Lyme disease vaccine as a strategy for prevention.
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Adolescent↗
Biomedical subjects
S K Sood
Publications and source records attributed to S K Sood.
Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways.
Hepatic steatosis is common in patients having severe hyperhomocysteinemia due to deficiency for cystathionine beta-synthase. However, the mechanism by which homocysteine promotes the development and progression of hepatic steatosis is unknown. We report here that homocysteine-induced endoplasmic reticulum (ER) stress activates both the unfolded protein response and the sterol regulatory element-binding proteins (SREBPs) in cultured human hepatocytes as well as vascular endothelial and aortic smooth muscle cells. Activation of the SREBPs is associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake and with intracellular accumulation of cholesterol. Homocysteine-induced gene expression was inhibited by overexpression of the ER chaperone, GRP78/BiP, thus demonstrating a direct role of ER stress in the activation of cholesterol/triglyceride biosynthesis. Consistent with these in vitro findings, cholesterol and triglycerides were significantly elevated in the livers, but not plasmas, of mice having diet-induced hyperhomocysteinemia. This effect was not due to impaired hepatic export of lipids because secretion of VLDL-triglyceride was increased in hyperhomocysteinemic mice. These findings suggest a mechanism by which homocysteine-induced ER stress causes dysregulation of the endogenous sterol response pathway, leading to increased hepatic biosynthesis and uptake of cholesterol and triglycerides. Furthermore, this mechanism likely explains the development and progression of hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia.
Animals↗
Safety and immunogenicity of a recombinant Borrelia burgdorferi outer surface protein A vaccine against lyme disease in healthy children and adolescents: a randomized controlled trial.
OBJECTIVE: A recombinant lipoprotein outer surface protein A (OspA) Lyme disease (LD) vaccine (LYMErix) has been shown to be safe and effective in preventing LD in adults and in adolescents 15 years of age and older. Children are at risk for developing LD. This clinical study was conducted to address the safety and immunogenicity of LD vaccine in children 4 to 18 years of age. METHODS: A randomized, placebo-controlled clinical trial was conducted at 17 investigational sites in Lyme-endemic areas in the United States. Immunogenicity data from this study also were compared with data obtained from the adult efficacy study. A total of 4090 healthy children and adolescents (age range: 4-18; mean age: 10.4 years) were randomized; 4087 were vaccinated, and a subset of 301 children participated in the immunogenicity analysis. Children were randomized to receive either 30 microgram of LD vaccine (N = 3063) or placebo (N = 1024) on a 0, 1, 12-month schedule. Safety assessments evaluated both solicited (local: redness, swelling, and pain; general: fever, headache, fatigue, arthralgia, and rash) and unsolicited adverse events. Serum specimens were collected at month 0 or month 2, and months 6, 12, and 13. RESULTS: Solicited reactogenicity data revealed a higher incidence of local injection site reactions and general symptoms (fever, headache, fatigue, and arthralgia) in vaccine than placebo recipients. The majority of events were limited in duration (mean: 2-3 days) and were mild to moderate in severity. The total IgG anti-OspA geometric mean titer (GMT) in the pediatric vaccine recipients at month 13 was as good as and statistically higher than the GMT in the adult cohort at month 13 (27 485 enzyme-linked immunosorbent assay units [EL.U]/mL vs 8216 EL.U /mL). All of the pediatric vaccine recipients attained a level of antibody concentration >/=1400 EL.U/mL (proposed seroprotective level) compared with 90% of adults attaining levels >/=1400 EL.U/mL in the efficacy trial. CONCLUSIONS: LD vaccine administered on a 0, 1, 12-month schedule generally is well tolerated and immunogenic in children 4 to 18 years of age. The safety profile consists of mild to moderate local injection site reactions and flu-like symptoms of limited duration and did not worsen with subsequent injections. IgG GMT at month 13 was threefold higher than the month 13 GMT obtained in the adult efficacy study. This higher immune response in children should provide protection against LD.
Adolescent↗
Immunization for children traveling abroad.
More children are travelling these days, often to underdeveloped countries with high prevalence of vaccine-preventable vector-borne, food-borne, zoonotic, and other infections. The pretravel office visit involves consideration of routine and travel vaccines. Epidemiology of typhoid fever, rabies, yellow fever, Japanese encephalitis, vaccines against them, and their recommended use are reviewed.
Child↗
Rapid recovery of hematopoiesis in patients given high-dose chemotherapy followed by infusion of refrigerated unprocessed autologous bone marrow and peripheral blood.
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Adolescent↗
Lyme arthritis in children: is chronic arthritis a common complication?
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Adolescent↗
Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells.
Alterations in the cellular redox potential by homocysteine promote endothelial cell (EC) dysfunction, an early event in the progression of atherothrombotic disease. In this study, we demonstrate that homocysteine causes endoplasmic reticulum (ER) stress and growth arrest in human umbilical vein endothelial cells (HUVEC). To determine if these effects reflect specific changes in gene expression, cDNA microarrays were screened using radiolabeled cDNA probes generated from mRNA derived from HUVEC, cultured in the absence or presence of homocysteine. Good correlation was observed between expression profiles determined by this method and by Northern blotting. Consistent with its adverse effects on the ER, homocysteine alters the expression of genes sensitive to ER stress (ie, GADD45, GADD153, ATF-4, YY1). Several other genes observed to be differentially expressed by homocysteine are known to mediate cell growth and differentiation (ie, GADD45, GADD153, Id-1, cyclin D1, FRA-2), a finding that supports the observation that homocysteine causes a dose-dependent decrease in DNA synthesis in HUVEC. Additional gene profiles also show that homocysteine decreases cellular antioxidant potential (glutathione peroxidase, NKEF-B PAG, superoxide dismutase, clusterin), which could potentially enhance the cytotoxic effects of agents or conditions known to cause oxidative damage. These results successfully demonstrate the use of cDNA microarrays in identifying homocysteine-respondent genes and indicate that homocysteine-induced ER stress and growth arrest reflect specific changes in gene expression in human vascular EC.
Activating Transcription Factor 4↗
Monitoring oral iron therapy with protoporphyrin/heme ratios in pregnant women.
Assessment of the efficacy of iron therapy has usually been done in populations/patients by monitoring changes in hemoglobin concentration, serum iron, percent transferrin saturation, and serum ferritin. In this study the protoporphyrin heme (P/H) ratio (a measure of free erythrocyte protoporphyrin) was measured before and after iron therapy in three groups of pregnant women, who received 60 mg (group A), 120 mg (group B), and 240 mg (group C) of elemental iron with folic acid (0.5 mg) per day for a period of 12 weeks, to evaluate its efficacy to monitor iron therapy. The three groups were comparable regarding the initial mean Hb concentration and serum ferritin levels. The initial mean P/H ratios were markedly elevated in all three groups and were different in the three groups, being highest in group A (113.2+/-92.6), intermediate in group B (87.5+/-62.5), and lowest in group C (69.8+/-43.3). The initial P/H ratio was significantly higher in group A than in group C (p<0.05). This probably affected the efficacy of iron therapy in the three groups. The P/H ratio decreased significantly in each of the three groups after iron therapy (A and B: p<0.001; C p<0.01). Mean Hb concentration and serum ferritin increased in all three groups post therapy; however, the magnitude of change in P/H ratio in all three groups was much greater. This indicated that the predominant contributory factor for anemia was iron deficiency in this group of pregnant women. Serum iron and percent transferrin saturation are difficult to interpret in our population, as iron is freely available over the counter and is prescribed as soon as anemia is detected in patients; therefore, the reduction in P/H ratio may be used to monitor response to iron therapy in population groups.
Administration, Oral↗
Serum transferrin receptors in detection of iron deficiency in pregnancy.
A prospective hospital-based study was conducted to evaluate the efficacy of serum transferrin receptors in the detection of iron deficiency in pregnant women. The iron status of 100 pregnant women with single uncomplicated term pregnancies in the first stage of labor was established using standard laboratory measures. These included complete hemogram, red cell indices, serum iron, percent transferrin saturation, and serum ferritin. In addition, serum transferrin receptor (STFR) was estimated. The results of 81 women with complete laboratory profiles were analyzed. Thirty-five (43.2%) women were anemic (hemoglobin <11 g/dl). Hemoglobin (Hb) showed a significant correlation with MCH, MCHC, serum iron, and percent transferrin saturation, suggesting that the anemia was likely to be due to iron deficiency. The mean STFR level was 18.05+/-9.9 mg/l in the anemic women and was significantly raised (p<0.001) compared with that of the nonanemic women. STFR correlated significantly with Hb (p<0.001), MCH (p<0.05), MCHC (p<0.01), serum iron (p<0.01), and percent transferrin saturation (p<0.01) and also showed a highly significant correlation with the degree of anemia. Serum ferritin in these women did not correlate with Hb, and only 54.4% of the women had levels <12 ng/ml, which does not reflect the true prevalence of iron deficiency. Serum transferrin receptor estimation is thus a useful measure for detecting iron deficiency in pregnancy.
Adult↗
Homocysteine-dependent alterations in mitochondrial gene expression, function and structure. Homocysteine and H2O2 act synergistically to enhance mitochondrial damage.
Mitochondrial abnormalities have been identified in hepatocytes of patients with hyperhomocysteinemia and in endothelial cells from the aortas of rats with diet-induced hyperhomocysteinemia. However, the mechanism by which homocysteine affects mitochondria is unknown. In this report, homocysteine-induced expression of the mitochondrial electron transport chain gene, cytochrome c oxidase III/ATPase 6,8 (CO3/ATPase 6,8), was identified in a human megakaryocytic cell line DAMI using mRNA differential display. Steady-state mRNA levels of CO3/ATPase 6,8, as well as other mitochondrial transcripts, were increased in DAMI cells by homocysteine in a concentration- and time-dependent manner. Despite an increase in mitochondrial RNA levels and changes in mitochondrial ultrastructure, no effect on either cell growth or mitochondrial respiration rates was observed in DAMI cells exposed to homocysteine at concentrations up to 1 mM. In contrast, 1 mM homocysteine in the presence of Cu2+, which is known to generate H2O2, significantly decreased mitochondrial RNA levels, caused gross morphological changes in mitochondrial ultrastructure, and inhibited both cell growth and mitochondrial respiration rates. However, precursors of cellular glutathione and preexposure to heat shock blocked the decrease in mitochondrial RNA levels caused by homocysteine and Cu2+. The observations that (i) homocysteine and H2O2, but not H2O2 alone, caused a decrease in mitochondrial RNA levels, (ii) intracellular levels of H2O2 were significantly increased in the presence of homocysteine and Cu2+, and (iii) catalase, but not free radical scavengers, prevented a decrease in mitochondrial RNA levels, provide evidence that homocysteine and H2O2 act synergistically to cause mitochondrial damage. Furthermore, our findings suggest that intracellular glutathione and heat shock proteins play a role in protecting mitochondria against the adverse effects elicited by homocysteine and H2O2.
Animals↗
Characterization of the stress-inducing effects of homocysteine.
The mechanism by which homocysteine causes endothelial cell (EC) injury and/or dysfunction is not fully understood. To examine the stress-inducing effects of homocysteine on ECs, mRNA differential display and cDNA microarrays were used to evaluate changes in gene expression in cultured human umbilical-vein endothelial cells (HUVEC) exposed to homocysteine. Here we show that homocysteine increases the expression of GRP78 and GADD153, stress-response genes induced by agents or conditions that adversely affect the function of the endoplasmic reticulum (ER). Induction of GRP78 was specific for homocysteine because other thiol-containing amino acids, heat shock or H2O2 did not appreciably increase GRP78 mRNA levels. Homocysteine failed to elicit an oxidative stress response in HUVEC because it had no effect on the expression of heat shock proteins (HSPs) including HSP70, nor did it activate heat shock transcription factor 1. Furthermore homocysteine blocked the H2O2-induced expression of HSP70. In support of our findings in vitro, steady-state mRNA levels of GRP78, but not HSP70, were elevated in the livers of cystathionine beta-synthase-deficient mice with hyperhomocysteinaemia. These studies indicate that the activation of stress response genes by homocysteine involves reductive stress leading to altered ER function and is in contrast with that of most other EC perturbants. The observation that homocysteine also decreases the expression of the antioxidant enzymes glutathione peroxidase and natural killer-enhancing factor B suggests that homocysteine could potentially enhance the cytotoxic effect of agents or conditions known to cause oxidative stress.
Animals↗
Pseudotumor cerebri in Lyme disease: a case report and literature review.
Pseudotumor cerebri is an unusual presentation of Lyme disease. The case of an 8-year-old girl with pseudotumor cerebri secondary to acute neuroborreliosis is reported. She presented with acute onset of headache, papilledema, sixth nerve palsy, increased intracranial pressure, and cerebrospinal fluid pleocytosis. Serum and cerebrospinal fluid Lyme antibodies were positive. Twelve reported cases that mostly presented with systemic findings and signs of Lyme disease before development of pseudotumor cerebri were reviewed. We conclude that acute neuroborreliosis can present with pseudotumor cerebri as an initial manifestation. It is important to include Lyme disease in the differential diagnosis of pseudotumor cerebri in an area endemic for Lyme disease.
Abducens Nerve↗
Emergence of Candida parapsilosis as the predominant species causing candidemia in children.
An increase in the rate of isolation of Candida parapsilosis, relative to other Candida species, in our children's hospital led us to analyze the clinical and epidemiological variables associated with candidemia. We sought to determine if these variables are different for patients infected with C. parapsilosis. All episodes of candidemia occurring over a 7-year period were analyzed retrospectively. Of 81 episodes in 80 patients, 35 (43%) were in neonates, and 46 (57%) were in nonneonates. C. parapsilosis was isolated in 40 episodes (49%). C. parapsilosis was significantly more likely than non-C. parapsilosis species to be associated with prematurity (P = .001), presence of a central venous catheter (P = .002), and use of total parenteral nutrition (P = .03). C. parapsilosis has emerged as the predominant species in our children's hospital. The mortality rate associated with candidemia in children is lower than previously reported and may be associated with the high rate of isolation of C. parapsilosis.
Adolescent↗
Beta-thalassaemia mutations in northern India (Delhi).
The present study was undertaken to define beta-thalassaemia mutations prevalent in northern India (Delhi). Forty six children of beta-thalassaemia major and their families were investigated. DNA was extracted from leucocytes and screened for mutations prevalent in the Indian population. These mutations included 619bp deletion, IVS 1-1 (G-T), IVS 1-5 (G-C), frameshift mutations FS 8/9 (+G), FS 41/42 (-CTTT), Codon 16(-C), Codon 15 (G-A), codon 30 (G-C), IVS 1-110 (G-A) and -88 (C-T). 619 bp deletion mutation was detected directly by amplification of DNA by PCR followed by agarose gel electrophoresis. Other mutations were studied by DNA amplification and dot blot hybridization using synthetic normal and mutant oligonucleotide probes labelled at 5' end with gamma-32 P-ATP. Five mutations accounted for all the chromosomes in 46 patients. 619 bp deletion mutation was found to be the commonest mutation (34.8%) followed by IVS 1-5 (G-C) in 22.8 per cent, IVS 1-1 (G-T) in 19.6 per cent, FS 8/9 (+G) in 13 per cent and FS 41/42 (-CTTT) in 9.8 per cent. Nineteen (41.3%) patients were homozygous and 27 (58.7%) double heterozygous for different beta-thalassaemia mutations. This observation of limited number of mutations is significant and will be useful in planning strategies for prenatal diagnosis of beta-thalassaemia in northern India.
Humans↗
Facial palsy in Lyme disease.
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Facial Paralysis↗
Carbamazepine and fatal eosinophilic myocarditis.
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Adolescent↗
Evaluation of awareness and utilization of an autologous blood transfusion programme.
Autologous blood transfusion (ABT) has an important role in transfusion practice in the developing world due to increasing incidence of HIV and hepatitis C virus infection. Our study was done to evaluate the level of awareness and utilization of an autologous blood transfusion programme in a teaching hospital in Delhi. We assessed the level of awareness of preoperative ABT amongst treating physicians from different specialties in a teaching hospital through an anonymous questionnaire. The utilization of this methodology in transfusion practice was estimated from records of the Blood Transfusion Service. Of the 150 doctors contacted 96 (64%) responded. Although 67.7% of them were aware of the technique and its advantages, only 21.8% used it for the patients under their care. In the preceding 24 months 133 (1.1%) of 12,090 blood collections in the transfusion service were from autologous donor-patients. Only one unit of blood was collected from each patient, although 41.8% of them received > or = 2 units of blood. Of the 11,123 patients transfused, 55 (0.49%) received the ABT. Thus only 55 (41.3%) of 133 total ABT collections were utilized. The study highlights that there is a general lack of awareness about ABT amongst physicians. This transfusion practice is rarely and inadequately used. The study was repeated the following year after an intensive intervention strategy was adopted. The results show a trend towards improvement in the practice of ABT. This study emphasizes the need for proper organization, planning and communication between clinicians and blood transfusion personnel for effective implementation of an ABT programme, especially in countries with a high incidence of transfusion-transmitted infections and acute shortages of blood for transfusion.
Adolescent↗