RESUMO
BACKGROUND: Biotin functions as a cofactor for several carboxylase enzymes with key roles in metabolism. At present, the dietary requirement for biotin is unknown and intake recommendations are provided as Adequate Intakes (AIs). The biotin AI for adults and pregnant women is 30 µg/d, whereas 35 µg/d is recommended for lactating women. However, pregnant and lactating women may require more biotin to meet the demands of these reproductive states. OBJECTIVE: The current study sought to quantify the impact of reproductive state on biotin status response to a known dietary intake of biotin. METHODS: To achieve this aim, we measured a panel of biotin biomarkers among pregnant (gestational week 27 at study entry; n = 26), lactating (postnatal week 5 at study entry; n = 28), and control (n = 21) women who participated in a 10- to 12-wk feeding study providing 57 µg of dietary biotin/d as part of a mixed diet. RESULTS: Over the course of the study, pregnant women excreted 69% more (vs. control; P < 0.001) 3-hydroxyisovaleric acid (3-HIA), a metabolite that accumulates during the catabolism of leucine when the activity of biotin-dependent methylcrotonyl-coenzyme A carboxylase is impaired. Interestingly, urinary excretion of 3-hydroxyisovaleryl-carnitine (3-HIA-carnitine), a downstream metabolite of 3-HIA, was 27% lower (P = 0.05) among pregnant (vs. control) women, a finding that may arise from carnitine inadequacy during gestation. No differences (P > 0.05) were detected in plasma biotin, urinary biotin, or urinary bisnorbiotin between pregnant and control women. Lactating women excreted 76% more (vs. control; P = 0.001) of the biotin catabolite bisnorbiotin, indicating that lactation accelerates biotin turnover and loss. Notably, with respect to control women, lactating women excreted 23% less (P = 0.04) urinary 3-HIA and 26% less (P = 0.05) urinary 3-HIA-carnitine, suggesting that lactation reduces leucine catabolism and that these metabolites may not be useful indicators of biotin status during lactation. CONCLUSIONS: Overall, these data demonstrate significant alterations in markers of biotin metabolism during pregnancy and lactation and suggest that biotin intakes exceeding current recommendations are needed to meet the demands of these reproductive states. This trial was registered at clinicaltrials.gov as NCT01127022.
Assuntos
Biotina/análogos & derivados , Biotina/metabolismo , Dieta , Lactação/sangue , Gravidez , Adulto , Biomarcadores/sangue , Biotina/sangue , Biotina/urina , Carbono-Carbono Ligases/metabolismo , Carnitina/análogos & derivados , Carnitina/urina , Colina/administração & dosagem , Cromatografia Líquida , Suplementos Nutricionais , Feminino , Humanos , Leucina/metabolismo , Leite Humano/química , New York , Cooperação do Paciente , Espectrometria de Massas em Tandem , Valeratos/urina , Adulto JovemRESUMO
The leucine metabolite, ß-hydroxy-ß-methylbutyrate (HMB), is a nutritional supplement that increases lean muscle and strength with exercise and in disease states. HMB is presently available as the Ca salt (CaHMB). The present study was designed to examine whether HMB in free acid gel form will improve HMB availability to tissues. Two studies were conducted and in each study four males and four females were given three treatments in a randomised, cross-over design. Treatments were CaHMB (gelatin capsule, 1 g), equivalent HMB free acid gel swallowed (FASW) and free acid gel held sublingual for 15 s then swallowed (FASL). Plasma HMB was measured for 3 h following treatment in study 1 and 24 h with urine collection in study 2. In both the studies, the times to peak plasma HMB were 128 (sem 11), 38 (sem 4) and 38 (sem 1) min (P < 0·0001) for CaHMB, FASW and FASL, respectively. The peak concentrations were 131 (sem 6), 249 (sem 14) and 239 (sem 14) µmol/l (P < 0·0001) for CaHMB, FASW and FASL, respectively. The areas under the curve were almost double for FASW and FASL (P < 0·0001). Daily urinary HMB excretion was not significantly increased resulting in more HMB retained (P < 0·003) with FASW and FASL. Half-lives were 3·17 (sem 0·22), 2·50 (sem 0·13) and 2·51 (sem 0·14) h for CaHMB, FASW and FASL, respectively (P < 0·004). Free acid gel resulted in quicker and greater plasma concentrations (+185%) and improved clearance (+25%) of HMB from plasma. In conclusion, HMB free acid gel could improve HMB availability and efficacy to tissues in health and disease.
Assuntos
Compostos de Cálcio/farmacocinética , Valeratos/farmacocinética , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Suplementos Nutricionais , Feminino , Géis , Humanos , Estudos Longitudinais , Masculino , Taxa de Depuração Metabólica , Sais/farmacocinética , Valeratos/sangue , Valeratos/química , Valeratos/urina , Adulto JovemRESUMO
OBJECTIVE: The purpose of this investigation was to determine the effects of biotin deficiency on maternal metabolism and embryonic development in pregnant mouse dams. METHODS: The pregnant mice were randomly assigned to one of three dietary groups and given a biotin-deficient diet, biotin-supplemented diet, or biotin-control diet during gestation. On days of gestation (dgs) 0, 4, 8, 12, and 16, organic acids including 3-hydroxyisovaleric acid in urine were discovered by high-performance liquid chromatography, and the biotin level in the serum and urine was determined by a bioassay. On dg 18, fetuses were examined for morphologic development. RESULTS: In the biotin-deficient group, biotin excretion in urine decreased on dg 4 and was subsequently below the lower limit, whereas the urinary concentration of 3-hydroxyisovaleric acid increased after dg 12. In contrast, the biotin concentration in urine significantly increased on dgs 4, 8 and 12 in the biotin-supplemented group, but decreased on dg 16 in the biotin-supplemented and biotin-control groups. The urinary excretion of pyruvic acid in the biotin-deficient group was significantly higher than that in the biotin-supplemented group throughout the entire gestation. These concentrations in urine significantly increased on dg 16 compared with dg 0. The inhibition of embryonic development and external malformations such as cleft palate (100%), micrognathia (100%), and micromelia (91.4%) were also detected in biotin-deficient fetuses. CONCLUSION: These findings indicated that, as the requirement of biotin increases during gestation and/or embryonic development, a large amount of biotin is necessary for maintaining normal reproductive performance during the late stage of gestation.
Assuntos
Biotina/deficiência , Biotina/metabolismo , Anormalidades Congênitas/etiologia , Desenvolvimento Embrionário , Metabolismo Energético/fisiologia , Prenhez/metabolismo , Animais , Biotina/sangue , Biotina/urina , Cromatografia Líquida de Alta Pressão/métodos , Anormalidades Congênitas/epidemiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Feto/metabolismo , Idade Gestacional , Masculino , Camundongos , Camundongos Endogâmicos ICR , Necessidades Nutricionais , Gravidez , Resultado da Gravidez , Distribuição Aleatória , Valeratos/urinaRESUMO
Pyruvate carboxylase (PC) is a biotin-dependent enzyme that plays a crucial role in gluconeogenesis, lipogenesis, Krebs cycle anaplerosis and amino acid catabolism. Biotin deficiency reduces its mass besides its activity. Enzyme mass is the result of its cellular turnover, i.e., its rates of synthesis and degradation. We have now investigated, by a pulse and chase approach in cultured primary hepatocytes, the effects of biotin deficiency on these rates. Wistar rats were fed a biotin-deficient diet and the controls were fed the same diet supplemented with biotin; their biotin status was monitored measuring lymphocytes propionyl-CoA carboxylase activity and urinary 3-hydroxyisovaleric acid. After 6-7 weeks primary hepatocytes were cultured in biotin-deficient or complete DMEM. PC activity was determined by measuring the incorporation of (14)C-bicarbonate into acid-non-volatile products, and its mass by streptavidin Western blots. Its synthesis rate was estimated from [(35)S] methionine incorporation into anti-PC antibody immunoprecipitate. Its degradation rate was calculated from the loss of radioactivity from previously labeled hepatocytes, in a medium containing an excess of non-radioactive methionine. PC synthesis rate in biotin-deficient hepatocytes was approximately 4.5-fold lower than in the controls, and its degradation rate was 5.1-fold higher. Therefore, the decrement of PC mass during biotin deficiency results both from a decrease in its synthesis and an increase in its degradation rates. To our knowledge, this is the first instance where a mammalian enzyme cofactor is necessary to sustain both processes.
Assuntos
Biotina/deficiência , Hepatócitos/enzimologia , Linfócitos/enzimologia , Metilmalonil-CoA Descarboxilase/metabolismo , Piruvato Carboxilase/metabolismo , Animais , Biotinilação , Hepatócitos/citologia , Linfócitos/citologia , Masculino , Ratos , Ratos Wistar , Valeratos/urinaRESUMO
A sensitive indicator of biotin status for lactating dairy cows is necessary to understand factors that affect milk yield responses to biotin supplementation. 3-Hydroxyisovaleric acid (3HIA) is an alternative metabolite in the pathway of Leu catabolism when the biotin-dependent enzyme methylcrotonyl-coenzyme A carboxylase is limiting. We evaluated urinary excretion of 3HIA as a determinant of biotin status in lactating dairy cows. We hypothesized that high-producing cows would have a greater biotin requirement and excrete more 3HIA than low-producing cows and that biotin supplementation would decrease 3HIA excretion. Twenty high-producing and 20 low-producing Holstein cows (43 +/- 5 and 23 +/- 4 kg/d of milk, respectively) were fed diets that contained either 0 or 0.96 mg/kg of supplemental biotin. On d 16 cows were given an intraruminal infusion of 1.4 mol of isovaleric acid and urine was sampled. Biotin supplementation did not affect basal urinary excretion of 3HIA. The infusion of isovaleric acid increased urinary excretion of 3HIA (maximum at 8 h after infusion), but biotin supplementation did not attenuate this increase. The increase in urinary 3HIA excretion was less for low-producing cows than for high-producing cows. Biotin increased yields of milk and milk components in high-producing cows but had no effect in low-producing cows. However, potential measures of biotin status (concentrations of avidin-binding substances in the plasma, milk, and urine, and urinary 3HIA excretion) responded similarly to biotin supplementation for both high- and low-producing cows. A sensitive indicator of biotin status for lactating dairy cows is still needed.
Assuntos
Biotina/administração & dosagem , Bovinos/fisiologia , Dieta/veterinária , Suplementos Nutricionais , Lactação/fisiologia , Animais , Indústria de Laticínios , Ácidos Graxos Voláteis/metabolismo , Feminino , Leite/química , Leite/metabolismo , Rúmen/química , Rúmen/metabolismo , Fatores de Tempo , Valeratos/administração & dosagem , Valeratos/urinaRESUMO
A patient with a severe neonatal variant of 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is reported. The first child of healthy consanguineous Turkish parents presented on the second day of life with dehydration, cyanosis, no sucking, generalized muscular hypotonia, encephalopathy, respiratory depression requiring mechanic ventilation, macrocephaly, severe acidosis and hypoglycaemia. Elevated C5-OH-carnitine in dried blood spot by tandem MS and elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine suggested MCC deficiency, confirmed by enzyme analysis in cultured fibroblasts. Cerebral ultrasonography and cranial CT findings revealed progressive changes such as disseminated encephalomalacia, cystic changes, ventricular dilatation and cerebral atrophy. Treatment with high-dose biotin and protein-restricted diet was ineffective and the patient died at the age of 33 days with progressive neurological deterioration. Mutation analysis revealed a homozygous mutation in the splice acceptor site of intron 15 in the MCC beta-subunit. Early-onset severe necrotizing encephalopathy should be included in the differential diagnosis of isolated MCC deficiency.
Assuntos
Carbono-Carbono Ligases/genética , Glicina/análogos & derivados , Leucoencefalite Hemorrágica Aguda/etiologia , Erros Inatos do Metabolismo/complicações , Carbono-Carbono Ligases/deficiência , Consanguinidade , Diagnóstico Diferencial , Evolução Fatal , Glicina/urina , Humanos , Lactente , Recém-Nascido , Leucoencefalite Hemorrágica Aguda/diagnóstico , Masculino , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Mutação , Sítios de Splice de RNA/genética , Valeratos/urinaRESUMO
Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing alpha subunits and smaller beta subunits, encoded by MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype that ranges from severe neonatal to asymptomatic adult forms. No reported patients have responded to biotin therapy. Here, we describe two patients with a biochemical and, in one case, clinical phenotype of MCC deficiency, both of whom were responsive to biotin. The first patient presented at 3 months with seizures and progressive psychomotor retardation. Metabolic investigation at 2 years revealed elevated excretion of 3-MCG and 3-HIVA, suggesting MCC deficiency. High-dose biotin therapy was associated with a dramatic reduction in seizures, normalization of the electroencephalogram, and correction of the organic aciduria, within 4 weeks. MCC activity in fibroblasts was 25% of normal levels. The second patient, a newborn detected by tandem-mass-spectrometry newborn screening, displayed the same biochemical phenotype and remained asymptomatic with biotin up to the age of 18 months. In both patients, sequence analysis of the complete open reading frames of MCCA and MCCB revealed heterozygosity for MCCA-R385S and for the known polymorphic variant MCCA-P464H but revealed no other coding alterations. MCCA-R385S is unusual, in that it has a normal amount of MCC alpha protein but confers no MCC activity. We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA-wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo.
Assuntos
Alelos , Biotina/uso terapêutico , Carbono-Carbono Ligases/deficiência , Carbono-Carbono Ligases/genética , Glicina/análogos & derivados , Doenças Mitocondriais/tratamento farmacológico , Sequência de Bases , Biotina/metabolismo , Análise Mutacional de DNA , Relação Dose-Resposta a Droga , Fibroblastos/metabolismo , Expressão Gênica , Vetores Genéticos/genética , Alemanha , Glicina/urina , Grécia , Humanos , Recém-Nascido , Masculino , Dados de Sequência Molecular , Mutação/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Transfecção , Valeratos/urinaRESUMO
We report the clinical course and biochemical findings of a 10-year-old, mentally retarded girl with late-onset holocarboxylase synthetase (HCS, gene symbol HLCS) deficiency and only partial response to biotin. On treatment, even with an unusually high dose of 200mg/day, activities of the biotin-dependent mitochondrial carboxylases in lymphocytes remained below 50% of the mean control values. Not only urinary 3-hydroxyisovaleric acid excretion has been persistently elevated, but also plasma and, with even higher concentrations, cerebrospinal fluid 3-hydroxyisovaleric acid have not normalized. The unusual and insufficient response of this patient to biotin treatment can be explained by the effect of the combination of the common HLCS allele IVS10 +5 g>a on one chromosome and a truncating mutation on the other. This case illustrates mechanisms involved in the genotype-phenotype correlation that unequivocally exists in HCS deficiency.
Assuntos
Biotina/uso terapêutico , Carbono-Nitrogênio Ligases/genética , Deficiência de Holocarboxilase Sintetase/tratamento farmacológico , Deficiência de Holocarboxilase Sintetase/genética , Idade de Início , Biotina/administração & dosagem , Carbono-Carbono Ligases/metabolismo , Carbono-Nitrogênio Ligases/deficiência , Criança , Análise Mutacional de DNA , Feminino , Genes Recessivos , Deficiência de Holocarboxilase Sintetase/sangue , Humanos , Metilmalonil-CoA Descarboxilase/metabolismo , Mutação , Fenótipo , Piruvato Carboxilase/metabolismo , Splicing de RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Valeratos/urinaRESUMO
BACKGROUND: The results of clinical studies have provided evidence that marginal biotin deficiency is more common than was previously thought. A previous study of 10 subjects showed that the urinary excretion of biotin and 3-hydroxyisovaleric acid (3HIA) are early and sensitive indicators of marginal biotin deficiency. OBJECTIVE: Marginal biotin deficiency was experimentally induced and corrected to assess the utility of 3 indicators of biotin status: urinary excretion of biotin and 3HIA and the increase in 3HIA excretion after leucine loading. DESIGN: Eleven healthy adults consumed an egg white diet for 28 d. Blood and 24-h urine samples were collected before the start of the diet and twice weekly thereafter. In 5 subjects, an oral leucine challenge was performed weekly for 4 wk. After depletion, biotin status was restored with a general diet with or without a supplement containing 80 micro g biotin. Urinary excretion of biotin, bisnorbiotin, and biotin sulfoxides was determined by avidin-binding assay after HPLC. Excretion of 3HIA, an indicator of reduced activity of the biotin-dependent enzyme methylcrotonyl-CoA carboxylase (EC 6.4.1.4), was measured by gas chromatography-mass spectrometry. RESULTS: 3HIA excretion increased significantly with time on the egg white diet (P < 0.0001), as did 3HIA excretion in response to the leucine challenge (P < 0.002); the excretion of both biotin and bisnorbiotin decreased significantly with time (P < 0.0001). In most subjects, biotin status returned to normal after 1 wk of a general diet. CONCLUSIONS: Excretion of 3HIA and of biotin are early and sensitive indicators of biotin deficiency. 3HIA excretion after a leucine challenge is at least as sensitive.
Assuntos
Biotina/análogos & derivados , Biotina/deficiência , Biotina/metabolismo , Leucina/farmacologia , Valeratos/urina , Adulto , Biotina/urina , Dieta , Relação Dose-Resposta a Droga , Clara de Ovo , Feminino , Humanos , Leucina/administração & dosagem , Masculino , Fatores de TempoRESUMO
We describe a 3-year-old boy with biotin dependency not caused by biotinidase, holocarboxylase synthetase, or nutritional biotin deficiency. We sought to define the mechanism of his biotin dependency. The child became acutely encephalopathic at age 18 months. Urinary organic acids indicated deficiency of several biotin-dependent carboxylases. Symptoms improved rapidly following biotin supplementation. Serum biotinidase activity and Biotinidase gene sequence were normal. Activities of biotin-dependent carboxylases in PBMCs and cultured skin fibroblasts were normal, excluding biotin holocarboxylase synthetase deficiency. Despite extracellular biotin sufficiency, biotin withdrawal caused recurrent abnormal organic aciduria, indicating intracellular biotin deficiency. Biotin uptake rates into fresh PBMCs from the child and into his PBMCs transformed with Epstein Barr virus were about 10% of normal fresh and transformed control cells, respectively. For fresh and transformed PBMCs from his parents, biotin uptake rates were consistent with heterozygosity for an autosomal recessive genetic defect. Increased biotin breakdown was ruled out, as were artifacts of biotin supplementation and generalized defects in membrane permeability for biotin. These results provide evidence for a novel genetic defect in biotin transport. This child is the first known with this defect, which should now be included in the identified causes of biotin dependency.
Assuntos
Biotina/deficiência , Ácido Láctico/análogos & derivados , Simportadores/deficiência , Amidoidrolases/metabolismo , Transporte Biológico , Biotinidase , Carbono-Carbono Ligases/metabolismo , Carboxiliases/metabolismo , Proteínas de Transporte/genética , Linhagem Celular Transformada , Pré-Escolar , Feminino , Humanos , Ácido Láctico/urina , Leucócitos Mononucleares/citologia , Masculino , Glicoproteínas de Membrana/genética , Metilmalonil-CoA Descarboxilase , Piruvato Carboxilase/metabolismo , Síndrome de Abstinência a Substâncias/enzimologia , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/urina , Valeratos/urinaRESUMO
BACKGROUND: Biotin deficiency is teratogenic in several mammalian species. Approximately 50% of pregnant women have an abnormally increased urinary excretion of 3-hydroxyisovaleric acid (3-HIA), which probably reflects decreased activity of the biotin-dependent enzyme methylcrotonyl-CoA carboxylase. However, increased 3-HIA excretion could result from pregnancy per se (eg, from an effect of pregnancy on renal handling of organic acids). OBJECTIVE: We tested the hypothesis that biotin supplementation significantly decreases 3-HIA excretion in pregnant women with abnormally increased 3-HIA excretion. DESIGN: Twenty-six pregnant women with increased 3-HIA excretion were studied in a randomized, placebo-controlled trial; 10 women were studied during early pregnancy (6-17 wk gestation) and 16 women during late pregnancy (21-37 wk gestation). Urine samples were collected before and after 14 d of supplementation with 300 microg (1.2 micromol) biotin/d or placebo. RESULTS: In the early-pregnancy group, 3-HIA excretion decreased (P < 0.006) by 11.7 +/- 3.6 mmol/mol creatinine (mean +/- SEM) in the 5 women who received biotin supplements, whereas 3-HIA excretion increased by 1.6 +/- 0.6 mmol/mol creatinine in the 5 women who received placebo. In the late-pregnancy group, 3-HIA excretion decreased (P < 0.002) by 7.1 +/- 1.2 mmol/mol creatinine in the 8 women who received biotin supplements, whereas 3-HIA excretion increased by 0.9 +/- 1.8 mmol/mol creatinine in the 8 women who received placebo. CONCLUSIONS: This study provides evidence that the increased excretion of 3-HIA seen frequently in normal pregnancy reflects reduced biotin status. The conclusion that marginal biotin deficiency occurs frequently in the first trimester further raises concern about potential human teratogenicity.
Assuntos
Biotina/deficiência , Valeratos/urina , Adulto , Biotina/uso terapêutico , Deficiências Nutricionais/tratamento farmacológico , Deficiências Nutricionais/urina , Feminino , Humanos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/urinaRESUMO
Biotin deficiency associated with total parenteral nutrition is an emerging clinical problem; criteria for diagnosis and dosage for treatment are unclear. We have diagnosed and successfully treated biotin deficiency in three patients. Each patient had alopecia totalis, hypotonia, and developmental delay. Two developed the characteristic scaly periorificial dermatitis; one had only an intermittent scaly rash on the cheeks and occipital scalp. Zinc and essential fatty acid supplements were adequate; serum zinc levels and triene/tetraene ratios confirmed sufficiency of these nutrients. None of the patients received biotin prior to diagnosis, and each had decreased excretion of urinary biotin and increased urinary excretion of organic acids diagnostic of deficiency of two biotin-dependent enzymes (methylcrotonyl-coenzyme A carboxylase and priopionyl-coenzyme A carboxylase). Only one patient had a plasma biotin concentration below the normal range (Ochromonicas danica assay). The rash, alopecia, and neurologic findings responded dramatically to biotin therapy (100 micrograms/day in all patients; an initial larger dose of 1 mg/day for 1 week plus 10 mg/day for 7 weeks in one patient), and did not recur. However, abnormal organic acid excretion persisted in one patient who did not receive the larger dose. We conclude that plasma biotin concentration does not reflect biotin status in all cases and speculate that the biotin supplement currently recommended for pediatric patients (20 micrograms/day) may not be adequate therapy for biotin deficiency and might not even be adequate to maintain normal biotin status during TPN.
Assuntos
Biotina/deficiência , Ácido Láctico/análogos & derivados , Nutrição Parenteral/efeitos adversos , Alopecia/etiologia , Biotina/urina , Citratos/urina , Diagnóstico Diferencial , Eritema/etiologia , Ácidos Graxos Essenciais/deficiência , Feminino , Glicina/análogos & derivados , Glicina/urina , Humanos , Lactente , Isomerismo , Lactatos/urina , Masculino , Doenças do Sistema Nervoso/etiologia , Valeratos/urina , Zinco/deficiênciaRESUMO
Hypoglycin A, the causative agent of the Jamaican vomiting sickness, produced a marked increase in concentration of isovaleric acid in the plasma of rats, when administered in a single dose. alpha-Methylbutyric acid, a position isomer, also accumulated. The use of hypoglycin A reproduced some features of human isovaleric acidemia. Accumulation of these branched pentanoic acids may be another factor contributing to the pathogenesis of the Jamaican vomiting sickness.