The Neural Processes Interlinking Social Isolation,Social Support,and Problem Alcohol Use

BackgroundSubjective feeling of social isolation, as can be measured by perceived burdensomeness (PB), is a major risk factor for alcohol misuse. Heightened PB is associated with elevated stress response and diminished cognitive control, both of which contribute to problem drinking. Here, we sought to identify the neural substrates underlying the relationship between PB and alcohol misuse.MethodsWe employed resting-state functional magnetic resonance imaging data collected from 61 problem drinkers to characterize the functional connectivity of the hypothalamus and ventral striatum (VS) in relation to PB. We specifically examined whether the connectivities of the hypothalamus and VS were differentially influenced by PB to produce contrasting effects on alcohol use. Finally, we evaluated how individual differences in social support modulate the inter-relationships of social isolation, neural connectivity, and the severity of problem drinking.ResultsWhole-brain multiple regressions show a positive relationship between PB and hypothalamic connectivity with the hippocampus and an inverse pattern for VS connectivity with the middle frontal gyrus. Difference in strength between the 2 connectivities predicted the severity of problem drinking, suggesting an imbalance involving elevated hypothalamic and diminished prefrontal cortical modulation in socially isolated problem drinkers. A path analysis further revealed that the lack of social support was associated with a bias toward low prefrontal connectivity, which in turn increased PB and facilitated problem drinking.ConclusionsAltered hypothalamus and VS connectivity may underlie problem drinking induced by social isolation. The current findings also highlight the important role of social support as a potential protective factor against alcohol misuse.     

WASP is activated by phosphatidylinositol-4,5-bisphosphate to restrict synapse growth in a pathway parallel to bone morphogenetic protein signaling

Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P₂] is a membrane lipid involved in several signaling pathways. However, the role of this lipid in the regulation of synapse growth is ill-defined. Here we identify PI(4,5)P₂ as a gatekeeper of neuromuscular junction (NMJ) size. We show that PI(4,5)P₂ levels in neurons are critical in restricting synaptic growth by localizing and activating presynaptic Wiscott-Aldrich syndrome protein/WASP (WSP). This function of WSP is independent of bone morphogenetic protein (BMP) signaling but is dependent on Tweek, a neuronally expressed protein. Loss of PI(4,5)P₂-mediated WSP activation results in increased formation of membrane-organizing extension spike protein (Moesin)-GFP patches that concentrate at sites of bouton growth. Based on pharmacological and genetic studies, Moesin patches mark polymerized actin accumulations and correlate well with NMJ size. We propose a model in which PI(4,5)P₂- and WSP-mediated signaling at presynaptic termini controls actin-dependent synapse growth in a pathway at least in part in parallel to synaptic BMP signaling.     

Modulation of metallothionein isoforms is associated with collagen deposition in proliferating keloid fibroblasts in vitro

Please cite this paper as: Modulation of metallothionein isoforms is associated with collagen deposition in proliferating keloid fibroblasts in vitro. Experimental Dermatology 2010; 19 : 987–993. Abstract: The keloid fibroblast (KF) is known to have higher proliferative capacity than normal dermal fibroblast (NF). Metallothionein (MT), a metal‐binding protein, has been reported to promote cell proliferation. In this study, we evaluated the expression of MT isoforms at the mRNA level in fetal bovine serum (FBS)‐stimulated proliferating KF. Although the morphological appearance of NF and KF was similar when viewed under light, confocal and transmission electron microscopy, there was surprisingly a generally lower expression of MT isoforms in KF when compared with NF and also reduced MT staining in dermal fibroblasts of keloids as opposed to normal skin. Primary cultures of KF grown in 5% FBS or 10% FBS compared to without FBS demonstrated significantly higher proliferative activity and more abundant deposition of collagen. Contrary to expectation, MT‐1A, ‐1F, ‐1G, ‐1X and ‐2A isoforms were significantly down‐regulated in proliferating KF. Moreover, stimulating KF with TGF β1, which is known to promote collagen synthesis and keloid formation, increased expression of Collagen 1A and 3A genes accompanied by reduction in MT‐2A gene expression. Furthermore, down‐regulation of the MT‐2A gene in proliferating KF by siRNA‐mediated silencing enhanced cell proliferation with concomitant up‐regulation of the NF‐κB gene and 10 of 13 other NF‐κB pathway–related genes analysed but no alteration of the Collagen 1 and Collagen 3 gene expression. It would appear that down‐regulation of MT isoforms in proliferating KF, in particular MT‐2A, enhances keloidogenesis with the possible involvement of the NF‐κB signalling pathway.     

The in vitro and in vivo proliferative capacity of serum-free cultivated human conjunctival epithelial cells

PURPOSE: To investigate the in vitro and in vivo proliferative capacity of human conjunctival epithelial cells cultured in serum-free media, and to compare this with current methods that utilize serum-containing media and 3T3 feeder layers. METHODS: Human conjunctival epithelial cells were cultivated in serum-free media alone, serum-free media with a 3T3 feeder layer, and serum-containing media with a 3T3 feeder layer. The areas of outgrowth, colony-forming efficiencies and number of population doublings were compared. The in vivo proliferative potential was assessed by analyzing the number of cells generated by the implantation of cultured cells into athymic mice. Cultured cells were evaluated for the expression of cytokeratins K3, K4, K12, K19, as well as the gel-forming goblet cell mucin, MUC5AC. RESULTS: Cells cultivated in serum-free media, serum-free media and feeder cells, and serum-containing media and feeder cells achieved colony-forming efficiencies of 14.5 +/- 4.1%, 10.1 +/- 3.1%, and 20.4 +/- 6.7%, respectively, and number of population doublings of 24.8 +/- 4.3, 14.8 +/- 3.6, and 30.0 +/- 5.0, respectively. Nine-day old athymic mice conjunctival cysts derived from serum-free cultures comprised 1.29 x 10(6) +/- 0.46 x 10(6) cells, while cysts derived from serum-containing cultures comprised 1.30 x 10(6) +/- 0.53 x 10(6) cells. The degree of epithelial stratification was similar in both conditions. Serum-free cultivated conjunctival cells retained their in vivo characteristics and expressed K4, K19 and MUC5AC. The presence of MUC5AC mRNA in these cells was confirmed by RT-PCR. CONCLUSIONS: Conjunctival epithelial cells propagated in serum-free media demonstrated a similar in vivo proliferative capability, as compared to serum-containing media with 3T3 feeder cells. This has important clinical implications, as the serum-free ex vivo expansion of cells for clinical transplantation overcomes the problems associated with the use of animal serum and cells.     

'Hit by the wind' and temperature-shift panic among Vietnamese refugees

Surveying 60 Vietnamese patients with either current or past post-traumatic stress disorder, this article aims to phenomenologically characterize the syndrome of 'hit by the wind' in a multidimensional manner. This includes determining the patient conceptualization of the disorder, profiling 'hit by the wind' episodes suffered by patients in the previous month, and presenting case vignettes. Eighteen of the 60 patients (30%) suffered at least one episode of 'hit by the wind' in the last month; all 18 patients had at least one episode of 'hit by the wind' in the last month that met panic attack criteria. For the 18 patients, 33 episodes of'hit by the wind' that met panic attack criteria were experienced in the previous month. For these 33 episodes, the most frequently reported DSM-IV panic attack symptoms were chills (100%; 33/33) and dizziness (88%; 29/33). Flashbacks played a role in the 'hit by the wind' episodes for 5 of the 18 patients (28%). In the discussion, a model of how the syndrome of 'hit by the wind' generates panic is adduced; also, possible Chinese origins of the disorder are discussed.     

Malaria epidemiology in a rural area of the Mekong Delta: a prospective community-based study

Over the past 10 years, the Mekong Delta region in Vietnam has experienced fast socio-economic development with subsequent changes in malaria vectors ecology. We conducted a 2-year prospective community-based study in a coastal rural area in the southern Mekong Delta to re-assess the malaria epidemiological situation and the dynamics of transmission. The incidence rate of clinical malaria, established on 558 individuals followed for 23 months by active case detection and biannual cross-sectional surveys, was 2.6/100 person-years. Over the 2-year study period, the parasite rate and malaria seroprevalence (Plasmodium falciparum and P. vivax) decreased significantly from 2.4% to almost 0%. Passive case detection (PCD) of clinical cases and serological follow-up of newborns carried out in a larger population confirmed the low and decreasing trend of malaria transmission. The majority of fever cases were seen in the private sector and most were unnecessarily treated with antimalarials. Training and involvement of the private sector in detection of malaria cases would greatly improve the quality of health care and health information system.     

Influence of Lifestyle Factors on Quantitative Heel Ultrasound Measurements in Middle-Aged and Elderly Men

We examined the distribution of quantitative heel ultrasound (QUS) parameters in population samples of European men and looked at the influence of lifestyle factors on the occurrence of these parameters. Men aged between 40 and 79 years were recruited from eight European centers and invited to attend for an interviewer-assisted questionnaire, assessment of physical performance, and quantitative ultrasound (QUS) of the calcaneus (Hologic; Sahara). The relationships between QUS parameters and lifestyle variables were assessed using linear regression with adjustments for age, center, and weight. Three thousand two hundred fifty-eight men, mean age 60.0 years, were included in the analysis. A higher PASE score (upper vs. lower tertile) was associated with a higher BUA (β coefficient = 2.44 dB/Mhz), SOS (β = 6.83 m/s), and QUI (β = 3.87). Compared to those who were inactive, those who walked or cycled more than an hour per day had a higher BUA (β = 3.71 dB/Mhz), SOS (β = 6.97 m/s), and QUI (β = 4.50). A longer time to walk 50 ft was linked with a lower BUA (β = ?0.62 dB/Mhz), SOS (β = ?1.06 m/s), and QUI (β = ?0.69). Smoking was associated with a reduction in BUA, SOS, and QUI. There was a U-shaped association with frequency of alcohol consumption. Modification of lifestyle, including increasing physical activity and stopping smoking, may help optimize bone strength and reduce the risk of fracture in middle-aged and elderly European men.     

Genetic Variation in Sex Hormone Genes Influences Heel Ultrasound Parameters in Middle‐Aged and Elderly Men: Results From the European Male Aging Study (EMAS)

Genes involved in sex hormone pathways are candidates for influencing bone strength. Polymorphisms in these genes were tested for association with heel quantitative ultrasound (QUS) parameters in middle‐aged and elderly European men. Men 40–79 yr of age were recruited from population registers in eight European centers for the European Male Aging Study (EMAS). Polymorphisms were genotyped in AR, ESR1, ESR2, CYP19A1, CYP17A1, SHBG, SRD5A2, LHB, and LHCGR. QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured in the heel and used to derive BMD. The relationships between QUS parameters and polymorphisms were assessed using linear regression adjusting for age and center. A total of 2693 men, with a mean age of 60.1 ± 11.1 (SD) yr were included in the analysis. Their mean BUA was 80.0 ± 18.9 dB/Mhz, SOS was 1550.2 ± 34.1 m/s, and BMD was 0.542 ± 0.141 g/cm². Significant associations were observed between multiple SNPs in a linkage disequilibrium (LD) block within CYP19A1, peaking at the TCT indel with the deletion allele associating with reduced ultrasound BMD in heterozygotes (β =?0.016, p = ?0.005) and homozygotes (β = ?0.029, p = 0.001). The results for BUA and SOS were similar. Significant associations with QUS parameters were also observed for the CAG repeat in AR and SNPs in CYP17A1, LHCGR, and ESR1. Our data confirm evidence of association between bone QUS parameters and polymorphisms in CYP19A1, as well as modest associations with polymorphisms in CYP17A1, ESR1, LHCGR, and AR in a population sample of European men; this supports a role for genetically determined sex hormone actions in influencing male bone health.     

Clinical efficacy of high dose monotherapy of oral dihydroartemisinin in uncomplicated falciparum malaria in viet nam

The clinical efficacy of the monotherapy involving the administration of a high dose of dihydroartemisinin (DHA 900 mg) for 5 days was compared with that of the combination regimen (DHA 600 mg + mefloquine [MQ] 750 mg) in an open randomized study in 90 patients with uncomplicated falciparum malaria in the southern part of Viet Nam. Patients were randomly treated with the DHA-5 day monotherapy regimen (300, 300, 100, 100, and 100 mg given at 0, 24, 48, 72, and 96 h) or the DHA-MQ combination regimen (300 mg DHA at 0 h, then 300 mg DHA plus 750 mg MQ at 24 h). The end points for comparison were the parasite and fever clearance times (PCT and FCT) and recrudescence rates (by day 28 for DHA-5 days and day 42 for DHA-MQ). Eighty-nine patients completed the trial per protocol, including 45 cases receiving DHA-5 day and 44 receiving DHA-MQ. There was no difference in clinical manifestations, parasitemia density or other laboratory tests between the two patient groups. The PCTs were 35.3 +/- 17.4 h (mean +/- SD; range, 12-96) and 37.8 +/- 19.2 h (range, 12-96), respectively for the DHA-5 day and DHA-MQ regimens (P > 0.05). Twelve patients receiving the DHA-5 day regimen relapsed with falciparum malaria by day 28 (26.7%) and 5 patients receiving the DHA-MQ regimen relapsed by day 42 (11.4%) (P=0.07). Survival analysis showed that the DHA-5 day regimen had a radical cure rate significantly lower than that of the DHA-MQ regimen (P=0.003). The high dose of DHA in the monotherapy regimen did not increase the efficacy of the treatment of patients with uncomplicated Plasmodium falciparum malaria. The DHA combination regimens are suggested to be the better regimens for DHA.     

Crotonkinins A and B and related diterpenoids from Croton tonkinensis as anti-inflammatory and antitumor agents

Cytotoxicity-guided phytochemical investigation of a methanolic extract of Croton tonkinensis afforded two new kaurane diterpenoids (1, 2) and 10 known ent-kaurane-type diterpenoids (3- 12). The structures of 1 and 2 were based on analysis of spectroscopic and mass spectral data. Compounds 3- 12 were identified by comparison of their spectroscopic and physical data with those reported in the literature. Selected compounds from this plant were examined for cytotoxic and anti-inflammatory activities. Compounds 4 and 9 showed the highest cytotoxic activity against the tested tumor cell lines. Compounds 3, 4, 6, 8, 9, and 11 had IC 50 values less than 5 microM and were more potent than the nonspecific NOS inhibitor L-NAME in inhibiting LPS-induced NO production.