Paradoxical hyperalgesic effect of exceedingly low doses of systemic morphine in an animal model of persistent pain (Freund's adjuvant-induced arthritic rats)

The effects of exceedingly low doses of morphine (3-50 micrograms/kg i.v.) were studied upon the vocalization threshold induced by paw pressure in rats with Freund's adjuvant-induced arthritis. The highest dose used (50 micrograms/kg i.v.) clearly induced an analgesic effect. No significant modification of the vocalization threshold was observed with 30 micrograms/kg. By contrast, a significant hyperalgesic effect resulted with doses of 10 down to 3 micrograms/kg. Maximum hyperalgesia was observed with 6 micrograms/kg.     

Ligand-induced changes in the subcellular distribution of insulin receptors in rat liver: effects of colchicine

The in vivo effects of colchicine on the subcellular distribution of insulin receptors have been studied in insulin-injected rats and in control animals. Colchicine (0.1 mg/100 g or 10 mg/100 g body weight, i.v.) did not affect the ability of plasma membranes and Golgi fractions of control rats to bind insulin. As previously reported (Desbuquois et al., 1982), the injection of native insulin (8 nmol, i.v.) caused a 50% decrease in the insulin binding activity of plasma membranes and a concomitant 50% increase in insulin binding to Golgi fractions. These changes occurred at 4 and 40 min after insulin injection but were no longer detectable at 3 h. Colchicine treatment did not affect the initial changes in the distribution of insulin receptors induced by insulin; however, in rats treated with the low dose of colchicine, insulin binding to plasma membranes at 3 h was not fully restored. Colchicine treatment did not alter the amount of acid-extractable insulin associated with Golgi fractions of insulin-injected rats. The time course of uptake of 125I-insulin was similar in plasma membranes, microsomal fraction and Golgi fractions of colchicine-treated (0.1 mg/100 g) and of untreated rats. These results suggest that colchicine does not interfere with the endocytosis of insulin receptors induced by their ligand and has little effect, if any, on the reinsertion of internalized receptors in the plasma membrane.     

Danazol in acquired amegakaryocytic thrombocytopenic purpura: A case report

Summary Acquired amegakaryocytic thrombocytopenic purpura is a rare disease. Most reported patients did not respond to any therapeutical approach. Recently we observed a striking improvement of this disorder in a female patient shortly after therapy with danazol had been initiated. This observation and its possible implication for the treatment of amegakaryocytic thrombocytopenia are reported herein.     

Essential Role of Osteopontin in Smoking-Related Interstitial Lung Diseases

Smoking-related interstitial lung diseases are characterized by the accumulation of macrophages and Langerhans cells, and fibrotic remodeling, which are linked to osteopontin (OPN) expression. Therefore, OPN levels were investigated in bronchoalveolar lavage (BAL) cells in 11 patients with pulmonary Langerhans cell histiocytosis (PLCH), 15 patients with desquamative interstitial pneumonitis (DIP), 10 patients with idiopathic pulmonary fibrosis, 5 patients with sarcoidosis, 13 otherwise healthy smokers, and 19 non-smoking controls. Furthermore, OPN overexpression was examined in rat lungs using adenoviral gene transfer. We found that BAL cells from patients with either PLCH or DIP spontaneously produced abundant amounts of OPN. BAL cells from healthy smokers produced 15-fold less OPN, and those cells from non-smoking healthy volunteers produced no OPN. BAL cells from patients with either idiopathic pulmonary fibrosis or sarcoidosis produced significantly less OPN, as compared with patients with PLCH. These data were confirmed by immunochemistry. Nicotine stimulation increased production of both OPN and granulocyte-macrophage colony stimulating factor by alveolar macrophages from smokers. Nicotinic acetylcholine receptor expression resembled the pattern of spontaneous OPN production and was dramatically increased in both PLCH and DIP. OPN overexpression in rat lungs induced lesions similar to PLCH with marked alveolar and interstitial accumulation of Langerhans cells. Our findings suggest a pathogenetic role of increased OPN production in both PLCH and DIP by promoting the accumulation of macrophages and Langerhans cells.Cigarette smoke is linked to a variety of lung diseases including chronic obstructive pulmonary disease, lung cancer, and interstitial lung diseases. Respiratory bronchiolar interstitial lung disease, desquamative interstitial pneumonitis (DIP), and pulmonary Langerhans cell histiocytosis (PLCH) belong to the group of smoking-related interstitial lung diseases.^1,2,3 Cigarette smoke is a complex mixture of more than 4000 compounds and is known to cause systemic and pulmonary effects.⁴ However, the underlying mechanisms as to how cigarette smoking leads to the changes observed in smoking-related interstitial lung diseases are largely unknown.^1,2,3Cigarette smoke induces inflammation, oxidative stress, and tissue injury, and has an important effect on the number, distribution, and activation state of macrophages and Langerhans cells.^5,6 There is a strong epidemiological link between PLCH and smoking. PLCH is characterized by the accumulation of activated Langerhans cells originating from the distal bronchiole walls.^1,2,3,7 The accumulations of Langerhans cells are poorly demarcated and extend to the adjacent alveoli, which often contain an abundance of pigmented macrophages. These areas show morphological changes similar to DIP.^7,8 In DIP, the predominant feature is the accumulation of alveolar macrophages, densely filling the alveolar lumen, combined with moderate fibrotic interstitial remodeling.^1,2As measured by bronchoalveolar lavage (BAL) in healthy individuals, cigarette smoking induces a 5- to 10-fold increase in alveolar macrophages in a dose-response curve.^9,10,11 It was shown that concentrations of granulocyte-macrophage colony stimulating factor (GMCSF) in patients with PLCH are increased,¹² but the mechanisms that lead to the expansion of the pulmonary macrophage pool and fibrosis in smokers are poorly understood.^1,2,3 Based on the findings of a microarray study, Woodruff et al¹³ have recently proposed that alveolar macrophages from smokers exhibit a distinctive macrophage activation state that is accompanied by increased OPN expression. Osteopontin is a glycoprotein found in the extracellular matrix of bone.¹⁴ However, multiple studies have reported cytokine properties of OPN in cell-mediated immunity.¹⁴ Further, OPN exhibits a strong chemotactic activity for macrophages, monocytes, Langerhans cells, and dendritic cells.^15,16,17In the context of these findings we speculated that OPN might be involved in the pathogenesis of smoking-related lung interstitial diseases. We found abundant OPN production by alveolar macrophages from patients with PLCH and DIP. Alveolar macrophages from both healthy smokers and patients with DIP and PLCH show up-regulated nicotine receptor expression as a sign of chronic nicotine stimulation. Further, nicotine directly induced OPN and GMCSF in alveolar macrophages. Our data provides evidence for a role of osteopontin in the pathogenesis of smoking- related interstitial lung diseases.     

Neurophysiologisches Konzept der Manuellen Medizin – mehr als Schmerztherapie

Ohne Zusammenfassung     

Effects of 17-day spaceflight on electrically evoked torque and cross-sectional area of the human triceps surae

The effects of spaceflight on triceps surae muscle torque and cross-sectional area (CSA) were investigated on four astronauts using electrically evoked contractions to by-pass neural control. Muscle twitch characteristics, ankle joint angle–twitch torque relation, frequency–torque relation, tetanic torque and fatigability were assessed before, during and after a 17-day Space Shuttle flight (STS-78). Muscle plus bone cross-sectional area (CSAm+b) was evaluated before and after the flight. Whereas no changes in muscle function were observed during the flight, marked alterations were found during the recovery period. Peak twitch (PTw) and tetanic torques at 50 Hz (PT₅₀) continued to fall up to the 8th recovery day (R+8) on which losses in PTw and PT₅₀ were 24.4% (P<0.01) and 22.0% (P<0.01), respectively. The decline in PTw was not joint-angle-specific. Post-flight, especially on R+8, torque decreased at all stimulation frequencies (1, 20, 30 and 50 Hz); however the shape of the frequency–torque curve, normalised for PT₅₀, was not modified. Similarly, no changes in twitch kinetics were observed. Post- flight, an 8% (P<0.01) reduction in CSAm+b was found on R+2. Normalisation of PT₅₀ values for CSAm+b showed a progressive loss in specific torque (PT₅₀/CSAm+b), which was maximal on R+2 (19.5%, P<0.05). Also, fatigability during 2-min intermittent stimulation at 20 Hz increased throughout recovery, reaching a nadir of 16.4% (P<0.01) on R+15. In conclusion, 17 days of spaceflight resulted in significant changes in muscle function during the recovery phase, but not in microgravity. The disproportionate loss of torque compared with that of muscle size suggests the presence of muscle damage due to reloading in 1 g.     

Maternal heart rate changes during labour

Objectives

Labour and delivery represent a considerable effort for pregnant women. Lack of aerobic fitness may limit pushing efforts during childbirth and represents increased cardiovascular strain and risk. Increasing prevalence of sedentary behaviour and lack of aerobic fitness may reduce heart rate reserve during labour.

Study design

We quantified maternal heart rate reserve (maximum heart rate minus resting heart rate) of 30 healthy pregnant women during labour and delivery and related it to habitual daily physical activity levels quantified during the third pregnancy trimester by the Pregnancy Physical Activity Questionnaire.

Results

Heart rates during labour reached values similar to those observed during moderate to heavy physical exercise. During active pushing one out of five women reached heart rates more than 90% of their heart rate reserve (188 ± 7 beats per min). Half of the women reached more than 70% of heart rate reserve (172 ± 14 beats per min). Physically inactive women used more of their heart rate reserve as physically more active women (87 ± 20% vs. 65 ± 12%, upper and lower tertile respectively, p < 0.05).

Conclusions

Use of heart rate reserve for the effort of labour is increased in physically inactive women and may potentially limit the intensity and duration of pushing efforts. Such higher cardiovascular strain in physically less active women may represent increased cardiovascular risk during labour.     

Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors

Androgen-independent recurrence is the major limit of androgen ablation therapy for prostate cancer. Identification of alternative pathways promoting prostate tumor growth is thus needed. Stat5 has been recently shown to promote human prostate cancer cell survival/proliferation and to be associated with early prostate cancer recurrence. Stat5 is the main signaling pathway triggered by prolactin (PRL), a growth factor whose local production is also increased in high-grade prostate cancers. The first aim of this study was to use prostate-specific PRL transgenic mice to address the mechanisms by which local PRL induces prostate tumorogenesis. We report that (i) Stat5 is the major signaling cascade triggered by local PRL in the mouse dorsal prostate, (ii) this model recapitulates prostate tumorogenesis from precancer lesions to invasive carcinoma, and (iii) tumorogenesis involves dramatic accumulation and abnormal spreading of p63-positive basal cells, and of stem cell antigen-1–positive cells identified as a stem/progenitor-like subpopulation. Because basal epithelial stem cells are proposed to serve as tumor-initiating cells, we challenged the relevance of local PRL as a previously unexplored therapeutic target. Using a double-transgenic approach, we show that Δ1–9-G129R-hPRL, a competitive PRL-receptor antagonist, prevented early stages of prostate tumorogenesis by reducing or inhibiting Stat5 activation, cell proliferation, abnormal basal-cell pattern, and frequency or grade of intraepithelial neoplasia. This study identifies PRL receptor/Stat5 as a unique pathway, initiating prostate tumorogenesis by altering basal-/stem-like cell subpopulations, and strongly supports the importance of further developing strategies to target locally overexpressed PRL in human prostate cancer.     

Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck

Although previous studies have documented a bottleneck in the transmission of mtDNA genomes from mothers to offspring, several aspects remain unclear, including the size and nature of the bottleneck. Here, we analyze the dynamics of mtDNA heteroplasmy transmission in the Genomes of the Netherlands (GoNL) data, which consists of complete mtDNA genome sequences from 228 trios, eight dizygotic (DZ) twin quartets, and 10 monozygotic (MZ) twin quartets. Using a minor allele frequency (MAF) threshold of 2%, we identified 189 heteroplasmies in the trio mothers, of which 59% were transmitted to offspring, and 159 heteroplasmies in the trio offspring, of which 70% were inherited from the mothers. MZ twin pairs exhibited greater similarity in MAF at heteroplasmic sites than DZ twin pairs, suggesting that the heteroplasmy MAF in the oocyte is the major determinant of the heteroplasmy MAF in the offspring. We used a likelihood method to estimate the effective number of mtDNA genomes transmitted to offspring under different bottleneck models; a variable bottleneck size model provided the best fit to the data, with an estimated mean of nine individual mtDNA genomes transmitted. We also found evidence for negative selection during transmission against novel heteroplasmies (in which the minor allele has never been observed in polymorphism data). These novel heteroplasmies are enhanced for tRNA and rRNA genes, and mutations associated with mtDNA diseases frequently occur in these genes. Our results thus suggest that the female germ line is able to recognize and select against deleterious heteroplasmies.Heteroplasmy (intra-individual variation) in mitochondrial DNA (mtDNA) plays an important role in mtDNA-related diseases and has also been implicated in aging and cancer (Greaves et al. 2012; Wallace 2012; Chinnery and Hudson 2013; Lombès et al. 2014). Most mtDNA mutations that cause diseases due to defects in mitochondrial function exist as heteroplasmies and only cause disease symptoms when the frequency of the mutant allele exceeds a particular threshold (Wallace and Chalkia 2013). Below this threshold, individuals are asymptomatic, presumably because there are sufficient functional mitochondria for normal metabolism. Changes in the frequency of pathogenic mutations during the transmission of heteroplasmies from mothers to offspring can thus play an important role in the disease risk of the offspring. However, most of our knowledge concerning the dynamics of heteroplasmy transmission comes from studies of pathogenic mutations (Monnot et al. 2011; Shen et al. 2012; de Laat et al. 2013; Wallace and Chalkia 2013), which in blood have been shown to decrease over time and hence may not accurately reflect the overall level of such pathogenic mutations within an individual (Poulton and Morten 1993; ‘t Hart et al. 1996; Rahman et al. 2001; Rajasimha et al. 2008). Mouse models have also been utilized (Cree et al. 2008; Fan et al. 2008; Freyer et al. 2012; Ross et al. 2013), but to date, there have been only a few studies of normal patterns of heteroplasmy transmission in humans (Sekiguchi et al. 2003; Goto et al. 2011; Sondheimer et al. 2011; Guo et al. 2013; Rebolledo-Jaramillo et al. 2014), including studies of oocytes and placenta (Marchington et al. 1997, 2002; Jacobs et al. 2007), and several questions remain.For example, although it is clear that a bottleneck occurs during the transmission of mtDNA genomes from mothers to offspring, the size of the bottleneck remains a contentious issue. Previous estimates of the effective number of transmitted mtDNA genomes range widely, from eight to 200 (Brown et al. 2001; Guo et al. 2013; Rebolledo-Jaramillo et al. 2014). However, all previous studies have assumed a constant size for the bottleneck across individuals; the effect of allowing the bottleneck size to vary among individuals has not been investigated. Moreover, it has been suggested that mtDNA genomes may not behave as independent entities but instead are organized into discrete units called “nucleoids,” each of which contains 5–10 mtDNA genomes (Jacobs et al. 2000; Cao et al. 2007; Khrapko 2008), although recently it has been suggested that the number may be much smaller, on the order of one mtDNA genome per nucleoid (Kukat et al. 2011). Each nucleoid is thought to be homoplasmic for mtDNA genome sequences; thus, mtDNA heteroplasmy at the cellular level would reflect nucleoids that are homoplasmic for different sequence variants. Nucleoid structures within cells have been studied microscopically and biochemically (Bogenhagen 2012), and nucleoid-based models have been found to provide a better fit to the segregation of heteroplasmic mtDNA genomes in cell lines than do simple bottleneck models in some studies (Cao et al. 2007; Khrapko 2008), but not in others (Cree et al. 2008). However, to date, nucleoid-based models have not been investigated in the transmission of mtDNA heteroplasmy from mothers to offspring.Another issue is the degree to which negative (or purifying) selection may act on deleterious variants during the transmission of mtDNA heteroplasmy. There are conflicting results and views as to whether changes in the frequency of a heteroplasmic mutation from mother to offspring are governed solely by genetic drift, or whether there is an additional role for negative (purifying) selection (Jenuth et al. 1997; Durham et al. 2006; Stewart et al. 2008a,b; Wonnapinij et al. 2008; Wallace and Chalkia 2013; Rebolledo-Jaramillo et al. 2014). Negative selection during heteroplasmy transmission, as evidenced by a decrease in the frequency of presumably deleterious heteroplasmic variants in offspring compared to mothers, must operate on the female germ line and/or early in development after fertilization, and hence differs from negative selection operating on homoplasmic variants that reduce viability or fertility (Holt et al. 2014). The opportunities for, and extent of, such negative selection during heteroplasmy transmission in humans remain largely unknown.Here, we utilize the Genomes of the Netherlands (GoNL) project (Boomsma et al. 2014; Genome of the Netherlands Consortium 2014), consisting of whole-genome sequence data from blood samples from 250 families, to carry out the largest study to date (to our knowledge) of the dynamics of heteroplasmy transmission across the entire mtDNA genome. We utilize the data on changes in minor allele frequency (MAF) from mothers to offspring at heteroplasmic sites to compare different models for the inheritance of mtDNA genomes, and we analyze the data for evidence of negative selection during heteroplasmy transmission.     

Facteurs de risque psychosociaux et troubles psychiatriques des jeunes pris en charge par l’aide sociale à l’enfance et ayant recours à des soins hospitaliers

Background

Children and adolescents involved with foster care are a population at high risk of developing psychiatric disorders. Here, we aimed to assess in children and adolescents admitted in a University Department of Child and Adolescent Psychiatry whether being involved with foster care would change psychopathology and risk factors they face.

Method

We conducted a case-control study in a sample of 103 inpatients aged 6 to 18 years (52 supported by foster care; 51 not supported). Assessment included family and medical histories, psychopathology using the MINI neuropsychiatric interviews (Kid and parents) for axis 1 diagnoses and the diagnostic interview for borderline for axis 2 diagnoses. We also scored the following scales: Global Assessment Functioning, Eysenck Impulsivity and Empathy Scale, Buss and Durkee Hostility Inventory, Harvey Affective Liability Scale.

Results

We found more psychosocial life events, both past and recent (occurring less than 2 years) in inpatients involved with foster care (family conflicts, single parent, repeated breaks in places of life, academic failures). We also found more family history of antisocial personality disorder, alcoholism and other drug abuses in first-degree relatives. Regarding axis 1 psychopathologies, we found significantly more conduct disorders, specific developmental disorders and learning difficulties among youths supported by foster care. Finally, we found several prevalent traits of the borderline personality and higher scores of impulsivity, emotional liability and hostility. However, we did not find significant difference for empathy score between the two groups. The results emphasize a condition of cumulative risk factors in the inpatients population involved with foster care.

Conclusion

The severity and prevalence of psychiatric disorders among youths involved with foster care and requiring psychiatric inpatient stay show the impact of interactions with the environment on the development of psychopathology in children and, for some of them, the inadequacy of the means of prevention.