Evaluation of fractionated total body irradiation and dose rate on cataractogenesis in bone marrow transplantation

PURPOSE: To assess dose rate effect on cataractogenesis in allogeneic or autologous bone marrow transplanted patients conditioned with fractionated total-body irradiation (FTBI). MATERIALS AND METHODS: Between 1987 and 2001, a total of 105 patients have received TBI conditioning for Bone Marrow Transplantation (BMT) for hematological malignancies at Gulhane Military Medical School. 12 Gy FTBI was applied in 6 fractions over 3 consecutive days with a Co60 teletherapy machine. 46 patients who have survived and were followed up after more than one year were evaluated for cataractogenesis in relation to dose rate. Conditioning therapy included only cyclophosphamide (60 mg/kg/day for two days) + TBI with no steroid and veno-occlusive disease prophylaxis. RESULTS: The median follow-up is 32 months. Posterior subcapsular cataract developed in 5 eyes of three patients out of 46 patients. The 5-year and 10-year estimated cataract incidence in the high-dose rate (> 0.04 Gy/min) group was 29% and 43% respectively while no cataracts occurred in the low-dose rate (< or = 0.04 Gy/min) group. Cataract development in the high-dose rate group versus low-dose rate group was statistically significant (p < 0.039). CONCLUSION: Cataract is a late side effect of TBI. Low-dose rate fractionated TBI is a reliable conditioning program in BMT with effective lens sparing to avoid cataractogenesis.     

The serotonin transporter gene as a QTL for ADHD.

Molecular studies of attention deficit hyperactivity disorder (ADHD) have identified susceptibility genes for the categorically diagnosed disorder using operational diagnostic criteria. Here, we take a QTL approach to mapping genes for ADHD using a composite continuous index of ADHD behavior in a large epidemiological sample. Previous studies of clinical ADHD suggest that two functional polymorphisms in the serotonin transporter gene (SLC6A4), one in the 5'-regulatory region of the gene (5-HTTLPR) and the other a VNTR (5-HTTVNTR) in the second intron, as well as a single nucleotide polymorphism in the 3'-untranslated region (3'-UTR SNP), may be associated with the disorder. Here, we investigate these polymorphisms as well as an additional ten SNPs spread across the gene. We found significant association with the long (L) allele of the 5-HTTLPR; P = 0.019, but neither the 5-HTTVNTR nor the 3'-UTR SNP were significantly associated. Significant associations (P < 0.05) were found for a further 5 the 10 other markers tested. We found evidence for two haplotype blocks spanning the region. We found strong evidence for association with the first haplotype block (comprised of four markers), with the significance of a combined primary and secondary test of association reaching an empirical P value = 0.0054 for the global test and an empirical P value = 0.00081 for the largest local test. Thus, we show here that SLC6A4, which has a major influence on brain serotonin availability, may be a QTL for ADHD.     

Endometrial and subendometrial blood flow measured during early luteal phase by three-dimensional power Doppler ultrasound in excessive ovarian responders

BACKGROUND: Impaired implantation in assisted reproduction cycles with high serum estradiol (E(2)) concentrations may be related to suboptimal endometrial perfusion. Endometrial and subendometrial blood flow were compared between excessive responders (serum E(2) on the day of HCG >20 000 pmol/l) and moderate responders (E(2) < or =20 000 pmol/l). METHODS: Three-dimensional (3D) ultrasound examination with power Doppler was performed 2, 4 and 7 days after HCG in 32 patients who did not have embryo transfer in order to measure endometrial thickness, pulsatility index (PI)/resistance index (RI) of uterine vessels, and endometrial volume, vascularization index (VI)/flow index (FI)/vascularization flow index (VFI) of endometrial and subendometrial regions. RESULTS: Excessive responders tended to have lower endometrial and subendometrial VI/VFI on HCG +2 and more absent endometrial/subendometrial blood flow. They had significantly higher endometrial FI and subendometrial VFI than moderate responders on HCG +7. Only in the excessive responder group, uterine PI/RI declined significantly from HCG +2 to HCG +7 and endometrial VI/VFI increased significantly from HCG +4 to HCG +7. CONCLUSION: Changes in uterine Doppler flow indices, and endometrial and subendometrial 3D power Doppler flow indices during the early luteal phase were significantly different between moderate and excessive responders.     

A randomized study comparing the use of sublingual to vaginal misoprostol for pre-operative cervical priming prior to surgical termination of pregnancy in the first trimester

BACKGROUND: Misoprostol is an effective agent for pre-operative cervical priming before surgical termination of pregnancy in the first trimester. Previous studies have shown that both oral and vaginal routes are equally effective for such a purpose. This study aimed to compare a new route of sublingual administration to the vaginal route of administration for pre-operative cervical priming in first trimester surgical abortion. METHODS: Eighty women with gestational age <12 weeks were randomized by a computer-generated model to receive 400 micro g of misoprostol either sublingually or vaginally 3 h prior to vacuum aspiration. The primary outcome measure was the degree of cervical dilatation, and secondary outcomes included the force required to dilate the cervix from 3 to 8 mm, intra-operative blood loss and incidence of pre-operative side-effects. RESULTS: There was no significant difference in the baseline cervical dilatation (sublingual: 7.6 +/- 1.3 mm; vaginal: 7.7 +/- 0.73 mm), cumulative force required to dilate the cervix from 3 to 8 mm (sublingual: 9.0 +/- 9.8 N; vaginal: 6.6 +/- 5.4 N) and total blood loss (sublingual: 52.1 +/- 20.2 ml; vaginal: 48.3 +/- 12.3 ml). Pre-operative side-effects were also similar. CONCLUSIONS: Both sublingual and vaginal misoprostol are effective in cervical priming before surgical termination of pregnancy in the first trimester. Sublingual misoprostol has the advantage of being more convenient to administer and may be more suitable for day surgery.     

Risk factors and human chorionic gonadotropin trends in patients with ruptured tubal ectopic pregnancies despite methotrexate treatment

This retrospective cohort study investigates the risk factors and beta-human chorionic gonadotropin (β-hCG) trends in patients with ruptured tubal ectopic pregnancies (EPs) despite methotrexate (MTX) treatment. All patients receiving MTX for sonographically confirmed tubal EPs at our fertility center between 2004 and 2014 were included. Baseline demographics and β-hCG trends of patients with EP rupture after MTX were compared to patients with resolved EPs after MTX. One-hundred-thirty-seven patients with EPs were treated with MTX during the study duration; 27 experienced EP rupture and 110 EP resolution. There was no difference in the baseline demographics or β-hCG levels on the day of MTX between the groups. Patients with ruptured EPs after MTX had higher β-hCG levels on day-4 (1223.9?±?243.5 vs. 1111.2?±?179.7 mIU/mL; p?<?.001) and day-7 (1156.9?±?206.2 vs. 872.4?±?690.2 mIU/mL; p?<?.001). The odds of EP rupture compared to EP resolution was 6.2 (95% CI 2.1–19.1), 13.7 (95% CI 4.8–38.9), and 3.0 (95% CI 1.2–7.2) times higher when the change in β-hCG levels was <5% between day-7 vs. day of MTX, day-7 vs. day-4, and day-4 vs. day of MTX, respectively. Our results demonstrate that ruptured tubal EPs despite MTX have <5% change in β-hCG levels between the day of MTX and day-4 or day-7 after MTX.     

Pharmacokinetics of different routes of administration of misoprostol

BACKGROUND: The pharmacokinetic parameters of four different routes of administration of a single dose of 400 microg of misoprostol were studied. METHODS: A total of 40 women undergoing termination of pregnancy by suction evacuation was randomized by computer model to receive 400 microg of misoprostol by one of four routes: (i) sublingual (ii) oral (iii) vaginal and (iv) vaginal with addition of water. Venous blood samples were taken at 0, 1, 2, 5, 10, 20, 30, 45, 60, 120, 240 and 360 min after the administration of misoprostol. Misoprostol acid (MPA) was determined in serum samples using gas chromatography/tandem mass spectrometry. RESULTS: Sublingual misoprostol achieved the highest serum peak concentration (Cmax) (574.8 +/- 250.7 pg/ml) of MPA and this was significantly higher than those in the other groups [Oral: 287.6 +/- 144.3 pg/ml (P < 0.01), vaginal: 125.2 +/- 53.8 pg/ml (P < 0.001) and vaginal with water: 162.8 +/- 57.1 pg/ml (P < 0.001)]. The time to peak concentration (Tmax) was similar in both the sublingual (26.0 +/- 11.5 min) and oral groups (27.5 +/- 14.8 min) and was significantly shorter than those in both vaginal groups. The area under the MPA concentration versus time curve up to 360 min in the sublingual group (743.7 +/- 291.2 pg.h/ml) was significantly greater than those in oral (402.8 +/- 151.6 pg.h/ml, P < 0.05) and vaginal (433.7 +/- 182.6 pg.h/ml, P < 0.05) groups, but no significant difference was found between sublingual and vaginal administration if water (649.3 +/- 333.8 pg.h/ml) was added. CONCLUSION: The new sublingual route of administration of misoprostol demonstrated a great potential to be developed into a method of medical abortion.     

Clinical Significance of Additional Ablation of Atrial Premature Beats after Catheter Ablation for Atrial Fibrillation

Purpose

The clinical significance of post-procedural atrial premature beats immediately after catheter ablation for atrial fibrillation (AF) has not been clearly determined. We hypothesized that the provocation of immediate recurrence of atrial premature beats (IRAPB) and additional ablation improves the clinical outcome of AF ablation.

Materials and Methods

We enrolled 200 patients with AF (76.5% males; 57.4±11.1 years old; 64.3% paroxysmal AF) who underwent catheter ablation. Post-procedure IRAPB was defined as frequent atrial premature beats (≥6/min) under isoproterenol infusion (5 µg/min), monitored for 10 min after internal cardioversion, and we ablated mappable IRAPBs. Post-procedural IRAPB provocations were conducted in 100 patients. We compared the patients who showed IRAPB with those who did not. We also compared the IRAPB provocation group with 100 age-, sex-, and AF-type-matched patients who completed ablation without provocation (No-Test group).

Results

1) Among the post-procedural IRAPB provocation group, 33% showed IRAPB and required additional ablation with a longer procedure time (p=0.001) than those without IRAPB, without increasing the complication rate. 2) During 18.0±6.6 months of follow-up, the patients who showed IRAPB had a worse clinical recurrence rate than those who did not (27.3% vs. 9.0%; p=0.016), in spite of additional IRAPB ablation. 3) However, the clinical recurrence rate was significantly lower in the IRAPB provocation group (15.0%) than in the No-Test group (28.0%; p=0.025) without lengthening of the procedure time or raising complication rate.

Conclusion

The presence of post-procedural IRAPB was associated with a higher recurrence rate after AF ablation. However, IRAPB provocation and additional ablation might facilitate a better clinical outcome. A further prospective randomized study is warranted.     

Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy

Idiopathic generalised epilepsy (IGE) is a common form of epilepsy, including several defined and overlapping syndromes, and likely to be due to the combined actions of mutations in several genes. In a recent study we investigated the calcium channel gene CACNA1A for involvement in IGE, unselected for syndrome, by means of association studies using several polymorphisms within the gene. We reported a highly significant case/control association with a silent single nucleotide polymorphism (SNP) in exon 8 that we confirmed by within-family analyses. In this present study we screened the gene for novel SNPs within 25 kb of exon 8, which have enabled us to define the critical region of CACNA1A in predisposing to IGE. Several intronic SNPs were identified and three, within 1.5 kb of exon 8 and in strong linkage disequilibrium with each other and with the original SNP, were significantly associated with IGE (P=0.00029, P=0.0015 and P=0.010). The associations were not limited to an IGE syndrome or other subgroup. Another SNP, 25 kb away, in intron 6 was also significantly associated with IGE (P=0.0057) but is not in linkage disequilibrium with the SNPs around exon 8. Haplotype predictions revealed even more significant associations (3-marker haplotype: P<10(-6)). Logistic regression showed that all the data can be explained by two of the SNPs, which is consistent with two functionally significant variants being responsible for all five associations, although a single variant cannot be excluded. The functionally significant variant(s) are unlikely to be exonic and suggests an effect on expression or alternative splicing.     

Brain volumes in familial and non-familial schizophrenic probands and their unaffected relatives

Structural brain abnormalities are consistently reported in schizophrenic subjects but the etiology of these abnormalities remains unclear. We tested the contribution of genetic predisposition and obstetric complications to the structural brain abnormalities found in schizophrenic probands and their relatives. MRI scans were carried out on 35 schizophrenic probands from families multiply affected with the disorder, and 63 of their unaffected relatives, including 10 parents who appeared to transmit genetic risk to their children; as well as 31 schizophrenic probands from families with no other affected members, 33 of their unaffected relatives; and finally 68 controls. Volumetric measurements of whole brain, lateral ventricles, third ventricle, cerebellum, and temporal lobes were completed for each subject. The impact of obstetric complications on brain structure was assessed across the gradient of presumed genetic predisposition. Both groups of schizophrenic probands displayed enlargement of the lateral and third ventricles, and there was a gradient of ventricular enlargement amongst the unaffected relatives in proportion to their likelihood of carrying schizophrenic genes. Ventricular enlargement was largely confined to males in both probands and unaffected relatives. Obstetric complications were associated with ventricular enlargement only in the familial probands. Non-familial probands displayed reduced volume of the temporal lobes bilaterally. In families with several schizophrenic members, ventricular enlargement is a marker for genetic liability, particularly in males. Individuals inheriting the susceptibility to schizophrenia appear particularly prone to develop ventricular enlargement in response to obstetric complications.