Pulmonary isolation of Actinobacillus porcitonsillarum in pigs in Europe.
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Actinobacillus↗
Biomedical subjects
J Maldonado
Publications and source records attributed to J Maldonado.
Impact of nocturnal heartburn on quality of life, sleep, and productivity: the SINERGE study.
The aim of the SINERGE study was to assess the impact of nocturnal heartburn on quality of life, sleep, and productivity. Ambulatory patients >/=18 years old and classified as defined cases of nocturnal heartburn (n=337), nonnocturnal heartburn (n=139), uncontrolled hypertension (n=198), and symptomatic depression (n=104) were included in this cross-sectional study. Information on age, gender, body mass index, and comorbidity was collected and the following validated questionnaires were applied: SF-12, Pittsburgh Sleep Quality Index, and Work Productivity and Activity Impairment questionnaire. The prevalence of primary care consultation for heartburn and nocturnal heartburn was 4.7% and 1.9%, respectively. Health-related quality of life, sleep, and productivity were significantly impaired in patients with frequent nocturnal heartburn symptoms as compared with those of the patients without nocturnal symptoms or patients with hypertension. Nocturnal heartburn poses a considerable burden for the sufferer because of the impact on quality of life, sleep, and daily activities.
Circadian Rhythm↗
Identification of viral pathogens in aborted fetuses and stillborn piglets from cases of swine reproductive failure in Spain.
The objective of the present study was to determine the presence of recognised abortifacient viruses such as porcine reproductive and respiratory virus (PRRSV), Aujeszky's disease virus (ADV), porcine parvovirus (PPV) and porcine circovirus type 2 (PCV2), in tissues from aborted fetuses and stillborn neonates in cases of late reproductive failure in swine. A total of 293 specimens (fetuses aborted in the last third of gestation and stillborn piglets) from 100 different cases of late-term abortions and premature farrowing from 15 different Spanish provinces were studied. PRRSV was detected in 9/100 cases by RT-PCR. Only 1/100 cases analysed (corresponding to a late-term aborted fetus with a negative PRRSV RT-PCR result) was positive for PCV2 by PCR. Neither ADV (monitored by viral isolation plus antigen detection) nor PPV (monitored by ELISA antigen capture test) infection was identified. The results suggest that PRRSV is one of the most important infectious agents, if not the most relevant one, associated with fetal infection leading to abortion or premature farrowing in Spain. Moreover, other viral pathogens such as ADV, PPV and PCV2 seem to have a minor impact on reproductive disease.
Abortion, Veterinary↗
Poly (ADP-ribose) polymerase-1 haplotypes are associated with coeliac disease.
In coeliac disease (CD) there is an inflammatory status of the intestinal mucosa because of a high expression of proinflammatory mediators. The nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) has been implicated in the initial inflammatory response by modulating transcription of inflammation-related genes. The aim of this work was to investigate the role of PARP-1 gene promoter region haplotypes in relation to coeliac disease susceptibility. We analysed a coeliac population consisting of a case-control panel with 120 CD patients and 311 healthy blood donors. A CA microsatellite, as haplotype-defining variant of the whole PARP-1 promoter, was typed using a polymerase chain reaction (PCR) method combined with fluorescence technology. We considered two promoter haplotypes: A defined by short CA alleles (83-87 bp) and B defined by long CA alleles (89-101 bp). Haplotype A was significantly increased within the coeliac patients group (P = 0.007 OR 1.6 95%CI 1.12-2.35). Additionally, we observed a significant dose effect, showing homozygous individuals for haplotype A higher risk for CD susceptibility (P = 0.007, OR 1.79 95%CI 1.14-2.82). Our results provide the first evidence that PARP-1 haplotypes are related with coeliac disease susceptibility.
Autoimmune Diseases↗
Expression of HLA-G in inflammatory bowel disease provides a potential way to distinguish between ulcerative colitis and Crohn's disease.
In addition to being involved in nutrient uptake, the epithelial mucosa constitute the first line of defense against microbial pathogens. A direct consequence of this physiological function is a very complex network of immunological interactions that lead to a strong control of the mucosal immune balance. The dysfunction of immunological tolerance is likely to be a cause of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD). HLA-G is a non-classical major histocompatibility complex (HLA) class I molecule, which is highly expressed by human cytotrophoblast cells. These cells play a role in immune tolerance by protecting trophoblasts from being killed by uterine NK cells. Because of the deregulation of immune system activity in IBD, as well as the immunoregulatory role of HLA-G, we have analyzed the expression of HLA-G in intestinal biopsies of patients with UC and CD. Our study shows that the differential expression of HLA-G provides a potential way to distinguish between UC and CD. Although the reason for this differential expression is unclear, it might involve a different mechanism of immune regulation. In addition, we demonstrate that in the lamina propria of the colon of patients with UC, IL-10 is strongly expressed. In conclusion, the presence of HLA-G on the surface of intestinal epithelial cell in patients with UC lends support to the notion that this molecule may serve as a regulator of mucosal immune responses to antigens of undefined origin. Thus, this different pattern of HLA-G expression may help to differentiate between the immunopathogenesis of CD and UC.
Biopsy↗
CA microsatellite polymorphism of the nuclear factor kappa B1 gene in celiac disease.
In the present work, we investigate the possible effect of a CAn microsatellite polymorphism in the nuclear factor kappa B1 (NFKB1) gene on predisposition to celiac disease (CD). Seventy-eight Spanish families with CD were genotyped using a polymerase chain reaction (PCR)-fluorescent method, and the transmission patterns of different CAn alleles were analysed. Furthermore, in order to type the CAn polymorphism more accurately, samples between 126 and 144 bp were cloned and sequenced. A trend of association with the 132-bp allele was found (P = 0.02). This allele was more frequently transmitted to affected sibs, although the results of statistical tests were not significant after correction for multiple comparisons. After sequencing, we found that the 132-, 138- and 142-bp alleles had two As at the end of the CA microsatellite, with the other alleles presenting the described pattern (NCB1 nucleotide U60337) for the microsatellite repeats. These results suggest that the NFKB1 CAn microsatellite does not play a major role in CD susceptibility. In addition, a more detailed molecular characterization of the CA microsatellite is described.
Base Sequence↗
Association of MICA-A5.1 allele with susceptibility to celiac disease in a family study.
OBJECTIVE: The aim of this study was to analyze the role of the major histocompatibility complex class I chain-related gene A (MICA) transmembrane polymorphism in celiac disease (CD) susceptibility. METHODS: Sixty-one celiac Spanish families were genotyped for MICA transmembrane polymorphism by a polymerase chain reaction method combined with fluorescent technology. A transmission disequilibrium test was performed to investigate the preferential transmission of MICA alleles to the affected offspring. RESULTS: The MICA A5.1 allele was shown to be significantly transmitted to the affected siblings. This association was independent of the CD-predisposing DQ2 haplotype. Additionally, we classified our celiac families into typical and atypical groups as we found a significant association with MICA A5.1 in typical celiac families. There was also an association tendency with atypical families. CONCLUSIONS: Our data suggest that the MICA A5.1 allele is associated with CD development independently of DQ2-extended haplotype and clinical forms of CD.
Alleles↗
CsA-based post-graft immunosuppression: the main factor for improving outcome of allografted patients with acquired aplastic anemia. A retrospective survey by the Spanish Group of Hematopoietic Transplantation.
A retrospective multicenter study was performed to assess the clinical results in patients with acquired aplastic anemia (AA) allografted over a 19 year period and to identify prognostic factors influencing survival. From April 1978 to December 1997, 176 patients were transplanted. Records from 160 receiving related matched bone marrow transplantation (BMT) were reviewed. Fifty-two percent of the patients were older than 20 years, 5% older than 40; 6.3% were untransfused at BMT and 56.2% had received prior treatments. Conditioning regimens were with chemotherapy in 43.7% of the procedures and with additional irradiation in 56.3%. Graft-versus-host disease (GVHD) prophylaxis was based on cyclosporin A (CsA) in 58.1% of the patients while methotrexate (MTX) was administered to 41.9%. Transplantation earlier on, a longer interval from diagnosis to BMT, GVHD prophylaxis with MTX, graft failure/rejection and acute severe GVHD were adverse factors for survival. The use of CsA emerged as the main factor for the improvement, inducing a significant decrease in graft failure/rejection rate and severe acute GVHD when compared with MTX alone. Radiation-containing regimens decreased the graft failure/rejection rate without improving survival due to the increased risk of acute GVHD. Age and number of transfusions pretransplant did not influence outcome. Survival achieved since 1991 is 79.79%, and graft failure and acute severe GVHD rates are 6.0% and 11.8%, respectively. In conclusion, CsA-based post-graft immunosuppression has been crucial in achieving improved survival in patients with acquired AA up to 40 years of age. Regardless of CsA use, further improvement in survival was apparent with time, probably due to better skills in patient care.
Adolescent↗
Circadian and seasonal variation of endogenous ubiquinone plasma level.
Coenzyme Q10 (CoQ10) or ubiquinone, a redox component of the mitochondrial electron transport chains, is a powerful antioxidant and membrane stabilizer that may prevent cellular damage during myocardial ischemia and reperfusion therapy. Coenzyme Q10 has been used primarily as an adjuvant therapy for some cardiomyopathies. However, one of the main problems in CoQ10 administration is the high variability of endogenous plasma and tissue levels, which seems to be dependent on several factors. This work explores temporal 24h and seasonal variation as well as gender and racial differences in endogenous plasma ubiquinone concentration. Coenzyme Q10 measurements (quantified by HPLC-UV) of 16 healthy volunteers were done during the daytime hours of activity beginning at 09:00h one day and ending at 09:00h the next day (13 different determinations) in two distinct months. April and October, of the year. A statistically significant circadian rhythm in plasma ubiquinone concentration that includes only the fundamental 24h component was demonstrated both in the April and October data. Furthermore, the time-point means of the ubiquinone concentration in the October study were invariably higher than those obtained in the April study. No statistically significant differences were found in CoQ10 concentration between male and female subjects, both in April and in October. In addition, racial differences were demonstrated; lower plasma ubiquinone levels were found in Caucasian compared to African subjects. However, the latter small group of subjects failed to demonstrate a circadian rhythm, neither in the April nor in the October analysis.
Adult↗
Clinical and pathological observations on pigs with postweaning multisystemic wasting syndrome.
The aim of this work was to characterise the lesions and agents present in clinically normal and clinically affected pigs on a farm during an outbreak of postweaning multisystemic wasting syndrome (PMWS), and to evaluate the diagnostic techniques for detecting porcine circovirus type 2 (PCV-2) and other microorganisms. Four pigs in the early stage and 11 pigs in the late stage of the disease, and eight clinically normal pigs were necropsied. Samples of lymphoid tissue and serum were also obtained from 12 slaughter pigs from the same farm. The tissues were examined histopathologically, and in situ hybridisation, serology and PCR were used to detect porcine circovirus type 1 (PCV-1) and/or PCV-2 in tissues and/or sera. The presence of porcine reproductive and respiratory syndrome virus (PRRSV), Aujeszky's disease virus (ADV) and porcine parvovirus (PPV) were also investigated. Characteristic microscopical lesions of PMWS were observed in the lymphoid tissues of the pigs in all three necropsied groups; the lesions were most common and severe in the pigs in the early stage of the disease, less so in the pigs in the late stage of the disease, and least in the clinically normal pigs. PCV-2 infection was detected in all the necropsied pigs by in situ hybridisation and PCR. Only three pigs had the PCV-1 genome in serum or lymph node tissue. In contrast, the slaughter pigs had no microscopical lesions and no PCV-2 nucleic acid in their serum or tissues, and only one of them had the pCV-1 genome in its serum. Immunohistochemical, serological and PCR studies revealed that PRRSV and ADV were also present on the farm during the outbreak.
Animals↗
The influence of dietary nucleotides on humoral and cell immunity in the neonate and lactating infant.
The organism constantly requires nucleotides, especially for tissues that present a high rate of turnover, such as the cells of the immune system. In certain circumstances, nucleotides may become semi-essential nutrients required by a particular organ. There is evidence of the potential role of exogenous nucleotides as regulators of the immune function. In experiments carried out with animals, studies have shown that dietary nucleotides stimulate the humoral immune response to T-dependent antigens and raise total antibody levels. The present study reveals an increase in the production of immunoglobulins, an improved response to vaccines, a reduction in morbidity and increased tolerance to dietary antigens. Therefore, the addition of nucleotides to formula appears to favour the immune function.
Antibody Formation↗
Screening for tuberculosis upon admission to shelters and free-meal services.
BACKGROUND: The homeless are at very high risk of suffering tuberculosis (TB). The aims of this study were to determine the prevalence and risk factors for tuberculosis infection and disease among the homeless in Barcelona and to evaluate the roles of case finding and contact investigation. METHODS: Observational prevalence study carried out between 1997 and 1998. PARTICIPANTS: 447 homeless patients (394 men and 53 women) were evaluated before admission to shelters and free-meal services. At the same time, 48 co-residents with smear-positive TB patients in 2 long-term shelters were evaluated too. A chest X-ray and Tuberculin Skin Test were performed on all subjects. Sputum smears were processed by the Ziehl-Neelsen and Löwenstein-Jensen procedures in patients with radiographic findings consistent with pulmonary TB. RESULTS: Of the 447 homeless examined, 335 (75%) were infected with Mycobacterium tuberculosis. Active pulmonary TB was diagnosed in five persons (1.11%), and 62 (13.8%) had radiographic evidence of inactive pulmonary TB. Tuberculosis infection was associated with age and smoking, but not with sex or alcohol abuse. No significant differences in infection rates were found between the main group and 48 homeless co-residents of smear-positive subjects. Only 16.9% of the homeless with active TB in Barcelona in the same period were diagnosed through active case-finding, the remainder being mainly detected in hospitals (69.8%) and other several centres (13.3%). CONCLUSIONS: Homeless individuals have a very high risk of TB infection and disease and contact investigation requires specific methods for them. Programmes of screening and supervised treatment should be ensured in this group.
Adolescent↗
Increased conventional chemotherapy does not improve survival in multiple myeloma: long-term results of two PETHEMA trials including 914 patients.
BACKGROUND: Melphalan and prednisone (MP) has been the standard treatment for multiple myeloma (MM) for the last 30 years. Combination chemotherapy at conventional doses has not shown a significant prolongation of survival when compared to MP. There are few data comparing conventional chemotherapy at standard doses with conventional treatment at higher doses. We present the long-term outcome of 914 patients from two randomized trials comparing three different dose intensity regimens. METHODS: From 1 January, 1985 to 31 December, 1989, 487 patients were randomized between MP (melphalan 9 mg/m(2) p.o. and prednisone 60 mg/m(2) days 1-4) and alternating VCMP (vincristine 1 mg i.v. on day 1, cyclophosphamide 500 mg/m(2) i.v. on day 1, melphalan 6 mg/m(2) p.o. on days 1-4, and prednisone 60 mg/m(2) on days 1-4) and VBAP (vincristine 1 mg i.v. on day 1, BCNU and doxorubicin 30 mg/m(2) i.v. each on day 1, and prednisone 60 mg/m(2) on days 1-4). From 1 January, 1990 to 31 May, 1994, 427 patients were randomized between VCMP/VBAP at the above detailed doses (VCMP/VBAP 'SD') and the same regimen increasing the doses of cyclophosphamide and doxorubicin from 500 to 1200 mg/m(2) and from 30 to 50 mg/m(2), respectively (VCMP/VBAP 'HD'). RESULTS: Increasing dose intensity produced a significantly higher partial response rate (31% vs 45% vs 51% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P < 0.01). However, a significantly early death rate was observed in the HD arm (7.7, 7.5 and 12.1% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = 0.05). Median duration of response (20 vs 18 vs 19 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) and median survival (25 vs 31 vs 29 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) were similar in the three groups. MP produced a higher degree of thrombocytopenia than combination chemotherapy at standard (P = 0.002) or high dose (P = 0.01), this leading to a significantly higher dose reduction in the MP arm (P < 0.001 and P = 0.003 for VCMP/VBAP 'SD' and VCMP/VBAP 'HD', respectively). CONCLUSION: In these trials the response rate significantly correlated with the regimen intensity. However, no significant differences in response duration and survival were found. This highlights the limited role of conventional chemotherapy in MM and the need for further trials, aimed at determining the impact of new treatment approaches such as high-dose therapy/autotransplantation.
Antineoplastic Combined Chemotherapy Protocols↗
Hypermethylation of the calcitonin gene in acute lymphoblastic leukaemia is associated with unfavourable clinical outcome.
We analysed calcitonin (CALC1) gene hypermethylation using semiquantitative differential polymerase chain reaction in 105 patients with adult (n = 49) and childhood (n = 56) acute lymphoblastic leukaemia (ALL), and studied the association of CALC1 hypermethylation with clinical presentation features and disease outcome. We also investigated the possible relationship between CALC1 methylation status and expression of the cell cycle inhibitor gene p57KIP2. We observed CALC1 hypermethylation in bone marrow cells from 43% (45 out of 105) of ALL patients. Clinical, molecular and laboratory features did not differ significantly between hypermethylated and hypomethylated patients, only T-cell lineage was associated with hypermethylation (14% vs. 47%, P = 0025). Complete remission rate was similar in both groups although hypermethylated patients had a higher relapse rate (68% vs. 19%, P < 0.00001) and mortality rate (55% vs. 36%, P = 0.06) than hypomethylated patients. Estimated disease-free survival (DFS) at 6 years was 66.1% for hypomethylated patients and 5.3% for hypermethylated patients (P < 0,00001). Multivariate analysis from potential prognostic factors demonstrated that CALC1 methylation status was an independent prognostic factor in predicting DFS (P = 0.0001). Separate analysis of adult and childhood ALL patients showed similar results to the whole series. In addition, hypermethylated patients showed downregulation of p57KIP2 expression. Our results suggest that CALC1 gene hypermethylation is associated with an enhanced risk of relapse independently of known poor-prognostic factors and we describe, for the first time, a possible implication of the p57KIP2 gene in the genesis and prognosis of ALL.
Adult↗
E1A3 as a unique, naturally occurring BCR-ABL transcript in an indolent case of chronic myeloid leukaemia.
A woman with Ph-positive chronic myeloid leukaemia (CML) with an atypical e1a3 BCR-ABL hybrid gene is described. To our knowledge, this is the first report of this transcript type as a unique naturally occurring BCR-ABL fusion in a CML patient. This case was characterized by a low leucocyte count and a very indolent course without treatment. Because the deletion of ABL exon 2 sequences results in deletion of an essential part of the ABL SH3 domain, our case suggests that this ABL SH3 domain is not absolutely necessary for efficient induction of a myeloproliferative disease in the context of BCR-ABL/p190.
Aged↗
Favourable effect of the combination of acute and chronic graft-versus-host disease on the outcome of allogeneic peripheral blood stem cell transplantation for advanced haematological malignancies.
To assess the influence of graft-versus-host disease (GVHD) on the outcome of patients with advanced haematological malignancies (AHM) who received a primary, unmodified allogeneic peripheral blood progenitor cells transplant (allo-PBT) from a human leucocyte antigen (HLA) identical sibling donor, we analysed 136 patients with myeloid neoplasms (n = 70) or lymphoproliferative disorders (n = 66), transplanted at 19 Spanish institutions. Median age was 35 years (range 1-61). The cumulative incidence of relapse for all patients was 34% (95% CI, 26-42%), 41% (95% CI, 33-49) for patients without GVHD and 14% (95% CI, 3-25) (P = 0.001) for patients with acute and chronic GVHD. After a median follow-up of 11 months (range 2-49), 60 (44%) patients remained alive with an actuarial probability of overall survival and disease-free survival (DFS) at 30 months of 31% (95% CI, 21-41%) and 28% (95% CI, 17-39%) respectively. In patients surviving > 100 d, the low incidence of relapse in those with acute and chronic GVHD led to a DFS of 57% (95% CI, 38-76%) compared with a DFS of 34% (95% CI, 17-51%) in the remaining patients (P = 0.03). Our results indicate a reduced incidence of relapse for patients with AHM receiving an unmodified allo-PBT and developing acute and chronic GVHD, which results in an improved DFS.
Acute Disease↗
Preoperative induction chemotherapy followed by concurrent chemoradiotherapy in advanced carcinoma of the oral cavity and oropharynx.
BACKGROUND: Combined modality therapy plays a central role in the management of advanced head and neck tumors. The objective of our Phase II study was to determine the feasibility, toxicity, and clinical and pathologic response of preoperative induction chemotherapy, followed by concurrent chemoradiotherapy in patients with Stage III or IV squamous cell carcinoma according to the American Joint Committee on Cancer Staging of the oral cavity and oropharynx with no distant metastases. METHODS: After staging, 62 patients with locally advanced carcinoma of the oral cavity and oropharynx were treated preoperatively with chemotherapy (1 cycle of cisplatin and 5-fluorouracil [P-5FU]) followed by concurrent chemoradiotherapy (3 cycles of P-5FU combined with radiotherapy, 60 grays [Gy] given in 33 fractions of 1.8 Gy). After evaluation, patients underwent surgery either as a diagnostic (biopsy) or therapeutic procedure (resection of the primary tumor and/or the neck). Surgery was performed with the intent to spare organ function. RESULTS: Grade 3-4 mucositis was observed in 37 patients (59%). Overall clinical response was obtained in 87%, and the complete clinical response rate was 50%. Surgery was performed in 53 patients, 50 at the primary tumor site (11 biopsies, 14 marginal excisions, and 25 wide excision) and 46 patients had neck dissection. Pathologic complete remission was observed in 29 patients (46%). After a median follow-up of 39 months, locoregional control rate was 76%, estimated 3-year disease free survival rate was 73% (+/- 4%), and estimated 3-year overall survival rate was 76% (+/- 4%). CONCLUSIONS: This intensive multimodality treatment is feasible, and toxicity is significant but tolerable. The treatment results appear promising and durable. Organ-preserving surgery can be performed in many patients.
Adult↗
Molecular analysis of lineage-specific chimerism and minimal residual disease by RT-PCR of p210(BCR-ABL) and p190(BCR-ABL) after allogeneic bone marrow transplantation for chronic myeloid leukemia: increasing mixed myeloid chimerism and p190(BCR-ABL) detection precede cytogenetic relapse.
We studied lineage-specific chimerism and minimal residual disease (MRD) in sequential posttransplant samples from 55 patients who underwent unmanipulated (n = 44) or partially T-cell-depleted (n = 11) allogeneic bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Chimerism was assessed by polymerase chain reaction (VNTR [variable number of tandem repeats]-PCR) analysis in highly purified CD19+, CD3+, CD15+, and CD56+ cell fractions, whereas MRD was investigated in whole blood by reverse transcriptase-PCR (RT-PCR) of both p210(BCR-ABL) and p190(BCR-ABL) hybrid transcripts. Of 55 patients, 14 (including 6 T-cell-depleted patients) had cytogenetic relapse at 5-80 months and progressed to hematologic relapse, while 41 patients remained in prolonged cytogenetic remission 12-107 months post-BMT. Before leukemia recurrence, patients in the relapse group showed a consistent evolution pattern sequentially featured by persistent p210(BCR-ABL) positivity, increasing mixed chimerism (MC) in myeloid cells, p190(BCR-ABL) positivity, and, finally, cytogenetic relapse. Myeloid MC preceded cytogenetic relapse by 2-12 months, whereas p190(BCR/ABL) was detected 1-6 months prior to cytogenetic relapse in 11 patients and concomitant with cytogenetic relapse in 3 patients. In the remission group, all patients invariably tested negative for p190(BCR-ABL); 10 patients tested positive for p210(BCR-ABL) at variable time-points but showed persistent full donor chimerism (DC), whereas 31 patients tested p210(BCR-ABL) negative and displayed full DC or transient MC due to the persistence of recipient T cells. Two patients in the relapse group were successfully reinduced into molecular remission with donor lymphocyte infusion. Sequential molecular analysis after such treatment showed the inverse pattern to that observed prior to relapse, ie, progressive disappearance of p190(BCR-ABL) transcripts, conversion of myeloid chimerism to donor type, and, finally, p210(BCR-ABL) negativity. We conclude that lineage-specific chimerism and p190(BCR-ABL) messenger RNA (mRNA) analyses contribute a better characterization of CML evolution after BMT and enable early identification of patients at the highest risk of relapse. (Blood. 2000;95:2659-2665)
Adolescent↗