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J Mallolas

Publications and source records attributed to J Mallolas.

At least 19 recordsLinked to original sources
PubMed2002

Pilot study for the neonatal screening of fragile X syndrome.

Fragile X syndrome (SFX) is the commonest form of inherited mental retardation. Due to the highly variable phenotype clinical diagnosis is complicated. In nearly all cases, the disorder is caused by expansion of a CGG-repeat in the 5'-untranslated region of the FMR1 (fragile X mental retardation-1) gene. We have evaluated the feasibility, efficiency and costs of two methodologies in order to develop a simple test to screen large populations: PCR and fragile X mental retardation-1 protein (FMRP) immunodetection. We studied 100 newborn males using PCR and immunodetection (26.91 Euro). All but one amplified the CGG repeat of the FMR1 gene within the normal size range. The sample that failed to amplify showed only 28% of FMRP expression by immunodetection study; both results indicated an affected male. A further 100 males were studied only by polymerase chain reaction (PCR) (7.8 Euro); all of them amplified within the normal size range. Both methodologies, PCR and immunodetection, are feasible for screening large populations, PCR being the most suitable, economical and less time-consuming. However, it is advisable to keep slides for immunodetection when PCR fails or the external control shows no amplification. Early detection of SFX-affected individuals would represent a great benefit for their maximum social integration, due to appropriate treatment and early stimulation and would permit a cascade screening in their pedigree.

Fragile X Messenger Ribonucleoprotein 1↗
PubMed2001

Determination of efavirenz in human plasma by high-performance liquid chromatography with ultraviolet detection.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor for the treatment of the HIV infection. A simple, high-performance liquid chromatographic method has been developed and validated for the quantitative determination of efavirenz in human plasma. The method involved solid-phase extraction of the drug and the internal standard (L-737,354) from 300 microl of human plasma. The analysis was via UV detection at 250 nm using a reversed-phase C8 analytical column and a isocratic mobile phase consisting of phosphate buffer (pH 5.75)-acetonitrile that resolved the drug and internal standard from endogenous matrix components and potential coadministered drugs. Within- and between-day precisions were less than 8.6% for all quality control samples. The lower limit of quantification was 0.1 microg/ml. Recovery of efavirenz from human plasma was greater than 83%. This validated assay is being used in pharmacokinetic studies with efavirenz.

Alkynes↗
PubMed2001

Lymphoid tissue viral burden and duration of viral suppression in plasma.

OBJECTIVES: To assess virological response in lymphoid tissue and its impact on the durability of response in plasma in HIV-1-infected persons who achieved sustained suppression of plasma viraemia with different antiretroviral regimens. METHODS: Consecutive patients on first-line antiretroviral therapy were included if they had a plasma HIV-1 RNA viraemia < 20 copies/ml within the last 6 months and tonsillar tissue accessible for biopsy. First-line therapy contained two nucleoside analogues: alone (2NRTI group, n = 3); plus a HIV-1 protease inhibitor (PI group, n = 11) or plus nevirapine (NVP group; n = 16). Patients were followed until virus was detectable in plasma, they changed therapy or were lost to follow-up. RESULTS: Tonsillar HIV-1 RNA could be detected (> 100 copies/mg) in 10 patients: one in the PI group (9%), six (38%) in the NVP group and in all three patients in the 2NRTI group. Primary resistance mutations could be detected in only 2 of these 10 patients. After a median of 9 months after the biopsies, viral suppression in plasma had failed in 6 of these 10 patients whereas failure had only occurred in 1 out of 20 with initially undetectable viral load in lymphoid tissue (P = 0.01; log rank test). CONCLUSIONS: In patients with sustained viral suppression in plasma, triple therapy including a HIV-1 protease inhibitor was more potent than triple therapy containing nevirapine or dual therapy with nucleoside analogues to reduce viral burden in lymphoid tissue. A worse response in lymphoid tissue could not be explained by local selection of resistance and was associated with a less durable virological response in plasma.

Adult↗
PubMed2001

Preliminary data of a prospective study on neuropsychiatric side effects after initiation of efavirenz.

OBJECTIVE: To assess baseline variables able to predict neuropsychiatric side effects (NPSEs) associated with the initiation of an efavirenz (EFV)-containing regimen in HIV-1-infected patients. DESIGN: Open-label, prospective, observational study. METHODS: Consecutive HIV-1-infected outpatients in whom EFV was prescribed underwent a psychiatric interview. At baseline and at 2, 4, and 12 weeks, patients completed the Symptoms Check List-90-Revised (SCL-90-R), the Medical Outcome Study for HIV-positive patients (MOS-HIV), and a standardized questionnaire concerning potential NPSEs. RESULTS: Preliminary data showed that discontinuation of EFV because of NPSEs occurred in 4 of 31 patients (13%). Patients who completed the follow-up showed a decrease in SCL-90-R total score (p =.004) and in several subscales such as Interpersonal Sensitivity (p =.009), Depression (p =.001), and Anxiety (p =.040), whereas no changes in MOS-HIV were observed. Having fewer years of education (p =.006), having fewer baseline central nervous symptoms (p =.000), reporting better baseline physical status (p =.013), and having higher baseline scores in the Heath Transition subscale of the MOS-HIV (p =.000) and in the Somatization subscale of the SCL-90-R (p =.002) were associated with more NPSEs. CONCLUSION: Patients maintained on EFV showed a decrease in psychologic distress related to self-image, depression, and anxiety, without any effect on quality of life. Patients with a lower level of education, those who feel physically and psychologically better at baseline than in the past, and those who suffer from more distress as a result of physical complaints may be at greater risk of reporting more NPSEs after EFV initiation.

Adult↗
PubMed2001

Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy.

OBJECTIVES: To assess the incidence and risk factors for hepatotoxicity associated with nevirapine. DESIGN: A prospective cohort study in a teaching and referral hospital involving all consecutive patients who were prescribed a nevirapine-containing antiretroviral regimen between September 1997 and May 2000. METHOD: Cutaneous and hepatic adverse reactions and clinical hepatitis were assessed. Blood analysis including plasma HIV-1 RNA CD4 cell counts, liver chemistry tests, and serology for hepatitis B and C viruses. Hepatotoxicity was defined as an increase of at least threefold in serum alanine aminotransferase or aspartate aminotransferase levels compared with baseline values. RESULTS: Of a total of 610 patients, 82 (13.4%) were antiretroviral naive when commencing nevirapine, and 46.2 and 8.9% were coinfected with hepatitis C and B viruses, respectively. Median duration of exposure to nevirapine was 8.7 months (interquartile range 3.4--14.3). Hepatotoxicity developed in 76 (12.5%), an incidence of 13.1/100 person-years. Kaplan--Meier estimated incidence of hepatotoxicity at 3, 6 and 12 months was 3.7, 9.7 and 20.1%, respectively. In seven (1.1%) patients, hepatotoxicity was associated with clinical hepatitis, which was reversible upon discontinuation of therapy. Multivariate analysis identified the duration of prior exposure to antiretroviral drugs, hepatitis C virus, and higher baseline levels of alanine aminotransferase as independent risk factors for hepatotoxicity. CONCLUSIONS: Hepatotoxicity but not clinical hepatitis was common in HIV-1-infected patients receiving nevirapine-containing regimens and the incidence steadily increased over time. Prolonged exposure to any antiretroviral therapy, coinfection with hepatitis C virus and abnormal baseline levels of alanine aminotransferase identified patients at a higher risk.

Adult↗
PubMed2001

Simultaneous determination of the HIV-protease inhibitors indinavir, amprenavir, ritonavir, saquinavir and nelfinavir in human plasma by reversed-phase high-performance liquid chromatography.

A rapid, simple and sensitive high-performance liquid chromatographic (HPLC) assay has been developed for the simultaneous quantification of the HIV-protease inhibitors indinavir, amprenavir, ritonavir, saquinavir and nelfinavir in human plasma. The method involved the solid-phase extraction of the five drugs and the internal standard (I.S., verapamil) from 400 microl of human plasma. The HPLC analysis used a reversed-phase C18 analytical column and a mobile phase consisting of a gradient with 15 mM phosphate buffer (pH 5.75)-acetonitrile and UV monitoring. The method was linear over the therapeutic concentration range for the five HIV-protease inhibitors. The accuracy of the method ranged from 98.2 to 106.7% and the precision values ranged from 1.4 to 8.1% for intra-day precision and from 3.1 to 6.4% for the inter-day values.

Carbamates↗
PubMed2001

Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study.

BACKGROUND: Risk factors for lipodystrophy in patients infected with HIV-1 treated with highly active antiretroviral therapy (HAART) containing HIV-1 protease inhibitors are poorly understood. We aimed to identify the risk factors for lipodystrophy in antiretroviral-naive HIV-1-infected adults on HAART. METHODS: Moderate or severe body-fat changes were clinically assessed and categorised as subcutaneous lipoatrophy, central obesity, or both, in all consecutive antiretroviral-naïve HIV-1-infected adults who began HAART with two nucleoside reverse transcriptase inhibitors plus at least one protease inhibitor from October, 1996, to September, 1999. A person-years analysis was used to calculate the incidence of types of lipodystrophy, and Cox proportional hazards models were used to describe the univariate and multivariate factors associated with progression to any lipodystrophy. FINDINGS: After a median follow-up of 18 months, 85 (17%) of the 494 patients developed some type of lipodystrophy. The incidences of any lipodystrophy, lipodystrophy with subcutaneous lipoatrophy, and lipodystrophy with central obesity were 11.7 (95% CI 9.2-14.2), 9.2 (7.0-11.4), and 7.7 (5.7-9.7) per 100 patient-years. An increased risk for any lipodystrophy was found among women as compared with men (relative hazard 1.87 [1.07-3.28]), heterosexuals (2.86 [1.50-5.48]), and homosexuals (2.17 [1.07-4.42]) as compared with intravenous drug users, with increasing age (1.33 per 10 years older [1.08-1.62]), and with the duration of exposure to antiretroviral therapy (1.57 per 6 months extra [1.30-1.88]) but not with any individual antiretroviral agent. The factors associated with an increased risk for lipodystrophy with subcutaneous lipoatrophy or lipodystrophy with central obesity were very similar to those associated with any lipodystrophy. The duration of indinavir use may represent an additional contribution for the development of lipodystrophy with central obesity (1.26 per 6 months extra [0.99-1.60]); p=0.064). INTERPRETATION: Risk factors associated with development of any lipodystrophy, lipodystrophy with subcutaneous lipoatrophy, and tipodystrophy with central obesity in patients infected with HIV-1 who were receiving HAART containing protease inhibitors are multifactorial and overlapping, and cannot be exclusively ascribed to the duration of exposure to an particular antiretroviral agent.

Adult↗
PubMed2001

Large de novo deletion in chromosome 12 affecting the PAH, IGF1, ASCL1, and TRA1 genes.

Phenylketonuria is one of the most common genetic diseases in humans, affecting 1 in 10,000 whites. Deletions are generally uncommon in genes in which no long highly homologous segments are present, and in phenylalanine hydroxylase (PAH) deficiency they represent only 5% of cases. We present the case of a girl affected by classical phenylketonuria who has been screened for mutations in the PAH gene. During the molecular study a large de novo deletion has detected in 12qter, including PAH, and the genes for insulin-like growth factor 1 (IGF1), human achaete-scute homolog 1 (ASCL1), and tumor rejection antigen (TRA1). The patient showed phenylketonuria, short stature, and pathological electro-oculography results in both eyes, with high affectation of the relative electrogenesis of the photoreceptor-pigment epithelium complex. She had previously been misdiagnosed as homozygous for the IVS8nt-7A-G mutation, instead of heterozygous for a mutation and a de novo deletion. As a result incorrect genetic counseling had been given. The deletion of the PAH, IGF1, and ASCL1 genes could explain the patient's phenotype corresponding to a contiguous gene syndrome. We stress the relevance of polymorphic marker haplotype analysis and the importance of family study in genetic recessive diseases, such as phenylketonuria, to avoid incorrect diagnosis and genetic counseling.

Antigens, Neoplasm↗
PubMed2001

Implications of the FMR1 gene in menopause: study of 147 Spanish women.

OBJECTIVE: To evaluate the relationship between the FMR1 premutation and premature ovarian failure (POF) in the Spanish population and the possible incorporation of this test in gynecological procedures for women with POF or early menopause (EM). DESIGN: Clinical and molecular genetic study. Ninety-eight premutated and six full-mutated carriers of fragile X syndrome and 43 women with POF were studied by polymerase chain reaction and Southern blot analysis for the CGG repeat expansion in the FMR1 gene. RESULTS: Among premutated carriers, 12.2% (12 of 98) presented with POF, and 15.3% (15 of 98) presented with EM. Neither POF nor EM was observed in any of the six full-mutated women. Two women of 43 from the POF population (4.65%) were carriers for the CGG premutation in the FMR1 gene. No correlation between CGG expansion size and age at menopause was found. A biased paternal origin of the premutation and a high twinning incidence was found in all premutated women, whether they had POF or not. CONCLUSIONS: Our data support the hypothesis that the FMR1 gene is one of the genes associated with POF and EM. Analysis of the CGG expansion in the FMR1 gene may be justified in women with POF and EM until the real role of the FMR1 premutation is determined.

Adult↗
PubMed2000

[Influence of highly active antiretroviral therapy on the evolution of AIDS-associated Kaposi's sarcoma].

BACKGROUND: To evaluate the highly active antiretroviral therapy (HAART) in the Kaposi's sarcoma evolution. PATIENTS AND METHOD: Retrospective analysis of a cohort of 126 HIV infected patients suffering from Kaposi's sarcoma with or without HAART. Clinical evolution, immunological status (CD4+ cell count) and response to therapy (HIV-RNA plasma viral load and human herpes-8 virus determination). RESULTS: All patients without HAART died and the cumulate probability survival (SD) among those who received HAART was 2.078 (74) days. The CD4+ count at baseline in the HAART group was 130 (125) * 106/l and the HIV-RNA viral load was 196,818 (244,195) copies/ml while at the moment of the clinical response was 235 (209) * 106/l CD4 + and 2,629 (6.444) copies/ml, respectively. CONCLUSION: HAART prolongs survival in HIV patients suffering from Kaposi's sarcoma. There is a clear relationship among clinical response, HAART and immunological recovery.

Adult↗
PubMed2000

Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy.

We prospectively followed 20 consecutive patients with human immunodeficiency virus type 1 (HIV-1) with viral loads of <200 RNA copies/mL. These patients had been treated with 2 nucleoside reverse transcriptase inhibitors and > or =1 HIV-1 protease inhibitor for > or =3 months; they developed body changes consistent with lipodystrophy and requested they be switched from protease inhibitor to efavirenz. At baseline and every 3 months, we assessed the following: body mass index, waist-to-hip ratio, regional fat thickness (assessed by sonography), fasting total and high-density lipoprotein cholesterol, triglycerides, glucose, insulin, CD4(+) cells, and viral load. At baseline, hypertriglyceridemia (> or =200 mg/dL) was present in 17 (85%) patients, hypercholesterolemia (> or =200 mg/dL) in 14 (70%), and impaired fasting glucose (> or =110 mg/dL) in 8 (40%); CD4(+) T cells were 280x10(6) cells/L (range, 64-942x10(6) cells/L). HIV-1 RNA had been at <200 copies/mL for a median of 14 months (range, 3-24 months). Six months after switching to efavirenz, there was a reduction in triglyceride levels (a decrease of 31%; P=.03) and fasting insulin resistance index (a decrease of 28%; P=.03), but total and high-density lipoprotein cholesterol and glucose did not change. Waist-to-hip ratio decreased from 0.92 to 0.87 (P=.06). Subcutaneous fat thickness did not change. CD4(+) cells remained stable (363x10(6) cells/L; range, 102-741x10(6) cells/L; P=.65). Nineteen patients (95%) had HIV-1 RNA levels that remained at <200 copies/mL. Although CD4(+) response and viral suppression remained preserved after 6 months of switching from protease inhibitor to efavirenz, the benefits of this approach on the evolution of lipodystrophy were limited, and our findings do not support its routine recommendation to treat lipodystrophy.

Adipose Tissue↗
PubMed2000

Dose-finding study of once-daily indinavir/ritonavir plus zidovudine and lamivudine in HIV-infected patients.

BACKGROUND: Strategies for treatment of HIV need to be considered in terms of combining potency, safety, and convenience of dosage. However, regimens including once-daily protease inhibitors are not yet available. We have performed a pilot study to determine an indinavir/ritonavir (IND/RTV) regimen for once-daily dosing, by monitoring plasma levels. METHODS: Antiretroviral-naive HIV-infected adults were eligible. Therapy was zidovudine/lamivudine 1 pill twice daily plus IND/RIT (liquid formulation) 800/100 mg twice daily with food. At 4-week intervals, plasma levels were measured and dosage of IND/RIT switched to 1000/100 mg daily and then 800/200 mg daily. If 12-hour minimum concentrations (Cmin12h) of IND were too low (<0.1 microg/ml) with IND/RIT 1000/100 mg once daily in the first half of the patients, it was planned to switch directly to 800/200 mg once daily in the other half. RESULTS: In all, 27 patients were recruited. Mean baseline CD4+ lymphocyte count was 107 x 106/L (range, 4-623 x 106/L). Eleven patients (40%) discontinued the study medication within the first 4 weeks due to clinical progression (n = 3) or grade 1-2 RTV related side effects (n = 8). Nine patients (group A) switched from 800/100 mg twice daily to 1000/100 mg once daily and then to 800/200 mg once daily. Seven patients (group B) switched directly to 800/200 mg once daily. At week 32, viral load was <5 copies/ml in 15 of 16 patients (94%). RTV levels were always <2.1 microg/ml. The mean and 95% confidence interval for IND Cmin and Cmax in microg/ml was: using IND/RTV 800/100 mg twice daily (n = 16) 1.4 (0.5-2.3) and 6.7 (4.4-9.1), respectively; using IND/RTV 1000/100 mg once daily (n = 9) 0.18 (0-0.41) and 8.6 (3.3-14), respectively; and using 800/200 mg once daily (n = 16) 0.38 (0-0.9), and 7.5 (0.8-14.8). For all 16 patients who received IND/RTV 800/100 mg twice daily, the Cmin value for IND was >/=0.1 microg/ml. Conversely, IND Cmin was <0.1 microg/ml in 4 of 9 receiving 1000/100 mg once daily but in only 1 of 16 receiving 800/200 mg once daily. CONCLUSION: Once-daily regimen of IND/RIT is feasible and deserves further evaluation in larger randomized trials. Liquid formulation of RIT was not well tolerated by our antiretroviral-naive patients despite lower than suggested doses.

Adult↗
PubMed2000

Rare variants in the promoter of the fragile X syndrome gene (FMR1).

Fragile X syndrome, the most common form of familial mental retardation, is mainly caused by the expansion of an unstable region of CGG repeats in the 5' untranslated region of the FMR1 (Fragile X Mental Retardation-1) gene. Molecular tools to detect an abnormal CGG expansion in FMR1 include Southern blot hybridization and PCR amplification. Southern blotting with the StB12.3 probe and Eco RI/Eag I double digestion is widely used as a routine test for fragile X syndrome diagnosis in laboratories around the world. A patient with mental retardation of unknown origin showed absence of digestion for Eag I due to a -149C-->G substitution in the CpG island of the FMR1 gene, which destroys that restriction enzyme site. Screening for other changes around that region also detected a -154insGGC in a patient with a phenotype highly suggestive of fragile X syndrome but without CGG expansion. Expression studies did not show any abnormal changes in FMR1 function. In summary, we have identified two different changes (a C to G substitution at -149 and a GGC insertion at -154) in the promoter of the FMR1 gene. These are the first variants described in the promoter of the FMR1 gene.

Adolescent↗
PubMed2000

Detection of the fragile X syndrome protein for the evaluation of FMR1 intermediate alleles.

Molecular screening programs in mentally retarded individuals have been performed in several populations worldwide. One finding has been an excess of FMR1 intermediate alleles in a population with learning difficulties. However, other published reports with similar characteristics did not corroborate those previous results. In order to contribute additional data from our population, we studied 563 patients affected with nonspecific mental retardation (MRX) that did not present a CGG expansion in the FMR1 gene and 208 individuals as a control population. Forty MRX patients presented alleles within the intermediate range. Among them, one case showed a pattern of expression of the FMR1 protein (FMRP) concordant with a fragile X syndrome case with an intermediate allele/full mutation mosaicism, although it was not detected by Southern blot analysis. Statistical analysis was performed again showing no statistically significant difference regarding the intermediate allele frequency in the MRX and control populations. This finding is in agreement with the hypothesis that the incidence of intermediate FMR1 alleles in MRX populations does not seem to be higher than in control populations, and it emphasizes the importance of FMRP detection as a diagnostic tool for fragile X syndrome.

Alleles↗
PubMed2000

Loss of heterozygosity in renal and hepatic epithelial cystic cells from ADPKD1 patients.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest genetic diseases in man, affecting 1:1000 individuals in the Caucasian population. It is caused by mutations in the PKD1 or PKD2 genes. Recently, controversial data regarding the mutational mechanism underlying cyst initiation have been reported: genetic analyses have shown that second somatic mutations may lead to cyst formation (detected as microsatellite loss of heterozygosity, LOH, and point mutations), but immunohistochemical studies show strong immunoreactivity for polycystin in some cysts. In order to further characterise this matter we have analysed 211 cysts from seven different patients for LOH, we have detected a 13.3% LOH for PKD1. This loss was specific to PKD1 as no LOH was detected when other chromosomal regions were studied. Whenever linkage analysis has been possible, it has been proved that the lost allele corresponded to the wild-type. Our data supports previous results in the two-hit theory for ADPKD due to the large number of cysts studied. ADPKD would occur through a recessive cellular mechanism. The probability of cyst development would depend on the probability of mutation in the second allele. The different phenotypical expression of the same mutation reported in ADPKD could be due to the different tendency of inactivation in the second allele in each individual.

Cells, Cultured↗