Frequency, Extent, and Correlates of Superficial Siderosis and Ependymal Siderosis in Premature Infants with Germinal Matrix Hemorrhage: An SWI Study.

BACKGROUND AND PURPOSE: Germinal matrix intraventricular hemorrhage is a common complication of prematurity. An underrecognized complication of germinal matrix intraventricular hemorrhage is superficial siderosis, and the clinical consequences of superficial siderosis are not well-known. We aimed to investigate the prevalence, anatomic distribution, and severity of superficial siderosis and ependymal siderosis in premature infants with germinal matrix intraventricular hemorrhage using SWI. MATERIALS AND METHODS: In this retrospective study, we included 88 patients across all grades of germinal matrix intraventricular hemorrhage who underwent MR imaging at term-equivalent age. Images were evaluated for the presence, distribution, and severity of superficial siderosis and ependymal siderosis. Univariate and multivariate logistic regression analyses were performed to determine factors associated with superficial siderosis and ependymal siderosis. The agreement among T1, T2, and SWI sequences was examined. RESULTS: Seventy-two patients had brain stem superficial siderosis, and 79 patients had ependymal siderosis. The presence, extent, and severity of superficial siderosis and ependymal siderosis were closely related to the grade of germinal matrix intraventricular hemorrhage and intraventricular hematoma volume. Brain stem superficial siderosis had a stronger correlation with intraventricular hemorrhage than with cerebellar hemorrhage. Compared with SWI, T1 and T2 sequences detected only small proportions of patients with superficial siderosis (12.5% and 6.9%, respectively). CONCLUSIONS: The incidence of superficial siderosis and ependymal siderosis is very high in preterm infants with germinal matrix intraventricular hemorrhage when assessed by SWI at term-equivalent age. The presence and extent of superficial siderosis and ependymal siderosis are closely related to germinal matrix intraventricular hemorrhage grade and intraventricular hematoma volume. Additional prospective studies using SWI are needed to clearly determine the clinical consequences of germinal matrix intraventricular hemorrhage with superficial siderosis and ependymal siderosis.

Transporting neonates with hypoxic-ischemic encephalopathy utilizing active hypothermia.

OBJECTIVE: The objective of this report was to evaluate a servo-controlled active hypothermia device used during the transport of neonates with HIE. STUDY DESIGN: Retrospective review of all cases of therapeutic hypothermia, both passive and active, using a servo-controlled device in a single regional referral neonatal intensive care unit from 2009-2013 RESULTS: An ambulance (43%), fixed wing aircraft (25%), or helicopter (32%) transported 28 neonates with active hypothermia. The servo-controlled device captured core temperatures in all 28 neonates, resulting in 2,985 minutes of data. All neonates attained a core temperature between 33-34 °C by 33 minutes of the transport. Once the neonates attained a core temperature, the average temperature for the remainder of the transport was 33 ± 0.2 °C. The neonates maintained the core temperature regardless of the type of transport vehicle. CONCLUSION: Servo-controlled hypothermia enables rapid attainment of targeted temperatures and maintains the temperature throughout the transport process in both ground and air transport.

Late-onset hereditary axonal neuropathies.

BACKGROUND: Hereditary motor-sensory neuropathy or the Charcot-Marie-Tooth syndrome is known to represent considerable genetic heterogeneity. Onset is usually in childhood, adolescence, or young adulthood. The objective of this study was to define late-onset forms of the disorder. METHODS: A clinical and genetic study of families with uniformly late onset of peripheral neuropathy was performed in a university neurogenetics setting. RESULTS: Six families were identified with consistently late onset of a primarily axonal neuropathy. Median age at symptom onset was 57 years (range 35-85 years) of a mixed motor and sensory neuropathy with electrophysiologic characteristics of an axonal rather than demyelinating condition. There was a possible association with deafness. Two families showed autosomal dominant inheritance whereas four families had only one affected generation with an excess of males. An extensive mutation screen of nine genes known to cause Charcot-Marie-Tooth was negative. CONCLUSIONS: There are late-onset forms of hereditary axonal neuropathies. The genetic causes remain unknown and genetic heterogeneity within this entity is likely.

A4V superoxide dismutase mutation in apparently sporadic ALS resembling neuralgic amyotrophy.

We report a case of apparently sporadic amyotrophic lateral sclerosis (ALS) in a young pregnant woman presenting subacutely with severe left shoulder pain followed by progressive weakness and wasting of the left arm, mimicking neuralgic amyotrophy. She was later found electrophysiologically to have widespread denervation involving more than just the arm and an alanine for valine substitution in codon 4 (A4V) in the gene for Cu/Zn superoxide dismutase 1 (SOD1). Her case illustrates that pain on initial presentation, though uncommon, does not exclude a diagnosis of ALS.

Self-inflicted tourniquet paralysis mimicking acute demyelinating polyneuropathy.

Tourniquet paralysis is an uncommon complication of surgery, and self-inflicted tourniquet paralysis has never been documented to our knowledge. We report a patient with bilateral self-induced tourniquet paralysis of the lower extremities, whose symptoms were initially attributed to an acute demyelinating sensorimotor polyneuropathy based on clinical presentation and electrodiagnostic study. After investigations failed to reveal a cause, he was found to have placed tourniquets on his legs because of a rare obsession with limb amputation known as apotemnophilia. Significant spontaneous partial resolution of clinical symptoms was noted after 6 weeks. Electrophysiologic evidence of segmental demyelination of multiple motor nerves localized to the same region may help to distinguish this condition from other forms of acute demyelinating polyneuropathy.

Ontogeny and localization of the neutral amino acid transporter ASCT1 in rat brain.

ASCT1 is a protein that encodes System ASC, a sodium-dependent amino acid transport activity that transports primarily zwitterionic amino acids at physiological pH. ASCT1 has a 39-44% identity to the EAAT family of glutamate transporters. At extracellular pH values below 7.4, ASCT1 shifts substrate specificity to transport anionic amino acids. In this study we have examined the location of the ASCT1 transporter by immunohistochemistry in the developing rat brain. In addition, we have examined the cellular localization of ASCT1 in glial and neuronal cultures. The presence of ASCT1 immunoreactivity (ASCT1ir) in the developing brain was detectable as early as 14 days of gestation. At the cellular level, ASCT1ir was prominent in hippocampal pyramidal and dentate granule neurons. In the cerebellum, Purkinje cells and their dendrites were intensely labeled, whereas the granule and molecular layers were moderately labeled. In the cerebral cortex, neuronal cell bodies in all lamina and scattered astrocytes showed intense ASCT1ir. Double labeling experiments in vitro confirmed that ASCT1 was localized to both glia and neurons. These data illustrate that the rat ASCT1 transporter is expressed in the developing brain at levels equivalent to those observed in adult tissue. In addition, the expression and localization of ASCT1 are consistent with its possible role in pathophysiological processes that involve glutamate toxicity.

Nerve conduction abnormalities in aging mice deficient for myelin-associated glycoprotein.

Ultrastructural, biochemical, and electrophysiological analyses were done on 12-14-month-old mice deficient for myelin-associated glycoprotein (MAG) to further characterize the neuropathy that develops as they age. Electron microscopy demonstrated normal myelin compaction and axonal degeneration in a large number of myelinated nerve fibers. Western blots showed that the proteins of compact myelin, P0 glycoprotein, and myelin basic protein were not significantly altered in the mutants; however, the Schwann cell protein, 2',3'-cyclic nucleotide 3'-phosphodiesterase, was reduced to less than half the control level. Also, both total and phosphorylated high-molecular-weight neurofilament proteins (TNFH and PNFH, respectively) were significantly decreased, as was the PNFH:TNFH ratio. Electrophysiological evaluation revealed a mild, but statistically significant, reduction of conduction velocity and a nonsignificant mild decrease in compound muscle action potential amplitudes. This constellation of findings in aging MAG-null mice is consistent with an axonopathy that resembles axonal Charcot-Marie-Tooth (CMT2) disease in many respects. Thus, mutation of a myelin-associated gene expressed by Schwann cells can induce axonal degeneration and cause a neuropathy with minimal signs of demyelination.

The underachieving advance directive: recommendations for increasing advance directive completion.

Advance directives have failed to achieve a substantial completion rate nationwide despite prior efforts. We hypothesize that the continued low completion rate itself inhibits their utility and application. In this commentary we recommend linking the completion of advance directives to the time when health insurance is initiated or renewed by amending the Patient Self Determination Act. This would relocate the time and locus of their completion from the emotional turmoil of hospital admission and acute illness to a more equanimous time when family and others can be consulted and involved. Moreover actuating increased utilization may require non-coercive incentives as well as education. Amending the Patient Self Determination Act to require providing advance directive forms at the initiation of healthcare insurance in conjunction with educational and/or incentives could be more effective than the current arrangements.

Oligodendrocytes in aging mice lacking myelin-associated glycoprotein are dystrophic but not apoptotic.

Although MAG-null mice myelinate relatively normally except for subtle structural abnormalities in the periaxonal region of myelin sheaths, they develop more severe pathological changes as they age. The purpose of this study was to further define the biochemical aspects of CNS pathology caused by an absence of MAG. Proteins associated with myelin and oligodendrocytes were quantified by densitometry of western blots in whole brain homogenates, as well as in isolated myelinated axons and myelin. Neither myelin yields, nor levels of myelin basic protein and proteolipid protein, were decreased in comparison to control levels in 14-month-old MAG-null mice. On the other hand, 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and the 120 kD neural cell adhesion molecule (N-CAM) were substantially reduced in whole brain, myelinated axons, and myelin. Tubulin, Na(+)K(+)ATPase and Fyn tyrosine kinase were also reduced significantly in myelin-related fractions, but not in whole brain homogenate. The decreased levels of these proteins suggest pathological abnormalities in oligodendrocytes. Furthermore, significant reductions of CNPase and 120 kD NCAM were also present at 2 months, indicating that the oligodendroglial abnormalities begin at a relatively early age. Neither TUNEL assays nor multiplex RT-PCR for mRNAs of apoptosis-related proteins in the aging MAG-null mice provided evidence for apoptotic oligodendrocytes. These biochemical findings suggest oligodendroglial damage in MAG-null mice and support the morphological observations pointing to a progressive "dying-back oligodendrogliopathy" as a consequence of MAG deficiency.

Necrotizing enterocolitis: pathophysiology and prevention.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in the neonatal intensive care unit. It is a disease of medical progress in that more very low-birth-weight neonates are surviving than ever before and are thus susceptible to this potentially devastating disease. NEC received very little attention in the literature before the 1970s but now is well known to all neonatologists and pediatric surgeons. The 1500 to 2000 infants that die every year from this disease in the United States and the large number of infants who develop short gut syndrome from this disease only represent the tip of the iceberg of the problems NEC causes. The widespread fear of NEC among neonatologists and pediatric surgeons has contributed in large part to the use of the IV route rather than the gastrointestinal tract for nourishing these infants for relatively long periods. The consequences of this include a high incidence of sepsis, high hospital costs, and potential long-term neurodevelopmental disability because of poor nutrition during a very vulnerable period of growth and development. The purpose of this review is to provide a brief overview of the clinical presentation and current treatment for NEC, then provide a discussion of the pathophysiology on which strategies for prevention can be formulated.

Autoantibodies associated with peripheral neuropathy.

High titers of serum antibodies to neural antigens occur in several forms of neuropathy. These include neuropathies associated with monoclonal gammopathy, inflammatory polyneuropathies, and paraneoplastic neuropathies. The antibodies frequently react with glycosylated cell surface molecules, including glycolipids, glycoproteins, and glycosaminoglycans, but antibodies to intracellular proteins have also been described. There are several correlations between antibody specificity and clinical symptoms, such as anti-MAG antibodies with demyelinating sensory or sensorimotor neuropathy, anti-GM1 ganglioside antibodies with motor nerve disorders, antibodies to gangliosides containing disialosyl moieties with sensory ataxic neuropathy and Miller-Fisher syndrome, and antibodies to the neuronal nuclear Hu antigens with paraneoplastic sensory neuronopathy. These correlations suggest that the neuropathies may be caused by the antibodies, but evidence for a causal relationship is stronger in some examples than others. In this review, we discuss the origins of the antibodies, evidence for and against their involvement in pathogenic mechanisms, and the implications of these findings for therapy.

Variability in the binding of anti-MAG and anti-SGPG antibodies to target antigens in demyelinating neuropathy and IgM paraproteinemia.

Densitometry of immunostained Western blots or thin layer chromatograms and enzyme-linked immunosorbent assays (ELISAs) were used to compare the relative strengths of IgM binding to myelin-associated glycoprotein (MAG), P0 glycoprotein, peripheral myelin protein-22 (PMP-22), sulfate-3-glucuronyl paragloboside (SGPG), and other potential target antigens in a series of eleven patients with sensory or sensorimotor demyelinating neuropathy and IgM paraproteinemia. The IgM from all patients exhibited reactivity with both MAG and SGPG, and there was a statistically significant correlation between the overlay assays and ELISAs for measuring the strength of IgM binding to MAG and to SGPG. However, the data revealed variations in the relative strengths with which the antibodies bound to the potential target antigens and heterogeneity in their fine specificities. First, there was a poor correlation between the strength of binding to MAG and to SGPG, respectively. Second, reactivity with MAG or SGPG in a few of the patients was only detected by one of the two assay systems. Third, about one-third of the patients' IgM absolutely required the sulfate on SGPG for reactivity, whereas the others retained some reactivity after removal of the sulfate. Fourth, IgM from two of the patients exhibited unusually strong reactivity with the proteins of compact myelin, P0 and PMP22. These relative differences in strengths of antibody binding to the potential antigens were compared with the patients' clinical presentations and with their responses to intravenous immunoglobulin (IVIg) therapy in a clinical trial in which they participated. For the most part, these variations did not correlate with clinical presentation, which was relatively homogeneous in this series of patients. However, an inverse relationship was noted between degree of reactivity to MAG by ELISA and response to IVIg. Two of the patients who responded had only mild elevations of IgM antibodies to nerve glycoconjugates and exhibited some unusual immunochemical and clinical characteristics in comparison to the other patients. The results demonstrate differences in the relative strengths with which anti-MAG and anti-SGPG IgM antibodies from different patients bind to potential neural target antigens which may affect pathogenic mechanisms and response to therapy.

Glutamine synthetase: a key enzyme for intestinal epithelial differentiation?

BACKGROUND: We have previously shown that glutamine synthetase protein and mRNA are concentrated in the crypt region of the rat small intestine and that the activity of this enzyme is highest around the time of weaning. This anatomical location and time of peak activity are sites and periods of active enterocyte differentiation. This led to our current hypothesis that glutamine synthetase is important in the differentiation of enterocytes. METHODS: To test our hypothesis, we treated Caco-2 cells with physiologic (0.6 mM) glutamine concentrations in cell culture medium. The experimental group was treated with methionine sulfoximine, an irreversible glutamine synthetase inhibitor, and the control group with phosphate buffered saline. Three standard and well-defined markers of intestinal differentiation-sucrase-isomaltase activity, microvillus formation, and electrical impedance in transwell plates-were compared between the two groups. RESULTS: The methionine-sulfoximine-inhibited group was found to have lower sucrase-isomaltase activity, a lower density of microvilli, and lower electrical impedance values over time compared with the control group. CONCLUSION: The experimental group was found to be less differentiated by all three markers of differentiation. Therefore, glutamine synthetase is important for Caco-2 cell differentiation.

Molecular mimicry in chronic inflammatory demyelinating polyneuropathy and melanoma.

Polyclonal immunoglobulin M antibodies to the monosialoganglioside GM2, sulfoglucuronyl glycolipids, and sulfatide were detected by thin-layer chromatography and enzyme-linked immunosorbent assay in the serum of a patient with melanoma and chronic inflammatory demyelinating polyneuropathy. Both the patient's serum and polyclonal antibodies against GM2 reacted strongly with a biopsy of melanomatous tissue from the patient, suggesting a process of molecular mimicry.

Standardizing work injury care in aligned systems.

Standardizing work injury care in aligned systems requires commitment toward the same goal from all system entities. One of the keys to the success of this process improvement is involvement of all stakeholders, including external customers, in the improvement process. Strengthening the communication processes between providers and company representatives is one step in helping employers to manage the high cost of health care for their employees.

Isolated facial nerve palsy from metastasis to the temporal bone: report of two cases and a review of the literature.

Isolated facial nerve paralysis is rarely the result of metastasis. We describe two cases (the fourth and fifth cases ever documented) with facial nerve palsy secondary to metastatic adenocarcinoma to the temporal bone. We also review the pathogenesis and presentation of facial nerve paralysis from metastasis and discuss a possible treatment strategy.

Temperature-sensitive repetitive discharges in paramyotonia congenita.

A 47-year-old female with paramyotonia congenita was studied with electromyography and showed minimal myotonic discharges but prominent repetitive discharges in hand muscles at room temperature. With cooling the hand, the repetitive discharges ceased as the myotonic potentials became prominent. With exercise and further cooling, the myotonic discharges increased and the strength of the muscle and recruitment pattern decreased. With warming, the myotonic discharges decreased as the repetitive discharges reappeared. This is the first report of repetitive discharges occurring in a patient with temperature-sensitive sodium channel myotonia. It is postulated that the repetitive discharges as well as the myotonic discharges are the manifestation of muscle membrane hyperexcitability secondary to the abnormal, noninactivating sodium channels.