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Background: Nucleoside reverse transcriptase inhibitor-sparing regimens have not yet been systematically evaluated in children. The nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz lower plasma levels of protease inhibitors in adults and children. Therefore, coadministration of lopinavir/ritonavir with nevirapine and efavirenz necessitates a 30% increase in the dose of lopinavir/ritonavir in adults. In children, the extent of the pharmacokinetic interaction between efavirenz and lopinavir/ritonavir has not yet been studied., Objective: To investigate the pharmacokinetics of increased-dose (300/75 mg/m2 twice-daily) lopinavir/ritonavir with normal-dose (14 mg/kg once-daily) efavirenz in HIV-1-infected children., Methods: Steady-state pharmacokinetics of lopinavir and efavirenz were determined and compared with historical data., Results: Fifteen children of median age 11.8 (range, 5.7-16.3) years were included. Area under the plasma concentration-time curve (AUC0-12), peak levels (Cmax), and trough levels (Cmin) of lopinavir were similar to historical data in adults and children. Medians (interquartile range) were 92.3 (43.5-138.5) mg/L.h, 12.5 (6.9-16.7) mg/L, and 5.7 (1.3-8.0) mg/L, respectively. Efavirenz pharmacokinetics approximated previous data in adults and children., Conclusion: The increased dose of 300/75 mg/m2 twice-daily lopinavir/ritonavir compensates for the enzyme-inducing effect of efavirenz in HIV-infected children.

We report the case of an 8-year-old girl with skin eruptions on both hands that were thought to be of viral origin and, therefore, had been treated with an unspecific immunostimulating agent, containing large amounts of inosine. Under this therapy, which is - despite contrasting knowledge - still thought to be harmless and without serious side effects in the opinion of many physicians and especially medical laymen, the girl's condition worsened rapidly. Diagnosis of juvenile dermatomyositis was made. Because inosine is able to enhance T-cell proliferation and reverse immunosuppression in vitro, both mechanisms may have aggravated the disease course in our patient, once the autoimmune process of dermatomyositis has been initiated.

Objective: To find out whether HIV-associated subclinical psychomotor slowing is present in HIV-infected children despite effective highly active antiretroviral therapy (HAART)., Patients and Methods: An electrophysiological motor test battery shown to sensitively describe HIV-associated CNS disease in adults (tremor peak frequency []TPF], most rapid alternating movements [MRAM], reaction time [RT] and contraction time [CT]) was performed in 17 HIV seropositive (+) right-handed children. Results were compared to 16 HIV seronegative (-) children., Results: HIV (-) children showed slower frequencies (TPF, MRAM) and longer RT and CT than (-) adults. They showed a significant correlation (p = 0.0263) between RT (right = dominant hand) and age. HIV (+) children showed significant prolongations of RT (right hand) and CT (both hands) compared to HIV (-) children. RT right hand did not accelerate with age in HIV (+) children. CT were significantly prolonged in 10 children with detectable HIV plasma viral burden and normal in 7 children with no detectable HIV plasma viral load. There was no correlation between CT and CD 4 cell counts., Conclusions: Despite effective HAART, electrophysiological motor testing in HIV (+) children reveals significant subclinical CNS dysfunction, especially in children with insufficient viral load suppression.

We hypothesise that T-cell apoptosis and the percentage of T cells expressing molecules involved in apoptosis modulation (CD95, CD28) are altered at the inflammation site and in peripheral blood (PB) of children with juvenile idiopathic arthritis (JIA). Paired JIA samples of synovial fluid (SF) and PB ( n=7) and PB samples from age-matched normal children ( n=23) were analysed immediately ex vivo. Apoptosis was measured by detection of phophatidylserine (PS) externalisation on T cells. CD95 or CD28 was detected by FACS, and soluble CD95 and CD95 ligand levels were detected by enzyme-linked immunosorbent assay (ELISA). In SF, the mean percentage of apoptotic T cells was somewhat higher than in PB. However, the percentages of T cells expressing CD95 and soluble CD95 levels were markedly higher in SF (CD4 cells 96+/-2%, CD8 91+/-6%, soluble CD95 6,420+/-2,571 pg/ml) than in PB (CD4 32+/-10%, CD8 36+/-9%, soluble CD95 4,296+/-2,142 pg/ml). Peripheral blood T-cell apoptosis in JIA (CD4 20+/-8%, CD8 42+/-19%) was higher than in the control group (CD4 5+/-2%, CD8 9+/-6%). Interestingly, the percentage of PB CD4 cells expressing CD28 was lower in JIA than controls. In conclusion, systemic T-cell apoptosis was higher in JIA while a substantial number of SF T cells survived locally, despite the fact that almost all cells express CD95.

Objective: To assess the effects of antiretroviral combination therapy that contains protease inhibitor (PI) on carbohydrate and lipid metabolism in human immunodeficiency virus (HIV)-infected children., Methods: A cross-sectional, descriptive clinical study was conducted in an outpatient clinic. Thirty-seven HIV-infected children who ranged from 1 to 17 years of age received nucleoside reverse transcriptase inhibitor treatment together with PI (PI group, n = 25) or without PI (non-PI group, n = 12). Age, gender, weight, length, CD4 cell count, and viral load did not differ between groups. Nonfasting total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, glucose, lactate, and blood gases were determined. In addition, c-peptide, insulin, hemoglobin A1c, free fatty acids, lipoprotein a, and apolipoproteins A1 and B were evaluated after fasting. PI and non-PI group values were compared with normal values taken from healthy children., Results: In nonfasting and fasting conditions, children of the PI group had higher total cholesterol (fasting PI group: 235 +/- 71 mg/dL; non-PI group: 176 +/- 25 mg/dL, mean +/- standard deviation), triglycerides (156 +/- 89 vs 87 +/- 31 mg/dL), and LDL cholesterol levels (159 +/- 58 vs 113 +/- 23 mg/dL) compared with the non-PI group. High-density lipoprotein cholesterol and apolipoprotein A1 levels did not differ in both groups; there was a trend toward higher apolipoprotein B levels in the PI group. After fasting, 8 (47%) of 17 patients in the PI group presented with hypercholesterolemia as a result of an increase of LDL cholesterol and 11 (65%) had hypertriglyceridemia. It is interesting that the non-PI group showed no pathologic deviations. Compared with normal values, lipoprotein a and free fatty acids were increased in the PI and non-PI groups. Glucose, lactate, blood gases, c-peptide, insulin, and hemoglobin A1c were normal in both groups., Conclusion: PI-containing antiretroviral treatment of HIV-infected children was associated with hypercholesterolemia, hypertriglyceridemia, and an increase of LDL cholesterol. The long-term complications of dyslipidemia are of major concern in the growing HIV-infected child.

Unlabelled: We report a Caucasian female who was diagnosed with glycogen storage disease type Ib (GSD-Ib) at the age of 4 months and whose clinical course was complicated by neutropenia and very frequent episodes of infection, including tonsillopharyngitis. Recurrent group A streptococcal infections resulted in multiple episodes of extremely high serum levels of antibodies to streptolysin O (5,000 IU/ml) and DNAse B (6,000 IU/ ml). At the age of 14 years she presented with carditis, migratory arthritis, fever, elevated erythrocyte sedimentation rate as well as serological evidence for recent streptococcal infection providing a diagnosis of acute rheumatic fever., Conclusion: the occurrence of these two very rare disorders in our patient may indicate that this association is not coincidental because neutrophil dysfunction in glycogen storage disease type Ib may have predisposed this patient to acute rheumatic fever due to increased susceptibility to group A streptococcal infections. aberrant glycogenolysis and gluconeogenesis, neutropenia and neutrophil dysfunction are regular findings in GSD-Ib. Neutropenia and neutrophil dysfunction in patients with GSD-Ib are due to defects in myeloid maturation, impaired neutrophil motility, defective chemotaxis and phagocytosis and diminished bactericidal activity resulting in recurrent bacterial infections.

Phosphatidylserine molecules are translocated to the outer plasma membrane of lymphocytes undergoing apoptosis and can be detected by the binding of fluorochrome-conjugated annexin V. Using the annexin V assay, we examined CD4 and CD8 T cells from human immunodeficiency virus (HIV)-infected children for apoptosis upon isolation or following in vitro culture. Immediate ex vivo analysis or overnight culture showed significantly higher levels of apoptosis in CD8 cells than in CD4 cells. Following culture with the activating stimulus phytohemagglutinin or anti-CD3 monoclonal antibody, we observed an increase in the percentage of apoptotic CD4 cells, whereas there was no change in the rate of CD8 cell death. These results demonstrate that in HIV-infected children, CD8 apoptosis may occur at a greater rate than CD4 apoptosis in vivo; greater CD4 depletion may be observed due to more efficient mechanisms for peripheral lymphocyte replacement in the CD8 compartment. Furthermore, our data suggest that CD8 lymphocytes may be maximally activated in vivo, a condition which may lead to the exhaustion of CD8-mediated immunity. These findings clarify the differences between the CD4 and CD8 apoptotic responses to HIV.

Increased apoptosis of lymphocytes represents a key event of immune destruction in HIV infection. In this study it was investigated at which stage of the disease and in which T lymphocyte subpopulation (CD4+ or CD8+) protection against apoptosis may be lost as measured by decreased CD28 expression. In 26 HIV-infected and 20 healthy children, as well as 10 infants exposed to HIV, expression of CD28 and the apoptosis-related marker CD95 was studied by fluorescence-activated cell sorting analysis. According to established Centers for Disease Control and Prevention definitions, children were divided into three immunologic categories. In the CD8 population, patients in category 1 already showed a markedly decreased mean CD28 (36.2%+/-16.1 SD) and increased CD95 expression (48.8+/-24.1%), compared with the age-matched control group (67.7+/-14.4%, 15.8+/-8.9%). In the CD4 population, mean CD28 and CD95 expression was not altered in category 1 patients. Of the exposed children, the child with the lowest CD28 expression on CD8 cells was determined later to be infected with HIV. Significant immunophenotypical alterations are observed in early stage pediatric HIV infection, which may indicate an early loss of protection against apoptosis in the CD8+ T cell population.