Microduplication of 15q13.3 and Xq21.31 in a family with tourette syndrome and comorbidities

Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder. Although it is widely accepted that genetic factors play a significant role in TS pathogenesis the etiology of this disorder is largely unknown. Identification of rare copy number variations (CNVs) as susceptibility factors in several neuropsychiatric disorders such as attention deficit‐hyperactivity disorder (ADHD), autism and schizophrenia, suggests involvement of these rare structural changes also in TS etiology. In a male patient with TS, ADHD, and OCD (obsessive compulsive disorder) we identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. The structural variations observed in this family may contribute to the observed symptoms, but further studies are necessary to investigate the possible involvement of the described variations in the TS etiology. © 2013 Wiley Periodicals, Inc.     

Thoracic pain possibly of esophageal origin. Results of a prospective study

We have studied the prevalence of esophageal pathology, by means of esophagogram, esophagogastroscopy, manometry, 24-hours ambulatory pH measurement and acid perfusion of the esophagus, in 44 patients with thoracic pain suggestive of angina. Esophageal pathology was demonstrated in 30 (68.3%) cases; 25 patients were diagnosed of reflux and 5 of primary motor alteration. All the patients received specific treatment; the response to treatment was good in 22 of them (17 with reflux and 5 with motor alterations). In conclusion, esophageal pathology is a common cause of thoracic pain, and reflux is the most frequent finding.     

Gamma-carboxylated isoforms of recombinant human protein S with different biologic properties

Human protein S (HPS), a regulator of hemostasis, is a vitamin K- dependent plasma protein with potential clinical utility. We have obtained high-level expression of the cDNA for HPS in two mammalian cell lines. Both cell lines secreted single chain recombinant HPS (rHPS) in serum-free medium as determined by Western blot analysis. The ability of the rHPS from both cell lines to act as a cofactor for human protein C (HPC) was determined; the rHPS secreted from the human 293 cell line had an activity six times that of the rHPS from the AV12-664 Syrian hamster cell line. Furthermore, the relative specific cofactor activity of rHPS from the 293 cell line was actually 2.5-fold higher than that of single-chain human plasma-derived HPS. Essentially all of the rHPS secreted from the 293 cell line exhibited a calcium-dependent elution profile on anion exchange chromatography, whereas only 25% to 35% of the hamster cell-derived rHPS exhibited this profile. However, the calcium-eluted rHPS from the AV12 cell line had a high specific cofactor activity, equivalent to that of the 293-derived rHPS. A NaCl- elutable rHPS fraction (calcium nondependent) was isolated from the recombinant AV12-664 cell line, further purified, and found to have reduced activity, only 40% that of the calcium-dependent rHPS. The only observable difference in the calcium-dependent and nondependent rHPS molecules was in the content of gamma-carboxyglutamic acid (Gla); the calcium-dependent material contained approximately 10 mol Gla/mol protein whereas the calcium-nondependent material contained only approximately 8 mol Gla/mol of protein. In addition, the calcium- nondependent rHPS had reduced ability to interact with phospholipid vesicles as evidenced by an eightfold increase in the apparent kd. Our data demonstrate the isolation of rHPS with high specific activity, and show that a reduction in as few as two Gla residues dramatically decreases its functional cofactor activity for HPC, due to a reduction in ability to interact with the phospholipid bilayer.     

Epitope mapping and characterization of antigenic determinants of heat-stable enterotoxin (STh) of enterotoxigenic Escherichia coli by using monoclonal antibodies.

A panel of monoclonal antibodies (MAbs) specific for the heat-stable enterotoxin (STh) of enterotoxigenic Escherichia coli was produced. All four MAbs (8G7, 53-4, 11C, and SH1) bound to native STh in an enzyme-linked immunosorbent assay to various degrees, with clone SH1 showing the best affinity. The MAbs were screened for neutralizing and guanylate cyclase-inhibiting activities by the suckling mouse assay and the cyclic GMP assay using T84 cells, respectively. The contact amino acid residues governing the reactivity of the four MAbs were precisely determined by using several chemically synthesized analogs of the various heat-stable enterotoxins (STa's). Three distinct antigenic sites of STh sufficiently removed from each other, one near the N terminus, another in the core functional region of the toxin, and the third in the C-terminal region, were recognized by the different MAbs. MAb SH1, which recognized Asn at position 4 and Tyr at position 5 from the N terminus was 100 times more potent in neutralizing the bioactivity of STh in the suckling mouse assay than was MAb 11C, which recognized Thr at position 16 and Tyr at position 19 from the N terminus of the STh molecule. The MAbs which recognized Leu at position 9 from the N terminus (MAb 53-4) and Tyr at position 19 from the N terminus (MAb 8G7) showed intermediate activities in the neutralization assay. The guanylate cyclase-inhibiting activities of SH1 and 11C essentially paralleled the results for the neutralization of bioactivity, while MAbs 53-4 and 8G7 exhibited reverse activity. These results indicate that MAbs that recognize the N-terminal residues which have been shown not to be essential for toxic activity have a potent protective capacity. None of the MAbs reacted with reduced and carboxy-methylated native STh. This suggests that all of the MAbs mediate their effect by reacting with conformation-dependent antigenic determinants.     

High blood pressure six weeks postpartum after hypertensive pregnancy disorders at term is associated with chronic hypertension

ObjectivesHypertension in pregnancy is associated with cardiovascular disease (CVD) later in life. Blood pressure monitoring in women who experienced hypertension in pregnancy after puerperium has been suggested to be important for early detection and prevention of CVD. The aim of this study is to evaluate if hypertension six weeks postpartum is associated with chronic hypertension in women with a history of term hypertensive pregnancy disorders.Study designWomen with a history of term gestational hypertension or preeclampsia were included in a follow up study of the HYPITAT trial. Blood pressures were measured six weeks and 2.5 years postpartum according to the study protocol.Main outcome measuresHypertension was defined as a diastolic blood pressure ?90 mmHg and/or a systolic blood pressure ?140 mmHg or use of antihypertensive medication. Differences in categorical variables between groups were analyzed by Chi-Square tests. Blood pressure was analyzed using unpaired t-tests and Wilcox ranked tests.ResultsAmong 187 women who had term hypertensive pregnancy disorders, 75 (40%) had hypertension at six weeks postpartum. Of these 46 (61%) had hypertension 2.5 years postpartum. In contrast, of 112 women without hypertension at six weeks postpartum, 36 (32%) had hypertension 2.5 years (OR 3.3, 95% CI 1.8–6.2).ConclusionAmong 61% of women who had hypertensive pregnancy disorders at term, high blood pressure at six weeks postpartum indicated chronic hypertension. This warrants the importance of identification of hypertension 6 weeks postpartum for women’s future health.     

The effect of treatment preference and treatment allocation on patients’ health-related quality of life in the randomized EMMY trial

Objectives

To determine the effect of preference and treatment allocation on health-related quality of life (HRQOL) in patients in the randomized EMMY trial of hysterectomy versus uterine artery embolization (UAE) for symptomatic uterine fibroids.

Study design

We invited 349 patients eligible for trial participation, of which 177 agreed to participate (the ‘randomized group’). Within the randomized group, patients were allocated to.UAE (n = 88) or hysterectomy (n = 89). The remaining 172 patients refused randomization and received the treatment of their preference (varying from hysterectomy to no treatment at all), of which 103 patients agreed to fill in questionnaires (the ‘preference group’). Patients’ treatment preferences and HRQOL were assessed at baseline and the patients were prospectively followed to evaluate HRQOL at 12 months after treatment.

Results

At baseline, most patients in the randomized group preferred UAE: 115/177 (65%). In the preference group most patients preferred hysterectomy: 100/172 (58%). At 12 months there was no effect of having had the preferred treatment on HRQOL, neither in the randomized nor in the preference group. The randomized group improved significantly in both mental and physical health, compared to baseline. In the preference group, only mental health improved compared to baseline, while physical health did not improve significantly.

Conclusions

In a randomized trial comparing UAE and hysterectomy for symptomatic fibroids, the pre-randomization preference for a specific treatment did not affect HRQOL.Trial participants improved better on physical HRQOL than women who refused to participate.     

Economic analysis comparing induction of labour and expectant management for intrauterine growth restriction at term (DIGITAT trial)

Objective

Pregnancies complicated by intrauterine growth restriction (IUGR) are at increased risk for neonatal morbidity and mortality. The Dutch nationwide disproportionate intrauterine growth intervention trial at term (DIGITAT trial) showed that induction of labour and expectant monitoring were comparable with respect to composite adverse neonatal outcome and operative delivery. In this study we compare the costs of both strategies.

Study design

A cost analysis was performed alongside the DIGITAT trial, which was a randomized controlled trial in which 650 women with a singleton pregnancy with suspected IUGR beyond 36 weeks of pregnancy were allocated to induction or expectant management. Resource utilization was documented by specific items in the case report forms. Unit costs for clinical resources were calculated from the financial reports of participating hospitals. For primary care costs Dutch standardized prices were used. All costs are presented in Euros converted to the year 2009.

Results

Antepartum expectant monitoring generated more costs, mainly due to longer antepartum maternal stays in hospital. During delivery and the postpartum stage, induction generated more direct medical costs, due to longer stay in the labour room and longer duration of neonatal high care/medium care admissions. From a health care perspective, both strategies generated comparable costs: on average €7106 per patient for the induction group (N = 321) and €6995 for the expectant management group (N = 329) with a cost difference of €111 (95%CI: €−1296 to 1641).

Conclusion

Induction of labour and expectant monitoring in IUGR at term have comparable outcomes immediately after birth in terms of obstetrical outcomes, maternal quality of life and costs. Costs are lower, however, in the expectant monitoring group before 38 weeks of gestation and costs are lower in the induction of labour group after 38 weeks of gestation. So if induction of labour is considered to pre-empt possible stillbirth in suspected IUGR, it is reasonable to delay until 38 weeks, with watchful monitoring.     

FTY720 treatment of kidney transplant patients: a differential effect on B cells, naïve T cells, memory T cells and NK cells

FTY720 alters lymphocyte recirculation and homing by interfering with S1P receptors on lymphocytes, possibly in combination with chemokine receptors, and induces a decrease in PBL counts. In fresh, whole blood samples of 14 kidney transplant patients, we analyzed by flow cytometry the effect of FTY on the number of NK cells, monocytes, na?ve (CCR7+) T cells, memory (CCR5+) T cells and B cells. Patients treated with 0.5, 2.5 or 5mg FTY/day showed a strong decrease in T and B cell numbers. NK cells and monocytes were not affected. FTY reduced primarily na?ve T cells. From the memory T cells (CCR5+), predominantly CD8 cells, 40-60% remained in the circulation. The majority of the CCR7+ cells disappeared from the circulation within 3-6h, while a further reduction was achieved later. The more slowly decrease in na?ve CCR7+ T cell numbers was also observed in the group treated with 0.25mg FTY/day. Elispot assays revealed no IL-4 producing cells and a low frequency of IFN-gamma producing cells. We suggest that both CCR7 dependent and independent mechanisms are involved in the depletion of T cells from peripheral blood.     

Prognostic value of postoperative high-sensitivity troponin T in patients with different stages of kidney disease undergoing noncardiac surgery

Background

Emerging evidence suggests that postoperative troponin release is a strong and independent predictor of short-term mortality. However, evaluating elevated troponins in patients with chronic kidney disease (CKD) is still controversial and is often disregarded. This study examines morbidity along with short- and long-term mortality risk associated with elevated high-sensitivity troponin T (hsTnT) in patients with different stages CKD undergoing noncardiac surgery.

Accidents and injuries among U.S. Navy crewmembers during extended submarine patrols, 1997 to 1999.

Accidents and injuries, the most common cause of morbidity in military populations, result in a significant number of work days lost each year and account for 75% of all active duty deaths. Rates of accidents and injuries during U.S. Navy submarine deployments have not been evaluated previously. A database designed to monitor the health of submarine crew-members was used to examine the rates and causes of accidents among deployed crewmembers aboard 196 submarine patrols between 1997 and mid 1999. The most common category of injuries was open wounds, followed by sprains and strains, contusions, superficial injuries, burns, and others. Rates of accidents and injuries decreased with increasing age and duration of military service. Among submariners working in supply departments, the rates were more than two times those of crewmembers working in other departments. Based on these data, among a submarine crew of 100 men at sea for 100 days, approximately four to five accidents or injuries might be expected and would result in an average of about 2 days of light or no duty per injury. Rates of accidents and injuries were very low; however, focused safety training could reduce rates among younger and less experienced crewmembers as well as among those working in particular areas of the submarine.