Neurologic crises in hereditary tyrosinemia

Hereditary tyrosinemia results from an inborn error in the final step of tyrosine metabolism. The disease is known to cause acute and chronic liver failure, renal Fanconi's syndrome, and hepatocellular carcinoma. Neurologic manifestations have been reported but not emphasized as a common problem. In this paper, we describe neurologic crises that occurred among children identified as having tyrosinemia on neonatal screening since 1970. Of the 48 children with tyrosinemia, 20 (42 percent) had neurologic crises that began at a mean age of one year and led to 104 hospital admissions. These abrupt episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (in 75 percent), vomiting or paralytic ileus (69 percent), muscle weakness (29 percent), and self-mutilation (8 percent). Eight children required mechanical ventilation because of paralysis, and 14 of the 20 children have died. Between crises, most survivors regained normal function. We found no reliable biochemical marker for the crises (those we evaluated included blood levels of tyrosine, succinylacetone, and hepatic aminotransferases). Urinary excretion of delta-aminolevulinic acid, a neurotoxic intermediate of porphyrin biosynthesis, was elevated during crises but also during the asymptomatic periods. Electrophysiologic studies in seven patients and neuromuscular biopsies in three patients showed axonal degeneration and secondary demyelination. We conclude that episodes of acute, severe peripheral neuropathy are common in hereditary tyrosinemia and resemble the crises of the neuropathic porphyrias.     

Evaluation of the Quantum II and Rapid E identification systems.

A total of 492 clinical isolates from the family Enterobacteriaceae were tested in the API 20E, Rapid E, and Quantum II identification systems. Discrepant identifications among these three systems were resolved by repeat testing in the identification systems or use of conventional biochemical tests. Of these isolates, 94.1% were correctly identified with the API 20E and Rapid E systems, and 97.0% were correctly identified with the Quantum II system. An additional 48 non-Enterobacteriaceae isolates were tested with the Quantum II system, and 83.3% were correctly identified. The majority of incorrect identifications with the Rapid E and Quantum II systems were caused by a single aberrant biochemical reaction. Reproducibility of the biochemical reactions obtained with these two systems was evaluated by testing 40 organisms in triplicate. Identical biocodes for all three tests were obtained for 10 organisms with the Quantum II system and for 19 organisms with the Rapid E system. Reproducibility of the Quantum II test results was improved with a subsequent modification of the photometer of this system. Both the Rapid E and Quantum II systems were inexpensive and were technically easy to inoculate and interpret.     

The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission

Factors involved in the stability of trinucleotide repeats during transmission were studied in 139 families in which a full mutation, premutation or intermediate allele at either FRAXA or FRAXE was segregating. The transmission of alleles at FRAXA, FRAXE and four microsatellite loci were recorded for all individuals. Instability within the minimal and common ranges (0-40 repeats for FRAXA, 0-30 repeats for FRAXE) was extremely rare; only one example was observed, an increased in size at FRAXA from 29 to 39 repeats. Four FRAXA and three FRAXE alleles in the intermediate range (41-60) repeats for FRAXA, 31-60 for FRAXE) were unstably transmitted. Instability was more frequent for FRAXA intermediate alleles that had a tract of pure CGG greater than 37 although instability only occurred in two of 13 such transmissions: the changes observed were limited to only one or two repeats. Premutation FRAXA alleles over 100 repeats expanded to a full mutation during female transmission in 100% of cases, in agreement with other published series. There was no clear correlation between haplotype and probability of expansion of FRAXA premutations. Instability at FRAXA or FRAXE was more often observed in conjunction with a second instability at an independent locus suggesting genomic instability as a possible mechanism by which at least some FRAXA and FRAXE mutations arise.      

Shunt surgery for treatment of portal hypertension in children

Shunt surgery in children suffering from portal hypertension (PH) is considered as an immediate and definite mode of prevention of recurrent gastrointestinal hemorrhage. Certain conditions must be met: (a) normal liver; (b) normal veins available within the portal system; (c) a sufficient portosystemic gradient of pressure; and (d) a surgical team with experience in portal venous surgery. In patients in whom PH is an epiphenomenon of severe liver disease, other means of hemostasis for bleeding esophageal varices should be sought. The difficult decision is in the child with specific liver alterations without major hepatocellular dysfunction but in whom the prognosis cannot be precisely foreseen. A few more years will be needed before one can tell if shunt surgery is the best choice for this category of patient.

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Resumen La cirugía derivativa (shunts portosistémicos) en los niños que sufren de hipertensión portal es considerada como una forma inmediata y definitiva de prevenir la hemorragia gastrointestinal recurrente. Ciertas condiciones deben existir para su realization: (a) hígado normal; (b) venas disponibles dentro del sistema porta; (c) suficiente gradiente en las presiones portosistémicas; y (d) disponibilidad de un equipo quirúrgico con experiencia en cirugía venosa portal. Otros medios de hemostasis de las várices esofágicas sangrantes deben ser utilizados en aquellos pacientes en quienes la hipertensión portal es un epifenómeno de enfermedad hepática severa. La decisión más difícil se presenta en el niño con alteraciones hepáticas específicas pero sin mayor disfunción hepatocelular en quien no se puede determinar con precisión el pronóstico. Todavía serán necesarios unos años más antes de poder afirmar que la cirugía derivativa representa la mejor escogencia para esta categoría de pacientes.

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Résumé La dérivation portale chez les enfants atteints d'hypertension portale constitue une méthode immédiate et définitive de prévention des hémorragies digestives récidivantes. Les conditions les plus favorables sont les suivantes: a) foie normal; b) veines disponibles dans le secteur porte pour l'anastomose; c) gradient de pression suffisant entre le système porte et le système cave et d) équipe entraînée à la chirurgie portale. Lorsque l'hypertension portale est un épiphénomène au cours d'une affection hépatique sévère, d'autres méthodes d'hémostase des varices oesophagiennes rompues doivent être envisagées. La décision du choix thérapeutique à adopter est difficile lorsqu'il existe une atteinte hépatique, sans altération hépatocellulaire majeure, mais de pronostic incertain à long terme. Quelques années encore seront nécessaires avant de pouvoir affirmer que la dérivation représente la meilleure opération pour traiter ce type d'hypertension portale.

     

Distinct immunopathological mechanisms of EBV-positive and EBV-negative posttransplant lymphoproliferative disorders

EBV-positive and EBV-negative posttransplant lymphoproliferative disorders (PTLDs) arise in different immunovirological contexts and might have distinct pathophysiologies. To examine this hypothesis, we conducted a multicentric prospective study with 56 EBV-positive and 39 EBV-negative PTLD patients of the K-VIROGREF cohort, recruited at PTLD diagnosis and before treatment (2013–2019), and compared them to PTLD-free Transplant Controls (TC, n = 21). We measured absolute lymphocyte counts (n = 108), analyzed NK- and T cell phenotypes (n = 49 and 94), and performed EBV-specific functional assays (n = 16 and 42) by multiparameter flow cytometry and ELISpot-IFNγ assays (n = 50). EBV-negative PTLD patients, NK cells overexpressed Tim-3; the 2-year progression-free survival (PFS) was poorer in patients with a CD4 lymphopenia (CD4⁺<300 cells/mm³, p <  .001). EBV-positive PTLD patients presented a profound NK-cell lymphopenia (median = 60 cells/mm³) and a high proportion of NK cells expressing PD-1 (vs. TC, p = .029) and apoptosis markers (vs. TC, p < .001). EBV-specific T cells of EBV-positive PTLD patients circulated in low proportions, showed immune exhaustion (p = .013 vs. TC) and poorly recognized the N-terminal portion of EBNA-3A viral protein. Altogether, this broad comparison of EBV-positive and EBV-negative PTLDs highlight distinct patterns of immunopathological mechanisms between these two diseases and provide new clues for immunotherapeutic strategies and PTLD prognosis.     

Beta-amyloid precursor protein is detectable on monocytes and is increased in Alzheimer's disease

Using the anti-beta-amyloid precursor protein (betaAPP) monoclonal antibodies 4G8, 6E10 and 22C11 and flow cytometry, we report that human circulating peripheral blood monocytes display surface immunoreactivity for betaAPP. In contrast, circulating lymphocytes do not possess cell surface betaAPP immunoreactivity, despite similar levels of betaAPP expression. Immunoblotting analysis showed that monocytes, but not lymphocytes, possess an 82 kDa C-terminal betaAPP fragment consistent with a processed transmembrane species. Monocyte surface betaAPP was upregulated approximately threefold by activation with lipopolysaccharide and interferon-gamma, activation did not produce detectable betaAPP on the cell surface of lymphocytes. Surface betaAPP immunoreactivity was reduced in a normal aged population compared to normal young controls (Young = 81.07 +/- 13.67 mean fluorescence units, Aged = 36.74 +/- 3.81, p < 0.01), but was significantly increased in AD subjects compared to age-matched healthy controls (AD = 60.31 +/- 7.42, p < 0.05). Our data suggest that a proportion of peripheral A beta may be derived from monocyte/macrophages, and that defects in brain cell processing of betaAPP in AD may be shared by this readily accessible peripheral cell.     

Monitoring universal precautions: a new assessment tool.

OBJECTIVES: Two pilot studies were conducted to produce efficacy data on an observational tool designed to assess the use of Universal Precautions (UP) in patient care settings. The instrument addresses barrier precautions, hand-washing, handling of sharps, and avoidance of unprotected mouth to mouth resuscitation. DESIGN: The Universal Precautions Assessment Tool was submitted to a panel of 3 experts to establish consensual validity. It was pilot tested by 2 simultaneous observers to establish interrater reliability. SETTING: Pilot Study I was conducted in 3 different units within a 100-bed U.S. Army hospital. Pilot Study II was conducted in the emergency department of a large university-based hospital. PARTICIPANTS: Subjects observed were registered nurses providing acute patient care. RESULTS: Two simultaneous raters calculated UP compliance rates of 76.4% and 78.6%, respectively, for 9 nurses in Pilot Study I, and 62% and 65%, respectively, for 5 nurses in Pilot Study II. The intraclass correlation coefficient for the raters' scores in Pilot Study I was 0.992 with a 95% confidence interval (0.979, 0.997). Consensual validity was established. CONCLUSIONS: The instrument has acceptable interrater reliability under the conditions used. Limitations to use include the possibility of a Hawthorne effect and the fact that assessing proper implementation of UP occasionally relies on a "judgment call" by the observer. With test conditions adjusted to minimize these limitations and with proper consideration of sample size, the tool can be used by researchers and by monitors of hospital quality control to measure UP compliance of caregivers individually or collectively.     

Hemin enhances the in vitro growth of primitive erythroid progenitor cells

Since exogenous hemin has been shown to exert a variety of stimulatory effects on erythroid cells, including the augmentation of hemoglobin synthesis, we determined its effect on early stages of erythroid development by employing clonal cells assays. The addition of hemin at a concentration of 2 X 10(-4) M to cultures of normal murine marrow substantially increased the observed number of primitive BFU-E, which was in contrast to its lack of an effect on more mature erythroid colony-forming cells. This cell-specific enhancement of primitive BFU-E resulted in marrow frequencies equivalent to or exceeding those reported in the presence of "burst-promoting activity." In the presence of hemin, the number of BFU-E was also observed to be linearly related to the number of cells plated at very low plating densities, and the cell titration curve was observed to extrapolate to the origin. The evidence suggests that hemin may be a primary growth regulator of early developmental stages of erythroid progenitor cells.