Loneliness in young people: a multilevel exploration of social ecological influences and geographic variation.

BACKGROUND: Loneliness is a growing public health concern, yet little is known about loneliness in young people. The current study aimed to identify social ecological factors related to loneliness and examine the extent to which geographic region may account for differences in loneliness. METHODS: The data come from a cross-sectional sample of 6503 young people living in the UK. Loneliness was measured using the UCLA 3-item scale. Bivariate analyses were used to test associations between each predictor and loneliness. Multilevel models were used to identify key social ecological factors related to loneliness, and the extent to which loneliness may vary across geographic regions (local authority districts). RESULTS: Sociodemographic, social, health and well-being, and community factors were found to be associated with loneliness. Geographic region was associated with 5-8% of the variation in loneliness. The effect of gender, sexual orientation and minority ethnic background on loneliness differed across regions. CONCLUSIONS: This is the first study to highlight modifiable social and community factors related to youth loneliness, and individual vulnerabilities, such as poor mental well-being. Results related to geographic differences suggest that local-level initiatives may be most appropriate in tackling loneliness, rather than wider, less contextualized national efforts.

Positive reinforcement targeting abstinence in substance misuse (PRAISe): Study protocol for a Cluster RCT & process evaluation of contingency management.

There are approximately 256,000 heroin and other opiate users in England of whom 155,000 are in treatment for heroin (or opiate) addiction. The majority of people in treatment receive opiate substitution treatment (OST) (methadone and buprenorphine). However, OST suffers from high attrition and persistent heroin use even whilst in treatment. Contingency management (CM) is a psychological intervention based on the principles of operant conditioning. It is delivered as an adjunct to existing evidence based treatments to amplify patient benefit and involves the systematic application of positive reinforcement (financial or material incentives) to promote behaviours consistent with treatment goals. With an international evidence base for CM, NICE recommended that CM be implemented in UK drug treatment settings alongside OST to target attendance and the reduction of illicit drug use. While there was a growing evidence base for CM, there had been no examination of its delivery in UK NHS addiction services. The PRAISe trial evaluates the feasibility, acceptability, clinical and cost effectiveness of CM in UK addiction services. It is a cluster randomised controlled effectiveness trial of CM (praise and financial incentives) targeted at either abstinence from opiates or attendance at treatment sessions versus no CM among individuals receiving OST. The trial includes an economic evaluation which explores the relative costs and cost effectiveness of the two CM intervention strategies compared to TAU and an embedded process evaluation to identify contextual factors and causal mechanisms associated with variations in outcome. This study will inform UK drug treatment policy and practice. Trial registration ISRCTN 01591254.

Neuroprotective potential of CB1 receptor agonists in an in vitro model of Huntington's disease.

BACKGROUND AND PURPOSE: The therapeutic potential of cannabinoids in Huntington's disease (HD) has been investigated by several groups with complex and sometimes contrasting results. We sought to examine key points of intersection between cannabinoid receptor 1 (CB(1)) signalling, survival and the formation of mutant huntingtin aggregates in HD. EXPERIMENTAL APPROACH: Using a simplified pheochromocytoma (PC12) cell model of HD expressing exon 1 of wild-type or mutant huntingtin, we assayed cell death and aggregate formation using high-throughput cytotoxicity and image-based assays respectively. KEY RESULTS: CB(1) activation by HU210 conferred a small but significant level of protection against mutant huntingtin-induced cell death. Pertussis toxin uncoupled HU210 from the inhibition of cAMP, preventing rescue of cell death. Phosphorylation of extracellular signal-regulated kinase (ERK) was also critical to CB(1)-mediated rescue. Conversely, treatments that elevated cAMP exacerbated mutant huntingtin-induced cell death. Despite opposing effects on HD cell survival, both HU210 and compounds that elevated cAMP increased the formation of mutant huntingtin aggregates. The increase in aggregation by HU210 was insensitive to Pertussis toxin and UO126, suggesting a G-protein alpha subtype s (G(s))-linked mechanism. CONCLUSIONS AND IMPLICATIONS: We suggest that the CB(1) receptor, through G-protein alpha subtype i/o (G(i/o))-linked, ERK-dependent signal transduction, is a therapeutic target in HD. However the protective potential of CB(1) may be limited by promiscuous coupling to G(s), the stimulation of cAMP formation and increased aggregate formation. This may underpin the poor therapeutic efficacy of cannabinoids in more complex model systems and suggest that therapies that are selective for the G(i/o), ERK pathway may be of most benefit in HD.

Simultaneous intrauterine and ovarian pregnancy following treatment with clomiphene citrate.

Heterotopic pregnancy is increasingly being diagnosed since the advent of assisted reproductive technology involving the use of superovulatory drugs and/or in-vitro fertilization and the availability of high-resolution ultrasound scans. There are reports of Heterotopic tubal pregnancies following clomiphene use. Heterotopic ovarian pregnancies are however rare. Clomiphene citrate, which is widely used in the primary care setting to treat anovulatory infertility, is felt safe. We present a case of heterotopic ovarian pregnancy following treatment with clomiphene citrate. The diagnosis and management of heterotopic ovarian pregnancy are also discussed.

Biaryl ether retrohydroxamates as potent, long-lived, orally bioavailable MMP inhibitors.

A novel series of biaryl ether reverse hydroxamate MMP inhibitors has been developed. These compounds are potent MMP-2 inhibitors with limited activity against MMP-1. Select members of this series exhibit excellent pharmacokinetic properties with long elimination half-lives (7 h) and high oral bioavailability (100%).

Discovery and characterization of the potent, selective and orally bioavailable MMP inhibitor ABT-770.

Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.

System integration: a necessity.

Healthcare organizations are undergoing tremendous change in an attempt to become more flexible and adaptive. To be successful in any such transformation, organizations must build processes and systems that allow them to move with change and create a culture that allows individuals to thrive amid change. The authors describe how a community teaching hospital has attempted this through its partnership in a vertically integrated delivery system, its reorganization to product line management, its adoption of a shared governance structure, and its commitment to building a culture with strong relationships. Many of these processes and systems are in their infancy, but an examination of the journey will inform other organizations as they respond to change.

Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors.

A series of succinyl hydroxamate MMP inhibitors were prepared incorporating an aryl amino ketone moiety in place of the more typical C-terminal amino acid amides. Compounds of the C-terminal ketone series displayed potent inhibition of MMPs. Several compounds of the series were shown to be orally bioavailable.

Improving the in vivo duration of 5-lipoxygenase inhibitors: application of an in vitro glucuronosyltransferase assay.

An in vitro glucuronidation assay was used to optimize a series of N-hydroxyurea-containing 5-lipoxygenase inhibitors for metabolic stability. The glucuronidation of these compounds in cynomolgus monkey microsomes followed Michaelis-Menten kinetics allowing calculation of V(max) and K(M). The V(max) values ranged from 0.02 to 7.9 nmol/min/mg microsomal protein, a 400-fold difference, whereas K(M) ranged from 204 to 2500 microM, only a 12-fold difference. In vitro intrinsic clearance values (CL(int) were calculated for 18 compounds tested in the kinetic assay and compared with the in vivo plasma clearance (CL(p)) calculated from intravenous studies done in cynomolgus monkeys. These initial results suggested a relationship between the in vitro CL(int) and in vivo duration as defined by CL(p). A more rapid in vitro assay was developed in a 96-well format using a single concentration of substrate (100 microM) from which a glucuronidation rate was calculated. The results from this assay for 40 compounds correlated with in vivo plasma clearance (r = 0.57). This more efficient assay was used to test more than 100 compounds and develop structure-metabolism relationships based on metabolic stability and improved duration. The culmination of this effort contributed to the discovery of ABT-761, a 5-lipoxygenase inhibitor with in vivo duration in monkey improved 40-fold over thefirst generation inhibitor. Further studies performed in human liver microsomes demonstrated a similar trend that was corroborated by the 8-fold increase in duration after oral dosing in humans observed with ABT-761.

Pharmacological modulation of eosinophil influx into the lungs of Brown Norway rats.

A model of lung inflammation was developed in Brown Norway rats. Intense lung eosinophilia was induced by a single intravenous injection of Sephadex G-200 particles. The eosinophilia observed was preceded by an increase in cysteinyl leukotrienes found in lung lavage fluids. Theophylline and albuterol were tested in the model and found to be inactive, while dexamethasone was effective. Zileuton, a specific leukotriene inhibitor, was found to effectively inhibit leukotriene formation and the influx of eosinophils into the lungs of these Sephadex-treated animals. Studies with specific leukotriene D4 antagonists of the cysLT1 type receptor indicate that this leukotriene receptor is probably not involved directly in the eosinophilic inflammation. This model appears to be useful in characterizing potential anti-inflammatory effects of inhibitors by evaluating their ability to prevent eosinophil influx into the lung.

Oxytocin deficiency at delivery with epidural analgesia.

The effect of epidural analgesia on oxytocin release during the second stage of normal labour was studied by comparing 10 primigravidae who had epidurals with 10 control subjects who did not have epidurals. A significant increment in oxytocin between paired peripheral blood samples taken at the onset of full cervical dilatation and crowning of the fetal head was found in the control subjects but not in those with epidurals. Forceps delivery was required more often in the group with epidural analgesia and was associated with lower oxytocin levels at crowning. Since distension of the lower birth canal and stimulation of pelvic autonomic nerves leads to oxytocin release, and the need for forceps associated with epidurals can be reduced by oxytocin, these differences are attributed to the lumbar epidural block.

6-oxo-prostaglandin F1 alpha and thromboxane B2 in uterine vein blood--a possible role in menstrual bleeding.

The role of the haemostatic system in relation to menstrual bleeding is poorly understood. Platelet retention to glass beads and plasma concentrations of 6-oxo-PGF1 alpha and thromboxane B2 were measured in uterine and peripheral venous blood obtained from 18 women undergoing abdominal hysterectomy. Concentrations of 6-oxo-PGF1 alpha were significantly (p less than 0.01) higher in uterine (1.4 +/- 0.3 ng/ml, mean +/- SEM) than in peripheral vein blood (0.2 +/- 0.1 ng/ml) as was the level of thromboxane B2 (0.5 +/- 0.1 and 0.2 +/- 0.1 ng/ml, respectively). Platelet retention in uterine vein blood (11 +/- 4%) was significantly lower than in peripheral blood (42 +/- 4%; p less than 0.01) and the degree of platelet retention correlated inversely with the plasma concentration of 6-oxo-PGF1 alpha (r -0.43; p less than 0.01). There was a significant rank correlation between time since menstruation and concentrations of 6-oxo-PGF1 alpha in uterine (tau + 0.69; p less than 0.001) and peripheral (tau + 0.56; p less than 0.05) vein blood. The results indicate that an increased local production of prostacyclin (PGI2) relative to thromboxane A2 at the time of menstruation could contribute to the mechanism of uterine bleeding.

The actions of composite trophoblast antigens in microvillus preparations upon cultured maternal lymphocytes from early first pregnancies.

The effect of placental microvillus preparations (MVP) on lymphocytes in whole blood cultures obtained from mothers in the early stages of their first pregnancies was studied. Variable dilutions and variable harvesting were used to construct kinetic curves of [6-3H]-thymidine uptake per day. Significant responses (P less than 0.02 to 0.05) were observed in autologous plasma and heterologous serum with and without phytohemagglutinin. The responses showed a variability which may be explained by chance combination of similar MVP and in vivo trophoblast antigens, some with stimulatory and others with suppressor actions. The presence of a blocking antibody to a suppressor antigen in autologous plasma could also contribute.

Extraction and identification of trophoblast cells circulating in peripheral blood during pregnancy.

Trophoblast cells circulating in peripheral venous blood during pregnancy were extracted by differential centrifugation and identified by indirect immunofluorescence with antitrophoblast microvillus antibody. In a study where trophoblast identification was checked by blind comparison with non-pregnant control subjects' trophoblast cells were detected in six out of 10 pregnant women studied.

Discrimination of the age of adolescent females on the basis of facial cues.

In an ongoing study of adolescent maternal-infant interaction, we investigated the accuracy with which judges could assign the age of two groups of females, based on videotaped facial cues alone. The two groups were eight "adolescents," whose ages were less than or equal to 17 years, and 20 "adults," whose ages were greater than 20 years. Twenty-seven judges, whose average age was 28.7 years with a range from 27 through 44 years of age, were asked to judge the ages of the subjects in the two groups. Overall, the judges were successful in identifying adolescents 41.8% of the time. There was no relationship between the ages of the judges and the accuracy of their judgments. On the basis of facial cues alone, our results clearly suggest that the process of assigning an individual to an adolescent or adult group is essentially random, approaching a 50/50 breakdown. This study supports the concept that observed differences between adolescents and adults interacting with their infants is due to actual differences in behavior and not the cultural bias of the judge.