Evaluation of safety, feasibility and efficacy of intra-ovarian transplantation of autologous adipose derived mesenchymal stromal cells in idiopathic premature ovarian failure patients: non-randomized clinical trial, phase I, first in human.

BACKGROUND: Premature ovarian failure (POF) is characterized by the loss of ovarian activity before the age of 40 years. Stem cell therapy has the capability to create a regenerative microenvironment and is a proposed treatment for POF-related infertility due to the presence of renewal folliculogenesis and germ cells in the adult ovaries. In this study, we assessed the safety, feasibility, efficacy and dose adjustment of autologous adipose-derived stromal cells (ADSCs) and their ability to improve ovarian function in POF patients. METHODS: This study was a non-randomized clinical trial, phase I. Nine women with a definitive diagnosis of POF were divided into three groups (n = 3 per group) that received either 5 × 106, 10 × 106, or 15 × 106 autologous ADSCs suspension transplanted in the one ovary. Participants were followed-up at 24 h after the transplantation, and at 1 and 2 weeks, and 1, 2, 3, 6, and 12 months after the transplantation. The primary objective was to evaluate the safety of ADSCs transplantation. Secondary objectives included the effects of ADSCs transplantation on the resumption of menstruation, hormones level (Follicle-stimulating hormone (FSH) and anti-Müllerian hormone), ovarian function (Antral follicle count and ovary volume by ultrasonography evaluation) as well as dose escalation. RESULTS: Participants had not shown any early-onset possible side effects and secondary complications during follow-up. The menstruation resumption was observed in four patients which established for several months. In the 15 × 106 group, two POF patients had a return of menstruation second months after the intervention. Two other POF patients in 5 × 106 and 10 × 106 cell groups reported menstruation resumption at 1 month after the intervention. We observed decreased serum FSH levels of less than 25 IU/l in four patients. In two patients in 5 × 106 and 10 × 106 cell groups, serum FSH showed an inconsistent decline during a 1 year follow up after ADSCs transplantation. The ovarian volume, AMH, and AFC were variable during the follow-up and no significant differences between cell groups (p > 0.05). CONCLUSIONS: We showed the intra-ovarian embedding of ADSCs is safe and feasible and is associated with an inconsistent decline in serum FSH. This should be further investigated with a large RCT. TRIAL REGISTRATION: NCT02603744 , Registered 13 November 2015 - Retrospectively registered, http://www.Clinicaltrials.gov.

Adaptive Continuous Integral-Sliding-Mode Controller for Wearable Robots: Application to an Upper Limb Exoskeleton.

This paper introduces an adaptive integral sliding mode controller for exoskeletons. The controller design is based on the hypothesis that only classical properties are known such as parameters' bounds, and all other functions are unknown. To ensure the convergence in position, velocity and acceleration for desired trajectories, disturbances are supposed to be bounded. The closed-loop stability of the system in the sense of Lyapunov is demonstrated. The effectiveness of the proposed approach is proved in real time using a 2-DOF upper limb exoskeleton in the rehabilitation context taking into account the security and the safety of the user.

Double mild stimulation and egg collection in the same cycle for management of poor ovarian responders.

PURPOSE: To evaluate the effect of double stimulations during the follicular and luteal phases in women with poor ovarian response (POR) in in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. BASIC PROCEDURES: This prospective clinical study was performed in Royan Institute from October 2014 to January 2016. 121 patients were diagnosed as POR on the basis of Bologna criteria were included. Double stimulations were performed during the follicular and luteal phases by Letrozole, Clomid, hMG and GnRH-agonist. The patients' present cycle outcomes were compared with those of the previous cycle results using appropriate statistical tests. MAIN FINDING: The total of 104 (85.9%) patients completed the stimulation stages. The analysis revealed the number of retrieved oocytes after the first and second stimulations did not differ (P = 0.2); however, the fertilization rate and the number of frozen embryos after the first stimulation were significantly higher than those of in the second stimulation (P < 0.001 and P = 0.03), indicating the better quality of retrieved oocytes after the first stimulation. The mean number of MII oocytes and the fertilization rate after Shanghai protocol were higher than those of the previous antagonist protocol with a substantial trend toward significance (P = 0.06), which can be clinically important. The cancellation rate (33%) due to no ovarian response and no embryo formation was still high in these patients. PRINCIPAL CONCLUSION: Since the intensity of stimulation in both stages was mild, this protocol can be considered a time-efficient and patient friendly regime; however, more studies are required with emphasis on its cost-effectiveness.

First complete genome sequence of circulating dengue virus serotype 3 in Jeddah, Saudi Arabia.

Here we report the first full-length genome sequence of dengue virus serotype 3 (DENV-3) from a strain isolated from a patient in Jeddah, Saudi Arabia, in 2014. The genome consists of 10 635 bp and shows close similarity to circulating genotype III isolates from Singapore, suggesting possible importation, most probably during religious pilgrimages to Saudi Arabia.

Testing for HTLV 1 and HTLV 2 among blood donors in Western Saudi Arabia: prevalence and cost considerations.

BACKGROUND: Screening all blood donors for human T-cell lymphotropic viruses 1 and 2 (HTLV 1 and HTLV 2) is mandatory in Saudi Arabia. The aim of this study is to evaluate the results and costs associated with the current testing policy for HTLV 1 and HTLV 2 in blood donors at King Abdulaziz University Hospital (KAUH), Jeddah. STUDY DESIGNS AND METHODS: Donor-testing results from Blood Transfusion Services at KAUH were reviewed over a 10-year period, from January 2006 through December 2015. All donors were screened using chemiluminescent microparticle immunoassay. Reactive samples were then tested by Western blot for confirmation. Costs associated with testing were calculated. RESULTS: Data of 107 419 donations in the study period were reviewed. Saudi nationals constituted 51 168 donors (47·6%). Of 107 419 blood donors tested for HTLV 1 and HTLV 2 antibody, and 95 (0·088%) donors were reactive to screening tests. None of the samples found to be reactive to screening tests was positive by Western blot. The average cost of testing was US$ 171 870 per year. CONCLUSION: No donors were confirmed to have HTLV 1 and HTLV 2 in this cohort exceeding 100 000 donors. We propose changes to the policy mandating universal testing by replacing it with universal leukodepletion coupled with targeted screening to donors coming from endemic area or donors at risk. Such changes are expected to lead to a reduction of testing cost without affecting safety.

A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF: a multicenter randomized non-inferiority trial.

STUDY QUESTION: In subfertile women with poor ovarian reserve undergoing IVF does a mild ovarian stimulation strategy lead to comparable ongoing pregnancy rates in comparison to a conventional ovarian stimulation strategy? SUMMARY ANSWER: A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF leads to similar ongoing pregnancy rates as a conventional ovarian stimulation strategy. WHAT IS KNOWN ALREADY: Women diagnosed with poor ovarian reserve are treated with a conventional ovarian stimulation strategy consisting of high-dose gonadotropins and pituitary downregulation with a long mid-luteal start GnRH-agonist protocol. Previous studies comparing a conventional strategy with a mild ovarian stimulation strategy consisting of low-dose gonadotropins and pituitary downregulation with a GnRH-antagonist have been under powered and their effectiveness is inconclusive. STUDY DESIGN, SIZE, DURATION: This open label multicenter randomized trial was designed to compare one cycle of a mild ovarian stimulation strategy consisting of low-dose gonadotropins (150 IU FSH) and pituitary downregulation with a GnRH-antagonist to one cycle of a conventional ovarian stimulation strategy consisting of high-dose gonadotropins (450 IU HMG) and pituitary downregulation with a long mid-luteal GnRH-agonist in women of advanced maternal age and/or women with poor ovarian reserve undergoing IVF between May 2011 and April 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples seeking infertility treatment were eligible if they fulfilled the following inclusion criteria: female age ≥35 years, a raised basal FSH level >10 IU/ml irrespective of age, a low antral follicular count of ≤5 follicles or poor ovarian response or cycle cancellation during a previous IVF cycle irrespective of age. The primary outcome was ongoing pregnancy rate per woman randomized. Analyses were on an intention-to-treat basis. We randomly assigned 195 women to the mild ovarian stimulation strategy and 199 women to the conventional ovarian stimulation strategy. MAIN RESULTS AND THE ROLE OF CHANCE: Ongoing pregnancy rate was 12.8% (25/195) for mild ovarian stimulation versus 13.6% (27/199) for conventional ovarian stimulation leading to a risk ratio of 0.95 (95% CI: 0.57-1.57), representing an absolute difference of -0.7% (95% CI: -7.4 to 5.9). This 95% CI does not extend below the predefined threshold of 10% for inferiority. The duration of ovarian stimulation was significantly lower in the mild ovarian stimulation strategy than in the conventional ovarian stimulation strategy (mean difference -1.2 days, 95% CI: -1.88 to -0.62). Also, a significantly lower amount of gonadotropins was used in the mild simulation strategy, with a mean difference of 3135 IU (95% CI: -3331 to -2940). LIMITATIONS, REASONS FOR CAUTION: A limitation of our study was the lack of data concerning the cryopreservation of surplus embryos, so we are not informed on cumulative pregnancy rates. Another limitation is that we were not able to follow up on the ongoing pregnancies in all centers, so we are not informed on live birth rates. WIDER IMPLICATIONS OF THE FINDINGS: The results are directly applicable in daily clinical practice and may lead to considerable cost savings as high dosages of gonadotropins are not necessary in women with poor ovarian reserve undergoing IVF. A health economic analysis of our data planned to test the hypothesis that mild ovarian stimulation strategy is more cost-effective than the conventional ovarian stimulation strategy is underway. STUDY FUNDING/COMPETING INTERESTS: This study was supported by NUFFIC scholarship (the Netherlands) and STDF short-term fellowship (Egypt). TRIAL REGISTRATION NUMBER: NTR2788 (Trialregister.nl). TRIAL REGISTER DATE: 01 March 2011. DATE OF FIRST PATIENT'S ENROLMENT: May 2011.

Serratia marcescens-contaminated baby shampoo causing an outbreak among newborns at King Abdulaziz University Hospital, Jeddah, Saudi Arabia.

During November 2008 to January 2009, 11 babies in the neonatal intensive care (NICU) and three babies in the nursery were infected with Serratia marcescens at King Abdulaziz University Hospital in Saudi Arabia. Overall, fifteen infections were identified among 11 newborns in the NICU: septicaemia (five cases), purulent conjunctivitis (three), urinary tract infection (two), meningitis (two) and cellulitis (one). Three newborns in the nursery had three infections: purulent conjunctivitis (two cases) and omphalitis (one). Thirteen of 14 babies recovered fully but one died from S. marcescens meningitis and septicaemia. All infections were traced to intrinsically contaminated baby shampoo introduced to the units five days before the first reported case. The outbreak terminated following withdrawal of the shampoo product.

Follicle stimulating hormone as a predictor of ovarian response in women undergoing controlled ovarian hyperstimulation for IVF.

OBJECTIVE: To evaluate the effect of basal follicle stimulating hormone (FHS) level on ovarian response in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. METHODS: A descriptive and analytic study of 212 cycles of IVF chosen from about 2200 files of women treated at Royan Institute, Tehran, Iran, from 1991 to 1999. Treatment was started with intranasal or subcutaneous buserlin (0.5 cm3), on day 21 (long protocol). On day 2 of the next cycle, stimulation with human menopausal gonadotropin (hMG) was initiated. When the number and size of follicles were suitable, human chorionic gonadotropin (hCG) was given intramuscularly for ovulation induction, followed by oocyte retrieval 36 to 40 h later. Embryos were transferred about 48 to 72 h after oocyte retrieval. The women were assigned to 2 groups on the basis of day 3 serum FSH levels (>or=15 IU/mL, group 1 and <15 IU/mL, group 2). RESULTS: There were statistically significant differences between the 2 groups in number of follicles, number of oocytes retrieved and embryos transferred (lower in group 1), and level of serum luteinizing hormone and number of canceled cycles (higher in group 1). There were no statistical differences in number of ampoules of hMG used or age of patients. CONCLUSION: Day-3 serum FSH level was a predictor of ovarian response and IVF outcome in this study.

Clinical features of culture-proven Mycoplasma pneumoniae infections at King Abdulaziz University Hospital, Jeddah, Saudi Arabia.

OBJECTIVE: This retrospective chart review describes the epidemiology and clinical features of 40 patients with culture-proven Mycoplasma pneumoniae infections at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. METHODS: Patients with positive M. pneumoniae cultures from respiratory specimens from January 1997 through December 1998 were identified through the Microbiology records. Charts of patients were reviewed. RESULTS: 40 patients were identified, 33 (82.5%) of whom required admission. Most infections (92.5%) were community-acquired. The infection affected all age groups but was most common in infants (32.5%) and pre-school children (22.5%). It occurred year-round but was most common in the fall (35%) and spring (30%). More than three-quarters of patients (77.5%) had comorbidities. Twenty-four isolates (60%) were associated with pneumonia, 14 (35%) with upper respiratory tract infections, and 2 (5%) with bronchiolitis. Cough (82.5%), fever (75%), and malaise (58.8%) were the most common symptoms, and crepitations (60%), and wheezes (40%) were the most common signs. Most patients with pneumonia had crepitations (79.2%) but only 25% had bronchial breathing. Immunocompromised patients were more likely than non-immunocompromised patients to present with pneumonia (8/9 versus 16/31, P = 0.05). Of the 24 patients with pneumonia, 14 (58.3%) had uneventful recovery, 4 (16.7%) recovered following some complications, 3 (12.5%) died because of M pneumoniae infection, and 3 (12.5%) died due to underlying comorbidities. The 3 patients who died of M pneumoniae pneumonia had other comorbidities. CONCLUSION: our results were similar to published data except for the finding that infections were more common in infants and preschool children and that the mortality rate of pneumonia in patients with comorbidities was high.

Methicillin-resistant Staphylococcus aureus in two tertiary-care centers in Jeddah, Saudi Arabia.

OBJECTIVE: To review clinical experience with methicillin-resistant Staphylococcus aureus (MRSA) in tertiary-care hospitals in Jeddah, Saudi Arabia. DESIGN: Retrospective review for the year 1998. SETTING: Two tertiary-care hospitals. METHODS: Results of MRSA-positive cultures of clinical specimens obtained as part of investigations for suspected infections were retrieved from the microbiology laboratories' records. Charts of patients were reviewed, with standardized data collection. RESULTS: Of 673 S. aureus isolates identified, 222 (33%, or 6.8 isolates/1,000 admissions) were MRSA. Overall MRSA prevalence was 2% in 1988. Nosocomial acquisition occurred in 84.2% of cases. All age groups were affected, and 52% of patients had at least one comorbidity. MRSA prevalence was highest in the intensive care units (26.6% of all isolates), the medical wards (24.8%), and the surgical wards (19.8%). Seventy-three percent of isolates caused infection; the rest represented colonization. Surgical wounds (35.2%), the chest (29%), and central venous catheters (13%) were the most common sites of infection. Bacteremia occurred in 15.4% of patients. Local signs (84%) and fever (75.9%) were the most common clinical manifestations. Respiratory distress and septic shock occurred in 30.2% and 13.6% of cases, respectively. Of 162 patients with MRSA infection and 60 patients with MRSA colonization, 95.7% and 70% received antibiotics in the preceding 6 weeks, respectively (P<.0001). The total mortality of patients with MRSA infection was 53.7%: 36.4% as a result of MRSA infection and 17.3% as a result of other causes. CONCLUSIONS: The prevalence of MRSA is high and rapidly increasing in the two hospitals, as it is worldwide. Control measures to prevent the spread of MRSA in hospitals should continue, with reinforcement of hygienic precautions and development of policies to restrict the use of antibiotics.

Clinical infections and bloodstream isolates associated with fever in patients undergoing chemotherapy for acute myeloid leukemia.

BACKGROUND: Patients with acute myeloid leukemia (AML) are at high risk for infections. The aim of this study was to identify the sources of fever and the type of pathogens that cause bloodstream infection in patients with AML undergoing cytotoxic chemotherapy and antibiotic prophylaxis. PATIENTS AND METHODS: The source of fever and the type of pathogens causing bloodstream infection were identified for 129 febrile episodes experienced by 42 patients with AML receiving cytotoxic chemotherapy and antibiotic prophylaxis. RESULTS: A source of fever was identified in 81% of all febrile episodes. Mucositis (21.7%), pneumonia (13.2%), central venous catheter infection (12.4%), neutropenic enterocolitis (9.3%) and invasive fungal disease (9.3%) were the most common sources of fever. Of 16 central venous catheter infections, seven (43.8%) were not associated with local signs. 49 febrile episodes (37.9%) were associated with bloodstream infections, of which 14 (28.6%) were polymicrobic and seven (14.3%) had an undefined source of infection. Bloodstream infection was commonly associated with cellulitis (60%), mucositis (57.1%), central venous catheter infection (55.6%), neutropenic enterocolitis (41.7%) and invasive fungal disease (41.7%). Gram-positive microorganisms were the most common blood isolates (75.8%). Gram-negative bacteremic infections occurred in eight episodes (12.1%) experienced by patients who were not receiving ciprofloxacin prophylaxes at the time of bacteremia. Noninfectious sources of fever accounted for 23 (17.8%) of the 129 febrile episodes. CONCLUSION: Although the spectrum of pathogens that cause infection in this group of patients has shifted from gram-negative to gram-positive bacteria, the most common sources of infection remain the same as previously described and they mainly involve integumental surfaces.

Enterococcal bacteremia in a tertiary care centre in Winnipeg.

OBJECTIVE: To review experience with enterococcal bacteremia before the emergence of vancomycin-resistant enterococcus at a tertiary care teaching hospital. DESIGN: Retrospective chart review of episodes of enterococcal bacteremia identified through the clinical microbiology laboratory from January 1990 to December 1994. Antimicrobial susceptibilities were performed for all isolates and pulsed-field gel electrophoresis for genetic typing of selected strains. RESULTS: One hundred and twenty-six episodes of bacteremia were identified in 109 patients: 108 Enterococcus faecalis, 13 Enterococcus faecium, four both E faecalis and E faecium, and one Enterococcus durans. Enterococcal isolates occurred with polymicrobial bacteremia in 62 (49%) episodes. The most common sites of infection were central venous catheters (45%) and the urinary tract (21%). Enterococcal bacteremia was usually nosocomially acquired (88%), and associated with older age, instrumentation, and prior or current antimicrobial therapy. Overall mortality was 22%, and 7.2% was partially or fully attributable to enterococcal bacteremia. Resistance to ampicillin, high level gentamicin and high level streptomycin were 0%, 32% and 31% for E faecalis, respectively, and 44%, 0% and 47% for E faecium, respectively. CONCLUSIONS: During this review, the frequency and impact of enterococcal bacteremia at this institution was relatively limited. Isolates resistant to ampicillin and aminoglycosides were emerging, but differences in patient outcomes were similar for resistant and susceptible isolates.

Screening pregnant women for group B streptococcal colonization.

The recovery rates of group B streptococcus (GBS) from anorectal swabs (RS) and vaginal swabs (VS) that were enriched were compared to the routine method to determine the optimal procedure. Separate RS and VS were collected from women attending antenatal clinics. RS and VS were placed in 2 ml enrichment and selective broth. Swabs were inoculated onto colistin/nalidixic acid agar (CNA) upon arrival in the laboratory and onto 5% sheep blood agar (SBA) and CNA after 24 h enrichment. The routine method consisted of a VS sent in transport medium and inoculated in the laboratory onto SBA (no enrichment). The overall GBS colonization rate was 24% (64/264). Of the 64 GBS carriers, 77% were colonized in the vagina and 89% were colonized in the anorectum. The anorectum was the only site of colonization in 24% of the women, whereas the vagina was the only site of colonization in 11% of cases. Enrichment increased the detection of GBS from both RS (55 versus 42; P < 0.025) and from VS (49 versus 27; P < 0.001). Of the 64 cases, enriched RS detected 86%, enriched VS detected 77% and the standard VS detected only 41%. Enriched RS and enriched VS collectively detected 99% of cases. SBA was better than CNA for subculture of the enrichment broth because of a higher recovery rate (98-100% versus 80-82%; P < 0.01) and the fact that the hemolysis on SBA made it easier to differentiate GBS from enterococci. The data confirm that optimal screening of pregnant women for GBS should include a combined RS/VS swab placed in enrichment broth that is then subcultured onto SBA after 24 h incubation.

Metabolic and anti-atherogenic effects of long-term benfluorex in dyslipidemic insulin-resistant sand rats (Psammomys obesus).

Benfluorex is a clinical lipid-lowering agent with antihyperglycemic properties. The effect of long-term oral treatment (10 mg/kg/day for 7.5 months) on carbohydrate and lipid metabolism and aortic morphology was investigated in 24 insulin-resistant sand rats receiving a standard laboratory diet supplemented with cholesterol (2%). Untreated controls (n=34) developed impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and elevated plasma LDL- and VLDL-cholesterol, positively correlated with the proportion of the thoracic aorta displaying oil red O-positive atherosclerosis; ultrastructural examination showed intimal lipid deposits, foam cells, polymorph infiltrates and fibrosis. Benfluorex-treated animals showed significant decreases in glucose intolerance, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and plasma LDL- and VLDL-cholesterol, with no evidence of aortic atheroma. The metabolic benefits of benfluorex may protect against the long-term development of atherosclerosis in the insulin-resistant dyslipidemic syndrome.

Reversible severe hereditary hemochromatotic cardiomyopathy.

Two cases of severe hereditary hemochromatotic cardiomyopathy are reported. Both patients responded remarkably well to treatment and are leading a normal life requiring no cardiac medications, following small volume phlebotomies for two years combined, in the first three and six months of treatment, with subcutaneous deferoxamine mesylate.

S15261, a novel agent for the treatment of insulin resistance. Studies on Psammomys obesus.

S15261 is a novel compound that has been proposed for the treatment of insulin resistance syndrome. We have studied the effects of this drug in insulin resistant sand rats (Psammomys obesus). When sand rats are transferred from their natural desert environment and placed on a laboratory chow diet, they become overweight, develop hypertriglyceridaemia, hypercholesterolaemia, become insulin resistant, and ultimately diabetic. In the present study glucose intolerant animals, with very mild if any hyperglycaemia were used. Chronic treatment for a month with S15261 normalised plasma levels of triglycerides and cholesterol. The effects on cholesterol were the result of a decrease in LDL- and VLDL-cholesterol without any modification of HDL-cholesterol. In this study only female sand rats showed elevated plasma glucose levels, which were normalised by S15261. The compound also decreased plasma insulin levels both in male and female sand rats. An oral glucose tolerance test showed a major improvement in glucose tolerance in both male and female animals treated with S15261. These data confirm in another animal model the therapeutic benefits of S15261 in insulin resistant states.