not absolutely required for the development of dermal vasculitis. In the skin, SOD, as well as the inhibitors of xanthine oxidase, have protective effects. These data suggest that the neutrophil-mediated pathways of immune complex injury in the dermal and pulmonary microvascular compartments are fundamentally different. As a measurement of neutrophil accumulation, measurements of myeloperoxidase in tissue extracts have been employed. In both the lung and skin, the protective effects of SOD and the xanthine oxidase inhibitors are paralleled by reductions in neutrophil influx into sites of injury. In contrast, catalase and deferoxamine have no effect on neutrophil accumulation. These data suggest that vascular beds in rat skin and lung are fundamentally different with respect to mechanisms of acute immune complex mediated injury. The data also provide evidence that O2- contributes significantly to the accumulation of neutrophils.

When prosody fails to cue syntactic structure: 9-month-olds' sensitivity to phonological versus syntactic phrases.

According to prosodic bootstrapping accounts of syntax acquisition, language learners use the correlation between syntactic boundaries and prosodic changes (e.g., pausing, vowel lengthening, large increases or decreases in fundamental frequency) to cue the presence and arrangement of syntactic constituents. However, recent linguistic accounts suggest that prosody does not directly reflect syntactic structure but rather is governed by independent prosodic units such as phonological phrases. To examine the implications of this view for the prosodic bootstrapping hypothesis, infants in Experiment 1 were presented with sentences in which pauses were inserted either between the subject noun phrase (NP) and verb or after the verb. Half of the infants heard sentences with lexical NP subjects, in which prosodic structure is consistent with syntactic structure. The other half heard sentences with pronoun subjects, in which prosodic structure does not mirror syntactic structure. In a preferential listening paradigm, infants in the lexical NP condition listened longer to materials containing pauses between the subject and verb, the main syntactic constituents. However, in the pronoun NP condition, infants showed no difference in listening times for the two pause locations. To determine if other sentence types containing pronoun subjects potentially provide information about the syntactic constituency of these elements, infants in Experiment 2 heard yes-no questions with pronoun subjects, in which the prosodic structure reflects the constituency of the subject. Infants listened longer when pauses were inserted between the subject and verb than after the verb. Taken together, our results suggest that the prosodic information in an individual sentence is not always sufficient to assign a syntactic structure. Rather, learners must engage in active inferential processes, using cross-sentence comparisons and other types of information to arrive at the correct syntactic representation.

Does sentential prosody help infants organize and remember speech information?

Theories that propose a mapping between prosodic and syntactic structures require that prosodic units in fluent speech be perceptually salient for infants. Although previous studies have demonstrated that infants are sensitive to prosodic markers of syntactic units, they do not show that prosodic information really has an impact on how infants encode the speech they hear. Two experiments were conducted to examine whether infants as young as 2 months old might actually use the prosody afforded by sentences to organize and remember spoken information. The results suggest that infants better remember the phonetic properties of (1) words that are prosodically linked together within a single clause as opposed to individual items in a list (Experiment 1); and (2) words that are prosodically linked within a single clausal unit as opposed to spanning two contiguous fragments (Experiment 2). Taken together, the evidence from both experiments suggests that the prosodic organization of speech into clausal units enhances infants' memory for spoken information. These findings are discussed with regard to their implications for theories of language acquisition.

Identification and voluntary reduction of vancomycin use for perioperative antibiotic prophylaxis during coronary artery bypass graft surgery.

Vancomycin prophylaxis for coronary artery bypass graft surgery without prosthetic valve implantation voluntarily decreased from 94% to 18% in one medical center. Median hospital stay (10 vs 9 days, P = .30) and number of postoperative infections (17.0% vs 14.3%, P = .60) did not differ among patients who received vancomycin and those who did not.

Evidence for purinergic neurotransmission in the urinary bladder of pithed rats.

The purpose of this study was to investigate the contribution of adenosine-5'-triphosphate (ATP) to segmental (L6-S2) spinal electrical stimulation evoked increases in intra-vesical pressure in pithed rats. Exogenous ATP and substance P produced dose-dependent increases in intra-vesical pressure (ED10 mmHg (dose required to elicit 10 mmHg increase in intra-vesical pressure)= 1.7 mg/kg and 1.1 microg/kg, i.v., respectively). Desensitisation (or antagonism) of P2x purinoceptors with alpha,beta-methylene ATP (alpha,beta-meATP; 30 microg/kg per min, i.v.) or pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS; 10 mg/kg, i.v.) significantly (p < 0.05) antagonized the intra-vesical pressure responses to ATP (> 8 and 3.6-fold increase in ED10 mmHg, respectively) but had no significant effect on intra-vesical pressure responses to substance P. Spinal stimulation evoked frequency-dependent increases in intra-vesical pressure (EF20 mmHg (frequency required to produce 20 mmHg increase in intra-vesical pressure) = 3.4 Hz). Blockade of muscarinic cholinoceptors and adrenoceptors with atropine (3 mg/kg, i.v.), propranolol (3 mg/kg, i.v.) and phentolamine (10 mg/kg, i.v.) produced marginal attenuation of the intra-vesical pressure responses to spinal stimulation indicating a major non-adrenergic non-cholinergic (NANC) component in the overall response. The NANC responses were significantly (p < 0.05) antagonized by alpha,beta-meATP (30 microg/kg per min, i.v.) and PPADS (10 mg/kg, i.v.) (> 2.6-fold increase in EF20 mmHg), consistent with involvement of a purinergic neurotransmitter, presumably ATP. Comparative studies in young (4-6 months) and old (21-23 months) Fischer rats revealed no age-dependent changes in the relative contribution of the cholinergic and purinergic systems, with the latter being the dominant one. These findings suggest that purinergic neurotransmission, presumably mediated by ATP acting via P2x purinoceptors, represents a major component of excitatory innervation to the urinary bladder in pithed rats.

Deficits in spontaneous behavior and cognitive function following systemic administration of kainic acid.

Recurrent seizures leading to status epilepticus were induced in rats by a 10 mg/kg subcutaneous injection of kainic acid (KA). After a 4-day recovery period, the KA-treated animals showed a syndrome of increased activity in an open field, hyperreactivity in response to handling, and deficits in acquisition of both passive avoidance and spatial learning tasks. The second experiment demonstrated that KA also caused deficits in learning to approach a visible platform in a water maze. Two months after the initial treatment, the animals were still hyperactive and deficient in passive avoidance acquisition; however, they performed normally on the spatial learning task. These results reflect both the convulsive effects of KA, which produce transient retardation, and the brain damage to limbic system structures, which accounts for the permanent deficits.

Counterfactual thinking and ascriptions of cause and preventability.

Research suggests that counterfactuals (i.e., thoughts of how things might have been different) play an important role in determining the perceived cause of a target outcome. Results from 3 scenario studies indicate that counterfactual content overlapped primarily with thoughts of how an outcome might have been prevented (preventability ascriptions) rather than with thoughts of how it might have been caused (causal ascriptions). Counterfactuals and preventability ascriptions focused mainly on controllable antecedents, whereas causal ascriptions focused mainly on antecedents that covaried with the target outcome over a focal set of instances. Contrary to current theorizing, causal ascriptions were unrelated to counterfactual content (Study 3). Results indicate that the primary criterion used to recruit causal ascriptions (covariation) differs from that used to recruit counterfactuals (controllability).

Nosocomial cutaneous abscesses in septic infants.

OBJECTIVE: To retrospectively study the epidemiology of nosocomial cutaneous abscesses in 46 consecutive septic infants. RESULTS: Ten infants had one abscess or more. Surviving infants with abscesses had a longer duration of bacteraemia, which disappeared within 24 hours of drainage. CONCLUSION: Infants with persistent bacteraemia should be examined regularly for the presence of abscesses.

Two unusual strains of Candida arthritis.

Candida arthritis is an uncommon cause of infectious arthritis that may occur in seriously ill or immunosuppressed patients. This report describes two patients, one who developed Candida tropicalis arthritis and another patient who developed C. parapsilosis arthritis. One patient developed nephrogenic diabetes insipidus secondary to amphotericin B therapy and was successfully treated with intravenous miconazole. The other was unsuccessfully treated with both intraarticular and intravenous amphotericin B.