Inhibitory activity of nociceptin/orphanin FQ on capsaicin-induced bronchoconstriction in the guinea-pig

In vivo studies were conducted in the guinea-pig to investigate the activity of the selective ORL1 receptor agonist nociceptin/orphanin FQ against capsaicin-induced bronchoconstriction, a response mediated by the release of tachykinins from pulmonary sensory nerves. Anesthetized guinea-pigs were ventilated with a rodent ventilator and placed in a whole-body plethysmograph, and pulmonary resistance (R(L)) and dynamic lung compliance (C(Dyn)) were monitored. Intravenous administration of nociceptin/orphanin FQ (0.3 mg/kg) inhibited the capsaicin-induced bronchoconstriction. The new nonpeptide ORL1 receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) administered intravenously (1 mg/kg) produced a significant blockade of the inhibitory effect of nociceptin/orphanin FQ (0.3 mg/kg) on capsaicin-induced bronchoconstriction, whereas the nonselective opioid receptor antagonist naloxone (1 mg/kg) had no effect. Nociceptin/orphanin FQ (0.3 mg/kg) did not affect the bronchoconstriction induced exogenously by the tachykinin NK2 receptor agonist [beta-ala8]-neurokinin A (4-10). We conclude that nociceptin inhibits in vivo capsaicin-evoked tachykinin release from sensory nerve terminals in the guinea-pig by a prejunctional mechanism. This inhibitory action does not involve activation of opioid receptors.     

Assessing transportation by the covariance of species with comments on contagious and random distributions

The paleoecologist must be able to distinguish a transported assemblage from an in situ one. A method is proposed to assess whether the post-mortem transport of individuals affected their observed spatial (horizontal) distribution. The spatial distribution of a species can be random or contagious. The spatial distribution of individuals of a species in the death assemblage produced by the cumulation of many temporally discrete inputs will be random if the individual inputs are random and contagious if the inputs are contagious. The spatial distribution patterns of several species should not covary in the absence of physical disturbance regardless of their own distributions, however. The degree of covariance between individuals of several species of similar hydrodynamic propensity is dependent on the amount and intensity of postmortem movement. The more species that covary, and the larger the size classes that covary, the more likely that transportation played an important role in the species' distribution patterns. Conversely, the absence of covariance suggests that, for at least some species, biological factors determined the species' spatial distributions. Similarly, covariance of vertical distribution patterns might suggest homogenization. by bioturbational or physical mixing.     

Reduction mammaplasty is a functional operation,improving quality of life in symptomatic women: a prospective,single-center breast reduction outcome study

Breast hypertrophy creates a functional disability, adversely affecting quality of life because of disproportionate upper body weight. No study to date has prospectively shown or statistically proved (using validated questionnaires) the functional benefits of breast reduction surgery. Moreover, no study has quantified the physical findings seen in these patients. A prospective trial was designed to illustrate objectively the functional benefits of breast reduction surgery and answer the question, Does surgically removing breast tissue in symptomatic patients (regardless of amount of tissue removed) improve their physical disabilities related to breast hypertrophy, and in turn, improve their quality of life? Fifty-five consecutive patients with an average age of 38 years (range, 18 to 73 years) undergoing breast reduction surgery by the senior surgeon (L.A.C.) were recruited for this study. The North American Spine Society (NASS) Lumbar Spine Outcome Assessment Instrument was used to assess patients' disability, expectations for treatment, and satisfaction with treatment. The visual analogue scale was used to quantify pain intensity. Muscle strengths of the pectoralis major, pectoralis minor, rhomboid, middle trapezius, and lower trapezius muscles and postural measures were obtained. Information was collected preoperatively and 6 months postoperatively for comparison. The mean cumulative preoperative NASS Lumbar Spine Outcome Assessment Instrument disability score was 1.94 +/- 0.68, and the mean cumulative postoperative disability score was 1.16 +/- 0.35 (p = 0.0001); 96.1 percent of patients met expectations to a certain degree and, of these patients, 96 percent were very satisfied with their surgery. The mean cumulative baseline preoperative visual analogue score for all participants was 6.2 +/- 2.06, and their mean cumulative postoperative score was 0.53 +/- 0.88 (p = 0.0001). There was statistically significant improvement of muscle strength in the rhomboids, middle trapezius, and lower trapezius muscles (p < 0.001). All postural measures showed improvement postoperatively, with head translation and cranial rotation showing statistical improvement (p < 0.05). This single-center, single-surgeon breast reduction outcome study showed that the signs and symptoms of breast hypertrophy are definable in a consistent manner. By standardizing and quantifying preoperative and postoperative evaluations with validated questionnaires, validated pain scoring, and standardized muscle and posture testing, it was shown that breast reduction for symptomatic breast hypertrophy can effect a statistically significant improvement in these objective measures of pain, disability, muscle weakness, and poor posture.     

Physico-chemical aspects of hemozoin (malaria pigment) structure and formation

Recent literature dealing with the chemical composition, structure and mechanism of formation of hemozoin and its synthetic counterpart, beta-hematin, is reviewed.     

Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes

A gut insulinotropic peptide, glucagon-like peptide-1 (GLP-1), when given continuously subcutaneously, has been shown to be an effective agent to treat type 2 diabetes. Because of inactivation by dipeptidyl peptidase IV (DPP IV), it has a very short half-life (90-120 s), hence the need for continuous administration. Exendin-4 is an agonist of the GLP-1 receptor. It is not a substrate for DPP IV, and we previously demonstrated that intravenous administration has potent insulinotropic properties in type 2 diabetic volunteers. We evaluated the efficacy of bolus subcutaneous exendin-4 in insulin-naive type 2 diabetic volunteers. Ten patients aged 44-72 yr with mean fasting glucose levels of 11.4 +/- 0.9 mmol/l were enrolled, and daily or twice-daily bolus subcutaneous exendin-4 was self-administered for 1 mo. Glycosylated hemoglobin, multiple daily capillary blood glucose, beta-cell sensitivity to glucose, and peripheral tissue sensitivity to insulin were compared before and after treatment. The greatest decline in capillary blood glucose was seen before bed, with a drop from 15.5 to 9.2 mmol/l (P < 0.0001). Glycosylated hemoglobin improved significantly with treatment, from 9.1 to 8.3% (P = 0.009). beta-Cell sensitivity to glucose was improved, as assessed by C-peptide levels during a hyperglycemic clamp. No significant adverse effects were noted or reported. Our data suggest that, even with this short duration of therapy, exendin-4 treatment had a significant effect on glucose homeostasis.     

The Drosophila SNR1 (SNF5/INI1) subunit directs essential developmental functions of the Brahma chromatin remodeling complex

The Drosophila melanogaster Brahma (Brm) complex, a counterpart of the Saccharomyces cerevisiae SWI/SNF ATP-dependent chromatin remodeling complex, is important for proper development by maintaining specific gene expression patterns. The SNR1 subunit is strongly conserved with yeast SNF5 and mammalian INI1 and is required for full activity of the Brm complex. We identified a temperature-sensitive allele of snr1 caused by a single amino acid substitution in the conserved repeat 2 region, implicated in a variety of protein-protein interactions. Genetic analyses of snr1(E1) reveal that it functions as an antimorph and that snr1 has critical roles in tissue patterning and growth control. Temperature shifts show that snr1 is continuously required, with essential functions in embryogenesis, pupal stages, and adults. Allele-specific genetic interactions between snr1(E1) and mutations in genes encoding other members of the Brm complex suggest that snr1(E1) mutant phenotypes result from reduced Brm complex function. Consistent with this view, SNR1(E1) is stably associated with other components of the Brm complex at the restrictive temperature. SNR1 can establish direct contacts through the conserved repeat 2 region with the SET domain of the homeotic regulator Trithorax (TRX), and SNR1(E1) is partially defective for functional TRX association. As truncating mutations of INI1 are strongly correlated with aggressive cancers, our results support the view that SNR1, and specifically the repeat 2 region, has a critical role in mediating cell growth control functions of the metazoan SWI/SNF complexes.     

Structure shows that a glycosaminoglycan and protein recognition site in factor H is perturbed by age-related macular degeneration-linked single nucleotide polymorphism

A common single nucleotide polymorphism in the factor H gene predisposes to age-related macular degeneration. Factor H blocks the alternative pathway of complement on self-surfaces bearing specific polyanions, including the glycosaminoglycan chains of proteoglycans. Factor H also binds C-reactive protein, potentially contributing to noninflammatory apoptotic processes. The at risk sequence contains His (rather than Tyr) at position 402 (384 in the mature protein), in the seventh of the 20 complement control protein (CCP) modules (CCP7) of factor H. We expressed both His(402) and Tyr(402) variants of CCP7, CCP7,8, and CCP6-8. We determined structures of His(402) and Tyr(402) CCP7 and showed them to be nearly identical. The side chains of His/Tyr(402) have similar, solvent-exposed orientations far from interfaces with CCP6 and -8. Tyr(402) CCP7 bound significantly more tightly than His(402) CCP7 to a heparin affinity column as well as to defined-length sulfated heparin oligosaccharides employed in gel mobility shift assays. This observation is consistent with the position of the 402 side chain on the edge of one of two glycosaminoglycan-binding surface patches on CCP7 that we inferred on the basis of chemical shift perturbation studies with a sulfated heparin tetrasaccharide. According to surface plasmon resonance measurements, Tyr(402) CCP6-8 binds significantly more tightly than His(402) CCP6-8 to immobilized C-reactive protein. The data support a causal link between H402Y and age-related macular degeneration in which variation at position 402 modulates the response of factor H to age-related changes in the glycosaminoglycan composition and apoptotic activity of the macula.     

Association of hormonal dysregulation with metabolic syndrome in older women: data from the InCHIANTI study

Metabolic syndrome (MetS) is a strong risk factor for type 2 diabetes and cardiovascular disease. Conditions associated with hyperandrogenism are often associated with glucose intolerance and other features of MetS in young women. As the prevalence of MetS increases with age and is probably multifactorial, it is reasonable to hypothesize that age-related changes in androgens and other hormones might contribute to the development of MetS in older persons. However, this hypothesis has never been tested in older women. We hypothesized that high levels of testosterone, dehydroepiandrosterone sulfate (DHEA-S), and cortisol and low levels of sex hormone-binding globulin (SHBG) and IGF-I would be associated with MetS in a representative cohort of older Italian women independently of confounders (including inflammatory markers). After exclusion of participants on hormone replacement therapy and those with a history of bilateral oophorectomy, 512 women (>/=65 yr) had complete data on testosterone, cortisol, DHEA-S, SHBG, fasting insulin, total and free IGF-I, IL-6, and C-reactive protein (CRP). MetS was defined according to ATP-III criteria. Insulin resistance was calculated according to HOMA. MetS was found in 145 women (28.3%). Participants with vs. those without MetS had higher age-adjusted levels of bioavailable testosterone (P < 0.001), IL-6 (P < 0.001), CRP (P < 0.001), and HOMA (P < 0.001) and lower levels of SHBG (P < 0.001). After adjustment for potential confounders, participants with decreased SHBG had an increased risk of MetS (P < 0.0001) vs. those with low SHBG. In a further model including all hormones and confounders, log SHBG was the only independent factor associated with MetS (OR: 0.44, 95% CI 0.21-0.91, P = 0.027). In older women, SHBG is negatively associated with MetS independently of confounders, including inflammatory markers and insulin resistance. Further studies are needed to support the notion that raising SHBG is a potential therapeutic target for prevention and treatment of MetS.