Don't panic. A guide to tryptophan depletion with disorder-specific anxiety provocation.

The 2002 paper "Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine" by Bell and colleagues - reprinted in this issue of the Journal - reports on a study undertaken in the halcyon days of David Nutt's Psychopharmacology Unit at the University of Bristol, England. In this invited commentary authors of the original work discuss the impact of this paper on the field of acute tryptophan depletion research (especially in the field of clinical anxiety disorders) and the development of disorder-specific anxiogenic provocations over the past decade.

Influence of hyaluronic acid on the time-dependent friction response of articular cartilage under different conditions.

Therapeutic lubricant injections of hyaluronic acid are a relatively recent treatment for osteoarthritis. Their efficacy, however, in vivo has been subject to much debate. Frictional properties of cartilage-cartilage contacts under both static and dynamic loading conditions have been investigated, using healthy cartilage and cartilage with a physically disrupted surface, with and without the addition of a therapeutic lubricant, hyaluronic acid. Most of the cartilage friction models produced typical time-dependent loading curves, with a rise in static friction with loading time. For the dynamic loading conditions the rise in friction with loading time was dependent on the spatial (and time) variation in the load on the cartilage plate. For sliding distances of 4 mm or greater, when the cartilage plate was unloaded during sliding, the dynamic friction remained low whereas, with shorter sliding distances, the dynamic friction increased with increasing loading time. Static friction was higher than dynamic friction (under the same tribological conditions). The 'damaged' cartilage models produced higher friction than healthy cartilage under equivalent tribological conditions. It was shown that hyaluronic acid was an effective boundary lubricant for articular cartilage under static conditions with both healthy and damaged cartilage surfaces. Hyaluronic acid was less effective under dynamic conditions. However, these dynamic conditions had low friction values with the control lubricant because of the effectiveness of the intrinsic biphasic lubrication of the cartilage. It was only under the tribological conditions in which the cartilage friction was higher and rising with increasing loading time because of depletion of the intrinsic biphasic lubrication, that the role of hyaluronic acid as an effective therapeutic lubricant was demonstrated.

The influence of design, materials and kinematics on the in vitro wear of total knee replacements.

Debris-induced osteolysis due to surface wear of ultra high molecular weight polyethylene (UHMWPE) bearings is a potential long-term failure mechanism of total knee replacements (TKR). This study investigated the effect of prosthesis design, kinematics and bearing material on the wear of UHMWPE bearings using a physiological knee simulator. The use of a curved fixed bearing design with stabilised polyethylene bearings reduced wear in comparison to more flat-on-flat components which were sterilised by gamma irradiation in air. Medium levels of crosslinking further improved the wear resistance of fixed bearing TKR due to resistance to strain softening when subjected to multidirectional motion at the femoral-insert articulating interface. Backside motion was shown to be a contributing factor to the overall rate of UHMWPE wear in fixed bearing components. Wear of fixed bearing prostheses was reduced significantly when anterior-posterior displacement and internal-external rotation kinematics were reduced due to decreased cross shear on the articulating surface and a reduction in AP displacement. Rotating platform mobile bearing prostheses exhibited reduced wear rates in comparison to fixed bearing components in these simulator studies due to redistribution of knee motion to two articulating interfaces with more linear motions at each interface. This was observed in two rotating platform designs with different UHMWPE bearing materials. In knee simulator studies, wear of TKR bearings was dependent on kinematics at the articulating surfaces and the prosthesis design, as well as the type of material.

Randomised controlled study of sleep after nefazodone or paroxetine treatment in out-patients with depression.

BACKGROUND: Sleep effects of antidepressants are important clinically and for elucidating mechanism of action: selective serotonin reuptake inhibitors disturb sleep and 5-HT(2) receptor-blocking compounds may enhance sleep quality. AIMS: To compare the objective and subjective effects on sleep of paroxetine and nefazodone in patients with moderate to severe depression. METHOD: Forty patients with depression were randomised to take paroxetine 20-40 mg/day or nefazodone 400-600 mg/day for 8 weeks. Objective and subjective quality of sleep and depression measures were assessed throughout. RESULTS: Nefazodone significantly increased objective sleep efficiency and total sleep time, and improved subjective sleep on days 3 and 10. Paroxetine decreased sleep efficiency early in treatment and some sleep disruption remained at week 8. Paroxetine but not nefazodone produced marked suppression of rapid eye movement (REM) sleep. CONCLUSIONS: Nefazodone improves sleep in early treatment compared with paroxetine in patients with moderate to severe depression. These effects are seen within the first 2 weeks of treatment and diminish thereafter.

Polyethylene wear characteristics in vivo and in a knee stimulator.

Validation of a wear simulator requires that the device produce a similar type and amount of wear and particles of a comparable morphology as occurs clinically. Using techniques previously established to compare polyethylene particles from hip simulators to those from retrieved tissues, particles isolated from six revised posterior stabilized knee replacements were characterized and compared to particles generated from the same knee design worn in a knee simulator. The particles produced in the knee simulator were of comparable size but had less variability in their form factor compared to the particles produced in vivo. Comparable wear features were seen on the articulating surfaces in both groups. These results indicate that this knee joint simulator is able to reproduce a baseline type of wear that is similar to that in vivo and should encourage further use of this device to better understand knee component wear and function.

Development of a sandwich ELISA and comparison with PCR for the detection of F11 and F165 fimbriated Escherichia coli isolates from septicaemic disease in farm animals.

The P fimbriae F11 and F165 that have been demonstrated on Escherichia coli septicaemic strains in poultry and calves, respectively, possess a nearly identical major subunit that demonstrates a serological cross-reaction. A polyclonal antibody-based sandwich ELISA (sELISA) that was specific for both F11 and F165 fimbriated strains was compared with a PCR method to detect F11/F165 fimbriated strains, in a collection of E. coli strains isolated from diseased animals. Of 298 isolates tested, 36 were positive by PCR of which only 14 were sELISA positive. There were no sELISA positive but PCR negative results. The 36 PCR positive isolates comprised 11 avian strains of which 10 were sELISA positive, 20 bovine strains of which 4 were sELISA positive and 3 ovine strains, 1 porcine strain and 1 equine strain all of which were sELISA negative. The F11/F165 incidence of 10.7% in 103 poultry and 18.3% in 109 bovine isolates demonstrates a moderate level of these factors in E. coli septicaemic cases in Northern Ireland.

Brain function in social anxiety disorder.

What have these studies revealed about SAD? First, few studies have been performed so far, with even fewer replications. Most of the work has been exploratory in nature and follows the paradigms used in PD. This approach has been justifiably criticized. The use of psychological (naturalistic) challenges may be more appropriate in SP than chemical challenges. The paradigms of public speaking, autobiographical scripts, or similar behavioral challenges merit further use, exploration, and validation if symptoms resembling those of the condition proper are to be induced in experimental circumstances. However, some tentative conclusions can be drawn from the research performed so far. There is no enough evidence to support the presence of structural brain abnormality in SAD. Admittedly, such a finding would have been very unlikely. On the other hand, evidence of subtle functional abnormalities is accumulating. On the nosologic question, there appear to be differences from PD. While in some challenges (e.g., CO2 and pentagastrin) the two conditions differ only in degree, in others (e.g., lactate, caffeine, and flumazenil), the separation is clearer. Equally, there is a strong argument to differentiate the generalized from the specific form of social anxiety on the basis of substantial (albeit accidental) findings outlined earlier. More sophisticated neuroimaging techniques, directly comparing patients from both groups before and after pharmacologic or psychological treatment, should provide more conclusive evidence on this issue. What might also help future research is the integration of biological investigations with specific personality profiles. In one study, SAD patients scored low in novelty seeking, self-directedness and cooperativeness and high in harm avoidance. It has been hypothesized that such results indicate serotonergic and dopaminergic dysregulation, which is consistent with the findings described earlier. The best evidence for neurotransmitter abnormality so far is for altered dopamine function at the level of the basal ganglia, either pre- or postsynaptic, which may result in reduced basal ganglia function so that the normal fluidity of social motor functions (e.g., smiling, eye movements, and speech) are impaired, thus leading to the cognitive symptoms of social anxiety and the subsequent generation of avoidance behavior. Such patients should respond poorly to antipsychotics, and additional challenges with these drugs could be used to test this theory. Furthermore, more research needs to be done to elucidate the mechanism by which SSRIs work in SAD. Neuroanatomical models of social anxiety (Fig. 4) [see structure: Text], explaining the site of action of drugs and psychological treatments, have been proposed in recent years. Central to these models is the notion of an innate anxiety circuit, which could be tentatively identified with the behavioral inhibition system, the septohippocampal system. This area receives 5-HT, NE, and dopamine input and has connections with the cortex and limbic structures. The relevance of these models remains to be assessed in experiments that are specifically designed to test them.

Sigma bond activation by cooperative interaction with s2 atoms: B+ + nCH4, n = 1, 2.

Ab initio investigations at the MP2 and CCSD(T) level with augmented double and triple zeta basis sets have identified various stationary points on the B+/nCH4, n = 1, 2 hypersurfaces. The electrostatic complexes show a strong variation in the sequential binding energy with De for the loss of one CH4 molecule calculated to be 16.5 and 6.8 kcal mol-1 for the n = 1 and n = 2 complexes, respectively. The covalent molecular ion, CH3BH+, is found to have the expected C3 nu geometry and to be strongly bound by 84.0 kcal mol-1 with respect to B+ + CH4. The interaction of CH4 with CH3BH+ is qualitatively very similar to the interaction of CH4 with HBH+, however, the binding is only about 50% as strong due to the electron donating characteristic of the methyl group. Of particular interest are the insertion transition states which adopt geometries allowing the B+ ion to interact with multiple sigma bonds. In the n = 1 case, the interaction with two CH bonds lowers the insertion activation energy by about 25 kcal mol-1 from that expected for a mechanism involving only one sigma bond. For n = 2, B+ interacts with two CH sigma bonds from one CH4 and one CH sigma bond from the other CH4 leading to an additional activation energy decrease of about 15.7 kcal mol-1 relative to B+ + nCH4.

Genome-wide scan of obesity in the Old Order Amish.

To identify the genetic determinants of typical obesity, we performed a genome-wide scan of obesity-related traits using data from the Amish. Multipoint linkage analysis was performed using a variance components procedure on body mass index (BMI), waist circumference, percentage of body fat, and serum leptin concentrations. All 672 individuals were genotyped for 357 markers in 22 autosomes. We observed modest evidence for linkage, with the maximum log odds (lod) scores for linkage for these traits occurring on chromosomes 3p (percentage of body fat: lod = 1.61, near the peroxisome proliferator-activated receptor-alpha gene), 14q (waist: lod = 1.80), and 16p (leptin: lod = 1.72; BMI: lod = 1.68). We also tested for linkage to BMI-adjusted leptin concentrations and observed suggestive evidence for linkage on chromosome 10p (lod = 2.73), approximately 10-20 cM telomeric from obesity loci previously reported in French and German Caucasians. Two additional linkage signals for this trait were observed on chromosomes 7q (lod = 1.77, approximately 20 cM from the leptin gene) and 14q (lod = 2.47). Follow-up studies may be warranted to pursue some of these linkage signals, especially those detected near known obesity candidate genes, and those in regions coinciding with linkage signals reported previously.

The Medicago Genome Initiative: a model legume database.

The Medicago Genome Initiative (MGI) is a database of EST sequences of the model legume MEDICAGO: truncatula. The database is available to the public and has resulted from a collaborative research effort between the Samuel Roberts Noble Foundation and the National Center for Genome Resources to investigate the genome of M.truncatula. MGI is part of the greater integrated MEDICAGO: functional genomics program at the Noble Foundation (http://www.noble.org ), which is taking a global approach in studying the genetic and biochemical events associated with the growth, development and environmental interactions of this model legume. Our approach will include: large-scale EST sequencing, gene expression profiling, the generation of M.truncatula activation-tagged and promoter trap insertion mutants, high-throughput metabolic profiling, and proteome studies. These multidisciplinary information pools will be interfaced with one another to provide scientists with an integrated, holistic set of tools to address fundamental questions pertaining to legume biology. The public interface to the MGI database can be accessed at http://www.ncgr.org/research/mgi.

Role of cyclooxygenase-2 in modulating gastric acid secretion in the normal and inflamed rat stomach.

Nonsteroidal anti-inflammatory drugs elevate gastric acid secretion, possibly contributing to their ability to interfere with gastric ulcer healing. Inhibitors of cyclooxygenase-2 have been shown to delay experimental gastric ulcer healing. In the present study, we tested the hypothesis that cyclooxygenase-2-derived prostaglandins modulate gastric acid secretion. Studies were performed in normal rats and in rats with iodoacetamide-induced gastritis. Inflammation in the latter group was confirmed histologically and by a threefold increase in tissue levels of the granulocyte marker myeloperoxidase and was also associated with overexpression of cyclooxygenase-2 in the stomach. Basal acid secretion in both groups of rats was not affected by pretreatment with DuP-697, a selective inhibitor of cyclooxygenase-2. A nonselective cyclooxygenase inhibitor, indomethacin, had no effect on acid secretion in normal rats but caused a doubling of acid secretion in the rats with gastritis. DuP-697 had no effect on pentagastrin-induced secretion in either group of rats. Gastritis itself was associated with significantly increased pentagastrin-induced acid secretion, and this was further increased in rats pretreated with indomethacin. These results suggest that in a setting of gastric inflammation, prostaglandins derived from cyclooxygenase-1, not cyclooxygenase-2, exert inhibitory effects on acid secretion.

Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study.

OBJECTIVE: The Old Order Amish (OOA) are a genetically well-defined closed Caucasian founder population. The Amish Family Diabetes Study was initiated to identify susceptibility genes for type 2 diabetes. This article describes the genetic epidemiology of type 2 diabetes and related traits in this unique population. RESEARCH DESIGN AND METHODS: The study cohort comprised Amish probands with diabetes who were diagnosed between 35 and 65 years of age and their extended adult family members. We recruited 953 adults who represented 45 multigenerational families. Phenotypic characterization included anthropometry, blood pressure, diabetes status, lipid profile, and leptin levels. RESULTS: The mean age of study participants was 46 years, and the mean BMI was 26.9 kg/m2. Subjects with type 2 diabetes were older, more obese, and had higher insulin levels. The prevalence of diabetes in the OOA was approximately half that of the Caucasian individuals who participated in the Third National Health and Nutrition Examination Survey (95% CI 0.23-0.84). The prevalence of diabetes in the siblings of the diabetic probands was 26.5% compared with a prevalence of 7.0% in spouses (lambdaS = 3.28, 95% CI 1.58-6.80). The heritability of diabetes-related quantitative traits was substantial (13-70% for obesity-related traits, 10-42% for glucose levels, and 11-24% for insulin levels during the oral glucose tolerance test; P = 0.01 to <0.0001). CONCLUSIONS: Type 2 diabetes in the Amish has similar phenotypic features to that of the overall Caucasian population, although the prevalence in the Amish community is lower than that of the Caucasian population. There is significant familial clustering of type 2 diabetes and related traits. This unique family collection will be an excellent resource for investigating the genetic underpinnings of type 2 diabetes.

QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31-34 in Old Order Amish.

BACKGROUND: Hypertension is a major risk factor for coronary heart disease, stroke, congestive heart failure, renal insufficiency, and peripheral vascular disease. Although the genetic contribution to variation in blood pressure is well recognized, the specific genes involved are mostly unknown. We carried out a genome-wide scan to identify loci influencing blood pressure in the Old Order Amish population of Lancaster County, Pennsylvania. METHODS AND RESULTS: Blood pressures were measured in 694 adult participants from families recruited without regard to blood pressure. We performed a quantitative linkage analysis by using 357 microsatellite markers. In multipoint analysis, strong evidence for linkage was observed with both diastolic (lod=3.36; P=0.00004) and to a lesser extent systolic (lod=1.64; P=0.003) blood pressure in the region of chromosome 2q31-34. Peak evidence for linkage occurred at map positions 217 and 221 cM from pter for diastolic and systolic blood pressure, respectively. CONCLUSIONS: A gene linked to familial primary pulmonary hypertension has recently been mapped to this same region, suggesting the intriguing hypothesis that other (attenuated) mutations in this same gene may influence variation in systolic and diastolic blood pressure in this population.

Control of the wrist in three-joint arm movements to multiple directions in the horizontal plane.

In a reaching movement, the wrist joint is subject to inertial effects from proximal joint motion. However, precise control of the wrist is important for reaching accuracy. Studies of three-joint arm movements report that the wrist joint moves little during point-to-point reaches, but muscle activities and kinetics have not yet been described across a range of movement directions. We hypothesized that to minimize wrist motion, muscle torques at the wrist must perfectly counteract inertial effects arising from proximal joint motion. Subjects were given no instructions regarding joint movement and were observed to keep the wrist nearly motionless during center-out reaches to directions throughout the horizontal plane. Consistent with this, wrist muscle torques exactly mirrored interaction torques, in contrast to muscle torques at proximal joints. These findings suggest that in this reaching task the nervous system chooses to minimize wrist motion by anticipating dynamic inertial effects. The wrist muscle torques were associated with a direction-dependent choice of muscles, also characterized by initial reciprocal activation rather than initial coactivation to stiffen the wrist joint. In a second experiment, the same pattern of muscle activities persisted even after many trials reaching with the wrist joint immobilized. These results, combined with similar features at the three joints, such as cosine-like tuning of muscle torques and of muscle onsets across direction, suggest that the nervous system uses similar rules for muscles at each joint, as part of one plan for the arm during a point-to-point reach.

Do eicosanoids cause colonic dysfunction in experimental E coli O157:H7 (EHEC) infection?

BACKGROUND: The pathophysiology of enterohaemorrhagic Escherichia coli (EHEC) infection remains unclear. Eicosanoids have been implicated as pathophysiological mediators in other colitides. AIMS: To determine if prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) contribute to mucosal inflammation and dysfunction in EHEC colitis. METHODS: Ten day old rabbits were infected with EHEC. For five days after infection, mucosal synthesis of PGE(2) and LTB(4) was measured in distal colonic tissue from control and infected animals and (51)Cr-EDTA permeability was assessed in vivo. Myeloperoxidase activity was measured and histological inflammation and damage were assessed at five days in control and infected animals and after treatment of infected animals with the LTB(4) synthesis inhibitor MK-886. In separate experiments, ion transport was measured in Ussing chambers, before and after in vitro addition of the cyclooxygenase inhibitor indomethacin. RESULTS: LTB(4) synthesis was increased from day 2 after infection onwards and PGE(2) synthesis was increased on day 3. Mucosal permeability did not increase until day 5 after infection. MK-886 inhibited colonic LTB(4) production but did not reduce diarrhoea, inflammation, or mucosal damage. Electrolyte transport was not significantly altered on day 3 after infection. However, both Cl secretion and reduced Na absorption found on day 5 were partially reversed by indomethacin. CONCLUSIONS: Tissue synthesis of PGE(2) and LTB(4) did not correlate temporally with EHEC induced inflammation or changes in mucosal permeability and ion transport. Cyclooxygenase inhibition partially reversed ion transport abnormalities but lipoxygenase inhibition did not affect mucosal inflammation or histological damage. We conclude that the contribution of eicosanoids to mucosal injury and dysfunction is more complex than previously suggested.

Methodology for long-term wear testing of total knee replacements.

This article begins to address the validation requirements of wear testing on total knee replacements in a knee simulator. The knee simulator has four stations. The axial force is variable but reaches a maximum of 2.3 kN. Physiologic anteroposterior shear force and rotational torques are supplied to the knee. The forces and displacements are timed to coincide with those of a typical gait cycle. Kinematics of the simulator are dependent on the type of knee being tested. Tests of designs with well known clinical histories were done to 10 million cycles. The relative amounts and types of wear shown by the designs were similar to that found in their clinical histories. Wear tracks on more conforming designs were larger, and the penetration into the plastic appeared to be less. This did not necessarily mean that wear, as measured by loss of material, was reduced on conforming designs. Delamination of the plastic was achieved only after aging the tibial components. Wear particles isolated from the lubricating fluid were similar in size and shape to those isolated from in vivo specimens. However, the relative amounts of wear particle shapes were different depending on the design. At the start of the tests, all of the flexibly mounted tibial components showed more motion than after 5 million cycles, indicating that the surface of the plastic became more conforming. This study showed that knee wear similar to wear observed in vivo can be reproduced in the laboratory. The parameters and methods elucidated in this introductory study should form the basis for use in preclinical wear tests of total knee replacements.

Melanocortin 3 receptor (MC3R) gene variants in extremely obese women.

OBJECTIVE: Following several reports of linkage of obesity related phenotypes to human chromosome 20q we sought to determine whether variations of the melanocortin 3 receptor (MC3R) gene are associated with obesity. DESIGN: We screened the MC3R gene coding region and approximately 2 kb of 5' and 3' flanking sequences for DNA variants in unrelated extremely obese women and average weight controls using polymerase chain reaction (PCR) single strand conformation polymorphism (SSCP) analysis and DNA sequencing. SUBJECTS: 124 unrelated extremely obese women (body mass index, (BMI)>/=40 kg/m2) and 85 average weight controls (BMI<27 kg/m2). MEASUREMENTS: Radiation hybrid (RH) mapping was performed to localize the MC3R gene. 5' and 3' flanking sequences of MC3R gene were cloned. PCR-SSCP and DNA sequencing were used to detect mutations in the MC3R gene coding region and flanking sequences. RESULTS: RH mapping localized the MC3R gene to 20q13, between markers D20S100 and D20S149. 1083 bp 5' and 653 bp 3' flanking region of the MC3R gene were cloned. A missense mutation (+241, codon 81 ATT/GTT, Ile-->Val) was found in the MC3R coding region. Four more variants were detected in the 5' flanking sequence: -201(C-->G), -239 (A-->G), -762(A-->T) and -769(T-->C). Compared with controls, no significant allele frequency differences were found. Racial differences were found for the +241, -201, -239 and -762 polymorphisms. CONCLUSIONS: Several sequence variants were found in the MC3R gene coding region and in 5' flanking sequences. However, none of the variants were associated with obesity phenotypes. The linkage of extreme human obesity on 20q13 is likely caused by genes other than MC3R. International Journal of Obesity (2000) 24, 206-210