Expression of foraging and Gp-9 are associated with social organization in the fire ant Solenopsis invicta.

The aim of this study was to investigate levels of expression of two major genes, the odorant binding protein Gp-9 (general protein-9) and foraging, that have been shown to be associated with behavioural polymorphisms in ants. We analysed workers and young nonreproductive queens collected from nests of the monogyne (single reproductive queen per nest) and polygyne (multiple reproductive queens) social forms of Solenopsis invicta. In workers but not young queens, the level of foraging expression was significantly associated with social form and the task performed (ie localization in the nest or foraging area). The level of expression of Gp-9 was also associated with social form and worker localization. In addition there was a higher level of expression of the Gp-9(b) allele compared with the Gp-9(B) allele in the heterozygote workers and the young nonreproductive queens. Finally, in the polygyne colonies the level of expression of foraging was not significantly associated with the Gp-9 genotype for either workers or young nonreproductive queens, suggesting that both genes have independent non-epistatic effects on behaviour in S. invicta.

Behavioural alteration in chronic pain: are brain glia involved?

Behavioural symptoms such as abnormal emotionality (including anxious and depressive episodes) and cognition (for instance weakened decision-making) are highly frequent in both chronic pain patients and their animal models. The theory developed in the present article posits that alterations in glial cells (astrocytes and microglia) in cortical and limbic brain regions might be the origin of such emotional and cognitive chronic pain-associated impairments. Indeed, in mood disorders (unipolar depression, anxiety disorders, autism or schizophrenia) glial changes in brain regions involved in mood control (prefrontal and cingulate cortices, amygdala and the hippocampus) have been recurrently described. Besides, glial cells have been undoubtedly identified as key actors in the sensory component of chronic pain, owing to the profound phenotypical changes they undergo throughout the sensory pathway. Hence, the possibility arises that brain astrocytes and microglia react in upper brain structures as well, mediating the related mood and cognitive dysfunctions in chronic pain. So far, only very few studies have provided results in this prospect, mainly indirectly in pain-independent researches. Nevertheless, the first scant available data seem to merge in a unified description of a brain glial reaction occurring after chronic peripheral lesion. The present article uses this scarce literature to formulate the provocative theory of a glia-driven mood and cognitive dysfunction in chronic pain, expounding upon its validity and putative therapeutical impact as well as its current limitations and expected future developments.

Alterations of bone microarchitecture in young patients with inflammatory bowel diseases are associated with fracture risk during growth

Aims: Inflammatory bowel diseases (IBD) appearing during childhood and adolescence compromise peak bone mass acquisition and increase fracture risk. The structural determinants of bone fragility in IBD however remain unknown. Methods: We investigated volumetric bone mineral density (vBMD), trabecular and cortical bone microstructure at distal radius and tibia by high-resolution pQCT (XtremeCT, Scanco, Switzerland), aBMD at distal radius, hip and spine and vertebral fracture assessment (VFA) by DXA in 107 young patients (mean age 22.8 yrs, range 12.2-33.7 yrs; 62 females and 45 males) with Crohn's disease (n=75), ulcerative colitis (n=25), undetermined colitis (n=2), and no definitive diagnosis (n=5), and in 389 healthy young individuals. Results: Mean disease duration was 6.1 yrs, 89/107 IBD patients received corticosteroids, 83 other immunomodulators, and 59 vitamin D. Clinical fractures were reported by 38 patients (mean age at 1st fracture, 12.6 yrs), the vast majority of the forearm, arm or hand; 5 had vertebral crush fractures (Grade 1 or 2) and 11 had multiple fractures. As compared to healthy controls (matched 2:1 for age, sex, height and fracture history), the 102 patients with established IBD had similar weight but significantly lower aBMD at all sites, lower trabecular (Tb) BV/TV and number, and greater Tb separation and inhomogeneous Tb distribution (1/SD TbN) at both distal radius and tibia, lower tibia cortical thickness (CTh), but no differences in cortical vBMD nor bone perimeter. Among IBD's, aBMD was not associated with fractures (by logistic regression adjusted for age, age square, sex, height, weight and protein intake). However, radius and tibia Tb BV/TV, thickness and SD 1/TbN, as well as radius Tb separation and perimeter, were significantly associated with fracture risk (fully adjusted as above), whereas cortical vBMD and CTh were not. After adjustment for aBMD at radius, respectively at femur neck, radius SD 1/TbN and tibia BV/TV, TbTh and perimeter remained independently associated with fracture risk. Conclusions: Young subjects with IBD have low bone mass and poor bone microarchitecture compared to healthy controls. Alterations of bone microarchitecture, particularly in the trabecular bone compartment, are specifically associated with increased fracture risk during growth.

How are "teaching the teachers" courses in evidence based medicine evaluated? A systematic review.

BACKGROUND: Teaching of evidence-based medicine (EBM) has become widespread in medical education. Teaching the teachers (TTT) courses address the increased teaching demand and the need to improve effectiveness of EBM teaching. We conducted a systematic review of assessment tools for EBM TTT courses.To summarise and appraise existing assessment methods for teaching the teachers courses in EBM by a systematic review. METHODS: We searched PubMed, BioMed, EmBase, Cochrane and Eric databases without language restrictions and included articles that assessed its participants. Study selection and data extraction were conducted independently by two reviewers. RESULTS: Of 1230 potentially relevant studies, five papers met the selection criteria. There were no specific assessment tools for evaluating effectiveness of EBM TTT courses. Some of the material available might be useful in initiating the development of such an assessment tool. CONCLUSION: There is a need for the development of educationally sound assessment tools for teaching the teachers courses in EBM, without which it would be impossible to ascertain if such courses have the desired effect.

C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L.

Interaction between CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ligand CD40L, a 39-kDa glycoprotein, is essential for the development of humoral and cellular immune responses. Selective blockade or activation of this pathway provides the ground for the development of new treatments against immunologically based diseases and malignancies. Like other members of the TNF superfamily, CD40L monomers self-assemble around a threefold symmetry axis to form noncovalent homotrimers that can each bind three receptor molecules. Here, we report on the structure-based design of small synthetic molecules with C3 symmetry that can mimic CD40L homotrimers. These molecules interact with CD40, compete with the binding of CD40L to CD40, and reproduce, to a certain extent, the functional properties of the much larger homotrimeric soluble CD40L. Architectures based on rigid C3-symmetric cores may thus represent a general approach to mimicking homotrimers of the TNF superfamily.

Hommes et femmes: sommes-nous tous égaux face à la douleur [Are there differences between men and women with pain?].

An increasing number of articles are published on the differences about pain in men and women. These differences seem to be due to the sex, the biological dimension of the person, and to the gender, which is the role given to that person in a given social and culture environment. The pain prevalence is higher in women, its threshold and tolerance are lower. The pain interpretation, its perception and the coping is also different in men and women. Finally doctors translate and treat pain differently. This article proposes some explanations on these differences which should help us to treat this frequent and noxious symptom for the quality of life in a better way.

Iodine-131-labeled MAb F(ab')2 fragments are more efficient and less toxic than intact anti-CEA antibodies in radioimmunotherapy of large human colon carcinoma grafted in nude mice.

During one week, beginning 18 days after transplantation, nude mice bearing human colon carcinoma ranging from 115 to 943 mm3 (mean 335 mm3) were treated by repeated intravenous injections of either iodine-131-(131I) labeled intact antibodies or 131I-labeled corresponding F(ab')2 fragments of a pool of four monoclonal antibodies (MAbs) directed against distinct epitopes of carcinoembryonic antigen (CEA). Complete tumor remission was observed in 8 of 10 mice after therapy with F(ab')2 and 6 of the animals survived 10 mo in good health. In contrast, after treatment with intact MAbs, tumors relapsed in 7 of 8 mice after remission periods of 1 to 3.5 mo despite the fact that body weight loss and depression of peripheral white blood cells, symptoms of radiation toxicity, and the calculated radiation doses for liver, spleen, bone, and blood were increased or equal in these animals as compared to mice treated with F(ab')2.

Are there vascular density gradients along myocardial laser channels?

BACKGROUND: Clinical studies suggest that transmyocardial laser revascularization may improve regional blood flow of the subendocardial layer. The vascular growth pattern of laser channels was analyzed. METHODS: Twenty pigs were randomized to undergo ligation of left marginal arteries (n = 5), to undergo transmyocardial laser revascularization of the left lateral wall (n = 5), to undergo both procedures (n = 5) or to a control group (n = 5). All the animals were sacrificed after 1 month. Computed morphometric analysis of vascular density of the involved area was expressed as number of vascular structures per square millimeter (+/-1 standard deviation). RESULTS: The vascular density of the scar tissue of the laser channel was significantly increased in comparison with myocardial infarction alone: 49.6+/-12.8/mm2 versus 25.5+/-8.6/mm2 (p < 0.0001). The vascular densities of subendocardial and subepicardial channel areas were similar: 52.9+/-16.8/mm2 versus 46.3+/-13.6/mm2 (p = 0.41). The area immediately adjacent to the channels showed a vascular density similar to that of normal tissue: 6.02+/-1.7/mm2 versus 5.2+/-1.9/mm2 (p = 0.08). In the infarction + transmyocardial laser revascularization group, the channels were indistinguishable from infarction scar. CONCLUSIONS: Scars of transmyocardial laser revascularization channels exhibit an increased vascular density in comparison with scar tissue of myocardial infarction, which does not extend into their immediate vicinity. There was no vascular density gradient along the longitudinal axis of the channels.

Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity.

AIMS: Aim of this study was to evaluate a possible association between endocannabinoid (EC) plasma levels, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and coronary circulatory function in obesity. METHODS AND RESULTS: Myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with (13)N-ammonia PET/CT. Study participants (n = 77) were divided into three groups based on their body mass index (BMI, kg/m(2)): control group 20 ≤ BMI <25 (n = 21); overweight group, 25 ≤ BMI <30 (n = 26); and obese group, BMI ≥ 30 (n = 30). Anandamide plasma levels, but not 2-AG plasma levels, were significantly elevated in obesity as compared with controls, respectively [0.68 (0.53, 0.78) vs. 0.56 (0.47, 0.66) ng/mL, P = 0.020, and 2.2 (1.21, 4.59) vs. 2.0 (0.80, 5.90) ng/mL, P = 0.806)]. The endothelium-related change in MBF during CPT from rest (ΔMBF) progressively declined in overweight and obese when compared with control group [0.21 (0.10, 0.27) and 0.09 (-0.01, 0.15) vs. 0.26 (0.23, 0.39) mL/g/min; P = 0.010 and P = 0.0001, respectively). Compared with controls, hyperaemic MBFs were significantly lower in overweight and obese individuals [2.39 (1.97, 2.62) vs. 1.98 (1.69, 2.26) and 2.10 (1.76, 2.36); P = 0.007 and P = 0.042, respectively)]. In obese individuals, AEA and 2-AG plasma levels were inversely correlated with ΔMBF to CPT (r = -0.37, P = 0.046 and r = -0.48, P = 0.008) and hyperaemic MBFs (r = -0.38, P = 0.052 and r = -0.45, P = 0.017), respectively. CONCLUSIONS: Increased EC plasma levels of AEA and 2-AG are associated with coronary circulatory dysfunction in obese individuals. This observation might suggest increases in EC plasma levels as a novel endogenous cardiovascular risk factor in obesity, but needing further investigations.

Fanconi-Bickel syndrome and autosomal recessive proximal tubulopathy with hypercalciuria (ARPTH) are allelic variants caused by GLUT2 mutations.

CONTEXT: Many inherited disorders of calcium and phosphate homeostasis are unexplained at the molecular level. OBJECTIVE: The objective of the study was to identify the molecular basis of phosphate and calcium abnormalities in two unrelated, consanguineous families. PATIENTS: The affected members in family 1 presented with rickets due to profound urinary phosphate-wasting and hypophosphatemic rickets. In the previously reported family 2, patients presented with proximal renal tubulopathy and hypercalciuria yet normal or only mildly increased urinary phosphate excretion. METHODS: Genome-wide linkage scans and direct nucleotide sequence analyses of candidate genes were performed. Transport of glucose and phosphate by glucose transporter 2 (GLUT2) was assessed using Xenopus oocytes. Renal sodium-phosphate cotransporter 2a and 2c (Npt2a and Npt2c) expressions were evaluated in transgenically rescued Glut2-null mice (tgGlut2-/-). RESULTS: In both families, genetic mapping and sequence analysis of candidate genes led to the identification of two novel homozygous mutations (IVS4-2A>G and R124S, respectively) in GLUT2, the gene mutated in Fanconi-Bickel syndrome, a rare disease usually characterized by renal tubulopathy, impaired glucose homeostasis, and hepatomegaly. Xenopus oocytes expressing the [R124S]GLUT2 mutant showed a significant reduction in glucose transport, but neither wild-type nor mutant GLUT2 facilitated phosphate import or export; tgGlut2-/- mice demonstrated a profound reduction of Npt2c expression in the proximal renal tubules. CONCLUSIONS: Homozygous mutations in the facilitative glucose transporter GLUT2, which cause Fanconi-Bickel syndrome, can lead to very different clinical and biochemical findings that are not limited to mild proximal renal tubulopathy but can include significant hypercalciuria and highly variable degrees of urinary phosphate-wasting and hypophosphatemia, possibly because of the impaired proximal tubular expression of Npt2c.

Treating high blood pressure: is reaching the target more important than the means? No, the means are important.

All major antihypertensive drug classes i.e. diuretics, beta-blockers, calcium antagonists and blockers of the renin-angiotensin system have been shown to effectively lower blood pressure and hence to reduce cardiovascular outcomes in hypertensive patients. These drugs decrease cardiovascular complications in hypertension essentially because they reduce systemic blood pressure. Nevertheless, there is growing evidence that the extent of the benefits differed between drug classes suggesting that the various classes of antihypertensive agents are not equivalent in their ability to protect against target organ damages and cardiovascular and renal endpoints. More recently, evidence has also accumulated to demonstrate that even combination therapies are not equally effective in reducing the occurrence of cardiovascular complications in hypertension. These recent observations suggest that the means to lower blood pressure are as important as the achieved target blood pressure in the management of hypertensive patients.

Connexins 43 and 26 are differentially increased after rat bladder outlet obstruction.

To evaluate the regulation of connexin expression by fluid pressure, we have studied the effects of elevated transmural urine pressure on Connexin43 (Cx43) and Cx26. We chose to focus on these two proteins out of the five connexins (Cx26, 43, 40, 37, and 45) which we found by RT-PCR to be expressed in the rat bladder, since in situ hybridization and immunofluorescence showed that Cx43 is the predominant connexin expressed by smooth muscle cells (SMC), whereas Cx26 is abundantly expressed only in the latter cell type. To evaluate whether these connexins are affected by changes in transmural urine pressure, we used a rat model of bladder outlet obstruction, in which a ligature is placed around the urethra. Under conditions of increased fluid pressure due to urine retention, we observed that the expression of both Cx43 and Cx26 increased at both transcript and protein levels, reaching a maximum 7-9 h after the ligature. Further analysis revealed that these changes were accounted for by a fourfold increase in Cx43 mRNA of SMC but not urothelial cell and by a fivefold increase in Cx26 mRNA of urothelium. Scrape-loading of propidium iodide showed that the latter change was paralleled by a twofold increase in coupling between urothelial cells. The data show that Cx43 and Cx26 are differentially regulated during bladder outlet obstruction and contribute to the response of the bladder wall to increased voiding pressure, possibly to control its elasticity.

Amyloid and non-amyloid forms of 5q31-linked corneal dystrophy resulting from kerato-epithelin mutations at Arg-124 are associated with abnormal turnover of the protein.

Mutations in kerato-epithelin are responsible for a group of hereditary cornea-specific deposition diseases, 5q31-linked corneal dystrophies. These conditions are characterized by progressive accumulation of protein deposits of different ultrastructure. Herein, we studied the corneas with mutations at kerato-epithelin residue Arg-124 resulting in amyloid (R124C), non-amyloid (R124L), and a mixed pattern of deposition (R124H). We found that aggregated kerato-epithelin comprised all types of pathological deposits. Each mutation was associated with characteristic changes of protein turnover in corneal tissue. Amyloidogenesis in R124C corneas was accompanied by the accumulation of N-terminal kerato-epithelin fragments, whereby species of 44 kDa were the major constituents of amyloid fibrils. R124H corneas with prevailing non-amyloid inclusions showed accumulation of a new 66-kDa species altogether with the full-size 68-kDa form. Finally, in R124L cornea with non amyloid deposits, we found only the accumulation of the 68-kDa form. Two-dimensional gels revealed mutation-specific changes in the processing of the full-size protein in all affected corneas. It appears that substitutions at the same residue (Arg-124) result in cornea-specific deposition of kerato-epithelin via distinct aggregation pathways each involving altered turnover of the protein in corneal tissue.