Investigations into the Signaling Pathways Involving Glucose-Stimulated Zinc Secretion (GSZS) from Prostate Epithelial Cells In Vitro and In Vivo.

PURPOSE: Recently, we reported that exposure of prostate cells in vitro or the in vivo prostate to high glucose results in release of Zn2+ ions, a process now referred to as glucose-stimulated zinc secretion (GSZS). To our knowledge, the metabolic event(s) that trigger GSZS remain largely unknown. Here, we explore several signaling pathways both in vitro using a prostate epithelial cell line and in vivo from the rat prostate. METHODS: PNT1A cells grown to confluence were washed and tagged with ZIMIR to monitor zinc secretion by optical methods. The expression levels of GLUT1, GLUT4, and Akt in cells cultured in either zinc-rich or zinc-poor media and after exposure to high versus low glucose were determined. Zinc secretion from the rat prostate in vivo as detected by MRI was compared in control animals after injection of glucose, deoxyglucose, or pyruvate to initiate zinc secretion and in animals pre-treated with WZB-117 (a GLUT1 inhibitor) or S961 (a peripheral insulin receptor inhibitor). RESULTS: PNT1A cells exposed to high levels of glucose secrete zinc whereas cells exposed to an equivalent amount of deoxyglucose or pyruvate do not. Expression of Akt was dramatically altered by zinc supplementation of the culture media but not after exposure to glucose while GLUT1 and GLUT4 levels were less affected. Rats pre-treated with WZB-117 prior to imaging showed a reduction in GSZS from the prostate compared to controls whereas rats pre-treated with S961 showed no difference. Interestingly, in comparison to PNT1A cells, pyruvate and deoxyglucose also stimulate zinc secretion in vivo likely through indirect mechanisms. CONCLUSIONS: GSZS requires metabolism of glucose both in vitro (PNT1A cells) and in vivo (rat prostate). Pyruvate also stimulates zinc secretion in vivo but likely via an indirect pathway involving rapid production of glucose via gluconeogenesis. These combined results support the conclusion that glycolytic flux is required to trigger GSZS in vivo.

MRI Methods for Imaging Beta-Cell Function in the Rodent Pancreas.

The role of Zn2+ ions in proper storage of insulin in ß-cell granules is well-established so when insulin is secreted from ß-cells stimulated by an increase in plasma glucose, free Zn2+ ions are also released. This local increase in Zn2+ can be detected in the pancreas of rodents in real time by the use of a zinc-responsive MR contrast agent. This method offers the opportunity to monitor ß-cell function longitudinally in live rodents. The methods used in our lab are fully described in this short report and some MR images of a rat pancreas showing clearly enhanced hot spots in the tail are presented.

Magnetic Resonance Imaging Detection of Glucose-Stimulated Zinc Secretion in the Enlarged Dog Prostate as a Potential Method for Differentiating Prostate Cancer From Benign Prostatic Hyperplasia.

OBJECTIVES: In the United States, prostate cancer (PCa) is the most common cancer in men. Multi-parametric magnetic resonance imaging (MRI) is increasingly being relied upon for the diagnosis and characterization of PCa, but differentiating malignancy from benign prostatic hyperplasia (BPH) in the transition zone using MRI can be challenging. The characteristically high levels of zinc in human prostate tissue and a close relationship between malignant proliferation and zinc homeostatic dysregulation create opportunities to visualize PCa with novel contrast media. In mouse models, glucose-stimulated zinc secretion (GSZS) can be preferentially observed in healthy prostate tissue compared with malignant tissue; in vivo, these differences can be captured with MRI by using Gdl1, a gadolinium-based zinc-responsive contrast agent. In this study, we examined whether this technology can be applied in a large animal model by imaging older dogs with clinically diagnosed BPH. MATERIALS AND METHODS: Four intact male dogs 6 years or older with enlarged prostates were imaged (T1-weighted turbo spin-echo, TE/TR, 12/400 milliseconds and T2-weighted, TE/TR, 112/5000 milliseconds) using a 3 T scanner before and at multiple time points after intravenous injection of 0.05 mmol/kg GdL1 plus either (a) 2 mL/kg of 50% dextrose in 1 session or (b) 2 mL/kg normal saline in another session. The two sessions were one week apart, and their order was randomly determined for each dog. During postprocessing, regions of interest were generated in prostate tissue and in paraspinal muscles to evaluate the contrast-to-noise ratio (CNR). The ratio of CNR at any postinjection time point compared with baseline CNR was defined as r-CNR. After the second imaging session, the dogs were euthanized, and their prostates were harvested for histopathological examination. Baseline and postintervention plasma and urine samples were analyzed for total zinc by inductively coupled plasma mass spectrometry. RESULTS: The mean ± SD r-CNR values at 13 minutes postinjection in the dextrose versus saline imaging sessions were 134% ± 10% and 127% ± 7%, respectively (P < 0.01). The histopathologic evaluation of prostate tissues confirmed BPH in all dogs. Interestingly, prostatic intraepithelial neoplasia was detected in 1 animal, and a suspicious mass was found in the same region on T2-weighted scans. The r-CNR of the mass was calculated as 113% ± 4% and 111% ± 6% in the dextrose and saline groups, respectively, with no significant differences between the 2 interventions (P = 0.54), whereas there was a statistically significant difference between the r-CNR of the whole prostate in the dextrose (130% ±11%) and saline (125% ± 9%) interventions (P = 0.03). Inductively coupled plasma mass spectrometry analyses showed a significantly higher urinary zinc in the dextrose versus saline groups, but no differences were found in plasma zinc levels. CONCLUSIONS: T1-weighted MRI of the enlarged canine prostate showed higher r-CNR after injection of GdL1 plus dextrose compared with GdL1 plus saline, consistent with GSZS from BPH tissues. One small region of neoplastic tissue was identified in a single dog on the basis of less GSZS from that region by MRI. These findings suggest a new method for the detection of PCa by MRI that could facilitate the differentiation of BPH from PCa in the transition zone.

Imaging ß-Cell Function Using a Zinc-Responsive MRI Contrast Agent May Identify First Responder Islets.

An imaging method for detecting ß-cell function in real-time in the rodent pancreas could provide new insights into the biological mechanisms involving loss of ß-cell function during development of type 2 diabetes and for testing of new drugs designed to modulate insulin secretion. In this study, we used a zinc-responsive MRI contrast agent and an optimized 2D MRI method to show that glucose stimulated insulin and zinc secretion can be detected as functionally active "hot spots" in the tail of the rat pancreas. A comparison of functional images with histological markers show that insulin and zinc secretion does not occur uniformly among all pancreatic islets but rather that some islets respond rapidly to an increase in glucose while others remain silent. Zinc and insulin secretion was shown to be altered in streptozotocin and exenatide treated rats thereby verifying that this simple MRI technique is responsive to changes in ß-cell function.

Imaging Tissue Physiology In Vivo by Use of Metal Ion-Responsive MRI Contrast Agents.

Paramagnetic metal ion complexes, mostly based on gadolinium (Gd3+), have been used for over 30 years as magnetic resonance imaging (MRI) contrast agents. Gd3+-based contrast agents have a strong influence on T1 relaxation times and are consequently the most commonly used agents in both the clinical and research environments. Zinc is an essential element involved with over 3000 different cellular proteins, and disturbances in tissue levels of zinc have been linked to a wide range of pathologies, including Alzheimer's disease, prostate cancer, and diabetes mellitus. MR contrast agents that respond to the presence of Zn2+ in vivo offer the possibility of imaging changes in Zn2+ levels in real-time with the superior spatial resolution offered by MRI. Such responsive agents, often referred to as smart agents, are typically composed of a paramagnetic metal ion with a ligand encapsulating it and one or more chelating units that selectively bind with the analyte of interest. Translation of these agents into clinical radiology is the next goal. In this review, we discuss Gd3+-based MR contrast agents that respond to a change in local Zn2+ concentration.

Lamivudine's efficacy and safety in preventing mother-to-child transmission of hepatitis B: A meta-analysis.

BACKGROUND/AIMS: Mother-to-child transmission (MTCT) is a common transmission mode of hepatitis B virus (HBV). It has been shown that the infection may occur in some infants despite the use of immunoprophylaxis, and many studies have demonstrated the efficacy of antivirals such as lamivudine to reduce such events. MATERIALS AND METHODS: A meta-analysis was conducted concerning the efficacy and safety of lamivudine during pregnancy, in the prevention of vertical transmission of HBV infection. Studies were identified by searching various databases up to January 2016 for variations of the following phrase: "lamivudine AND (pregnancy or pregnant) AND (HBV or hepatitis)." Subjects who had received lamivudine were included in the case group, and those who had not were included in the control group. RESULTS: Our search identified a total number of 881 citations, of which 25 studies (with a total number of 2,667 pregnant women) were included in the meta-analysis. The analysis showed a significant difference between the seropositive HBsAg infants from the case and control groups (RR= 16.97, 95% confidence interval 8.36-34.45), which is the most critical factor in determining the MTCT of HBV. No significant difference was reported between the prevalence of side effects in the case and control groups. CONCLUSION: This meta-analysis strongly suggests the use of lamivudine in the prevention of HBV vertical transmission in carrier pregnant women with the HBV DNA levels greater than 106 copies/mL. And for women with the HBV viral loads lower than 106 copies/mL, we suggest clinicians to examine the use of lamivudine on a case-to-case basis, noting that lamivudine seems to be a safe drug for the mother and the fetus.

Brachydactyly mental retardation syndrome with growth hormone deficiency.

Deletion of chromosome 2q37 results in a rare congenital syndrome known as brachydactyly mental retardation (BDMR) syndrome; a syndrome which has phenotypes similar to Albright hereditary osteodystrophy (AHO) syndrome. In this report, we describe a patient with AHO due to microdeletion in long arm of chromosome 2 [del(2)(q37.3)] who had growth hormone (GH) deficiency, which is a unique feature among reported BDMR cases. This case was presented with shortening of the fourth and fifth metacarpals which along with AHO phenotype, brings pseudopseudohypoparathyroidism (PPHP) and pseudohypoparathyroidism type Ia (PHP-Ia) to mind; however, a genetic study revealed del(2)(q37.3). We recommend clinicians to take BDMR in consideration when they are faced with the features of AHO; although this syndrome is a rare disease, it should be ruled out while diagnosing PPHP or PHP-Ia. Moreover, we recommend evaluation of IGF 1 level and GH stimulation test in patients with BDMR whose height is below the 3rd percentile. LEARNING POINTS: Clinicians must have brachydactyly mental retardation (BDMR) syndrome in consideration when they are faced with the features of Albright hereditary osteodystrophy.Although BDMR syndrome is a rare disease, it should be ruled out while diagnosing PPHP or PHP-Ia.Evaluation of IGF1 level in patients diagnosed with BDMR whose height is below the 3rd percentile is important.

Screening of congenital hypothyroidism in preterm, low birth weight and very low birth weight neonates: A systematic review.

Evidence from different screening programs indicated that the rate of congenital hypothyroidism (CH) was higher in pre-term and low-birth-weight (LBW) newborns than normal ones. Incomplete development of hypothalamic-pituitary axis in this group of neonates results in the delayed rise of TSH and missing cases with CH. Hence, there is a great need for a practicable systematic screening method for proper diagnosis of CH in this group of neonates. In this review, we systematically reviewed papers with the following key words ([Congenital Hypothyroidism AND Screening AND Thyroxine AND Thyroid Stimulating Hormone AND Low Birth Weight AND Premature]) in international electronic databases including PubMed, Scopus, and Google Scholar. After quality assessment of selected documents, data of finally included papers were extracted. In this review, 1452 papers (PubMed: 617; Scopus: 714; Google scholar: 121) were identified through electronic database search. One hundred and ninety four articles were assessed for eligibility, from which 36 qualified articles were selected for final evaluation. From the reviewed articles, 38.9%, 11.11% and 8.3% recommended rescreening in this group of neonates, lowering the screening cutoff of TSH and using cutoffs according to the gestational age, respectively. Some of them (13.9%) recommended using both TSH and T4 for screening of preterm infants. After reviewing available data, we recommend repeating the screening test in pre-term, LBW and very-low- birth-weight (VLBW) infants at age of two, six and ten weeks by measuring TSH and FT4 levels simultaneously and considering TSH = 10 mU/L as the cutoff level for positive and suspicious cases.

A systematic review on the adverse health effects of di-2-ethylhexyl phthalate.

Di (ethylhexyl) phthalate (DEHP) is a global environmental pollutant. This study aims to systematically review the literature on health effects of exposure to DEHP including effects on reproductive health, carcinogenesis, pregnancy outcome, and respiratory system. The literature search was done through Scopus, ISI Web of Science, Google Scholar, PubMed, Medline, and the reference lists of previous review articles to identify relevant articles published to June 2016 in each subject area. The inclusion criteria were as follows: original research, cross-sectional studies, case-control studies, cohort studies, interventional studies, and review articles. Both human and animal studies were included. The search was limited to English language papers. Conference papers, editorials, and letters were not included. The systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Overall, 152 of the 407 papers met the inclusion criteria. We provided an up-to-date comprehensive and critical assessment of both human and animal studies undertaken to explore the effects of DEHP. It revealed that in experimental studies, exposure to DEHP mainly targeted the reproductive, neurodevelopment, and respiratory systems. Human studies reported that exposure to this contaminant had carcinogenic effects and influenced neurodevelopment in early life. This systematic review underscored the adverse health effects of DEHP for pregnant women and the pediatric age group. It summarizes different response of humans and experimental animals to DEHP exposure, and some suggested underlying mechanisms.

Changes in blood glucose level during and after light sedations using propofol-fentanyl and midazolam-fentanyl in diabetic patients who underwent cataract surgery.

BACKGROUND: Surgeries may trigger the stress response which leads to changes in blood glucose level, and studies suggest that different sedation and anesthesia methods have different effects on blood glucose level. The aim of this study was to investigate changes of blood glucose levels in diabetic patients and compare them in two sedation methods of propofol + fentanyl and midazolam + fentanyl. MATERIALS AND METHODS: Totally, 80 diabetic candidates for cataract surgery who had all the inclusion criteria, underwent cataract surgery using two methods of propofol (1 mg/kg/h) + fentanyl (2 µg/kg) (Group P) and midazolam (0.03 mg/kg) + fentanyl (2 µg/kg) (Group M) for light sedation. In the end, 70 patients (Group P n = 35 and Group M n = 35) remained in the study. Patients' blood glucose levels, vital signs, and hemodynamic data were assessed 30 min prior to the surgery, each 15 min during surgery and at the end of surgery. RESULTS: Hemodynamic parameters did not have a statistically significant difference between the two groups mean blood glucose level in Group M was 149.15 mg/dl and in Group P was 149.2 mg/dl, and based on repeated measures analysis of variance test, significant differences were not observed between the two groups (P = 0.99). T-test showed no significant differences in the blood glucose level at any time of the study between the two groups. CONCLUSIONS: Light sedation methods of propofol + fentanyl and midazolam + fentanyl did not have any differences in alteration of blood glucose level.

Efficacy of Varicocele Repair in Different Age Groups.

OBJECTIVE: To compare semen parameters and spouse pregnancy rates after varicocele repair in 2 age groups. MATERIALS AND METHODS: Mean changes in spermatozoa concentration, motility, and morphology after varicocele repair in 83 patients were compared between patients aged 30 years or younger (group 1) and those older than 30 years (group 2). Spouse pregnancy rates were compared between the 2 age groups. RESULTS: The mean sperm concentration increased significantly in both groups (P <.05). The percentage of motile sperm increased from 48.2% to 56.6% in group 1 and from 47.2% to 53.2% in group 2 one year after varicocele repair. The increase in motility was statistically significant for both groups (P <.05), but there was no statistically significant difference in the increase in sperm motility between the 2 groups (P = .01). The percentage of sperm with abnormal morphology decreased significantly in both groups 12 months postoperatively (from 62.7% to 59.6% in group 1 and from 61.3% to 58% in group 2; P = .03). However, there was no statistically significant difference in the improvement in sperm morphology between the 2 groups (P >.05). The pregnancy rates in the patients' spouses were 51.1% and 44.7% in groups 1 and 2, respectively. This difference was not statistically significant (P = .9). CONCLUSION: There was no statistically significant difference in semen parameter improvement and spouse pregnancy rates after varicocelectomy in the 2 age groups.

Short-term Effects of a Physical Activity Intervention on Obesity and Aerobic Fitness of Adolescent Girls.

BACKGROUND: In the past two decades, physical activity has decreased during both childhood and adolescence, and particularly adolescence. It seems that schools are attractive settings in which to implement interventions designed in order to promote physical activity in children; but in Iranian students, few studies have evaluated the effects of such interventions on overweight and obese children. The aim of this study was to evaluate the effects of a short-term school-based physical activity on obesity and aerobic fitness in 12-14 years aged girls. METHODS: This is a study with single group pretest and posttest design, in which 129 middle school girls in city of Isfahan were assessed based on preventive plan of inactivity in children at the Provincial Health Office. Variables, including weight, height, body mass index (BMI), waist-hip ratio (WHR), body fat percentage and aerobic power of subjects were measured using valid tests. RESULTS: This study showed that subjects' body fat percentage changed about 3.6% (37.74% pretest vs. 36.39% posttest), VO2 max changed 7.43% (29.72 pretest vs. 31.93 posttest), WHR changed 1.12% (0.89 pretest vs. 0.88 posttest), whereas BMI was changed 1.65% (27.80 pretest vs. 27.34 posttest). Findings also revealed that there were significant differences between fat percent, (P = 0.001) and VO2 max (P = 0.001) of subjects, but there was no difference between BMI of them in pre- and post-tests (P = 0.361). CONCLUSIONS: These results suggest that even a short-term exercise intervention may lead to positive changes in body fat percentage, WHR and aerobic fitness of overweight children. Therefore, school-based physical activity interventions can be an effective preventive strategy to control obesity and overweight in students.

Short-term Effects of a Physical Activity Intervention on Obesity and Cardiovascular Fitness of 12-14-year-old Boy Students.

BACKGROUND: Some local governments have implemented strategies to increase physical activity as a way to control obesity in children, but in Iranian students few studies have evaluated the effects of such interventions on overweight and obese children. The aim of this study was to evaluate the effects of a short-term school-based physical activity on obesity and cardiovascular fitness in 12-14-year-old boy students. METHODS: This study showed an intervention effect on some health-related fitness factors in students. A number of 127 boy students aged 12-14 years, in the city of Isfahan, based on preventive plan of inactivity in children at the provincial Health office selected randomly as subjects. Measurement variables include; weight, height, body mass index (BMI), waist-hip ratio (WHR), body-fat percent and aerobic power of subjects measured by valid tests. RESULTS: This study revealed that body-fat percentage of this students changed near to 17.84% (42.25% pretest vs. 34.71% posttest), WHR 0.44%, (0.915 pretest vs. 0.911 posttest), VO2 max changed 8.54% (27.84 pretest vs. 30.22 posttest) whereas BMI was changed 2.61% (26.81 pretest vs. 26.03 posttest). Results also revealed that there were significant differences between fat percent, (P = 0.001) and VO2 max (P = 0.001), but there was no difference between BMI of subjects in pre and posttests (P = 0.452). CONCLUSIONS: Findings of this study signify that an implementation of short-term intervention components in the school system may have a beneficial effect on body-fat percentage and cardiovascular fitness of overweight/obese children.

Prevalence of Obesity and Overweight in 12-14-year-old Students in Isfahan-Iran.

BACKGROUND: Childhood obesity is a worldwide major public health problem in both developed and developing countries. The purpose of this study was to determine the prevalence of obesity and overweight in 12-14-year-old students in the city of Isfahan. METHODS: This study was conducted among 10,531 girls and 2415 boys aged 12-14 years in the city of Isfahan. Percentage of children in the corresponding body mass index (BMI) categories for overweight and obesity (specified by the Centers for Disease Control and Prevention criteria percentiles) were assessed, based on preventive plan of inactivity in children and youth of Isfahan province. RESULTS: Findings revealed that prevalence of overweight in children varied by age from 15.3% to 26.9% in boys and 12.9% to 29.9% in girls, and prevalence of obesity varied from 14.8% to 33.7% and 15% to 29.9% in boys and girls, respectively. Percentile norms for BMI of subjects were computed based on sex categories. CONCLUSIONS: To conclude, results of the study revealed that subjects have approximately the same percentage of overweight/obesity compared to other children have been studied; however, in comparison to previous studies, a higher rate was witnessed in grade 8 boy students. These situations indicate that there are needs to implement some intervention programs, as well as management policies.

Postoperative ureteral obstruction after endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer (Vantris®).

PURPOSE: To investigate the incidence and presentations of ureteral obstruction following periureteral injection of polyacrylate polyalcohol copolymer (PPC) for the treatment of vesicoureteral reflux (VUR). MATERIALS AND METHODS: From Jan 2010 to Dec 2012, 88 patients (28 male, 60 female) with 128 renal refluxing units (RRU), 131 ureters and a mean age of 6.7 ± 5.9 years (range: 4 months to 32 years) underwent endoscopic correction of their VUR, using PPC. Exclusion criteria were dysmorphic appearing distal ureter, extravesical position of the ureteral orifice, persistent urethral obstruction (e.g. after previous valve ablation) and severe bladder trabeculation, making ureteral orifice unidentifiable. Patients were followed up by ultrasound one month after the injection and then every three months. Cystography was performed 3 months post-operation. Mean follow-up time was 13.1 ± 6.8 months (range: 3-27 months). RESULTS: Two patterns of obstruction were observed: early, during the first 3-4 days post-operation, in four patients (4 ureters; 3%) which was associated with transient hydroureteronephrosis (HUN) in 2 patients (2 ureters; 1.5%); and late-onset obstruction in 3 patients (4 ureters; 3%) which appeared 3 months to 1 year after surgery. It manifested itself by urinary tract infection and uremia in one patient with bilateral obstruction but was asymptomatic in the other two. Early obstruction was managed expectantly and resolved in 3-12 months; however, late-onset obstruction needed catheter placement or open ureteroneocystostomy. CONCLUSIONS: Patients who undergo endoscopic treatment for their VUR using PPC need long-term follow up until the safety of this substance is confirmed.

Renal Solid Mass as a Rare Presentation of Wagener's Granulomatosis: A Case Report.

Wagener's granulomatosis (WG) is a rheumatologic disease with unknown etiology which renal and pulmonary involvement is commonly seen. Renal involvement in Wagener's granulomatosis represents as a segmental necrotizing glomerulonephritis which is not visible with imaging techniques and usually presents with proteinuria, microhematuria, and hypertension. A rare presentation of the disease is a renal mass which can be mistaken as renal tumors, abscess, or lymphoma. We report a 22-year-old female with flank pain and fever who was admitted in our hospital. The patient underwent renal tumor biopsy and diagnosed with Wagener's granulomatosis in pathologic staining. The aim of this work is introduction of Wagener's granulomatosis as a differential diagnosis of renal tumors, to prevent unnecessary interventions and delayed treatment.