A polymorphism in XKR4 is significantly associated with serum prolactin concentrations in beef cows grazing tall fescue.

Fescue toxicosis is a common syndrome of poor growth and reproductive performance of beef cattle grazing endophyte-infected tall fescue infected with Lolium arundinaceum Schreb. Together with decreased feed intake, decreased growth rates and tissue necrosis due to vasoconstriction, depressed circulating serum prolactin concentrations are typically observed in cattle afflicted with fescue toxicosis. Polymorphisms within the XK, Kell blood group complex subunit-related family, member 4 (XKR4) gene located on BTA14 have been previously reported to be associated with rump fat thickness, residual feed intake, average daily feed intake and average daily gain in cattle. Associations also have been reported between XKR4 genotype and effectiveness of the dopamine antagonist iloperidone as a treatment of schizophrenia in humans. Domperidone, a related dopamine antagonist, mediates effects of fescue toxicosis on livestock, including restoring depressed concentrations of prolactin. A mixed-breed population of 592 beef cattle grazing endophyte-infected tall fescue was used to examine the association between XKR4 genotype and circulating prolactin concentrations. The SNP rs42646708 was significantly (P = 0.0002) associated with serum prolactin concentrations and explained 2.45% of the phenotypic variation. Effect of genotype at the SNP was tested across five breeds, with significant associations within both Angus (P = 0.0275) and Simmental (P = 0.0224) breeds. These results suggest XKR4 may play a role in mediating the negative effects of fescue toxicosis, and polymorphisms within this gene may be useful markers for selection for genetic resistance to the debilitating effects of endophyte-infected tall fescue.

Patients' misunderstanding of common orthopaedic terminology: the need for clarity.

INTRODUCTION: Patients' understanding of their medical problems is essential to allow them to make competent decisions, comply with treatment and enable recovery. We investigated patients' understanding of orthopaedic terms to identify those words surgeons should make the most effort to explain. METHODS: This questionnaire-based study recruited patients attending the orthopaedic clinics. Qualitative and quantitative data were collected using free text boxes for the patients' written definitions and multiple choice questions (MCQs). RESULTS: A total of 133 patients took part. Of these, 74% identified English as their first language. 'Broken bone' was correctly defined by 71% of respondents whereas 'fractured bone' was only correctly defined by 33%. 'Sprain' was correctly defined by 17% of respondents, with 29% being almost correct, 25% wrong and 29% unsure. In the MCQs, 51% of respondents answered correctly for 'fracture', 55% for 'arthroscopy', 46% for 'meniscus', 35% for 'tendon' and 23% for 'ligament'. 'Sprained' caused confusion, with only 11% of patients answering correctly. Speaking English as a second language was a significant predictive factor for patients who had difficulty with definitions. There was no significant variation among different age groups. CONCLUSIONS: Care should be taken by surgeons when using basic and common orthopaedic terminology in order to avoid misunderstanding. Educating patients in clinic is a routine part of practice.

Psychophysics of CNS pain-related activity: binary and analog channels and memory encoding.

The forebrain neuronal system signaling pain has been poorly characterized. The pain pathway afferent to the thalamus may be a labeled line consisting of neurons in the pain-signaling pathway to the brain (spinothalamic tract, STT) that respond only to painful stimuli. It has recently been proposed that the STT contains a series of analog-labeled lines, each signaling a different aspect of the internal state of the body (interoception), for example, visceral/cold/itch sensations. In this view, pain is the unpleasant emotion produced by disequilibrium of the internal state. The authors now show that stimulation of an STT receiving zone (thalamic principal somatic sensory nucleus, ventral caudal) in awake humans produces two different exteroceptive responses. The first is a binary response signaling the presence of painful stimuli. The second is an analog response in which nonpainful and painful sensations are graded with intensity of the stimulus. Such stimulation can evoke both the sensory and emotional components of previously experienced pain. These results illustrate the diverse functions of human pain signaling pathways.

Septic shock and sepsis: a comparison of total and free plasma cortisol levels.

CONTEXT: Severe systemic infection leads to hypercortisolism. Reduced cortisol binding proteins may accentuate the free cortisol elevations seen in systemic infection. Recently, low total cortisol increments after tetracosactrin have been associated with increased mortality and hemodynamic responsiveness to exogenous hydrocortisone in septic shock (SS), a phenomenon termed by some investigators as relative adrenal insufficiency (RAI). HYPOTHESIS: Free plasma cortisol may correspond more closely to illness severity than total cortisol, comparing SS and sepsis (S). DESIGN: This was a prospective study. SETTING: This study took place in a tertiary teaching hospital. PATIENTS: Patients had SS (n = 45) or S (n = 19) or were healthy controls (HCs; n = 10). AIM: The aim of the study was to compare total with free cortisol, measured directly and estimated by Coolens' method, corticosteroid-binding globulin (CBG), and albumin in patients with SS (with and without RAI) and S during acute illness, recovery, and convalescence. RESULTS: Comparing SS, S, and HC subjects, free cortisol levels reflected illness severity more closely than total cortisol (basal free cortisol, SS, 186 vs. S, 29 vs. HC, 13 nmol/liter, P < 0.001 compared with basal total cortisol, SS, 880 vs. S, 417 vs. HC, 352 nmol/liter, P < 0.001). Stimulated free cortisol increments varied greatly with illness category (SS, 192 vs. S, 115 vs. HC, 59 nmol/liter, P = 0.004), whereas total cortisol increments did not (SS, 474 vs. S, 576 vs. HC, 524 nmol/liter, P = 0.013). The lack of increase in total cortisol with illness severity is due to lower CBG and albumin. One third of patients with SS (15 of 45) but no S patients met a recently described criterion for RAI (total cortisol increment after tetracosactrin < or = 248 nmol/liter). RAI patients had higher basal total cortisol (1157 vs. 756 nmol/liter; P = 0.028) and basal free cortisol (287 vs. 140 nmol/liter; P = 0.017) than non-RAI patients. Mean cortisol increments in RAI were lower (total, 99 vs. 648 nmol/liter, P < 0.001; free, 59 vs. 252 nmol/liter, P < 0.001). These differences were not due to altered CBG or albumin levels. Free cortisol levels normalized more promptly than total cortisol in convalescence. Calculated free cortisol by Coolens' method compared closely with measured free cortisol. CONCLUSIONS: Free cortisol is likely to be a better guide to cortisolemia in systemic infection because it corresponds more closely to illness severity. The attenuated cortisol increment after tetracosactrin in RAI is not due to low cortisol-binding proteins. Free cortisol levels can be determined reliably using total cortisol and CBG levels.

Routine neonatal postextubation chest physiotherapy: a randomized controlled trial.

OBJECTIVE: To test the effects of a neonatal postextubation programme on the incidence of postextubation collapse and adverse outcomes. METHODS: A randomized controlled trial was carried out at the Mater Mothers' Hospital, Brisbane. Mechanically ventilated infants were randomized into one of two groups, physiotherapy group--which involved a regimen of chest wall percussion and oropharyngeal suctioning and control group - which involved suctioning without the percussion unless indicated. Chest X-rays were taken at 6 h and at 24 h postextubation. The primary outcome measure was postextubation collapse as determined by a paediatric radiologist blinded to the group allocation. RESULTS: One hundred and seventy-seven neonates were enrolled in the trial between 1997 and 1999. After an interim analysis, the trial was stopped early. No statistically significant difference was shown in the rate of postextubation collapse (15 of 87 (17.2%) physiotherapy group and 17 of 86 (19.8%) control group (P = 0.85)). No differences were shown between the groups in the number of apnoeic or bradycardic events, duration of requirement for supplemental oxygen or the need for re-intubation within 24 h postextubation. CONCLUSION: The results of this trial suggest that a routine neonatal postextubation chest physiotherapy programme for all infants is not indicated. There was no evidence that chest physiotherapy is associated with any adverse outcomes.

Pregnancy-associated corticosteroid-binding globulin: high resolution separation of glycan isoforms.

Corticosteroid-binding globulin (CBG) is a glycoprotein that functions as a specific carrier of cortisol in the circulation. CBG contains six sites for N-glycosylation with, on average, five sites occupied by a mixture of biantennary and triantennary oligosaccharides with variable additional terminal sialic acid residues leading to glycoforms with significant heterogeneity in mass and isoelectric points. During pregnancy, a form of CBG possessing only triantennary oligosaccharides comprising approximately 10 % of total CBG appears specifically. We describe the first application of two-dimensional gel electrophoresis to the separation of human CBG glycoforms. This technique resolved a greater degree of charge heterogeneity than previous studies, and allowed simultaneous visualization of changes to the size and isoelectric points of CBG during pregnancy. Profiles of CBG glycoforms during pregnancy showed a general increase in size followed by a shift to lower pI in a large proportion of the glycoprotein. This may result from the enhancement of triantennary glycosylation, with the extent of incorporation of sialic acid increasing with the number of available sites for its addition. The pregnancy-specific CBG previously defined probably represents a subset of the acidic and high molecular weight glycoforms we have resolved by two-dimensional electrophoresis and now describe as pregnancy-associated CBG.

Peptide insertions in domain 4 of hbeta(c), the shared signalling receptor subunit for GM-CSF, IL3 and IL5, induce ligand-independent activation.

A mutant form of the common beta-subunit of the GM-CSF, interleukin-3 (IL3) and IL5 receptors is activated by a 37 residue duplicated segment which includes the WSXWS motif and an adjacent, highly conserved, aliphatic/basic element. Haemopoietic expression of this mutant, hbeta(c)FIDelta, in mice leads to myeloproliferative disease. To examine the mechanism of activation of this mutant we targetted the two conserved motifs in each repeat for mutagenesis. Here we show that this mutant exhibits constitutive activity in BaF-B03 cells in the presence of mouse or human GM-CSF receptor alpha-subunit (GMRalpha) and this activity is disrupted by mutations of the conserved motifs in the first repeat. In the presence of these mutations the receptor reverts to an alternative conformation which retains responsiveness to human IL3 in a CTLL cell line co-expressing the human IL3 receptor alpha-subunit (hIL3Ralpha). Remarkably, the activated conformation is maintained in the presence of substitutions, deletions or replacement of the second repeat. This suggests that activation occurs due to insertion of extra sequence after the WSXWS motif and is not dependent on the length or specific sequence of the insertion. Thus hbeta(c) displays an ability to fold into functional receptor conformations given insertion of up to 37 residues in the membrane-proximal region. Constitutive activation most likely results from a specific conformational change which alters a dormant, inactive receptor complex, permitting functional association with GMRalpha and ligand-independent mitogenic signalling.

Structural and functional hot spots in cytokine receptors.

The activation of cytokine receptors is a stepwise process that depends on their specific interaction with cognate cytokines, the formation of oligomeric receptor complexes, and the initiation of cytoplasmic phosphorylation events. The recent determination of the structure of extracellular domains of several cytokine receptors allows comparison of their cytokine-binding surfaces. This comparison reveals a common structural framework that supports considerable diversity and adaptability of the binding surfaces that determine both the specificity and the orientation of subunits in the active receptor complex. These regions of the cytokine receptors have been targeted for the development of specific agonists and antagonists. The physical coupling of signaling intermediates to the intracellular domains of their receptors plays a major role in determining biological responses to cytokines. In this review, we focus principally on the receptors for cytokines of the granulocyte-macrophage colony-stimulating factor (GM-CSF) family and, where appropriate, compare them with related cytokine receptors. Several paradigms are beginning to emerge that focus on the ability of the extracellular portion of the cytokine receptor to recognize the appropriate cytokine and on a phosphorylated motif in the intracellular region of the GM-CSF receptor that couples to a specific signaling pathway.

Tasco-Forage: I. Influence of a seaweed extract on antioxidant activity in tall fescue and in ruminants.

Seaweed (Ascophyllum nodosum) is a known source of plant growth regulators, and application to turfgrasses has increased activity of the antioxidant superoxide dismutase (SOD) and specific vitamin precursors. Increased antioxidant activity in both plants and animals diminishes oxidative stress. Two pasture experiments investigated effects of Tasco-Forage (a proprietary seaweed-based product) applied to tall fescue (Festuca arundinacea) on antioxidant activity in plants and in ruminants that grazed the forage. In Exp. 1, fescue was 70 to 100% infected with the endophyte fungus Neotyphodium coenophialum ([Morgan-Jones and Gams] Glenn, Bacon, and Hanlin). Twenty-four wether lambs (initial BW 41 kg; SD = 5) grazed fescue treated with 0, 1.7, or 3.4 kg Tasco/ha applied in April and July, 1994, with four replications per treatment. Grazing occurred for 26 d beginning April 21 and for 22 d beginning July 19. In July, there was a linear increase in daily gains (P < 0.05), and serum vitamin A (P < 0.13) and whole-blood Se (P < 0.10) tended to increase in lambs grazing Tasco-treated fescue. In Exp. 2,48 Angus and Angus x Hereford steers (initial BW 245 kg; SD = 20) grazed infected or uninfected tall fescue in Virginia that was treated (3.4 kg/ ha) or untreated with Tasco in April and July, 1995. Steers that grazed infected tall fescue had lower (P < 0.02) serum vitamin A and E and tended (P < 0.07) to have lower whole-blood Se in September compared with steers that grazed uninfected tall fescue. Tasco decreased (P < 0.06) serum vitamin E but tended to increase whole-blood Se (P < 0.10) in September and serum vitamin A in July (P < 0.12). During 1996 and 1997, the experiment was repeated in Virginia with Angus steers and was replicated at Prairie, MS, where 1/4 Brahman x 3/4 Angus steers were used. Forty-eight steers were included at each location in each year (n = 192 total steers for 1996 and 1997). Steers that grazed infected tall fescue in Mississippi had lower (P < 0.05) serum vitamin E by the end of the grazing season. At both locations Tasco increased (P < 0.05) activity of superoxide dismutase in both infected and uninfected fescue. The endophyte in tall fescue seemed to decrease antioxidant activity in grazing steers, whereas Tasco seemed to increase antioxidant activity in both the forage and the grazing ruminant. Tasco may provide opportunities to reduce oxidative stress in plants and animals.

Tasco-Forage: II. Monocyte immune cell response and performance of beef steers grazing tall fescue treated with a seaweed extract.

Effects of applying Tasco-Forage, an Ascophyllum nodosum seaweed-based product prepared by a proprietary process, to endophyte (Neotyphodium coenophialum [Morgan-Jones and Gams] Glenn, Bacon, and Hanlin)-infected and endophyte-free tall fescue (Festuca arundinacea Schreb.) were studied in each of 3 yr (1995, 1996, and 1997) in Virginia and in 1996 and 1997 in Mississippi. There were 48 steers at each location in each year (n = 240) in a 2 x 2 x 2 factorial arrangement with two replications at each location. Steers in Virginia were Angus and Angus x Hereford with initial weights of 245 kg (SD = 20), 234 kg (SD = 9), and 265 kg (SD = 5) in yr 1, 2, and 3, respectively. Steers in Mississippi were 3/4 Angus and 1/4 Brahman and weighed 230 kg (SD = 8) and 250 kg (SD = 2) in yr 2 and 3, respectively. Tasco (3.4 kg/ha) was dissolved in water and applied to pastures in April before grazing was begun and again in July at the same rate. The grazing period was from mid-April to late September or mid-October. Total gains were higher (P < 0.05) for steers grazing uninfected than for those grazing endophyte-infected tall fescue. Rectal temperatures were increased (P < 0.05) due to endophyte infection at both locations; Tasco application decreased temperature of steers grazing infected fescue in Virginia (interaction, P < 0.07) but increased temperatures of steers grazing infected fescue in Mississippi (interaction, P < 0.05). Presence of the endophyte resulted in rough hair coats and loss of hair color, but the effect was partially offset (P < 0.05) by Tasco application in Virginia in 1995. Both monocyte phagocytic activity (all years and locations) and major histocompatibility complex class II expression (1995 only) were decreased (P < 0.05) in steers due to endophyte infection, but this effect was reversed (P < 0.05) by application of Tasco to pastures. Application of the extract from A. nodosum seems to have use in alleviating adverse effects of endophyte on immune function and may improve hair coat condition in cattle grazing infected fescue, but effects on rectal temperature varied due to location.

Tasco-Forage: III. Influence of a seaweed extract on performance, monocyte immune cell response, and carcass characteristics in feedlot-finished steers.

Tall fescue (Festuca arundinacea Schreb.) infected with the endophyte Neotyphodium coenophialum ([Morgan-Jones and Gams] Glenn, Bacon, and Hanlin) causes fescue toxicosis in cattle grazing the forage, but effects of the endophyte were considered to be abated soon after removal of the animals from pastures. Tasco-Forage, a proprietary extract from the brown seaweed Ascophyllum nodosum, is a known source of cytokinins and has increased antioxidant activity in both plants and the animals that graze the forage. Tasco was applied at 0 and 3.4 kg/ha to infected and uninfected tall fescue pastures in Virginia and Mississippi. Forty-eight steers grazed the pastures at each location during each of 2 yr (n = 192) before being transported to Texas for feedlot finishing. On arrival at the feedlot, steers from Tasco-treated pastures had higher (P < 0.01) monocyte phagocytic activity and tended (P < 0.07) to have higher major histocompatibility complex class II expression than steers that grazed the untreated pastures. A depression (P < 0.05) in monocyte immune cell function due to grazing infected fescue was detected throughout the feedlot finishing period but was reversed by Tasco. Rectal temperatures were elevated (P < 0.07) in steers that had grazed the infected tall fescue when they arrived in Texas, but by d 14 no difference was detected. However, by d 28 the temperature effects of infected tall fescue were reversed. Steers that had grazed infected fescue had lower (P < 0.01) rectal temperatures on d 112 of the feedlot period, demonstrating a much longer-lasting effect of the endophyte on thermoregulatory mechanisms than previously thought. Steers that had grazed Tasco-treated pastures had higher (P < 0.01) rectal temperatures on d 56 than steers that had grazed untreated fescue. Steers that had grazed the Tasco-treated pastures had higher marbling scores (P < 0.05) regardless of the endophyte, but no effect of Tasco or endophyte on gain was measured. Our data suggest that Tasco application to tall fescue pastures alleviated some of the negative effects of tall fescue toxicity.

Tasco-Forage: IV. Influence of a seaweed extract applied to tall fescue pastures on sensory characteristics, shelf-life, and vitamin E status in feedlot-finished steers.

Tasco-Forage is an Ascophyllum nodosum seaweed-based product that has increased antioxidant activity in both plants and animals. Endophyte (Neotyphodium coenophialum ([Morgan-Jones and Gams] Glenn, Bacon, and Hanlin)-infected and uninfected tall fescue (Festuca arundinacea Schreb.) pastures in Virginia and Mississippi during 1997 were treated or not with 3.4 kg Tasco/ha in April and July. There were two replications of each treatment at each location. Forty-eight steers (6/replication) grazed pastures at each location (n = 96) from April to October prior to transportation to Texas Tech, Lubbock, for finishing during a 160-d period in the feedlot. Blood (antemortem) and liver (postmortem) samples were collected. After slaughter and chilling, the left strip loins (IMPS #180) were collected from three randomly selected steers from within each pasture replication (n = 48). Strip loins were vacuum-packaged and stored at 2 degrees C. At postmortem d 7, 14, 21, and 28, strip loins were removed from packaging and fabricated into 2.54-cm steaks. Following each fabrication day postmortem, the strip loins were repackaged and stored at 2 degrees C until the following postmortem time. After the prescribed fabrication, steaks were overwrapped with polyvinyl chloride film, subjected to simulated retail display at 2 degrees C for up to 3 d, and subjective and objective color were evaluated daily by a trained panel. Steaks from Mississippi steers that had grazed Tasco-treated fescue retained higher (P < 0.05) CIE a* color scores throughout retail display. Steaks were more uniform and had less discoloration and less browning (P < 0.05) if they were from steers that had grazed Tasco-treated fescue, and the effect was greatest for steers from Mississippi (location x Tasco interaction; P < 0.05). The endophyte in tall fescue may decrease uniformity and increase lean discoloration and two-toning of beef steaks when removed from vacuum packaging on or beyond d 21 postmortem (endophyte x Tasco x postmortem day interaction: P < 0.05). Vitamin E in liver was increased (P < 0.06) and serum vitamin E was decreased (P < 0.09) in steers that had grazed the treated pastures. These experiments indicated that Tasco applied to tall fescue during the grazing season can improve color stability and extend beef shelf-life, particularly in cattle grazing infected tall fescue. The mode of action of Tasco is not clear, but antioxidants and specific vitamins may be involved.

New approaches in the treatment of asthma.

Asthma is a common and complex inflammatory disease of the airways that remains incurable. Current forms of therapy are long term and may exhibit associated side-effect problems. Major participants in the development of an asthma phenotype include the triggering stimuli such as the allergens themselves, cells such as T cells, epithelial cells and mast cells that produce a variety of cytokines including IL-5, GM-CSF, IL-3, IL-4 and IL-13 and chemokines such as eotaxin. Significantly, the eosinophil, a specialized blood cell type, is invariably associated with this disease. The eosinophil has long been incriminated in the pathology of asthma due to its ability to release preformed and unique toxic substances as well as newly formed pro-inflammatory mediators. The regulation of eosinophil production and function is carried out by soluble peptides or factors. Of these IL-5, GM-CSF and IL-3 are of paramount importance as they control eosinophil functional activity and are the only known eosinophilopoietic factors. In addition they regulate the eosinophil life span by inhibiting apoptosis. While one therapeutic approach in asthma is directed at inhibiting single eosinophil products such as leukotrienes or single eosinophil regulators such as IL-5, we believe that the simultaneous inhibition of more than one component is preferable. This may be particularly important with eosinophil regulators in that not only IL-5, but also GM-CSF has been repeatedly implicated in clinical studies of asthma. The fact that GM-CSF is produced by many cells in the body and in copious amounts by lung epithelial cells highlights this need further. Our approach takes advantage of the fact that the IL-5 and GM-CSF receptors (as well as IL-3 receptors) utilize a shared subunit to bind, with high affinity, to these cytokines and the same common subunit mediates signal transduction culminating in all the biological activities mentioned. By generating the monoclonal antibody BION-1 to the cytokine binding region of the common subunit (betac) we have shown that the approach of inhibiting IL-5, GM-CSF and IL-3 binding and the resulting stimulation of eosinophil production and function with a single agent is feasible. Furthermore we have used BION-1 as a tool to crystallize and define the structure of the cytokine binding domain of betac. This knowledge and this approach may lead to the generation of novel therapeutics for the treatment of asthma.

Multi-criminal and violent groups among child sex offenders: a heuristic typology in a 2-year cohort of 374 men in two English counties.

OBJECTIVE: To determine the lifetime criminality of men charged with a sexual offence against a child and to identify any heuristic typologies. METHOD: The police files of a 2-year cohort of 462 men charged with a sexual offence against a minor (<17) in two English counties were analyzed; 374 were convicted. The patterns of their convictions produced a typology based upon judicially substantiated parameters. RESULTS: Half the guilty men had prior convictions for non-sexual crimes, including 24% with convictions for violent offences. Three heuristic groups emerged: "Sex-Only" offenders (S.O., n = 186); "Sex And Other" offenders (S.A.O., n = 97); and "Sex and Violent" offenders (S.V., n = 91), averaging three sex convictions each. However, the S.A.O. and S.V. men had more non-sexual than sex convictions, averaging 5.1 versus 10.5, justifying the designation of "multi-criminal" child sex abusers. However, the patterns of these men's sexual offending did not differ, except that the S.O. men's victims were significantly more often intra-family, 36%, 31%, and 13%, respectively; indicating that the majority of these men's victims were extra-familial (71%). Significantly, 19% of the convicted men had at least one "not guilty" verdict for a sex charge, as opposed to 4% for non-sexual crimes. CONCLUSIONS: While the S.O. group appear to consist of traditional types of fixated and regressed offenders, in men charged with offences, they are atypical of most sex abusers since their victims are mainly extra-familial. These "multi-criminal" men present particular challenges for custodial and therapeutic settings, and the potential dangerousness of these offenders should not be underestimated.

The solution structure of the cytokine-binding domain of the common beta-chain of the receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3 and interleukin-5.

The haemopoietic cytokines, granulocyte-macrophage colony-stimulating factor, interleukin-3 and interleukin-5 bind to cell-surface receptors comprising ligand-specific alpha-chains and a shared beta-chain. The beta-chain is the critical signalling subunit of the receptor and its fourth domain not only plays a critical role in interactions with ligands, hence in receptor activation, but also contains residues whose mutation can lead to ligand-independent activation of the receptor. We have determined the NMR solution structure of the isolated human fourth domain of the beta-chain. The protein has a fibronectin type III fold with a well-defined hydrophobic core and is stabilised by an extensive network of pi-cation interactions involving Trp and Arg side-chains, including two Trp residues outside the highly conserved Trp-Ser-Xaa-Trp-Ser motif (where Xaa is any amino acid) that is found in many cytokine receptors. Most of the residues implicated in factor-independent mutants localise to the rigid core of the domain or the pi-cation stack. The loops between the B and C, and the F and G strands, that contain residues important for interactions with cytokines, lie adjacent at the membrane-distal end of the domain, consistent with their being involved cooperatively in binding cytokines. The elucidation of the structure of the cytokine-binding domain of the beta-chain provides insight into the cytokine-dependent and factor-independent activation of the receptor.

Elevated rates of suicidal behavior in gay, lesbian, and bisexual youth.

Both clinical and epidemiological literature point to elevated rates of suicidal behaviors in gay, lesbian, and bisexual youth (GLBY). Recent North American and New Zealand studies of large populations (especially the US Youth Risk Behavior Surveys from several states) indicate that gay, lesbian, and bisexual adolescents (males in particular) can have rates of serious suicide attempts at least four times those of apparently heterosexual youth. There are various reasons why this figure is likely to be an underestimate. Reasons for these elevated rates of suicidal behavior include a climate of homophobic persecution in schools, and sometimes in family and community--values and actions that stigmatize homosexuality and that the youth who has not yet "come out" has to endure in silence.