Citations

SUMMARYMurine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 × CBA)F1 mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3+ mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves’ hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.

Nutritional rickets has occasionally been described in children with lamellar ichthyosis, but their vitamin D endocrine status has not been described. We report 3 cases of vitamin D-deficiency rickets associated with ichthyosis in African children. A 13-month-old Nigerian boy with lamellar ichthyosis had rib beading, elevated alkaline phosphatase, and rachitic changes on radiographs. His rickets did not resolve with calcium therapy, and his 25-hydroxyvitamin D level was low. His rickets resolved with parenteral vitamin D treatment, but his skin did not improve. Topical 0.005% calcipotriene (an analog of 1,25-dihydroxyvitamin D that has been useful in treating adults with psoriasis) was similarly ineffective in improving the child's skin condition. An 8-year-old Nigerian boy with life-long skin findings consistent with lamellar ichthyosis had windswept deformity of the legs with rib beading and enlargement of the wrists and ankles. Radiographs showed active rickets, and the boy had an elevated alkaline phosphatase level and a decreased calcium level. Before knowing that his 25-hydroxyvitamin D level was low, he was treated with calcium and showed radiologic improvement. The skin did not improve with resolution of the rickets but did improve with unilateral topical application of 0.005% calcipotriene. A 7-year-old South African girl presented with progressive windswept deformities of the legs and a 4-year history of skin disease (and a skin biopsy consistent with X-linked ichthyosis). Radiographs and biochemical data confirmed active rickets. Her rickets improved dramatically with vitamin D treatment. Thus, 3 African children with ichthyosis developed vitamin D-deficiency rickets, probably because of a combination of impaired skin production and sunlight avoidance. This is consistent with previous findings of hypovitaminosis D in adults with ichthyosis and other disorders of keratinization. Measurement of 25-hydroxyvitamin D may be indicated in children with ichthyosis to identify those at risk for vitamin D-deficiency rickets, because it is possible that the cutaneous synthesis of vitamin D in such children is impaired. Although the ichthyosis did not improve with resolution of vitamin D deficiency and rickets, 1 of 2 children treated with topical calcipotriene showed improvement in the treated areas of skin. Calcipotriene does not seem to be effective in reversing systemic vitamin D deficiency but can be effective in improving the severity of skin disease in children with ichthyosis.

Objective. Anaphylaxis after immunization, although rare, is serious and potentially life-threatening. Understanding risk factors for this reaction is therefore important. Gelatin is added to many vaccines as a heat stabilizer. Japanese researchers have demonstrated a strong association between immediate hypersensitivity reactions to measles, mumps, rubella, varicella, and Japanese encephalitis immunizations and subsequent detection of anti-gelatin immunoglobulin E (IgE) antibodies. They suggested that previous receipt by these patients of diphtheria-tetanus-acellular pertussis vaccines with trace amounts of gelatin was responsible for the sensitization. We aimed to assess whether a similar association exists for vaccinees in the United States who reported anaphylaxis after receipt of measles-mumps-rubella (MMR) or measles vaccines and to review recent trends in reporting of hypersensitivity reactions. Methods. We conducted a retrospective case-control study. Cases of anaphylaxis that met a predefined case definition were identified from the US Vaccine Adverse Event Reporting System (VAERS). Mayo Clinic patients who received MMR vaccine uneventfully served as controls. The study subjects were interviewed to obtain the history of allergies. Sera from study subjects and their matched controls were tested for IgE antibodies to gelatin, whole egg, and vaccine viral antigens using solid-phase radioimmunoassay. Data from the Biologics Surveillance System on annual numbers of doses of MMR and varicella vaccines distributed in the United States were used to evaluate possible changes in reporting of selected allergic adverse events. Results. Fifty-seven study subjects were recruited into the study and interviewed. Of these, 22 provided serum samples for IgE testing. Twenty-seven subjects served as a comparison group and provided a sample for IgE testing; 21 of these completed an allergy history questionnaire. Self-reported history of food allergies was present more frequently in the interviewed study subjects than in the controls, whereas the proportions of people with other characteristics were similar in both groups. None of the interviewed people had a history of food allergy to gelatin. The level of anti-gelatin IgE antibodies was significantly higher among study subjects than among controls, whereas the levels of IgE antibodies against egg and all 3 viral antigens did not differ significantly. Of 22 study subjects, 6 (27%) tested positive for anti-gelatin IgE, whereas none of the 27 controls did. The rate of anaphylactic reactions reported to VAERS after measles virus-containing immunization in the United States between 1991 and 1997 is 1.8 per 1 million doses distributed. No substantial increase in the number of reported allergic events after frequently used gelatin containing MMR and varicella vaccines could be observed during the first 4 years (1997–2000) since the introduction of diphtheria-tetanus-acellular pertussis vaccines for use in infancy. Conclusion. Anaphylactic reactions to MMR in the United States are rare. The reporting rate has the same order of magnitude as estimates from other countries. Almost one fourth of patients with reported anaphylaxis after MMR seem to have hypersensitivity to gelatin in the vaccine. They may be at higher risk of developing anaphylaxis to subsequent doses of other gelatin-containing vaccines. These people should seek an allergy evaluation before such immunization.

Very long chain fatty acid dehydrogenase (VLCAD) deficiency is a rare but treatable cause of cardiomyopathy, fatty liver, skeletal myopathy, pericardial effusions, ventricular arrhythmias, and sudden death. Unrecognized, VLCAD deficiency may be rapidly progressive and fatal, secondary to its cardiac involvement. Because early diagnosis improves outcome, we present a neonate with VLCAD deficiency in whom retrospective analysis of the newborn screening card revealed that a correct diagnosis could have been made by newborn screening using tandem mass spectrometry. Our patient demonstrated a classic neonatal course with transient hypoglycemia at birth, interpreted as culture-negative sepsis, followed by a quiescent period notable only for hypotonia and poor feeding. At 3 months, he presented with cardiorespiratory failure and pericardial effusions, requiring pericardiocentesis, tracheostomy, and prolonged mechanical ventilation. Plasma free-fatty acid and acylcarnitine profiles demonstrated small but significant elevations of C14:2, C14:1, C16, and C18:1 acylcarnitine species, findings consistent with a biochemical diagnosis of VLCAD deficiency. Enteral feeds were changed to Portagen formula with marked improvement in cardiac symptoms over several weeks. To confirm the biochemical diagnosis, molecular analysis was performed by analysis of genomic DNA on a blood sample of the patient. Sequencing analysis and delineation of VLCAD mutations were performed using polymerase chain reaction and genomic sequencing. The patient was heterozygous for 2 different disease-causing mutations at the VLCAD locus. The maternal mutation was a deletion of bp 842–3 in exon 8, causing a shift in the reading frame. The paternal mutation was G+1A in the consensus donor splice site after exon 1; this splice-site mutation would likely result in decreased mRNA. The likely consequence of these mutations is essentially a null phenotype. To determine whether this case could have been picked up by tandem mass spectrometry analysis at birth when the patient was asymptomatic, acylcarnitine analysis was performed on the patient's original newborn card (after obtaining parental consent, the original specimen was provided courtesy of Dr Kenneth Pass, Director, New York State Newborn Screening Program). The blood sample had been obtained at 1 week of age and stored at room temperature for 6 months and at 70°C thereafter for 18 months. Electrospray tandem mass spectrometry used a LC-MS/MS API 2000 operated in ion evaporation mode with the TurboIonSpray ionization probe source. The acylcarnitine profile obtained from the patient's original newborn card was analyzed 2 years after it was obtained. In comparison with a normal control, there was a significant accumulation of long chain acylcarnitine species, with a prominent peak of tetradecenoylcarnitine (C14:1), the most characteristic metabolic marker of VLCAD deficiency. This profile would have likely been even more significant if it had been analyzed at the time of collection, yet 2 years later is sufficient to provide strong biochemical evidence of the underlying disorder. Discussion. VLCAD was first discovered in 1992, and clinical experience with VLCAD deficiency has been accumulating rapidly. Indeed, the patients originally diagnosed with long chain acyl-CoA deficiency suffer instead from VLCAD deficiency. The phenotype of VLCAD deficiency is heterogeneous, ranging from catastrophic metabolic and cardiac failure in infancy to mild hypoketotic, hypoglycemia, and exertional rhabdomyolysis in adults. This case demonstrates that VLCAD deficiency could have been detected from the patient's own neonatal heel-stick sample. Most likely, a presymptomatic diagnosis would have avoided at least part of a lengthy and intensive prediagnosis hospitalization that had an estimated cost of $400 000. Although VLCAD is relatively rare, timely and correct diagnosis leads to dramatic recovery, so that detection by newborn screening could prevent the onset of arrhythmias, heart failure, metabolic insufficiency, and death. Fatty acid oxidation defects, including VLCAD deficiency, may account for as many as 5% of sudden infant death patients. Recent instrumentation advances have made automated tandem mass spectrometry of routine neonatal heel-stick samples technically feasible. Pilot studies have demonstrated an incidence of fatty acid oxidation defects, including short chain, medium chain, and very long chain acyl-CoA dehydrogenase deficiencies, of approximately 1/12 000. As a result, cost-benefit ratios for this approach should be systematically examined.

Objective. To evaluate factors related to the development and persistence of adolescent sleep problems. Methods. In this longitudinal, population-based study, the Teenage Attitudes and Practices Survey was administered by telephone to 7960 adolescents (3921 girls and 4039 boys) 12 to 18 years old in 1989 and at follow-up in 1993. Sleep problems at both time points were assessed using a single item on the Teenage Attitudes and Practices Survey. Those who responded that they “often or sometimes” had trouble going to sleep or staying asleep during the past 12 months were categorized as reporting sleep problems, whereas those who responded “often” were categorized as having frequent sleep problems. Multiple logistic regression analyses were used to identify baseline characteristics predictive of the development and persistence of sleep problems or frequent sleep problems, respectively, from baseline to follow-up. Results. Of the 4866 adolescents without sleep problems at baseline, 28% developed sleep problems by 1993, and 9% developed frequent sleep problems. Of the 3094 adolescents who reported sleep problems at baseline, 52% reported sleep problems in 1993, and 21% reported frequent sleep problems. Female sex and notable depressive symptoms were associated with the development and persistence of sleep problems and frequent sleep problems at follow-up. Cigarette smoking status showed a dose–response relationship with development of sleep problems and frequent sleep problems, and with persistence of frequent sleep problems at follow-up. Conclusion. The reduction of depressive symptoms and cigarette smoking among adolescents are important factors to consider in prevention and treatment efforts focused on adolescent sleep problems.

Abstract OBJECTIVE AND IMPORTANCE A case of acutely symptomatic epidural hematoma caused by metastatic hepatocellular carcinoma (HCC) to the cranium is reported. This is a rare case of metastatic HCC without known primary presenting as an epidural hematoma. CLINICAL PRESENTATION The patient presented with an acute onset of headache, aphasia, and right hemiparesis 2 weeks after he experienced minor trauma to the cranium. An emergency computed tomographic scan of the head revealed the presence of a left parietal epidural hematoma. INTERVENTION An emergency evacuation of the epidural hematoma was performed, and metastatic HCC was diagnosed. CONCLUSION The patient's neurological deficits were reversed with surgical intervention, and he is now undergoing palliative chemotherapy. This was the first clinical manifestation of HCC in this patient. This case reaffirms the neurosurgeon's role in the complex, multidisciplinary care of patients with craniospinal metastasis.