Reversible multiorgan system involvement in a neonate with complex IV deficiency

Mitochondrial respiratory chain deficiencies can present as fulminant liver failure or disease, and the prognosis when associated with severe neonatal lactic acidosis is frequently guarded. We report the case of a neonate who presented with acute liver failure and fulminant lactic acidosis with profound complex IV deficiency documented in muscle and liver biopsies. The neonate subsequently experienced clinical resolution by 3 months of age, and was observed to have reversibility of the biochemical deficiency noted in muscle. This case illustrates that resolution of this severe neonatal phenotype does occur, of importance for accurate prognostic and genetic counseling for such affected neonates.     

Trimethylaminuria is caused by mutations of the FMO3 gene in a North American cohort.

Trimethylaminuria (TMAuria) (McKusick 602079) first described in 1970 is an autosomal recessive condition caused by a partial or total incapacity to catalyze the N-oxygenation of the odorous compound trimethylamine (TMA). The result is a severe body odor and associated psychosocial conditions. This inborn error of metabolism, previously thought to be rare, is now being increasingly detected in severe and milder presentations. Mutations of a phase 1 detoxicating gene, flavin-containing monooxygenase 3 (FMO3), have been shown to cause TMAuria. Herein we describe a cohort of individuals ascertained in North America with severe TMAuria, defined by a reduction of TMA oxidation below 50% of normal with genotype-phenotype correlations. We detected four new FMO3 mutations; two were missense (A52T and R387L), one was nonsense (E314X). The fourth allele is apparently composed of two relatively common polymorphisms (K158-G308) found in the general population. On the basis of this study we conclude that one common mutation and an increasing number of private mutations in individuals of different ethnic origins cause TMAuria in this cohort.     

Effects of an anti-TNF-alpha monoclonal antibody, administered throughout pregnancy and lactation, on the development of the macaque immune system

PROBLEM: The use of anti-TNF-alpha therapies during pregnancy and lactation on the development of the neonatal immune system has not been fully established. The purpose of this study was to evaluate whether treatment of macaques with an anti-TNF-alpha monoclonal antibody (golimumab) during pregnancy and lactation would result in defects in the developing immune system. METHOD OF STUDY: Pregnant macaques were treated with golimumab during pregnancy and lactation. Immune system development was evaluated by histopathology, lymphocyte subset analysis and functional challenging of the infant immune system (humoral immune response to KLH and TTX, and DTH skin reaction). RESULTS: In utero and postnatal exposure to golimumab had no effect on T and B cell populations in blood and lymphoid tissues and did not impair the ability of the infants to mount an immune response to antigen challenge. CONCLUSION: Treatment of pregnant macaques with golimumab throughout pregnancy and lactation did not affect the development and maturation of the immune system in the offspring.     

Self‐harm in young people: Prevalence,associated factors,and help‐seeking in school‐going adolescents

Adolescent self‐harm is recognized as a serious public health problem; however, there is little reliable comparative data on its prevalence or characteristics, or on the extent of help‐seeking for self‐harm. The aims of the present study were to determine the prevalence and associated factors of adolescent self‐harm in an urban region in Ireland, and to investigate help‐seeking behaviours for self‐harm. This was a cross‐sectional study of 856 school‐going adolescents, employing an anonymous self‐report questionnaire. A lifetime history of self‐harm was reported by 12.1% of adolescents. Factors independently associated with self‐harm included exposure to self‐harm of a friend/family member. Professional help‐seeking was uncommon prior to (9%) and after (12%) self‐harm. Furthermore, only 6.9% of adolescents presented to hospital as a result of their last self‐harm act. These findings indicate that self‐harm is common in adolescents; however, seeking professional help is not a common phenomenon, and those who present to hospital represent the ‘tip of the iceberg’ of adolescent self‐harm. Identifying the prevalence of self‐harm and associated factors, in addition to help‐seeking behaviours, in young people is important to determine the preventative programmes to target ‘at‐risk’ groups. Mental health nurses have an important and increasing role to play in such school‐based initiatives.     

Improvement in Chronic Low Back Pain in an Obese Patient With Topiramate Use

The objective of this study was to demonstrate efficacy, benefit, and potential use of topiramate in treating obese patients with chronic low back pain. This is a case report from an outpatient academic pain multidisciplinary clinical center. The patient was a 30-year-old morbidly obese (body mass index [BMI]: 61.4 kg/m²) female suffering from chronic low back pain. With a known association between obesity and chronic low back pain, and a possible role of topiramate in treating both simultaneously, the patient was started on a therapeutic trial of topiramate. Over a period of a 12-week topiramate therapy, the patient experienced clinically meaningful and significant weight loss as well as improvement in her chronic low back pain and functionality. With more substantial evidence, pain physicians may start considering using topiramate in the multimodal management of obesity-related chronic low back pain based on their thoughtful consideration of the drug's efficacy and side effects and the patient's comorbidities and preferences.     

Echicetin: a snake venom protein that inhibits binding of von Willebrand factor and alboaggregins to platelet glycoprotein Ib

Echicetin, a new protein isolated from Echis carinatus venom by reverse phase and ion exchange chromatography specifically inhibited agglutination of fixed platelets induced by several platelet glycoprotein Ib (GPIb) agonists, such as bovine von Willebrand factor (vWF), alboaggregins, and human vWF in the presence of botrocetin. Unlike alboaggregins, echicetin bound to GPIb but did not induce agglutination of washed or fixed platelets. In contrast to disintegrins, it did not block adenosine 5'-diphosphate (ADP)-induced platelet aggregation in the presence of fibrinogen. The apparent molecular weight of echicetin measured on sodium dodecyl sulfate (SDS) gel electrophoresis was 26 Kd under nonreducing conditions. On reduction, echicetin showed 16 and 14-Kd subunits suggesting that the molecule is a dimer. Reduced echicetin retained its binding activity and its inhibitory effect on the agglutination of fixed platelets induced by bovine vWF. 125I-echicetin bound to fixed platelets with high affinity (kd = 30 +/- 1.8 nmol/L) at 45,000 +/- 2,400 binding sites per platelet. The binding was selectively inhibited by a monoclonal antibody to the 45-Kd N-terminal domain of platelet GPIb, but not by monoclonal antibodies to other regions on GPIb. Binding of 125I-bovine vWF to fixed platelets was strongly inhibited by echicetin. In contrast, bovine vWF showed a much weaker inhibitory activity on binding of 125I-echicetin to platelets. The half life of echicetin in blood was approximately 170 minutes with no detectable degradation. Echicetin significantly prolonged the bleeding time of mice, suggesting that it may inhibit vWF binding to GPIb in vivo as well as in vitro.     

Effect of surfaces on fluid-phase prekallikrein activation

The activation of prekallikrein by factor XII fragments (XIIf), during incubation in plastic tubes was previously noted to be increased by high molecular weight (HMW) kininogen as well as other plasma proteins. In this report, we investigated the mechanism responsible for this increase. Although we confirmed that HMW kininogen, bovine serum albumin, fibrinogen, cold insoluble globulin, and mixed phospholipids apparently increased prekallikrein activation, we found that the product of prekallikrein activation (kallikrein) lost substantial activity in less than 0.5 min after exposure to a variety of fresh surfaces. This loss was partially prevented by the presence of various proteins and phospholipids. Similar protection against inactivation of XIIf, the enzyme in this reaction, was also found. In contrast, no loss of the substrate, prekallikrein, was observed during incubation. The loss of kallikrein activity was found to be proportional to the surface area of the incubation vessel as well as the concentration of kallikrein. Further loss of kallikrein activity could also be prevented by pretreating the vessel with kallikrein. We therefore conclude that various substances apparently affect prekallikrein activation in a purified system by preventing the enzyme and product in the reaction mixture from losing activity due to adsorption to a surface.     

A prospective study of mortality among drug misusers during a 4-year period after seeking treatment

Aims The opportunity to study deaths as they occur within the framework of a prospective cohort study is relatively uncommon. This study investigates deaths among drug misusers over a 4‐year period, with specific attention to the circumstances and causes of death, and risk factors for mortality. The study also critically examines the recording of drug‐related deaths. Design, Setting, Participants Prospective cohort study of 1075 drug misusers recruited to 54 treatment programmes during 1995. Measurements Data derived from interviews conducted with clients at intake, death certificates and post‐mortem examinations. Findings The annual mortality rate was 1.2%, about six times higher than that for a general, age‐matched population. Fourteen per cent of the deaths were due to self‐inflicted injuries, accidents or violence and 18% were due to medical causes. The majority of deaths (68%) were associated with drug overdoses. Opiates were the drugs most commonly detected during post‐mortem examinations. In the majority of cases, more than one drug was detected. Polydrug use and, specifically, heavy drinking, and use of benzodiazepines and amphetamines, were identified as risk factors for mortality. Anxiety and homelessness were also predictive of increased mortality. Conclusions We suggest that drug misusers and those working with drug misusers need to be more alert to the risks of polydrug use, including the combined use of alcohol with illicit drugs. The study revealed inconsistencies in the recording of drug‐related deaths on death certificates. The routine recording of all substances detected during toxicological examination would improve the accuracy of death certification.