Lipid levels and their genetic regulation in patients with familial hypercholesterolemia and familial defective apolipoprotein B-100: the MEDPED Slovakia Project

We examined, from a cohort of 165 families, 529 individuals for familial hypercholesterolemia (FH). Utilising clinical criteria for diagnosis, we identified 122 patients (n=41 families) as having FH. With PCR testing, 31 individuals (n=12 families) were found to have familial defective Apo B-100 (FDB). From the cohort, 102 normolipidemic (NL) individuals served as a control group. Patients with FH had the highest levels of total cholesterol (TC), LDL-cholesterol (LDL-C) and apolipoprotein B (Apo B), followed by FDB patients and the normolipidemic relatives had the lowest levels (P<0.0001 for all parameters). We did not find any effect of Apo E genotypes on lipid levels in the NL or FH group. Therefore, other genetic and/or environmental factors may be responsible for the diversity in the clinical expression in these populations.     

Optimization of cardiac resynchronization therapy in non-responders

BackgroundCardiac resynchronization therapy plays important role in treatment of heart failure patients with low left ventricular ejection fraction. However, a significant number of patients do not improve after implantation. Optimization of atrioventricular and interventricular delay could improve clinical status of these patients.ObjectivesThe purpose of this study was to compare optimization of atrioventricular (AV) and interventricular (VV) delays with aortic velocity-time integral (VTI) and with maximal value of the first derivative of a left ventricular pressure signal (LVdP/dt_max).MethodsFifteen non-responders were optimized with aortic VTI method and QuickOpt. After 3 months the follow up echocardiography and clinical evaluation were done. Ten non-responders were optimized with LVdP/dt_max and QuickOpt. After 3 month follow up echocardiography and clinical evaluation were done.ResultsIn the first group of patients (age 74.3 years (65.3, 84.3), 83.4% male, etiology 66% ischemic heart disease, NYHA class before optimization III 66.7%, III-IV 33.3%, LVEF 23.0% (15.0; 32.0)), no correlation between AV and VV delays setting obtained from aortic VTI and QuickOpt was found. Optimization generated shorter QRS complex. After 3 months of follow up, there was no change in echo parameters or NYHA class. In the second group of patients (age 76.7 years (66.6, 82.4), 90% male, etiology 60% ischemic heart disease, NYHA class before optimization III 50%, III-IV 50%, LVEF 29.5% (10.0; 35.0)), no correlation between AV and VV delays setting obtained from LVdP/dt_max and QuickOpt was found. Optimization in this group of patients also generated shorter QRS complex. After 3 months, increase in LVEF was observed, but other echo parameters and NYHA class remained unchanged.ConclusionUsing aortic VTI guided optimization in CRT devices did not bring any profit for non-responder patients. Echocardiography parameters and NYHA status did not changed in 3 months follow up. Using invasive LVdP/dt_max leads to a change in left ventricular ejection fraction, but NYHA class remains unchanged.     

A case of an epignathus with intracranial extension appearing as a persistently open mouth at 16 weeks and subsequently diagnosed at 20 weeks of gestation

We report a rare case of oral mass (epignathus) with intracranial extension originally suspected antenatally at 16 weeks' gestation because of a persistent open mouth. Postmortem MRI and pathologic examination of the fetus confirmed an oral teratoma with bilateral ventricular dilatation, corpus callosum agenesis, and a neuroepithelial intracranial cyst. The relevant literature regarding this anomaly is reviewed.     

Study on the metabolism of 5,6-methylenedioxy-2-aminoindane (MDAI) in rats: identification of urinary metabolites

1.?5,6-Methylenedioxy-2-aminoindane (MDAI) is a member of aminoindane drug family with serotoninergic effect, which appeared on illicit drug market as a substitute for banned stimulating and entactogenic drugs.

2.?Metabolism of MDAI, which has been hitherto unexplored, was studied in rats dosed with a subcutaneous dose of 20?mg MDAI.HCl/kg body weight. The urine of rats was collected within 24?h after dosing for analyses by HPLC-ESI-HRMS and GC/MS.

3.?The main metabolic pathways proceeding in parallel were found to be oxidative demethylenation followed by O-methylation and N-acetylation. These pathways gave rise to five metabolites, namely, 5,6-dihydroxy-2-aminoindane, 5-hydroxy-6-methoxy-2-aminoindane, N-acetyl-5,6-methylenedioxy-2-aminoindane, N-acetyl-5,6-dihydroxy-2-aminoindane and N-acetyl-5-hydroxy-6-methoxy-2-aminoindane, which were found predominantly in the form of corresponding glucuronides and sulphates. However, the main portion of administered MDAI was excreted unchanged.

4.?Minor metabolites formed primarily by hydroxylation at various sites include cis- and trans-1-hydroxy-5,6-methylenedioxy-2-aminoindane, 5,6-methylenedioxyindan-2-ol and 4-hydroxy-5,6-methylenedioxy-2-aminoindane.

5.?Identification of all metabolites except for glucuronides, sulphates and tentatively identified 4-hydroxy-5,6-methylenedioxy-2-aminoindane was supported by synthesised reference standards.     

Novel substrate-based inhibitors of human glutamate carboxypeptidase II with enhanced lipophilicity

Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance of nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII.     

Right ventricular perforation with an ICD defibrillation lead managed by surgical revision and epicardial leads--case reports.

The authors present two cases of patients with perforation of the right ventricular wall by the implantable cardioverter defibrillator (ICD) lead. The complication was resolved by cardiosurgical revision and epicardial leads stitched onto the diaphragmatic wall of the heart. The perforation was identified by electrical parameter changes of the leads, echocardiography, and computed tomography. Both patients had satisfactory values of electrical parameters and ICD function with epicardial leads. The importance of regular follow-up and a check of the lead parameters are emphasized.     

Clinical results and development of heterotopic ossification in total cervical disc replacement during a 4-year follow-up

Cervical total disc replacement (CTDR) aims to decrease the incidence of adjacent segment disease through motion preservation in the operated disc space. Ongoing data collection and increasing number of studies describing heterotopic ossification (HO) resulting in decreased mobility of implants, forced us to carefully evaluate our long-term clinical and morphological results of patients with CTDR. We present the first 54 consecutive patients treated with 65 ProdiscC™ prostheses during a 12-month period (2/2004–3/2005). All patients signed an informed consent and were included in prospective long-term study approved by hospital ethical committee. The 1- and 2-year follow-up analysis were available for all patients included and 4-year results for 50 patients (60 implants). Clinical (neck disability index-NDI, visual analog scale-VAS) and radiological follow-up was conducted at 1-, 2- and 4-years after the procedure. The Mehren/Suchomel modification of McAfee scale was used to classify the appearance of HO. Mean preoperative NDI was 34.5%, VAS for neck pain intensity 4.6 and VAS for arm pain intensity 5.0. At 1-, 2- and 4-year follow-up, the mean NDI was 30.7, 27.2, and 30.4, mean VAS for neck pain intensity 2.5, 2.1 and 2.9 and mean VAS for arm pain intensity pain 2.2, 1.9 and 2.3, respectively. Significant HO (grade III) was present in 45% of implants and segmental ankylosis (grade IV) in another 18% 4 years after intervention. This finding had no clinical consequences and 92% of patients would undergo the same surgery again. Our clinical results (NDI, VAS) are comparable with fusion techniques. Although, advanced non-fusion technology is used, a significant frequency of HO formation and spontaneous fusion in cervical disc replacement surgery must be anticipated during long-term follow-up.     

Diagnostic accuracy of postnatal ultrasound screening for urinary tract abnormalities

The study was aimed at (1) the determination of the incidence of abnormalities of the urinary tract in newborn infants detected by postnatal ultrasound screening, and (2) the evaluation of the diagnostic accuracy of postnatal ultrasound screening for detecting surgical urinary tract abnormalities. The prospective study was of full-term neonates born in the University Hospital of Olomouc in 2005–2008 who underwent renal ultrasound screening after 72 h of life. Significant findings were recorded. Subsequent diagnostic and therapeutic procedures were recorded and evaluated in a group of children with detected renal pelvic dilatation (RPD). (1) A total of 6,088 newborn infants was examined. The absolute and relative RPD incidence rates (anteroposterior diameter, APD) were as follows: 5–7 mm, 146 (2.4%); 7–10 mm, 70 (1.15%); 10–15 mm, 13 (0.21%), and 15 mm or more, 5 (0.08%). Of those, 16 children were operated on for abnormalities of the urinary tract, of which nine (56%) had been detected by prenatal screening. Other findings: six cases of unilateral renal agenesis, four cases of multicystic renal dysplasia, four of renal dystopia, one of polycystic kidney disease and one of renal hypoplasia. (2) A group of 224 children with postnatally detected RPD was examined, of whom 40 (17.9%) underwent voiding cystourethrography and/or scintigraphy and 16 (7.1%) were treated surgically. The receiver operating characteristic curves were analyzed, and the areas under the curves were calculated. Postnatal renal ultrasound screening is probably a suitable test for detecting significant urinary tract abnormalities.     

Salivary gland extract from <Emphasis Type="Italic">Ixodes ricinus</Emphasis> tick modulates the host immune response towards the Th2 cytokine profile

In our previous work, the salivary gland extract (SGE) from Ixodes ricinus ticks impaired T-lymphocyte proliferation and clearly modulated the immune response towards the Th2 pattern in human peripheral blood mononuclear cell culture. In the present work, the results obtained on mouse splenocytes are compared with those on human leukocytes. ELISA (protein level) and RNAse protection assay (mRNA level) showed that SGE enhanced interleukin (IL)-1alpha, IL-1beta, IL-1Ra, IL-6, and IL-12p40 cytokines, whereas production of IL-2, IL-5, IL-10, and IL-13 was decreased. The minute levels of IL-9, IL-15 and IL-12p70 were not changed after the addition of tick saliva. IL-4 was upregulated, whereas the production of gamma interferon and migratory inhibition factor was downregulated after the addition of SGE. Tick saliva decreased concanavalin A-stimulated spleen cell proliferation and the percentage of activated T-cells. We conclude that the Th2 polarization did not involve all of the cytokines tested. However, the Th2 subset-augmenting effect of tick saliva was confirmed.     

Laparoscopic Colorectal Surgery in Obese Patients

Background: The aim of the study was to the evaluate results of laparoscopic colorectal surgery in obese patients. Methods: All patients who underwent elective laparoscopic colorectal surgery from January 1993 to December 2003 were included in the study. BMI >30 was used as an objective obesity criterion. The evaluated parameters included BMI, age, sex, diagnosis and associated diseases, American Society of Anesthesiologists classification score (ASA), type and duration of procedure, peroperative and postoperative complications, postoperative course, reoperation, length of hospitalization, morbidity and early mortality. Results: 435 patients were evaluated. There were 80 patients (18%) in the obese group, and 355 patients (82%) were non-obese. The samples were comparable in terms of age, gender, ASA, diagnosis and procedure. Peroperative complications occurred more frequently in the obese group of patients (4% vs 2.5%, P>0.05) and the operating time was longer as well (151 min vs 141 min, P>0.05), both statistically not significant. There was no difference in postoperative course in both groups with regard to intravenous administration of analgesics (2 days), start of solid diet (day 3) and first bowel movement (day 4). Morbidity was higher in the obese group of patients (33% vs 24%, P>0.05), and reoperations were also more frequent here (13% vs 7%, P>0.05), which was reflected in prolonged hospital stay (14 days vs 12 days, P>0.05). On the other hand, early mortality was surprisingly lower in the obese group of patients (2.5% vs 6%, P>0.05). However, none of these differences achieved statistical significance on the set significance level of P=0.05. Conclusion: With sufficient experience, laparoscopic colorectal surgery in obese patients is feasible and safe. It is associated with no increased risk of complications and preserves all benefits of the mini-invasive approach.