Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication

Microdeletions encompassing 14q11.2 locus, involving SUPT16H and CHD8, were shown to cause developmental delay, intellectual disability, autism spectrum disorders and macrocephaly. Variations leading to CHD8 haploinsufficiency or loss of function were also shown to lead to a similar phenotype. Recently, a 14q11.2 microduplication syndrome, encompassing CHD8 and SUPT16H, has been described, highlighting the importance of a tight control of at least CHD8 gene-dosage for a normal development. There have been only a few reports of 14q11.2 microduplications. Patients showed variable neurodevelopmental issues of variable severity. Breakpoints of the microduplications were non-recurrent, making interpretation of the CNV and determination of their clinical relevance difficult. Here, we report on two patients with 14q11.2 microduplication encompassing CHD8 and SUPT16H, one of whom had normal intelligence. Review of previous reports describing patients with comparable microduplications allowed for a more precise delineation of the condition and widening of the phenotypic spectrum.

     

Circumstances of substance use by street youth in Egypt support the case for intervening to prevent adverse childhood experiences

Background: Egyptian street youth use substances including tobacco, illicit drugs, and pharmaceutical drugs. To understand the circumstances, including adverse childhood experiences, that place adolescents at risk for engaging in substance use, we conducted in-depth interviews among a sample of Egyptian street children. Methods: From youth residing at or attending Caritas, a non-profit organization, which provides shelter and education to street youth, seven girls and twelve boys, aged 12–18 years, participated in open-ended, in-depth interviews. Results: Eight out of the 19 participants reported family history (early exposure) to substance use; and seven of them were initiated by either a family member (sibling), friend or coworker. Most of the participants reported a history of conflict with or abuse (verbal or physical) by their parents or siblings, or stressful situations at home; they used substance(s) to alleviate their stress. Few attended school, and some were forced to work and help their family. Conclusions: Among Egyptian youth, adverse childhood experiences, such as poverty, child abuse, and family substance use, challenge somewhat susceptible youths and lead them to the path of substance use and addiction. Prevention intervention should be multifaceted, culturally adaptable, and primarily targeting the social environment during childhood.     

Insurance-mandated preoperative dietary counseling does not improve outcome and increases dropout rates in patients considering gastric bypass surgery for morbid obesity

BACKGROUND: Preoperative dietary counseling (PDC) before bariatric surgery is mandated by a growing number of insurance payers. Their claim is that PDC improves outcomes and postoperative compliance. We compared outcomes of GBP patients undergoing a mandatory 13 weeks of PDC (n = 72) to a contemporaneous group of patients with no such requirement (no-PDC; n = 252) who underwent operation between January 2000 and December 2002. METHODS: The PDC and no-PDC groups were characterized by similar male:female ratios (1:4 vs 1:4.6), mean age (42 years), mean body weight (324 lb vs 309 lb), and mean body mass index (BMI) (52 kg/m2 vs 50 kg/m2). The PDC group had a higher incidence of obstructive sleep apnea compared with the no-PDC group (41% vs 28%; P < .04) but otherwise the two groups had similar incidences of obesity-related comorbidities. The presurgery dropout rate was 50% higher in the PDC group than in the no-PDC group (28% vs 19%; P < .05). RESULTS: At 1 year follow-up, the no-PDC patients had a statistically greater percentage excess weight loss (67% vs 60%; P < .0001), lower BMI (32 vs 35; P < .015), and lower body weight (197 vs 218; P < .01). Resolution of major comorbidities, complication rates, 30-day postoperative mortality, and postoperative compliance with follow-up were similar in the two groups. CONCLUSIONS: The data demonstrate that insurance-mandated PDC is an obstacle to patient access for surgical treatment of severe obesity and has no impact on weight loss outcome or postsurgical compliance. PDC should be abandoned by the insurance industry.     

Dexmedetomidine in combination with morphine PCA provides superior analgesia for shockwave lithotripsy

PURPOSE: To compare the analgesic effects of dexmedetomidine/morphine with those of tramadol/midazolam in patients undergoing extracorporeal shockwave lithotripsy (ESWL) for urinary calculi. METHODS: Sixty patients were randomized to receive either dexmedetomidine 1 micro g*kg(-1) iv followed by 0.5 micro g*kg(-1)*hr(-1) infusion together with morphine patient-controlled analgesia [(PCA); 2 mg bolus, five minutes lockout, 2 mg*hr(-1) infusion; (Group DEX)], or tramadol 1.5 mg*kg(-1) pre-mixed with midazolam 30 micro g*kg(-1) iv followed by tramadol PCA [20 mg bolus, five minute lockout, 20 mg*hr(-1) infusion; (Group TRA)]. Pain was assessed at baseline and every 15 min thereafter. Patients' and urologist's satisfaction with analgesia and sedation were determined on a seven-point scale ranging from 1 (extremely dissatisfied) to 7 (extremely satisfied). Patient's discharge time was also documented. RESULTS: Visual analogue scale scores over time were consistently lower in Group DEX compared with Group TRA (P = 0.001). Patients' satisfaction with analgesia (5 +/- 1 vs 4 +/- 2, P = 0.012) and with sedation (6 +/- 1 vs 5 +/- 1, P = 0.020), and urologist's satisfaction (6 +/- 1 vs 4 +/- 2, P = 0.001) were all higher amongst Group DEX patients compared with Group TRA. There was no difference between discharge times of patients in Group DEX compared with those in Group TRA [85 (60,115) min vs 65 (40,95) min, P = 0.069]. CONCLUSION: Dexmedetomidine in combination with morphine PCA provided better analgesia for ESWL and was associated with higher patients' and urologist's satisfaction when compared with a tramadol/midazolam PCA combination.     

Outcome of frozen embryo replacement cycles following elective cryopreservation of all embryos in women at risk of developing ovarian hyperstimulation syndrome

Aim: Our aim was to compare the outcome in subsequent frozen embryo replacement cycles in four groups of patients who had elective cryopreservation of all their embryos because they were considered to be at increased risk of developing severe ovarian hyperstimulation syndrome. Design: Sixty-two (91%) of 68 IVF cycles (68 patients) in which elective cryopreservation of all embryos was performed were analyzed. All patients continued on the GnRH agonist, buserelin, after oocyte recovery until the onset of vaginal bleeding. Frozen embryo replacement occurred in a hormone replacement cycle that started either on day 3 of the withdrawal bleed (group I;N=15) or after serum estradiol levels had fallen to <100 pmol/L (group II;N=16). The other patients commenced a frozen embryo replacement cycle several months later in either a hormone replacement (group III;N=15) or a natural (group IV;N=16) cycle. Results: Two patients developed severe ovarian hyperstimulation syndrome. There were no significant differences among the four groups regarding demographic variables, the dose of hMG used, and the clinical outcome. There was a higher but not significantly different clinical pregnancy rate in group I (26.7%), compared to group II (12.5%), group III (13.3%), and group IV (18.8%). Conclusions: Several options exist for the timing and protocol used for frozen embryo replacement in patients who had elective cryopreservation for the prevention of ovarian hyperstimulation syndrome, none of which was found to be clearly superior in this observational report.Presented at the 1994 Annual Conference of the American Fertility Society.     

Burns during pregnancy: a gloomy outcome

The effect of burns on fetal and maternal survival is known to be detrimental. This prospective study describes the performance of pregnant burned patients who were managed and followed up for fetal and maternal outcomes at Ain Shams University's burn unit and Maternity Hospital during the period from October 1995 to September 1996. During the 12-month period, 27 pregnant burned patients were managed. Fetal and maternal mortality correlated with the total body surface area (TBSA) burned, the mortality rate being 63 per cent for both mothers and fetuses in the 25–50 per cent TBSA group. A fetal loss of 56 per cent with no maternal loss were recorded in the 15–25 per cent TBSA group. Experience in dealing with pregnant burned patients proves that early surgical excision and skin grafting, with timely termination of pregnancy are the best lines of treatment. Prevention or minimizing the effects of the burns may be achieved by proper education and guidance of the pregnant woman.     

Concomitant administration of cyclosporine and ketoconazole in idiopathic nephrotic syndrome.

BACKGROUND: The deliberate use of ketoconazole to reduce the need for cyclosporine (CsA) is not new, but it is particularly relevant because of the high cost of CsA. Many studies have documented this benefit in renal and cardiac transplants, but this co-administration has not been reported in patients with nephrotic syndrome. METHODS: This retrospective study included 207 nephrotic patients who were steroid resistant, dependent or frequent relapsers and received CsA therapy. Among these patients 153 received daily ketoconazole therapy in a dose of 50 mg with concomitant decrease of one-third of the CsA dose while 54 patients received CsA alone. The majority of our cases were children (179 were below 18 years) and male to female ratio was 1.7:1. RESULTS: The great majority of the study population received the drugs for 1-2 years. Patients who received CsA and ketoconazole were comparable with those who received CsA alone regarding age, sex, duration of renal disease, renal pathology, severity of nephrotic syndrome, renal function, hepatic function and steroid response. Co-administration of ketoconazole significantly reduced mean doses of CsA by 37% after 1 month and 47% at 1 year with overall net cost savings of 37%. Hepatic functions remained within the normal range in both groups. Additionally, co-administration of ketoconazole significantly improved the response to CsA therapy, successful steroid withdrawal and decreased the frequency of renal impairment. CONCLUSIONS: Co-administration of keto with CsA in idiopathic nephrotic patients significantly reduces CsA costs and may improve its response.     

Diminution in Kerosene-Mediated Induction of Drug Metabolizing Enzymes by Asbestos in Rat Lungs

Abstract: In order to determine the pulmonary toxicity of kerosene and its ignition product (soot) in asbestos exposed subjects, the activities of phase I and phase II drug metabolizing enzymes in rat lungs after single intratracheal coexposure to Indian chrysotile asbestos and kerosene or its soot and Indian chrysotile were assayed. Exposure to kerosene or its soot resulted in a significant increase in the level of microsomal cytochrome P-450 and the activity of P-450 dependent monooxygenase, benzo(a)pyrene hydroxylase, as well as in the activities of microsomal epoxide hydrase and cytosolic glutathione-S-transferase (GST). However, in chrysotile exposed animals a reverse pattern in these parameters was recorded. The co-exposure to chrysotile and kerosene or chrysotile and soot led to a significant depletion in cytochrome P-450 level and a decrease in the activities of benzo(a)pyrene hydroxylase, epoxide hydrase and GST when compared to kerosene and soot controls, respectively. These results suggest that asbestos by altering the pulmonary drug metabolizing enzyme system may increase the toxic potential of kerosene and its ignition product in the respiratory system.     

In vitro metabolism of ferroquine (SSR97193) in animal and human hepatic models and antimalarial activity of major metabolites on Plasmodium falciparum.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.