Use of an active fixation lead and a subpectoral pacemaker pocket may not avoid Twiddler's syndrome.

Manipulation of a pacemaker with consequent malfunction of the device has been called Twiddler's syndrome. Use of active-fixation leads and subpectoral pacemaker pockets has been considered to help in avoiding this problem. We describe a child in whom twiddling was not prevented despite implantation of a lumenless atrial lead and insertion of the pacemaker generator in a subpectoral pocket.

Cardiac malformation of partial trisomy 7p/monosomy 18p and partial trisomy 18p/monosomy 7p in siblings as a result of reciprocal unbalanced malsegregation--and review of the literature.

We report two unbalanced translocations involving the short arms of chromosomes 7 and 18 due to a balanced translocation 7;18 in the mother. Karyotyping and fluorescence in situ hybridization analysis of the female fetus revealed an unbalanced subtelomeric translocation(karyotype 46,XX,der(18)t(7;18)(p22.3;p11.32)mat resulting in a partial trisomy 7p and a partial monosomy 18p.Array comparative genomic hybridization (CGH) detected a4.44-Mb heterozygous duplication at 7p22.3 to 7p22.1 and a0.178-Mb heterozygous deletion at 18p11.32. Clinical characteristics comprised a mildly stenotic bicuspid aortic valve and a small aortic arch without coarctation. The patient's older brother displayed a reciprocal version of her chromosomal aberration (46,XY,der(7)t(7;18)(p22;p11.32) resulting in a partial monosomy 7p and a partial trisomy 18p. Array CGH revealed a 4.75-Mb heterozygous deletion at 7p22.3p22.1 and a 0.579-Mb duplication at 18p11.32. He presented with tetralogy of Fallot, cleft palate, microcephalus without craniosynostosis, growth retardation, ptosis of the right eyelid, right-sided renal agenesis, unilateral cryptorchism,and mental retardation. In this report, we present the clinical phenotype in patients with aberrations of chromosomes 7p and 18p and reviewed the literature to summarize cardiovascular malformations in these patients.

Schimke immunoosseous dysplasia: defining skeletal features.

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.

Serum and glucocorticoid-inducible kinase in pulmonary tissue of preterm fetuses exposed to chorioamnionitis.

OBJECTIVES: The interaction between inflammation and transepithelial Na(+) transport is poorly understood. Chorioamnionitis has been shown to be associated with preterm labor and postnatal pulmonary morbidity of preterm infants. The human isoform of serum and glucocorticoid-inducible kinase (SGK1) is upregulated by proinflammatory cytokines and stimulates epithelial Na(+) channel ENaC and the Na(+)/K(+)-ATPase activity, an effect presumably participating in the regulation of transepithelial Na(+) transport. STUDY DESIGN: Lung tissue sections from 31 stillborn fetuses (range 21-41 weeks of gestational age) with or without chorioamnionitis were analyzed. Macrophages, neutrophils and lymphocytes were stained immunohistochemically. In addition, in situ hybridization for the detection of SGK1 mRNA was performed in fetal lung tissue. Positively labeled cells were compared by semiquantitative assessment. RESULTS: A marked influx of macrophages into the pulmonary tissue of fetuses exposed to intrauterine inflammation when compared to fetuses without exposure to chorioamnionitis was observed (p < 0.05). There was also a tendency towards an increased density of neutrophils in fetuses exposed to chorioamnionitis. However, only small numbers of lymphocytes were detected in both groups. In fetuses exposed to chorioamnionitis, 6 of 8 fetuses did not express SGK1; however, in the group of fetuses without exposure to intrauterine inflammation 15 of 23 cases exhibited a profound SGK1 detection rate in lung tissue and airway epithelium, independent of the gestational age of the fetuses (p < 0.05). CONCLUSIONS: Human serine threonine kinase SGK1 mRNA is observed in fetal lung tissue. On the basis of this study, we speculate that exposure to chorioamnionitis is associated with a downregulation of SGK1 in fetal lung tissue. The possible consequences of a decreased rate of SGK1 mRNA could be an impaired ability to clear the lungs from excessive fluid immediately after preterm birth.

Trithiocarbonates: exploration of a new head group for HDAC inhibitors.

Inhibition of histone deacetylases class I/II enzymes is a new, promising approach for cancer therapy. In the present study, we disclose a new structural class of HDAC inhibitors with the trithiocarbonate motif. A clear structure-activity-relationship was obtained for the cap-linker motif and the putative Zn(2+) complexing head group. Selected analogs display potent inhibition of HDAC enzymatic activity and a cellular potency comparable to that of suberoylanilide hydroxamic acid (SAHA), recently approved for treatment of patients with advanced cutaneous T-cell lymphoma.

Prospective volumetric analysis of gallbladders in critically ill newborns: the impact of nutrition.

BACKGROUND: Neonatal reference values of gallbladder size have been assessed in healthy newborns with enteral feeding regimen. Their applicability to critically ill patients under total parenteral nutrition (TPN) remains to be questioned. OBJECTIVE: Our aim was to evaluate the impact of short-term TPN versus enteral nutrition (EN), gender and birth weight on neonatal gallbladder volume. METHOD: A prospective pilot study was initiated with a single sonographic investigator blinded towards feeding regimen. In total, 61 neonates (33 males, 28 females) were consecutively enrolled on the intensive care unit; 31 newborns were examined both under TPN and bolus EN (breast milk/formula). Patients with malformations of the biliary tract were excluded. Prior to ultrasound examinations, a minimum fasting period of 2 h was maintained. Sonographic measurements of gallbladder length, depth and width were performed to calculate gallbladder volume using the ellipsoid formula. RESULTS: Neonatal gallbladder volume differed significantly between TPN and EN (p < 0.001). Using TPN, range of gallbladder length, width and volume exceeded reference values. Birth weight was weakly correlated with gallbladder volume (correlation index 0.3776, p = 0.01). We found no gender-related differences. CONCLUSIONS: Neonatal gallbladder volume under TPN was significantly larger compared to EN. Using TPN, gallbladder dimensions exceeded reference values without causing clinical complications. The benign course of gallbladder enlargement required no specific medication or surgical treatment.

Schimke immunoosseous dysplasia: suggestions of genetic diversity.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

Prospective sonographic evaluation of fentanyl side effects on the neonatal gallbladder.

OBJECTIVE: In an effort to minimise the stress and pain of mechanically ventilated neonates, the application of opioids has increased markedly. Abdominal adverse effects of opioid analgesics are constipation and increased pressure in the biliary system. Our aim was to evaluate the impact of continuous intravenous infusion of fentanyl on the volume of the neonatal gallbladder and to assess potential gastrointestinal side effects. METHODS: We prospectively matched pairs of 40 mechanically ventilated neonates (28-42 gestational weeks) under total parenteral nutrition and midazolam sedation. One group (20 patients) received continuous fentanyl infusions (dose 0.5-2 microg kg(-1) h(-1)) the other group (20 patients) served as controls. Sonographic measurements of gallbladder length, depth and width were performed to calculate gallbladder volume using the ellipsoid method. Repeated ultrasound images, date of meconium release and serum bilirubin levels were documented. RESULTS: Fentanyl application was not associated with gallbladder sludge/stones, gallbladder hydrops, hyperbilirubinemia or prolonged meconium release. Neonatal gallbladder length, width and volume did not differ significantly (data expressed as mean, standard deviation, median, interquartile range: length (cm) 3.16+/-0.68, 3.3, 0.675 vs 3.06+/-0.62, 3.3, 1.1; P=0.645; width (cm) 1.02+/-0.23, 1.0, 0.28 vs 0.89+/-0.27, 0.9, 0.38, P=0.12; volume (cm(3)) 1.52+/-0.67, 1.7, 0.86 vs 1.22+/-0.77, 1.09, 1.19, P=0.20). CONCLUSION: In our study fentanyl caused no major complications in the biliary system and intestine of ventilated preterm and term neonates. Sonographic investigations of the gallbladder under fentanyl treatment may be dispensable. Further investigations are required to assess adverse gastrointestinal effects.

Impaired working speed and executive functions as frontal lobe dysfunctions in young first-degree relatives of schizophrenic patients.

The aim of the investigation was to detect neuropsychological markers, such as sustained and selective attention and executive functions, which contribute to the vulnerability to schizophrenia especially in young persons. Performance was assessed in 32 siblings and children of schizophrenic patients and 32 matched controls using Wisconsin Card Sorting Test, Colour-Word-Interference-Test, Trail Making Test, and d2-Concentration-Test. The first-degree relatives showed certain impairments on all four tests, in particular, slower times on all time-limited tests. These results suggest the need for more time when completing neuropsychological tasks involving selected and focused attention, as well as cognitive flexibility, as a possible indicator of genetic vulnerability to schizophrenia.

Association of migraine-like headaches with Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia, nephropathy, and T-cell deficiency. SIOD is caused by mutations in the putative chromatin remodeling protein SMARCAL1. We report an 8-year-old boy with SIOD and recurrent, severe, refractory migraine-like headaches. Through a retrospective questionnaire-based study, we found that refractory and severely disabling migraine-like headaches occur in nearly half of SIOD patients. We have also found that the vasodilator minoxidil provided symptomatic relief for one patient. We hypothesize that these headaches may arise from an intrinsic vascular, neuroimmune, or neurovascular defect resulting from loss of SMARCAL1 function.

In vitro and in vivo anti-inflammatory activity of the new glucocorticoid ciclesonide.

The glucocorticoid ciclesonide is the 2'R-epimer of 2'-cyclohexyl-11beta-hydroxy-21-isobutyryloxy-16bH-dioxolo[5',4':16,17]pregna-1,4-diene-3,20-dione. The active metabolite desisobutyryl-ciclesonide (des-CIC) is derived from ciclesonide by esterase cleavage of isobutyrate at the C21 position. The relative binding affinities at the rat glucocorticoid receptor were dexamethasone, 100; ciclesonide, 12; des-CIC, 1212; and budesonide, 905. Des-CIC potently inhibited the activation of murine and human lymphocytes in a series of different in vitro systems. With the exception of concanavalin A-stimulated rat spleen cells, des-CIC was more potent than the parent compound. Des-CIC compared well with budesonide in all in vitro systems. Furthermore, the respective 2'S-epimers were always significantly less potent than the 2'R-epimers. In vivo, ciclesonide (intratracheal administration), des-CIC, and budesonide inhibited antigen-induced accumulation of eosinophils, protein, and tumor necrosis factor-alpha into the bronchoalveolar lavage fluid of ovalbumin-sensitized and -challenged Brown Norway rats with an ED(50) value ranging from 0.4 to 1.3 mg/kg, indicating similar potency, which suggests in vivo activation of the parent compound. Ciclesonide and budesonide inhibited the bradykinin-induced protein leakage into the rat trachea. In the rat cotton pellet model, ciclesonide inhibited granuloma formation (ED(50):= of 2 microg/pellet), whereas budesonide and des-CIC were 15- and 20-fold less active; thymus involution was induced with an ED(50) of 303, 279, and 154 microg/pellet, respectively. When applied orally to rats for 28 days, ciclesonide showed low potency in reducing weight of thymus and adrenals, suggesting low oral bioavailability. The in vivo data on ciclesonide highlight its effective local action and a reduced potential for side effects.

Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.