Successful TAT-mediated enzyme replacement therapy in a mouse model of mitochondrial E3 deficiency

Medicine today offers no cure for patients suffering from mitochondrial disorders, such as lipoamide dehydrogenase (LAD; also known as E3) deficiency, and treatment is limited to symptomatic care. LAD is one of the components of the α-ketoacid dehydrogenase complexes, which are mitochondrial multienzyme complexes crucial for the metabolism of carbohydrates and amino acids. Recently, we tested the therapeutic approach for treating mitochondrial disorders whereby the activity of multicomponent complexes in the mitochondria is restored by TAT-mediated enzyme replacement therapy (ERT). The LAD deficiency disease was used before as a proof-of-principle in vitro, in patients' cells, utilizing the TAT-LAD fusion protein. In this report, we present successful TAT-mediated ERT in an in vivo mouse model using E3-deficient mice. We demonstrate the delivery of TAT-LAD into E3-deficient mice tissues and that a single administration of TAT-LAD results in a significant increase in the enzymatic activity of the mitochondrial multienzyme complex pyruvate dehydrogenase complex within the liver, heart and, most importantly, the brain of TAT-LAD-treated E3-deficient mice. We believe that this TAT-mediated ERT approach could change the management of mitochondrial disorders and of other metabolic diseases in modern medicine.     

Infantile encephalopathy due to vitamin deficiency in industrial countries

Introduction

Severe avitaminosis causing life-threatening conditions in the infantile age group is extremely uncommon and has been reported in babies with malabsorption receiving prolonged inadequate vitamin supplements.

Case reports

We report two infants who presented with neurological deterioration. Immediate work-up and treatment for infectious and inborn metabolic disorders were initiated and the diagnosis, made with a few days delay, was prolonged avitaminosis of thiamine (B1) and cobalamin (B12). B1 deficiency was suspected when further neurological deterioration was observed during administration of intravenous fluids containing glucose in an infant with high lactate levels in the cerebrospinal fluid. High transketolase activity that normalized after thiamine treatment and the findings in the MRI and MRS of the brain confirmed the suspected diagnosis. B12 deficiency was suspected in an infant of a strict vegetarian mother who presented with neurological deterioration and severe megaloblastic anemia. The diagnosis was confirmed when low serum levels of B12 and methylmalonic aciduria were detected and treatment with B12 resulted in normalization of urinary methymalonic acid.

Conclusion

Avitaminosis, even in industrialized countries, should be considered in an atypical age group with no known risk factors. Early diagnosis and prompt treatment may accomplish a quick recovery with fewer sequelae.

     

Neurodevelopmental outcome of children with intrauterine growth retardation: a longitudinal, 10-year prospective study

One hundred twenty-three children with intrauterine growth retardation were prospectively followed from birth to 9 to 10 years of age in order to characterize their specific neurodevelopmental and cognitive difficulties and to identify clinical predictors of such difficulties. Perinatal biometric data and risk factors were collected. Outcome was evaluated at age 9 to 10 by neurodevelopmental, cognitive, and school achievement assessments. Sixty-three children served as controls who were appropriate for gestational age. Significant differences in growth (P < .001), neurodevelopmental scores (P < .001), intelligence quotient (IQ) (P < .0001), and school achievements measured by the Kaufmann Assessment Battery for Children (P < .001) were found between the children with intrauterine growth retardation and controls. Children with intrauterine growth retardation demonstrated a specific profile of neurocognitive difficulties at school age, accounting for lower school achievements. The best perinatal parameter predictive of neurodevelopment and IQ was the Cephalization Index (P < .001). Somatic catch-up growth at age 2 and at age 9 to 10 correlated with favorable outcome at 9 to 10 years of age.     

Impaired neutrophil functions in patients with leukocytoclastic vasculitis

Background Leukocytoclastic vasculitis (LV) is characterized by segmental inflammation of small blood vessels, resulting in ischemic damage to the surrounding tissue. It is considered to be related to a type III hypersensitivity reaction, although the exact etiologic mechanism is not clear. Objective The purpose of this study was to evaluate neutrophil functions in patients with LV in order to understand their role in the pathogenesis of the disease. Methods Neutrophil functions were examined in 25 LV patients. The patients were divided into two groups: Group A consisted of 14 patients with drug-induced LV and Group B consisted of 11 patients where LV was induced by other factors. Results Both groups of patients showed significantly reduced chemotaxis and phagocytosis. Superoxide generation was significantly lower (P < 0.001) only in neutrophils from patients in Group A: 5.8 ± 0.5 nmoles O₂/10⁶ cells/min compared to 9.08 ± 0.8 nmoles O2/106 cells/min in the controls. Preincubation on normal neutrophils with the patients' sera caused an increase in their superoxide generation in accordance with the high IL-8 levels in these sera. Conclusions Neutrophil functions were significantly impaired in patients with LV. It is likely that factors present in LV plasma may chronically activate neutrophils, so that they become refracfory to further stimulation. Our study showed that neutrophil superoxide generation is low only in drug-induced LV; this test may assist in distinguishing such patients from those with LV induced by other causes.     

Proximal and distal determinants of community resilience under threats of terror

Community resilience (CR) is a positive trajectory of adaptation of a commune after a disturbance, stress, or adversity. Previous studies have successfully predicted CR in times of stress by distal factors, such as demographic characteristics of the community members and by their psychological attributes. We submit that since all these variables are distal predictors, which are not directly related to the actual stressful condition, CR would be predicted more readily by proximal factors, which portray people's responses to the investigated adversity (i.e., trust in the community emergency team). A sample of 1,515 adults, living in terror‐stricken border communities in northern Israel has been examined. Their perceived CR has been predicted concurrently by distal and by proximal factors. Results have supported the research hypotheses, indicating the importance of proximal variables in determining and promoting CR.     

Blood pressure treatment and cognition in the elderly

While the health and longevity benefits of antihypertensive treatment have been established in past research, the cognitive consequences of blood pressure control in the elderly are still under debate. In this paper, the authors review the current evidence and the different ways in which cognition is measured. Since research on the cognitive consequences of blood pressure control in the elderly population is characterized by a variety of research questions, designs, and cognitive measurements, the authors conclude that a large-scale study that compares the cognitive benefits of different methods of blood pressure reduction is urgently needed.     

Blood pressure and cognitive functioning among independent elderly

BACKGROUND: The morbidity and mortality benefits of blood pressure (BP) control for the elderly is well documented. The cognitive consequences of hypertension control in this population, however, are still under debate. We aim to study the association between BP and cognitive performance in the elderly. Specifically, we explore 1) the possibility that BP is differentially associated with various cognitive domains; and 2) the utility of analyzing both BP and cognitive scores as continuous variables to unravel possible nonlinear associations. METHODS: Four hundred ninety-five community living 70 to 85 year olds completed eight cognitive tests that measured memory, concentration, visual retention, verbal fluency, and the mini-mental state examination (MMSE). The performance of each test was analyzed first by comparing four groups (normotensives, normalized hypertensives, untreated hypertensives, and treated but uncontrolled hypertensives). Then, using BP values as continuous variables, linear, U-curve, and J-curve associations were estimated. RESULTS: On all cognitive tests, except for verbal fluency, normotensives performed poorest, treated but uncontrolled hypertensives achieved the highest scores. The MMSE scores and the lighter concentration task were linearly related to BP; J-curve association was observed between memory and visual retention; prolonged concentration was related to pulse pressure alone. CONCLUSIONS: Low BP, as observed among the normotensive subjects, was associated with poor cognitive performance. Mild hypertension appeared to enhance cognitive functioning among the subjects of this study. Moreover, we found support for the hypothesis that the association between BP and different dimensions of cognition take on different patterns.