Time-dependent beneficial effect of chronic polyphenol treatment with catechin on endothelial dysfunction in aging mice

A controlled redox environment is essential for vascular cell maturation and function. During aging, an imbalance occurs, leading to endothelial dysfunction. We hypothesized that, according to the concept of hormesis, exposure to physiologic oxidative stress during the maturation phase of the endothelium will activate protective pathways involved in stress resistance. C57Bl/6 mice were treated with the polyphenol catechin for the last 3 (post-maturation) or 9 months prior study at 12 months of age. Endothelial dysfunction, assessed by acetylcholine-induced dilations of isolated renal arteries, was present at 12 months (P<0.05). Only the 3-month treatment with catechin fully prevented the decline in efficacy and sensitivity to acetylcholine (P<0.05). Splenocytes adhesion to the native endothelium, expression of CD18 and shedding of CD62L and PSGL-1 augmented in 12 months old mice (P<0.05): only 3-month catechin fully normalized adhesion and prevented the expression of adhesion molecules on splenocytes (P<0.05). Aging was associated with vascular gene alterations, which were prevented by 3-month catechin treatment (P<0.05). In contrast, 9-month catechin further increased COX-2, p22(phox) and reduced MnSOD (P<0.05). In conclusion, we demonstrate a pivotal role of cellular redox equilibrium: exposure to physiologic oxidative stress during the maturation phase of the endothelium is essential for its function.     

Pseudotumor Cerebri in a Case of Ulcerative Colitis with Sagittal Sinus Thrombosis

Background

Thromboembolic events are a known complication of Inflammatory Bowel Disease (IBD) especially during disease relapse, more commonly in deep veins of extremities and lung, and rarely as Cerebral Sinovenous Thrombosis (CSVT).

Case Presentation

We describe an 11 year, old male patient with 3 months history of Ulcerative Colitis (UC) who presented as pseudotumor cerebri due to superior sagittal sinus thrombosis during an acute exacerbation of his colitis, that was successfully treated with heparin and then warfarin.

Conclusion

In any known cases of UC presenting as acute severe headache, consider CSVT and request brain MRI and MRV to facilitate the diagnosis and early treatment.     

Alpha 1 Antitrypsin Deficiency in Infants with Neonatal Cholestasis

Objective

Alpha1-antitrypsin deficiency (A1ATD) is the most important indication for liver transplantation in children. The gene frequencies vary in different ethnic groups. In the present study, we attempt to determine the frequencies of the most common defective alleles, Z and S, in Iranian children suffering from idiopathic neonatal cholestasis. Eighty-seven infants were typed for Z and S alleles.

Methods

In a single center study, 87 consecutive liver biopsies from infants with cholestasis were reviewed and patients with neonatal cholestasis enrolled in the study and cases with confirmed biliary tract atresia excluded. Formalin fixed paraffin embedded blocks were used for DNA extraction. AAT genotype was determined by polymerase chain reaction (PCR) assay and amplification of the two most common deficiency variants, S and Z alleles, and then sequencing of PCR products.

Findings

There were 48 (55.2%) males and 39 (44.8%) females, with a median age of 60 days. Out of 87 of the study subject, 2 (2.2%) were heterozygous for the S allele, and no ZZ, SS or MZ individual was found in the patients. No other polymorphism was found in the sequencing results.

Conclusion

In comparison to other populations, AAT deficiency seems not to be an important etiologic factor for neonatal cholestatic liver disease in Iran; however, further studies are recommended to estimate the true mutant gene frequencies.     

Comparison of myo-inositol and metformin on mental health parameters and biomarkers of oxidative stress in women with polycystic ovary syndrome: a randomized,double-blind,placebo-controlled trial

Introduction: Data on comparison of myo-inositol and metformin on mental health parameters and biomarkers of oxidative stress in subjects with polycystic ovary syndrome (PCOS) are scarce. This purpose of this study was to compare of myo-inositol and metformin on mental health parameters and biomarkers of oxidative stress in subjects with PCOS.

Methods: This randomized controlled trial was conducted among 60 subjects diagnosed with PCOS according to the Rotterdam criteria. Subjects were randomly assigned into two groups to intake either myo-inositol (n?=?30) or metformin (n?=?30) for 12?weeks. Parameters of mental health were recorded at baseline and after the 12-week intervention. Fasting blood samples were obtained at baseline and the end of the study to determine biomarkers of biomarkers of oxidative stress.

Results: After the 12-week intervention, changes in beck depression inventory total score (?1.0?±?1.7 vs. ?0.3?±?0.7, p?=?0.03), general health questionnaire scores (?1.7?±?2.9 vs. ?0.5?±?1.2, p?=?0.02), depression anxiety and stress scale scores (?3.9?±?6.4 vs. ?0.9?±?1.9, p?=?0.01) and plasma total antioxidant capacity (TAC) concentrations (+106.1?±?69.6 vs. +2.1?±?132.4?mmol/L, p?<?0.001) in the myo-inositol group were significantly different from the changes in these indicators in the metformin group. Myo-inositol supplementation for 12?weeks among patients with PCOS did not affect plasma glutathione and malondialdehyde levels.

Conclusions: Overall, our data supported that myo-inositol supplementation for 12?weeks among patients with PCOS had favorable effects on parameters of mental health and plasma TAC levels.     

Red Flags of Organic Recurrent Abdominal Pain in Children: Study on 100 Subjects

Objective

A variety of sign, symptoms and laboratory findings are more common in children with organic abdominal pains. This study was performed to evaluate the prevalence of organic and functional abdominal pains and relation of red flags to organic pains in 100 children with recurrent abdominal pain (RAP).

Methods

One hundred consecutive patients with RAP were enrolled in the study. A complete interview and physical examination was made for each patient, accompanied by a series of laboratory, clinical and para-clinical examinations. The data were recorded and analyzed. Logistic regression analysis was used to model and formulize correlations between sign, symptoms, and laboratory findings with organic and functional abdominal pain.

Findings

Among 100 patients (52% male, 48% female, Age: 9.29±3.17) diagnostic works up revealed organic pain for 57 patients. The most common symptoms of the patients included constipation, diarrhea, chest pain, cough, headache, vomiting, hematuria, and dysuria. Fecal incontinence, delayed puberty, organomegaly, jaundice, and family history of inflammatory bowel disease were reported in none of the patients with RAP. Fever, pain not located in periumbilical area, nocturnal pain, elevated erythrocyte sedimentation rate, weight loss, growth disorder, and abdominal tenderness were among the red flags which revealed diagnosis of organic pain in this study.

Conclusion

A series of red flags could increase likelihood of finding organic pain in children with RAP.     

Correlation between follicular diameters and flushing versus no flushing on oocyte maturity,fertilization rate and embryo quality

Objective

To determine (a) the correlation between follicular sizes, oocyte maturity, normal fertilization rate, cleavage and embryo quality; and (b) to establish whether oocytes recovered with or without follicular flushing have different developmental competence.

Design

Prospective observational study.

Setting

Academic medical center.

Patients

Forty nine cycles (37 ICSI and 12 IVF).

Interventions

Measurement of 360 follicular diameters on the day of egg retrieval and classification into three groups Group A (mean diameter 12–14.5 mm.), group B (mean diameter 15–18 mm.) and group C (diameter >18.5 mm.).

Main outcome measure

Correlation between follicular size at the time of retrieval and oocyte maturity, fertilization and cleavage rate in 226 oocytes (163 ICSI and 63 IVF). Developmental competence of oocytes retrieved with flushing versus non flushing.

Results

Almost all (99 %) of the oocytes recovered from follicles of group C were in metaphase II as opposed to 80 % in group A and 81 % in group B (p < 0.01). Overall there was a progressive and significant increase in fertilization rates from group A follicles to group C (47 % vs. 67 %, p 0.05). Overall 53 % of oocytes retrieved from group A follicles showed either no fertilization or abnormal fertilization versus 27 % in group C (p 0.05). The oocyte recovery rate with follicular flushing improved from group A to group B and to group C follicles (65 % vs. 49 % vs.37 % respectively p < 0.01). There were no differences in rates of immature oocyte, fertilization, abnormal or not fertilization and cleavage.

Conclusions

The results of this study shows that: a) Follicles larger than 18 mm at retrieval have consistently mature oocytes with a higher rate of fertilization; b) Small size follicles are still capable of containing mature oocytes, but their rate of abnormal or no fertilization is high; c) Oocytes recovered with flushing are still able to produce embryos with full developmental competence.     

Meiotic segregation and sperm DNA fragmentation in Tunisian men with dysplasia of the fibrous sheath (DFS) associated with head abnormalities

Purpose

Dysplasia of the Fibrous Sheath (DFS) is a primitive flagellar pathology for which a broad spectrum of ultrastructural flagellar abnormalities has been described responsible for a severe to total asthenozoospermia. To this phenotype other morphological abnormalities including cephalic and abnormalities in nuclear structure can be associated that could compromise embryonic development in case of use of Assisted Reproductive Technology (ART). The aim of this study was to evaluate the level of DNA fragmentation and aneuploidy rate in ejaculated spermatozoa of Tunisian men presented with DFS sperm defect associated to high percentage of head abnormalities and to compare the results with those from fertile men.

Methods

Sperm DNA fragmentation was evaluated by the terminal desoxynucleotidyl transferase mediated deoxyuridine triphosphate biotin nick-end labelling (TUNEL) assay. The study of meiotic segregation was performed by Fluorescence in situ hybridization (FISH) for chromosomes X, Y and 18.

Results

The mean DNA fragmentation index was significantly higher in patients compared to the control group. FISH revealed a significantly higher incidence of sperm aneuploidies compared with controls. All patients showed elevated frequencies of sex chromosomes disomy, disomy 18 and diploidy.

Conclusions

In some cases of syndromic teratozoospermia due to sperm tail structural abnormalities, such as DFS, other morphological cephalic abnormalities may be associated. In these cases we have demonstrated impaired sperm nuclear quality which will affect the results in ICSI. Hence the interest of a thorough study of the sperm nucleus in these forms of infertility in order to predict the chances of success in ART.     

Pharmacokinetic-pharmacodynamic modeling of apratastat: a population-based approach

Apratastat is an orally active, potent, and reversible dual inhibitor of tumor necrosis factor-α converting enzyme (TACE) and matrix metalloproteinases (MMPs). This study characterizes the pharmacodynamic (PD) effect of apratastat following oral administration on tumor necrosis factor-alpha (TNF-α) release. Data were obtained from 3 clinical studies carried out in healthy subjects. Apratastat was administered orally in these studies as single doses or multiple doses (twice daily). The inhibition of TNF-α release by apratastat was investigated in studies of in vitro, ex vivo, and in vivo. Inhibitory E(max) models were used to characterize the inhibition of TNF-α release in both in vitro and ex vivo studies. Apratastat inhibited TNF-α release with a population mean IC(50) of 144 ng/mL in vitro and of 81.7 ng/mL ex vivo, respectively. The relationship between TNF-α and apratastat plasma concentration in the endotoxin-challenged study in healthy subjects was well characterized by a mechanism-based PD population model with IC(50) of 126 ng/mL. Apratastat can potently inhibit the release of TNF-α in vitro, ex vivo, and in vivo. Even though the dosage provided adequate exposure to inhibit TNF-α release, apratastat was not efficacious in rheumatoid arthritis (RA). This inconsistency between TNF-α inhibition and the clinical response requires further investigation.