Anti-JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial.

BACKGROUND AND PURPOSE: Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of JC virus (JCV) infection due to combined host and viral factors. Anti-JCV antibodies provide a means to assess JCV exposure and stratify PML risk. The reported seroprevalence of anti-JCV antibodies varies from 39% to 91% depending on assay methodology and population studied. A two-step anti-JCV antibody assay (STRATIFY JCV™; Focus Diagnostics, Cypress, CA, USA) detected anti-JCV antibodies in approximately 55% of multiple sclerosis (MS) patients. This study describes the prevalence of anti-JCV antibodies in a large, multinational MS population. METHODS: This cross-sectional epidemiology study was designed to enroll a minimum of 2000 patients with an MS diagnosis of any type, irrespective of treatment, from Europe, Canada and Australia. Anti-JCV antibody prevalence was determined by STRATIFY JCV; the effects of demographic and disease characteristics were evaluated. RESULTS: A total of 7724 patients from 10 countries participated in the study. Overall anti-JCV antibody prevalence was 57.1% (95% confidence interval 56.0%-58.2%). Seroprevalence was significantly associated with increasing age, gender and country of current residence (P < 0.0001). No significant differences in anti-JCV antibody prevalence were associated with MS disease characteristics, including duration and type of MS and number and duration of MS therapies. CONCLUSIONS: Overall seroprevalence of anti-JCV antibodies in MS patients from Europe, Canada and Australia was consistent with previous studies using the STRATIFY JCV assay. Anti-JCV prevalence differed significantly by age, gender and country, but no geographical pattern was evident. Disease and treatment type were not associated with differences in anti-JCV antibody status.

Pharmacokinetics and pharmacodynamics of tonapofylline in subjects with severe renal impairment and in elderly subjects.

OBJECTIVE: The study was conducted to characterize the pharmacokinetics and pharmacodynamics of tonapofylline in subjects with severe renal impairment and in elderly subjects. METHOD: Subjects with severe renal impairment were matched demographically with healthy subjects. Elderly subjects with normal renal function for their ages were also enrolled. All subjects (n = 8 per group) received a single intravenous administration of tonapofylline at 1 mg/kg. RESULTS: The pharmacokinetics of tonapofylline was not significantly different in subjects with severe renal impairment, or in elderly subjects, as compared to healthy subjects. Among all pharmacokinetic parameters, the only statistically significant difference was observed for Cmax between the healthy and the severe renal impairment groups, which was 21% and considered clinically insignificant. Pharmacodynamic assessment demonstrated the natriuretic effects of tonapofylline across groups, with little accompanying kaliuresis. No change in renal function occurred after single dose of tonapofylline, despite substantial increases in excretion of urinary sodium. Single 1 mg/kg intravenous administration of tonapofylline was generally safe. CONCLUSION: The pharmacokinetics of tonapofylline in subjects with severe renal impairment and elderly subjects with normal renal function for age is similar to that in healthy subjects. It has been demonstrated in all groups that tonapofylline has natriuretic effects and is able to maintain renal function, which can be beneficial to patients with congestive heart failure.

Conservation of sequence and expression of Xenopus and zebrafish dHAND during cardiac, branchial arch and lateral mesoderm development.

dHAND and eHAND are related basic helix-loop-helix transcription factors that are expressed in the cardiac mesoderm and in numerous neural crest-derived cell types in chick and mouse. To better understand the evolutionary development of overlapping expression and function of the HAND genes during embryogenesis, we cloned the zebrafish and Xenopus orthologues. Comparison of dHAND sequences in zebrafish, Xenopus, chick, mouse and human demonstrated conservation throughout the protein. Expression of dHAND in zebrafish was seen in the earliest precursors of all lateral mesoderm at early gastrulation stages. At neurula and later stages, dHAND expression was observed in lateral precardiac mesoderm, branchial arch neural crest derivatives and posterior lateral mesoderm. At looping heart stages, cardiac dHAND expression remained generalized with no apparent regionalization. Interestingly, no eHAND orthologue was found in zebrafish. In Xenopus, dHAND and eHAND were co-expressed in the cardiac mesoderm without the segmental restriction seen in mice. Xenopus dHAND and eHAND were also expressed bilaterally in the lateral mesoderm without any left-right asymmetry. Within the branchial arches, XdHAND was expressed in a broader domain than XeHAND, similar to their mouse counterparts. Together, these data demonstrate conservation of HAND structure and expression across species.

The bHLH transcription factor hand2 plays parallel roles in zebrafish heart and pectoral fin development.

The precursors of several organs reside within the lateral plate mesoderm of vertebrate embryos. Here, we demonstrate that the zebrafish hands off locus is essential for the development of two structures derived from the lateral plate mesoderm - the heart and the pectoral fin. hands off mutant embryos have defects in myocardial development from an early stage: they produce a reduced number of myocardial precursors, and the myocardial tissue that does form is improperly patterned and fails to maintain tbx5 expression. A similar array of defects is observed in the differentiation of the pectoral fin mesenchyme: small fin buds form in a delayed fashion, anteroposterior patterning of the fin mesenchyme is absent and tbx5 expression is poorly maintained. Defects in these mesodermal structures are preceded by the aberrant morphogenesis of both the cardiogenic and forelimb-forming regions of the lateral plate mesoderm. Molecular analysis of two hands off alleles indicates that the hands off locus encodes the bHLH transcription factor Hand2, which is expressed in the lateral plate mesoderm starting at the completion of gastrulation. Thus, these studies reveal early functions for Hand2 in several cellular processes and highlight a genetic parallel between heart and forelimb development.

Heterotaxy: associated conditions and hospital-based prevalence in newborns.

PURPOSE: To provide insight into the possible etiology and prevalence of heterotaxy, we studied conditions associated with heterotaxy in a consecutive hospital population of newborns. METHODS: From 1972 to March, 1999 (except February 16, 1972 to December 31, 1978), 58 cases of heterotaxy were ascertained from a cohort of 201,084 births in the ongoing Active Malformation Surveillance Program at the Brigham and Women's Hospital. This registry includes livebirths, stillbirths, and elective abortions. Prevalence among nontransfers (i.e., patients whose mothers had planned delivery at this hospital) was calculated as approximately 1 per 10,000 total births (20 of 201,084). RESULTS: We analyzed a total of 58 patients consisting of 20 (34%) nontransfers and 38 (66%) transfers. Patients were categorized by spleen status as having asplenia (7 nontransfers, 25 total), polysplenia (8, 20), right spleen (4, 11), normal left (0, 1), and unknown (1, 0). Among the 20 nontransfer and 59 total heterotaxy patients, the following associated medical conditions were present: chromosome abnormality (1 nontransfer, 2 total), suspected Mendelian or chromosome microdeletion disorder (1 nontransfer, 6 total), and maternal insulin-dependent diabetes mellitus (1 nontransfer, 2 total). There were 6 twins (1 member each from 6 twin pairs including 1 dizygous, 4 monozygous, 1 conjoined; 2 were nontransfers). An associated condition occurred in 5 (25%) nontransfer and 16 (28%) total patients, or among 10 of 53 singleton births (19%). CONCLUSIONS: Although most cases of heterotaxy in this series were sporadic events, an associated condition was present in about one-fourth of the cases. Not all of these conditions would be considered causative etiologies. Based on this small series alone, maternal insulin-dependent diabetes cannot be viewed as a risk factor for heterotaxy. However, the specific association of diabetes with polysplenia with/without left atrial isomerism is noteworthy, and adds weight to animal and epidemiologic case-control data.

Extracardiac anomalies in the heterotaxy syndromes with focus on anomalies of midline-associated structures.

The extracardiac defects in patients with heterotaxy have not been examined as extensively as cardiac defects. We found a high incidence of midline-associated defects in 160 autopsied cases of heterotaxy (asplenia, polysplenia, or single right-sided spleen). Fifty-two percent of patients with left-sided polysplenia had a midline-associated defect, as did 45% of those with asplenia. Most common were musculoskeletal or genitourinary anomalies, as well as cleft palate. Fused adrenal glands and anal stenosis or atresia occurred exclusively among patients with asplenia. A midline anomaly was twice as likely to be detected on complete autopsy than from clinical findings alone. Linkage studies should take into account that affected subjects may have isolated subclinical midline defects. The high incidence of midline-associated defects supports the theory that the midline plays a critical role in establishing left-right asymmetry in the body. Comparison of these defects with mouse models of laterality defects suggests that mutations that disrupt the transforming growth factor beta pathway may result in heterotaxy.

Structural and functional brain asymmetries in human situs inversus totalis.

OBJECTIVE: To determine whether individuals with situs inversus totalis (SI), a condition in which there is a mirror-image reversal of asymmetric visceral organs, have alterations in brain asymmetries. BACKGROUND: The human brain is asymmetric in structure and function. Although correlations between anatomic asymmetries and functional lateralization in human brain have been demonstrated, it has been difficult to further analyze them. Characterization of asymmetries of brain structure and function in SI might advance the understanding of these relationships. METHODS: Using anatomic and functional MRI techniques, we analyzed asymmetries in the brains of three individuals with SI. RESULTS: Two major anatomic asymmetries of the cerebral hemispheres, the frontal and occipital petalia, were reversed in individuals with SI. In contrast, SI subjects had left cerebral hemisphere language dominance on functional MRI analysis as well as strong right-handedness. CONCLUSION: These observations suggest that the developmental factors determining anatomic asymmetry of the cerebral petalia and viscera are distinct from those producing the functional lateralization of language.

Mucoepidermoid carcinoma of the eyelid skin.

PURPOSE: Mucoepidermoid carcinoma involving the eye or its adnexa generally arises from the conjunctiva. We describe a nodular lesion of the lower eyelid skin with histologic features consistent with low-grade mucoepidermoid carcinoma. METHOD: Case report. RESULTS: By histology, the tumor demonstrated areas of squamous cell carcinoma and scattered islands of mucin-secreting cells. Histochemistry showed hyaluronidase-resistant mucin and intense immunoreactivity with an antibody against carcinoembryonic antigen suggesting that the tumor originated from acrosyringeal structures. CONCLUSIONS: To our knowledge, this is the first report of a mucoepidermoid carcinoma arising from sweat glands in the eyelid skin.

Complications of extraocular muscle surgery.

This article reviews the goals, complications, interventions, and potential outcomes of extraocular muscle surgery. The information will support nursing interventions in the operating room and ambulatory care arenas, as well as those in school or public health settings.

Utility of direct measurement of low-density lipoprotein cholesterol in dyslipidemic pediatric patients.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) levels are the primary basis for treatment guidelines established for hyperlipidemic children and adolescents. Levels of LDL-C are commonly monitored by means of the Friedewald formula, an indirect calculation that requires an overnight fast. A new method has been developed for the direct measurement of LDL-C (DLDL-C) that does not require fasting. We evaluated the clinical utility of this method. DESIGN: We determined LDL-C concentrations simultaneously by the DLDL-C method, Friedewald equation, and beta-quantification (reference procedure). SETTING: Pediatric dyslipidemia clinic at Children's Hospital, Boston, Mass. PATIENTS: Ninety-two fasting hyperlipidemic pediatric patients. RESULTS: At the LDL-C concentration cutoffs commonly used for making therapeutic decisions, the DLDL-C method had a significant negative bias (P< or =.05) and misclassified patients into incorrect treatment groups more often than the Friedewald method. The negative predictive value for the DLDL-C method was lower than that for the Friedewald method (P< or =.05), and the cost of determining LDL-C level with the new method was 3 times greater. CONCLUSIONS: The misclassification potential for LDL-C, and the assay costs, were greater for the DLDL-C method than for the Friedewald calculation. Despite the apparent advantages of the DLDL-C method, we conclude that for hyperlipidemic children the utility of this new method is not advantageous over the conventional Friedewald method. In some conditions, such as in diabetes or marked hypertriglyceridemia, the DLDL-C method may be useful.

Patterning the heart's left-right axis: from zebrafish to man.

Normal left-right asymmetry is highly conserved among vertebrates. Errors in the proper patterning of this axis are believed to lead to congenital anomalies of the heart and abdominal viscera, often with profound clinical consequences. We review briefly the nature of potential signals and signaling sources that lead to the break in left-right symmetry. The evidence suggests that left-right reversal, or homogenization, of these signals may lead to different consequences, and we explain some malpositions and malalignments of the atria, ventricles, and/or outflow tract that are seen in a variety of congenital cardiac diseases. We speculate that there are units of organ assembly responsive to laterality signals, and these units may be driven independently. One crucial source of signals appears to be the notochord and floorplate. In order to examine the clinical relationship of these midline structures to putative disorders of laterality, we review all patients with disturbances of normal laterality seen at the Massachusetts General Hospital over the past 20 years. We find a significant association between laterality defects and anomalies of the spine and other midline structures.

Retinopathy of prematurity.

Research studies have provided advancements in knowledge regarding retinopathy of prematurity. Examination identifies premature infants with threshold disease that indicates need for treatment. It is hoped that timely evaluation and treatment will reduce the incidence of ROP-related blindiness.

Three zebrafish MEF2 genes delineate somitic and cardiac muscle development in wild-type and mutant embryos.

The zebrafish is an important experimental system for vertebrate embryology, and is well suited to the molecular analysis of muscle development. Transcription factors, such as the MEF2s, regulate skeletal and cardiac muscle-specific genes during development. We report the identification of three zebrafish MEF2 genes which, like their mammalian counterparts, encode factors that function as DNA-binding transcriptional activators of muscle specific promoters. The pattern of MEF2 expression in zebrafish defines discrete cell populations in the developing somites and heart and has mechanistic implications for developmental regulation of the MEF2 genes, when compared with other species. Alteration of MEF2 expression in two mutants affecting somitogenesis provides insight into the control of muscle formation in the embryo.

Analytical performance and clinical utility of a direct LDL-cholesterol assay in a hyperlipidemic pediatric population.

This study compares a new latex immunoseparation method for the direct determination of plasma low-density lipoprotein cholesterol (LDL-C) with the reference procedure for LDL-C (beta-quantification) in a pediatric hyperlipidemic population. The direct LDL-C assay has a mean bias of -98 mg/L in a fasting group (n = 96) of patients (mean triglycerides 1057 +/- 720 mg/L) and a bias of +177 mg/L in a nonfasting group (n = 42, mean triglycerides 4854 +/- 5457 mg/L). The mean total analytical error calculated from our data is 13.8%. The direct LDL-C assay and the commonly used Friedewald calculation respectively classified 81% and 84% of fasting patients correctly, according to the cutoffs of 1100 and 1300 mg/L for LDL-C set by the National Cholesterol Education Program for pediatric patients. Of combined fasting and nonfasting patients, 80% were correctly classified by the direct LDL-C assay. Therefore, despite several analytical shortcomings, the direct LDL-C assay may be useful in managing hyperlipidemic children without the need for a fasting specimen.

Lack of detection of enteroviral RNA or bacterial DNA in magnetic resonance imaging-directed muscle biopsies from twenty children with active untreated juvenile dermatomyositis.

OBJECTIVE: To investigate for the presence of increased titers of circulating antibody to putative infectious agents and for detectable viral RNA or bacterial DNA in children with active recent-onset juvenile dermatomyositis (DM). METHODS: Magnetic resonance imaging-directed muscle biopsies were performed in 20 children with active, untreated, recent-onset juvenile DM and in age-matched children with neurologic disease. Sera were tested for complement-fixing antibody to Coxsackievirus B (CVB), influenza A and B, parainfluenza 1 and 3, Mycoplasma pneumoniae, mumps, respiratory syncytial virus, and Reovirus; and by immunofluorescence for IgG antibody to Toxoplasma gondii cytomegalovirus and IgM antibody to Epstein-Barr virus. Muscle from juvenile DM patients and control children, CD-1 Swiss mice with and without CVB1 infection, and viral stock positive for CVB1-6 were tested using reverse-transcriptase polymerase chain reaction with 5 primer sets, 4 probes (1 Coxsackievirus, 3 Enterovirus), and universal primers for DNA. RESULTS: No increased antibody, viral RNA, or bacterial DNA was present in the juvenile DM patients or the control children. CONCLUSION: Juvenile DM may be triggered by unidentified agent(s) in the genetically susceptible host.

Bilateral diffuse iris nodular nevi. Clinical and histopathologic characterization.

BACKGROUND: Diffuse nodular nevus of the iris is an uncommon condition that presents with multiple verrucous excrescences distributed diffusely on the iris surface. METHODS: The authors describe 30 patients with bilateral diffuse iris nodular nevi and report associations with bilateral congenital cataract, neurofibromatosis, oculodermal melanocytosis, congenital ptosis, morning glory anomaly, Axenfeld anomaly, or Peters anomaly. RESULTS: Iris nodules were uniform in size and distribution and were brown, as was the surrounding iris. Light and electron microscopy of iridectomy specimens from one patient showed elevated plaques composed of aggregates of plump, lightly pigmented nevoid cells interwoven with mature, densely pigmented spindle-shaped uveal melanocytes. CONCLUSIONS: The authors report the largest clinical series and first ultrastructural description of bilateral diffuse iris nodular nevi, which represents a variant of neural crest development. No ocular complications could be attributed to the iris nodules, which should be differentiated from Lisch nodules and other pathologic iris lesions.

Intraocular dexamethasone penetration via subconjunctival or retrobulbar injections in rabbits.

Using high-performance liquid chromatography, we compared tissue levels of dexamethasone in the aqueous, vitreous, retina, and choroid of rabbits, 1 and 4 hours following subconjunctival or retrobulbar injection. One hour following injection, dexamethasone levels in all of these tissues were similar in both the subconjunctival and retrobulbar groups. Four hours following injection, the concentrations in the two groups also were similar, except in the choroid, in which the subconjunctival injection yielded significantly lower dexamethasone levels than the retrobulbar injection. Tissue steroid levels were comparable ipsilateral and contralateral to the injected eyes in both treatment groups after 4 hours, except in the retina, in which the levels were lower in the contralateral eye after subconjunctival injection. These data suggest that dexamethasone absorption and delivery is predominantly hematogenous following both subconjunctival and retrobulbar injection, especially in highly vascular tissues, such as the choroid. Hematogenous delivery of dexamethasone appears to peak earlier in the choroid and presumably in other intraocular tissues following subconjunctival injections, while retrobulbar injections provide more steady, long-term delivery.