Adiponectin reduces connective tissue growth factor in human hepatocytes which is already induced in non-fibrotic non-alcoholic steatohepatitis

Connective tissue growth factor (CTGF) is induced in liver fibrosis and enhances the activity of transforming growth factor β (TGFβ). Recently we have shown that the hepatoprotective adipokine adiponectin downregulates CTGF in primary human hepatocytes (PHH). In the current study, the mechanisms mediating suppression of CTGF by adiponectin and the well described downstream effector of adiponectin receptor 2 (AdipoR2), peroxisome proliferator activated receptor α (PPARα), were analyzed in more detail. Adiponectin downregulated CTGF mRNA and protein in primary human hepatocytes (PHH) and suppression was blocked by a PPARα antagonist indicating that AdipoR2 is involved. The PPARα agonists fenofibrate and WY14643 also reduced CTGF protein in these cells. Adiponectin further impaired TGFβ-mediated upregulation of CTGF. Phosphorylation of the TGFβ downstream effectors SMAD2 and –3 was reduced in PHH incubated with adiponectin or PPARα agonists suggesting that early steps in TGFβ signal transduction are impaired. CTGF and TGFβ mRNA levels were increased in human non-fibrotic non-alcoholic steatohepatitis (NASH), and here AdipoR2 expression was significantly reduced. Current data show that CTGF and TGFβ are already induced in non-fibrotic NASH and this may be partly explained by low adiponectin bioactivity which interferes with TGFβ signaling by reducing phosphorylation of SMAD2/3 and by downregulating CTGF.     

Pain behavior and spinal cell activation due to carrageenan-induced inflammation in two inbred rat strains with differential hypothalamic–pituitary–adrenal axis reactivity

Lewis (LEW) and Fischer (FIS) inbred rats were used to study the relationship of hypothalamic–pituitary–adrenal (HPA) axis reactivity with inflammation-related pain behavior. LEW rats are susceptible to the development of autoimmune and chronic inflammatory disorders, whereas FIS rats are resistant. Since contradictory data have previously been collected under conditions of acute inflammation, we investigated the onset and maintenance of thermal and mechanical hyperalgesia and spinal activation of neurons and glia cells in a model of ongoing inflammation in both strains. Hind paw volumes and mechanical and thermal pain thresholds were measured prior to and during one week after intraplantar injection of carrageenan. The activation of nociceptive neurons (FosB), astroglia (GFAP) and microglia (OX-42) in the spinal cord of segments L5/L6 was assessed using immunohistochemistry. Inflammation increased paw volume, pain sensitivity and cell activation in both strains. FIS rats were more sensitive to sensory stimulation and developed a more severe edema on day 1, but recovered faster up to day 7 than LEW rats. At that time a higher amount of activated nociceptive neurons and corticosterone was seen in FIS rats, but microglial activation was more pronounced in LEW rats. Our results suggest a biphasic role of the HPA axis in pain behavior and spinal cell activation associated with ongoing inflammation. In the acute stage, the stronger reaction in FIS rats might be explained by an activating effect of corticosteroids on neutrophil function. Under ongoing inflammatory conditions the immunosuppressive actions of corticosteroids may dominate and lead to a quicker recovery of paw volume and pain sensitivity in FIS rats.     

Baseline C-reactive protein level as a predictor of mortality in bacteraemia patients: a population-based cohort study

We examined the association between C-reactive protein (CRP) level at time of blood culture (BC) draw and mortality following bacteraemia. Our population-based cohort study comprised all first-time monomicrobial bacteraemia episodes in adults in a Danish county during 1996–2004 (n = 5267). CRP was measured within 24 h of the first positive BC draw. Cox regression was used to compute mortality rate ratios (MRRs) associated with CRP level quartiles (10–64 (reference), 65–143, 144–240 and 241–688 mg/L), controlling for age, gender, comorbidity, specialty, acquisition of infection, and infection focus. We also looked for a biological interaction between CRP level and high magnitude of bacteraemia (three of three culture bottles positive). Thirty-day mortality increased with higher CRP level: adjusted 0–30-day MRRs for patients in the second, third and fourth CRP quartiles were 1.38 (95% CI 1.13–1.69), 1.70 (95% CI 1.40–2.06), and 2.38 (95% CI 1.96–2.87), respectively (p for trend <10⁾⁴). In contrast, mortality associations with CRP during 31–365 days of follow-up were weak (adjusted MRRs for the second to fourth quartiles ranged from 1.18 to 1.28). A high magnitude of bacteraemia strengthened the association between high CRP level and 30-day mortality. We conclude that the CRP level, measured concurrently with the first positive BC, independently predicted 30-day mortality in adult bacteraemia patients.     

To gamble or not to gamble: at risk for craving and relapse--learned motivated attention in pathological gambling

In recent research similarities between pathological gambling and drug addiction have been identified, suggesting excessive gambling to constitute an addiction. So far, we have insufficient knowledge concerning the psychophysiological mechanisms underlying this kind of non-substance-related addiction. The objective of the study was to investigate emotional processing of gambling-relevant and -irrelevant stimuli in pathological gamblers and non-gambling controls using an EEG cue-reactivity paradigm. Whereas gambling-irrelevant stimuli were processed similarly in non-gambling controls (HC) and pathological gamblers (PG), PG showed significantly stronger gambling-relevant stimulus-induced psychophysiological cue-reactivity (larger gambling stimulus-induced late positive potential, LPP, higher arousal and more positively toned valence ratings as well as higher stimulus-induced craving for gambling cues compared to HC - but not the expectable increase of general craving over time and after stimulus presentation). Our findings suggest enhanced cue-reactivity in pathological gamblers indicative of learned motivated attention that may induce subjective craving and relapse.     

Motor disturbances during non-REM and REM sleep in narcolepsy-cataplexy: a video-polysomnographic analysis

Motor events during sleep can be frequently observed in patients with narcolepsy-cataplexy. We hypothesized that increased motor events and related arousals contribute to sleep fragmentation in this disease. We aimed to perform a detailed whole-night video-polysomnographic analysis of all motor events during non-rapid eye movement and rapid eye movement sleep in a group of narcolepsy-cataplexy patients and matched controls, and to assess the association with arousals. Video-polysomnographic registrations of six narcolepsy-cataplexy patients and six sex- and age-matched controls were analysed. Each motor event in the video was classified according to topography, number of involved body parts, duration and its association with arousals. The mean motor activity index was 59.9 ± 23.0 h(-1) in patients with narcolepsy-cataplexy compared with 15.4 ± 9.2 h(-1) in controls (P = 0.004). Distribution of motor events was similar in non-rapid eye movement and rapid eye movement sleep in the patient group (P = 0.219). In narcolepsy-cataplexy, motor events involved significantly more body parts (≥ 2 body regions: 38.2 ± 15.6 versus 14.9 ± 10.0; P = 0.011). In addition, the proportion of motor events lasting longer than 1 s was higher in patients than controls (88% versus 44.4%; P < 0.001). Both total and motor activity-related arousal indices were increased in narcolepsy-cataplexy (total arousal index: 21.6 ± 9.0 versus 8.7 ± 3.5; P = 0.004; motor activity-related arousal index: 17.6 ± 9.8 versus 5.9 ± 2.3; P = 0.002). Motor activity and motor activity-related arousal indices are increased in both non-rapid eye movement and rapid eye movement sleep in narcolepsy-cataplexy compared with controls. This supports the concept of a general sleep motor dysregulation in narcolepsy-cataplexy, which potentially contributes to or even underlies sleep fragmentation in this disease.     

Effectiveness,tolerability and acceptance of an oral estradiol/levonorgestrel formulation for the treatment of menopausal complaints: a non-interventional observational study over six cycles of 28 days

Background: Use of hormone therapy for menopausal complaints is a subject of controversy and increased uncertainty and concerns. This non-interventional study aimed to investigate a marketed oral formulation containing 1?mg estradiol and 0.04?mg levonorgestrel for continuous treatment of menopausal symptoms for approximately 6 months in women visiting gynecological practices in Germany.

Methods: Changes in the menopause rating scale (MRS) total and sub-domain scores after three and six 28-d cycles served as primary endpoint. Skin- and hair-related complaints, quality of sexual life and subjective satisfaction with the treatment were assessed. Adverse drug reactions (ADRs), adverse events (AEs) and vaginal bleeding were evaluated.

Results: MRS scores improved significantly above 5 points of clinical relevance as compared to baseline (n?=?736, p?75% of the subjects were amenorrheic throughout the study. Medication's effectiveness and tolerability was rated very good/good by >80% of the participants, who also continued treatment.

Conclusion: This estradiol/low-dose levonorgestrel formulation safely alleviates menopausal symptoms in peri- and postmenopausal women with add-on benefits regarding dermatological and sexual life complaints.     

Patient-reported quality-of-life and sexual-function outcomes after laparoscopic supracervical hysterectomy (LSH) versus total laparoscopic hysterectomy (TLH): a prospective,questionnaire-based follow-up study in 915 patients

Purpose

To compare patient-reported quality-of-life and sexual function outcomes in women after laparoscopic supracervical hysterectomy (LSH) or total laparoscopic hysterectomy (TLH) for benign uterine disease.

Methods

Out of a cohort of 1,952 patients from a previous implementation study of LSH and TLH, 1,886 patients who had not undergone intraoperative conversion to laparotomy or were ineligible for other reasons were invited by mail to participate in this prospective, questionnaire-based follow-up study.

Results

Of the 915/1,952 (48.5 %) survey respondents included in the analysis, 788 (86.1 %) and 127 (13.9 %) had undergone LSH or TLH, respectively. Women undergoing LSH reported significantly lower pain levels (p = 0.037) and faster partial (p = 0.015) and complete (p < 0.001) resumption of normal daily activities compared to those undergoing TLH. As regards sexual function, women undergoing LSH resumed sexual activity significantly sooner (p = 0.018), rated sexual desire as higher (p = 0.023), and reported more frequently that their sexual life had improved postoperatively (p = 0.008) than did women undergoing TLH.

Conclusions

Women undergoing LSH for benign uterine disease may have better outcomes regarding certain quality-of-life and sexual function parameters than women undergoing TLH for benign uterine disease.     

Donor‐specific alloreactive T cells can be quantified from whole blood,and may predict cellular rejection after renal transplantation

Preformed cellular alloreactivity can exist prior to transplantation and may contribute to rejection. Here, we used a rapid flow‐cytometric whole‐blood assay to characterize the extent of alloreactive T cells among 1491 stimulatory reactions from 61 renal transplant candidates and 75 controls. The role of preformed donor‐specific alloreactive T cells in cellular rejection was prospectively analyzed in 21 renal transplant recipients. Alloreactive CD8⁺ T cells were more frequent than respective CD4⁺ T cells, and these levels were stable over time. CD8⁺ T cells were effector‐memory T cells largely negative for expression of CD27, CD62L, and CCR7, and were susceptible to steroid and calcineurin inhibitor inhibition. Alloreactivity was more frequent in samples with higher number of HLA mismatches. Moreover, the percentage of individuals with alloreactive T cells was higher in transplant candidates than in controls. Among transplant candidates, 5/61 exhibited alloreactive CD8⁺ T cells against most stimulators, 23/61 toward a limited number of stimulators, and 33/61 did not show any alloreactivity. Among 21 renal transplant recipients followed prospectively, one had donor‐specific preformed T‐cell alloreactivity. She was the only patient who developed cellular rejection posttransplantation. In conclusion, donor‐specific alloreactive T cells may be rapidly quantified from whole blood, and may predict cellular rejection after transplantation.     

A novel mutation L1425P in the GAP-region of the NF1 gene detected by temperature gradient gel electrophoresis (TGGE). Mutation in brief no. 230. Online

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an incidence of between 1: 3000 and 1: 4000. Common clinical signs include more than six café-au-lait spots, multiple cutaneous neurofibromas and iris Lisch nodules. Rarer are skeletal anomalies, learning disabilities and an increased risk of malignancy. The NF1 gene contains at least 60 exons with intron sizes ranging from 60 bp to more than 40 kb. Despite using different techniques including PTT, SSCP heteroduplex analyses and direct sequencing, only a relatively small number of mutations have been reported world-wide. Using the more sensitive technique of temperature gradient gel electrophoresis (TGGE), we analysed a part of the NF1-GAP-region, namely exon 25, in DNA samples from 131 unrelated patients. We have identified a novel mutation L1425P in exon 25 of the NF1 gene in a 12-year-old boy (clinically diagnosed with NF1 at the age of 7). In contrast to those cases diagnosed with having both GAP-region mutations and malignant tumours, neither the proband nor four clinically affected family members with this mutation showed any evidence of malignancies.