Cerebral Palsy

OBJECTIVE: Mutations of the selenoprotein N gene (SEPN1) cause SEPN1-related myopathy (SEPN1-RM), a novel early-onset muscle disorder formerly divided into four different nosological categories. Selenoprotein N (SelN) is the only selenoprotein involved in a genetic disease; its function being unknown, no treatment is available for this potentially lethal disorder. Our objective was to clarify the role of SelN and the pathophysiology of SEPN1-RM to identify therapeutic targets. METHODS: We established and analyzed an ex vivo model of SelN deficiency using fibroblast and myoblast primary cultures from patients with null SEPN1 mutations. DCFH assay, OxyBlot, Western blot, Fura-2, and cell survival studies were performed to measure intracellular oxidant activity, oxidative stress markers, calcium handling, and response to exogenous treatments. RESULTS: SelN-depleted cells showed oxidative/nitrosative stress manifested by increased intracellular oxidant activity (reactive oxygen species and nitric oxide) and/or excessive oxidation of proteins, including the contractile proteins actin and myosin heavy chain II in myotubes. SelN-devoid myotubes showed also Ca(2+) homeostasis abnormalities suggesting dysfunction of the redox-sensor Ca(2+) channel ryanodine receptor type 1. Furthermore, absence of SelN was associated with abnormal susceptibility to H(2)O(2)-induced oxidative stress, demonstrated by increased cell death. This cell phenotype was restored by pretreatment with the antioxidant N-acetylcysteine. INTERPRETATION: SelN plays a key role in redox homeostasis and human cell protection against oxidative stress. Oxidative/nitrosative stress is a primary pathogenic mechanism in SEPN1-RM, which can be effectively targeted ex vivo by antioxidants. These findings pave the way to SEPN1-RM treatment, which would represent a first specific pharmacological treatment for a congenital myopathy. Ann Neurol 2009;65:677-686.

Neurologist S. Weir Mitchell first described “causalgia” following wartime nerve injury, with its persistent distal limb burning pain, swelling, and abnormal skin color, temperature, and sweating. Similar post-traumatic symptoms were later identified in patients without overt nerve injuries after trauma. This was labeled reflex sympathetic dystrophy (RSD; now complex regional pain syndrome type I [CRPS-I]). The pathophysiology of symptoms is unknown and treatment options are limited. We propose that persistent RSD/CRPS-I is a post-traumatic neuralgia associated with distal degeneration of small-diameter peripheral axons. Small-fiber lesions are easily missed on examination and are undetected by standard electrophysiological testing. Most CRPS features-spreading pain and skin hypersensitivity, vasomotor instability, osteopenia, edema, and abnormal sweating-are explicable by small-fiber dysfunction. Small fibers sense pain and temperature but also regulate tissue function through neuroeffector actions. Indeed, small-fiber-predominant polyneuropathies cause CRPS-like abnormalities, and pathological studies of nerves from chronic CRPS-I patients confirm small-fiber-predominant pathology. Small distal nerve injuries in rodents reproduce many CRPS features, further supporting this hypothesis. CRPS symptoms likely reflect combined effects of axonal degeneration and plasticity, inappropriate firing and neurosecretion by residual axons, and denervation supersensitivity. The resulting tissue edema, hypoxia, and secondary central nervous system changes can exacerbate symptoms and perpetuate pathology. Restoring the interest of neurologists in RSD/CRPS should improve patient care and broaden our knowledge of small-fiber functions. Ann Neurol 2009;65:629-638.

Japan is one of the few countries to have enacted legislation on eugenics. Consequently, there has been active public debate about the practice of selective abortion for over 35 years. Furthermore, discrimination against disabilities is deep-rooted in Japanese society and the quality of offspring is a common concern. Given this background, the obvious conclusion might be that couples in Japan would have no hesitation in using reproductive technologies to ensure the best possible chance of giving birth to higher quality offspring. Yet, research indicates that when it comes to decision-making in the course of a pregnancy, not all individuals choose testing or termination, even when prenatal diagnosis indicates the presence of congenital conditions. Other factors play a role in reproductive decision-making, including age at time of pregnancy and reproductive history including infertility treatment. Against this background, this paper analyses accounts of five pregnancies – two of which resulted in termination and three which went to full term despite receiving test results showing possible birth defects – with the aim of identifying factors influencing whether or not to terminate a pregnancy.

Primary objective: To look for differences in vulnerability of corpus callosum (CC) in patients of mild and moderate traumatic brain injury (TBI) in the acute stage using quantitative diffusion tensor imaging (DTI) and to correlate these with neuropsychometric tests (NPT) done at 6 months post-injury. Research design, methods and procedures: Conventional MRI, DTI and NPT were performed on 83 patients (moderate TBI, n = 57; mild TBI, n = 26) within 5-14 days after TBI. Thirty-three age- and sex-matched healthy controls were also included for comparison. Results: Significantly decreased fractional anisotropy (FA) in genu and splenium; significantly increased radial diffusivity (RD) values in genu, midbody and splenium with significant increase in mean diffusivity (MD) and a decrease in axial diffusivity (AD) only in genu, respectively, in patients with moderate TBI compared to healthy controls were observed. However, in moderate TBI, significantly decreased FA was found only in genu compared to mild TBI. Moderate TBI showed poor NPT scores compared to mild TBI, but this did not reach statistical significance. Conclusions: It is concluded that DTI abnormalities in the regions of CC were more in patients with moderate TBI compared to mild TBI and this was associated with relatively poor neuropsychological outcome 6 months post-injury.

Mutations in the fms-like tyrosine kinase 3 (FLT3) gene (internal tandem duplication (ITD) and point mutation in the tyrosine kinase domain, FLT3/D835) as well as the nucleophosmin (NPM1) gene are the most common abnormalities in adult acute myeloid leukemia (AML). Their significance in pediatric AML is still unclear. In this study we evaluated the frequency of FLT3 and NPM1 mutations in childhood AML. We also examined clinical features and outcome of these patients. FLT3 and NPM1 mutations were analysed in 42 and 37 childhood AML patients, respectively, using polymerase chain reaction (PCR) and direct sequencing. FLT3 mutations were detected in 4/42 patients (9.5%). The frequencies of FLT3/ITD and FLT3/D835 were the same, 2/42 (4.7%). NMP1 mutations were found in 1/37 patients (2.7%). FLT3 gene mutations were correlated with induction failure. Here we report the results of the study of FLT3 and NPM1 gene mutations in childhood AML patients in Serbia. Low frequencies of these molecular markers point out that these abnormalities are rare in this cohort of patients. Comparative study of data on NPM1 mutations in childhood AML revealed that various NPM1 gene mutation types are associated with childhood AML. Our findings as well as previously reported data, contributes to a hypothesis of different biology and etiology of adult and childhood AML. More extensive studies of NPM1 and FLT3 mutations in childhood AML are needed to determine their biological and clinical importance.

PURPOSE OF REVIEW: Several lines of evidence suggest that the normal integration of cerebral function may be compromised in schizophrenia. Abnormalities in white matter tracts, which connect brain regions into functional networks, may be directly relevant to its pathophysiology. Diffusion tensor imaging (DTI) has increasingly been used to study white matter abnormalities in schizophrenia; in this review, we will discuss recent DTI findings focusing on the early stages of the disorder. RECENT FINDINGS: Deficits in white matter integrity as inferred by DTI appear to be present in the early stages of schizophrenia, even in neuroleptic-naive patients, and may be the result of interaction between illness-related processes and normal development. The pattern of identified abnormalities is not totally consistent across all studies, with frontotemporal, frontoparietal and temporooccipital connections as well as projection fibers and cerebellar white matter being among the affected tracts. SUMMARY: Recent DTI findings further support the hypothesis of structural dysconnectivity in schizophrenia. The presence of white matter abnormalities early in the course of the illness is suggestive of these being related to the emergence of the disorder.

Systolic heart failure is a feed-forward phenomenon with devastating consequences. Impaired cardiac function is the initiating event, but central nervous system mechanisms activated by persistent altered neural and humoral signals from the periphery play an important sustaining role. Animals with experimentally induced heart failure have neurochemical abnormalities in the brain that, when manipulated, profoundly affect sympathetic drive, volume regulation, and cardiac remodeling-critical determinants of outcome. This brief review explores recent studies that provide a strong rationale for the development of pharmaceutical agents that target central nervous system abnormalities in heart failure.Clinical Pharmacology & Therapeutics (2009); advance online publication 24 June 2009. doi:10.1038/clpt.2009.117.

Phocomelia is a devastating, rare congenital limb malformation in which the long bones are shorter than normal, with the upper portion of the limb being most severely affected. In extreme cases, the hands or fingers are attached directly to the shoulder and the most proximal elements (those closest to the shoulder) are entirely missing. This disorder, previously known in both autosomal recessive and sporadic forms, showed a marked increase in incidence in the early 1960s due to the tragic toxicological effects of the drug thalidomide, which had been prescribed as a mild sedative. This human birth defect is mimicked in developing chick limb buds exposed to X-irradiation. Both X-irradiation and thalidomide-induced phocomelia have been interpreted as patterning defects in the context of the progress zone model, which states that a cell’s proximodistal identity is determined by the length of time spent in a distal limb region termed the ‘progress zone’. Indeed, studies of X-irradiation-induced phocomelia have served as one of the two major experimental lines of evidence supporting the validity of the progress zone model. Here, using a combination of molecular analysis and lineage tracing in chick, we show that X-irradiation-induced phocomelia is fundamentally not a patterning defect, but rather results from a time-dependent loss of skeletal progenitors. Because skeletal condensation proceeds from the shoulder to fingers (in a proximal to distal direction), the proximal elements are differentially affected in limb buds exposed to radiation at early stages. This conclusion changes the framework for considering the effect of thalidomide and other forms of phocomelia, suggesting the possibility that the aetiology lies not in a defect in the patterning process, but rather in progenitor cell survival and differentiation. Moreover, molecular evidence that proximodistal patterning is unaffected after X-irradiation does not support the predictions of the progress zone model.

Objective:Umbilical artery catheter (UAC) use is common in the management of critically ill neonates; however, little information exists regarding the anatomic and vascular effects of UAC placement in premature newborns.Study Design:Baboons were delivered at 125 days of gestation (term=185 days), treated with surfactant, had UACs placed and were ventilated for either 6 or 14 days. Animals were assigned to short-term (6 days, n=6) and long-term (14 days, n=30) UAC placement. At necropsy, aortas were removed with UACs still in place. Histological examination of upper, middle and lower aorta specimens stained with hematoxylin and eosin and immunolabeled to detect smooth muscle (alpha-actin) was carried out in a blinded manner. Controls were delivered at 125, 140 and 185 days and the aortas acquired immediately after birth. None of the non-catheterized control animals (125 days, n=4; 140 days, n=5; and 185 days, n=5) had aortic vessel thrombi or vascular wall abnormalities.Result:All 6 animals with short-term (6/6, 100%) and 18 animals with long-term (18/30, 60%) UAC placement displayed aortic thrombi and neointimal proliferation of the vascular wall. The majority (60%) of analyzed animals with UAC placement displaying neointimal hyperplasia were immunopositive for alpha-actin, indicating the presence of smooth muscle in these lesions.Conclusion:Our findings suggest that both short- and long-term UAC use is associated with aortic wall pathological abnormalities compared with control animals. This study emphasizes the judicious use and early removal of UACs if possible in order to potentially prevent significant hemostatic and aortic wall vascular complications.Journal of Perinatology advance online publication, 25 June 2009; doi:10.1038/jp.2009.73.

BACKGROUND: Frequency doubling technology (FDT) perimetry measures contrast sensitivity. The magnocellular component of ganglion cells in human retina is isolated as a whole by the FDT stimulus. The aim of this study is to investigate the role of Humphrey Matrix threshold testing in the detection of early functional retinal impairment in ocular hypertensive patients compared to standard automated perimetry (SAP). METHODOLOGY: Forty hypertensive patients were enrolled in this longitudinal observational clinical study. Functional testing included randomly Humphrey Matrix perimetry and white-on-white Humphrey visual field perimetry. Ibopamine test was performed in all forty patients. The cut-off of 3 mmHg was considered positive for this provocative test. RESULTS: Out of 40 patients, we included 21 in ibopamine positive group and 19 in ibopamine negative group. These two groups are sex- and age-matched. In ibopamine positive group the mean increase in IOP is 4.6 mmHg (ranging from 3 to 10 mmHg). Statistics showed that correlation between FDT and SAP was statistically significant in ibopamine negative group and not statistically significant in ibopamine positive group. Only one patient, coming from IBO + group, converted from ocular hypertension to glaucoma. All the other subjects remained stable in both groups without any therapy and visual field abnormalities. CONCLUSIONS: FDT showed to be more sensitive and specific than SAP mostly in detection of early visual field impairment in ocular hypertensive patients.