Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms

Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.     

Cerebrospinal fluid insulin-like growth factors IGF-1 and IGF-2 in infantile autism

There has been little exploration of major biologic regulators of cerebral development in autism. We measured insulin-like growth factors (IGF) -1 and -2 from cerebrospinal fluid (CSF) by radio immunoassay in 25 children with autism (median age 5y 5mo; range 1y 11mo-15y 10mo; 20 males, 5 females), and in 16 age-matched comparison children without disability (median age 7y 4mo; range 1y 1mo-15y 2mo; eight males, eight females). IGF-1 and -2 concentrations were further correlated with age of patients and head size. CSF IGF-1 concentration was significantly lower in patients with autism than in the comparison group. The CSF concentrations of children with autism under 5 years of age were significantly lower than their age-matched comparisons. The head circumferences correlated with CSF IGF-1 in children with autism but no such correlation was found in the comparison group. There was no difference between the two groups in CSF IGF-2 concentrations. No patients with autism had macrocephaly. We conclude that low concentrations of CSF IGF-1 at an early age might be linked with the pathogenesis in autism because IGF-1 is important for the survival of Purkinje cells of the cerebellum. The head growth might be explained by the actions of IGF-1 and -2 reflected in CSF concentrations.     

CSF nerve growth factor (β-NGF) is increased but CSF insulin-like growth factor-(IGF-1) is normal in children with tuberous sclerosis and infantile spasms

Tuberous sclerosis is associated with epilepsy that is often refractory. We examined cerebrospinal fluid (CSF) concentrations for neurotrophins, nerve growth factor (β-NGF) and insulin-like growth factor (IGF-1) in children with infantile spasms between 1997 and 2010. We classified the patients as follows: tuberous sclerosis (n = 5), cryptogenic spasms (n = 6), postinfectious spasms (n = 5) and other symptomatic spasms (n = 22). We had 22 age- and sex-matched controls for CSF-NGF and 14 for CSF-IGF-1. The median of CSF-NGF was higher in those with tuberous sclerosis, 56 (minimum–maximum, 8.0–131) ng/L, in relative to age- and sex-matched controls, 6.7 (0.0–22) ng/L, and symptomatic infantile spasms, 0.0 (0.0–4.5) ng/L or cryptogenic cases of infantile spasms, 6.2 (3.9–8.8) ng/L, respectively. CSF-NGF were highest in children with postinfectious aetiology, 408 (89–778) ng/L. CSF-IGF-1 of tuberous sclerosis, 0.65 (0.35–0.98) μg/L, did not differ from the cryptogenic spasms, 0.68 (0.32–0.87) μg/L, or from age- and sex-matched controls 0.52 (0.22–0.77) μg/L. Patients with tuberous sclerosis and cryptogenic spasms had normal development prior the ACTH therapy. We suggest that increased CSF-NGF might indicate a persistent activation of inflammatory pathways in cortical tubers in tuberous sclerosis and this would reflect in CSF concentrations.     

One-year mortality,quality of life and predicted life-time cost-utility in critically ill patients with acute respiratory failure

Introduction  

High daily intensive care unit (ICU) costs are associated with the use of mechanical ventilation (MV) to treat acute respiratory failure (ARF), and assessment of quality of life (QOL) after critical illness and cost-effectiveness analyses are warranted.     

Gabapentin for the prevention of postoperative pain after vaginal hysterectomy

Gabapentin alleviates and/or prevents acute nociceptive and inflammatory pain both in animals and volunteers, especially when given before trauma. Gabapentin might also reduce postoperative pain. To test the hypothesis that gabapentin reduces the postoperative need for additional pain treatment (postoperative opioid sparing effect of gabapentin in humans), we gave 1200 mg of gabapentin or 15 mg of oxazepam (active placebo) 2.5 h prior to induction of anaesthesia to patients undergoing elective vaginal hysterectomy in an active placebo-controlled, double blind, randomised study. Gabapentin reduced the need for additional postoperative pain treatment (PCA boluses of 50 microg of fentanyl) by 40% during the first 20 postoperative hours. During the first 2 postoperative hours pain scores at rest and worst pain score (VAS 0-100 mm) were significantly higher in the active placebo group compared to the gabapentin-treated patients. Additionally, pretreatment with gabapentin reduced the degree of postoperative nausea and incidence of vomiting/retching possibly either due to the diminished need for postoperative pain treatment with opioids or because of an anti-emetic effect of gabapentin itself. No preoperative differences between the two groups were encountered with respect to the side effects of the premedication. However, 15 mg oxazepam was more effective in relieving preoperative anxiety than 1200 mg gabapentin.     

Complications associated with central venous access device in children with haemophilia: a nationwide multicentre study in Finland

Children with haemophilia require venous access for regular infusion of coagulation factors. A central venous access device (CVAD) ensures long‐term access but associates with infectious and non‐infectious complications with proposed risk factors of young age at initial CVAD implantation and presence of an inhibitor. Our aim was to evaluate the incidence and risk factors for complications associated with CVAD usage in a retrospective nationwide multicentre study in five Finnish Paediatric Haemophilia Treatment Centers. Our study investigated 106 CVADs in 58 patients with 137 971 CVAD days. The median access survival was 1159 CVAD days, and most often a malfunction led to CVAD removal after a long survival (median of 1640 CVAD days). We detected a very low bloodstream infection rate (0.12/1000 CVAD days). The presence of neutralizing inhibitor was a significant risk factor for infection. Heparin vs. saline flushing did not influence the CVAD outcome. We detected a lower infection rate than previously reported, although 90% of the patients were very young (<2 years) at first insertion (median age = 1.02 year). Port access was frequent after initial implantation: six patients (10%) used the port daily for immune tolerance induction therapy and 74% at least twice weekly for prophylaxis. Young age did not increase the risk of infections, as 59% of the CVAD‐related infections were recorded in children over 6 years of age. Our national experience confirms the safety of prophylactic factor concentrate administration via ports even in very young children.