Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells

Lysine ?-acetylation is a post-translational modification that alters the biochemical properties of many proteins. The reaction is catalyzed by histone/protein acetyltransferases (HATs), and is reversed by histone/protein deacetylases (HDACs). As a result, HATs and HDACs constitute an important, though little recognized, set of proteins that control the functions of T-regulatory (Treg) cells. Targeting certain HDACs, especially HDAC6, HDAC9, and Sirtuin-1 (Sirt1), can augment Treg suppressive potency by several distinct and potentially additive mechanisms. These involve promoting Forkhead box p3 (Foxp3) gene expression and preserving Foxp3 lysine ?-acetylation, which infers resistance to ubiquitination and proteasomal degradation, and increases DNA binding. Moreover, depleting certain HDAC can enhance the heat shock response, which increases the tenacity of Treg to survive under stress, and helps preserve a suppressive phenotype. As a result, HDAC inhibitor therapy can be used to enhance Treg functions in vivo and have beneficial effects on allograft survival and autoimmune diseases.     

Remifentanil, Isoflurane, and Preconditioning Attenuate Renal Ischemia/Reperfusion Injury in Rats

Background

The purpose of this investigation was to examine the effect of isoflurane, remifentanil, and preconditioning in renal ischemia/reperfusion injury (IRI).

Methods

All 52 male Wistar rats were anesthetized with isoflurane, intubated and mechanically ventilated. The animals were randomly divided into: S group (sham; n = 11) that underwent only right nephrectomy; as well as the I group of right nephrectomy and ischemia for 45 minutes by clamping of left renal artery. (n = 11); the IP (n = 9), the R (n = 10), and the RP (n = 11) groups. In addition, the R and RP animals received remifentanil (2 μg · kg⁻¹ · min⁻¹) during the entire experiment. The IP and RP group underwent ischemic preconditioning (IPC = three cycles of 5 minutes). Serum creatinine values were determined before and after IRI, as well as 24 hours later. In addition to an Histological study, cells from the left kidney were evaluated for apoptosis by flow cytometry (FCM).

Results

The Creatinine value of 0.8 ± 0.2 mg/dl in the S group was significantly lower at 24 hours than the I 3.9 ± 1.5 mg/dl; IP 2.6 ± 1.7 mg/dl; R 3.3 ± 2.8 mg/dl; or RP 1.8 ± 0.5 mg/dl groups. The RP group value was significantly lower than those of the I, IP, and R groups (p < 0.05). The S group showed less proximal tubular cell damage than the I, IP, R, and RP groups (p < 0.05). The percentages of apoptotic cells (FITC⁺/PI⁻) were: S group = 11.6 ± 6.5; I = 16.7 ± 7.3; IP = 37.0 ± 28.4; R = 11.7 ± 6.6, and RP = 8.8 ± 1.5. The difference between the IP vs RP group was significant. Similar percentages of necrotic cells (FITC⁺/PI⁺) and intact cells (FITC⁻/PI⁻) were observed among the groups.

Conclusions

Ischemic preconditioning showed no protective effect in the isoflurane group (IP) but when isoflurane was administered associated with remifentanil (RP), there was a beneficial effect on the kidney, as demonstrated by flow cytometry and serum creatinine values.     

Breast cancer seeding associated with core needle biopsies: A systematic review

Background

Preoperative diagnosis has become the standard in breast cancer (BC) management. Recently, ultrasound guided core needle biopsy (CNB) and stereotactic needle core biopsy have replaced fine needle aspiration cytology. Epithelial cell displacement (DE) occurs frequently after core needle biopsy (CNB) for breast cancer diagnosis.

Aim

Systematically review (between 1900 and 2008) the clinical significance of DE after CNB in BC patients, and associated risk factors (delay between biopsy and surgery, needle passes, duration of the procedure, tumor size, histological type, tumor grade, margins, type of surgery, and of adjuvant treatment).

Materials and methods

We selected 15 studies: 9 assessed the rate of DE after CNB and 6 the impact of CNB on outcome endpoints.

Results

We found 3 prospective and 12 retrospective studies. However these had numerous biases such as insufficient power, confounding factors, selection of cases and controls, surrogate endpoints, heterogeneity of measured displacement. Malignant DE on surgical specimens occurred in 22% of the patients. A short interval between CNB and surgical excision increased the risk of detecting displaced cells. No increase in local recurrence was reported after CNB. Contradictory results were found in terms of sentinel node metastases. Only one study evaluated overall survival data and reported no worse survival in patients with preoperative CNB.

Conclusion

Although data are limited, no increased morbidity has been associated with iatrogenic seeding after CNB.     

Clinical features of chromosome 22q11.2 microdeletion syndrome in 208 Chilean patients

Patients with chromosome 22q11 deletion syndrome exhibit significant phenotypic variability. Epidemiologic data suggest a higher incidence in Hispanics, but limited clinical information is available from Latin-American patients. We describe the clinical features of Chilean patients with 22q11 deletion syndrome and compare their findings with those reported in large European, Japanese and US series. Data were obtained from 208 patients from five medical centers. Mean age at diagnosis was 5.2 years, with a median of 2.3 years. Congenital heart defects were present in 59.6%, lower than other large series that averaged 75.8%. Palate abnormalities were present in 79%, higher than previous reports averaging 56%. Patients with congenital heart disease were diagnosed earlier (median 0.3 years of age) than those without heart defects (median 5.6 years) and had greater mortality attributable to the syndrome (9.8% vs 2.4%, respectively). The differences in frequencies of major anomalies may be due to growing awareness of more subtle manifestations of the syndrome, differences in clinical ascertainment or the presence of modifier factors. These observations provide additional data useful for patient counseling and for the proposal of health care guidelines.     

How Unusual are the Contents of Paraphilias? Paraphilia-Associated Sexual Arousal Patterns in a Community-Based Sample of Men

IntroductionThis is a report of a cross-sectional study on paraphilia-associated sexual arousal patterns (PASAP) among men in a metropolitan city in Germany, EU.AimTo determine the prevalence of PASAP during sexual fantasies, fantasies accompanying masturbation, and real-life sociosexual behavior.MethodsIn a cross-sectional study, self-reported sexual history data were collected by questionnaire from 367 volunteers recruited from a community sample of 1,915 men aged 40–79 years.Main Outcome MeasuresThe Derogatis Symptom Checklist—Revised (SCL-90–R) and the Life Satisfaction Questionnaire (LSQ; German original, Fragebogen zur Lebenszufriedenheit, [FLZ]) were administered to obtain a general subjective health measure and a measure of general as well as sex life satisfaction. The Questionnaire on Sexual Experiences and Behaviour was administered to comprehensively assess all relevant sexo-medical data.ResultsThe percent of men that reported at least one PASAP was 62.4%. In 1.7% of cases, PASAP were reported to have caused distress. The presence of PASAP was associated with a higher likelihood of being single (odds ratio [OR] 2.6; 95%; confidence interval [CI] 1.047–6.640), masturbating at least once per week (OR 4.4; 95%; CI 1.773–10.914), or having a low general subjective health score (OR 11.9; 95%; CI 2.601–54.553). Pedophilic PASAP in sexual fantasies and in real-life sociosexual behavior was reported by 9.5% and 3.8% of participants, respectively.ConclusionThe findings suggest that paraphilia-related experience can not be regarded as unusual from a normative perspective. At the same time, many men experience PASAP without accompanying problem awareness or distress, even when PASAP contents are associated with potentially causing harm to others. In view of the relevance for sex life and relationship satisfaction, presence of PASAP should be assessed in all sexual medicine consultations. Future research should focus on conditions in which PASAP reach clinical significance in the sense of mental disorders. Ahlers CJ, Schaefer GA, Mundt IA, Roll S, Englert H, Willich SN, and Beier KM. How unusual are the contents of paraphilias? Paraphilia-associated sexual arousal patterns in a community-based sample of men.     

Effects of Piclamilast,a Selective Phosphodiesterase-4 Inhibitor,on Oxidative Burst of Sputum Cells From Mild Asthmatics and Stable COPD Patients

Oxidative stress associated with increased presence of neutrophils is an important feature of inflammatory airways diseases like asthma or chronic obstructive pulmonary disease. We studied the in vitro effect of piclamilast (RP73401), a selective phosphodiesterase (PDE)-4 inhibitor, compared to theophylline and prednisolone, on respiratory burst of sputum cells from mild asthmatics and COPD patients. Sputum cells were harvested from mild asthmatics and stable COPD patients and treated with piclamilast, theophylline or prednisolone. Respiratory burst was assessed by luminol-dependent chemoluminescence after stimulation with 10 M n-formyl-met-leu-phe (FMLP). Piclamilast inhibited FMLP-induced respiratory burst of sputum cells in a concentration-dependent manner (asthma: EC₅₀ approximately 100 nM, max. inhibition: 97.5±5% at 100 M; COPD: EC₅₀ approximately 1 M, max. inhibition: 70.6±4.5% at 100 M), whereas maximal inhibition observed with theophylline (asthma: max. inhib. 27±15%; COPD: 6±2%, both p < 0.05 vs. piclamilast) and prednisolone (asthma: 16±6%; COPD: 7.8±6.2%, both p < 0.05 vs. piclamilast) was weaker. Inhibition by piclamilast was largely reversed through pretreatment of cells with the adenylcyclase inhibitor SQ22536. We concluded that piclamilast, a selective PDE-4 inhibitor, attenuates the respiratory burst of sputum cells from mild asthmatics and COPD patients in vitro. These data underline the potential of PDE-4 inhibition as a novel therapeutic approach to inflammatory airway diseases like asthma or COPD.     

Coronavirus genotype diversity and prevalence of infection in wild carnivores in the Serengeti National Park, Tanzania

Knowledge of coronaviruses in wild carnivores is limited. This report describes coronavirus genetic diversity, species specificity and infection prevalence in three wild African carnivores. Coronavirus RNA was recovered from fresh feces from spotted hyena and silver-backed jackal, but not bat-eared fox. Analysis of sequences of membrane (M) and spike (S) gene fragments revealed strains in the genus Alphacoronavirus, including three distinct strains in hyenas and one distinct strain in a jackal. Coronavirus RNA prevalence was higher in feces from younger (17 %) than older (3 %) hyenas, highlighting the importance of young animals for coronavirus transmission in wild carnivores.     

House dust mite allergen avoidance and self-management in allergic patients with asthma: randomised controlled trial

BACKGROUND: The efficacy of bed covers that are impermeable to house dust mites has been disputed. AIM: The aim of the present study was to investigate whether the combination of 'house dust mite impermeable' covers and a self-management plan, based on peak flow values and symptoms, leads to reduced use of inhaled corticosteroids (ICS) than self-management alone. DESIGN OF STUDY: Prospective, randomised, double blind, placebo-controlled trial. SETTING: Primary care in a south-eastern region of the Netherlands. METHOD: Asthma patients aged between 16 and 60 years with a house dust mite allergy requiring ICS were randomised to intervention and placebo groups. They were trained to use a self-management plan based on peak flow and symptoms. After a 3-month training period, the intervention commenced using house dust mite impermeable and placebo bed covers. The follow-up period was 2 years. Primary outcome was the use of ICS; secondary outcomes were peak expiratory flow parameters, asthma control, and symptoms. RESULTS: One hundred and twenty-six patients started the intervention with house dust mite impermeable or placebo bed covers. After 1 and 2 years, significant differences in allergen exposure were found between the intervention and control groups (P<0.001). No significant difference between the intervention and control groups was found in the dose of ICS (P = 0.08), morning peak flow (P = 0.52), peak flow variability (P = 0.36), dyspnoea (P = 0.46), wheezing (P = 0.77), or coughing (P = 0.41). There was no difference in asthma control between the intervention and control groups. CONCLUSION: House dust mite impermeable bed covers combined with self-management do not lead to reduced use of ICS compared with self-management alone.