Therapeutic effects of docosahexaenoic acid ethyl ester in patients with generalized peroxisomal disorders.

Generalized peroxisomal disorders are severe congenital diseases that involve the central nervous system, leading to severe psychomotor retardation, retinopathy, liver disease, and early death. In these disorders, peroxisomes are not normally formed and their enzymes are deficient. Characteristically, plasmalogen synthesis and beta-oxidation of very-long-chain fatty acids (VLCFAs) are affected. We found that patients with generalized peroxisomal disorders have a profound brain deficiency of docosahexaenoic acid (DHA; 22:6n-3) and low DHA concentrations in all tissues and the blood. Given the fundamental role of DHA in neuronal and retinal membranes, a DHA deficiency of this magnitude might be pathogenic. Thus, we studied the possible therapeutic effect of normalizing DHA concentrations in patients with peroxisomal disorders. We chose the DHA ethyl ester (DHA-EE) because of its high degree of purity at daily oral doses of 100-500 mg. This article summarizes the results of treatment of 13 patients with DHA-EE, with some follow-up evidence of clinical improvement. Supplementation with DHA-EE normalized blood DHA values within a few weeks. Plasmalogen concentrations increased in erythrocytes in most patients and after DHA concentrations were normalized, amounts of VLCFAs decreased in plasma. Liver enzymes returned almost to normal in most cases. From a clinical viewpoint, most patients showed improvement in vision, liver function, muscle tone, and social contact. In 3 patients, normalization of brain myelin was detected by magnetic resonance imaging. In 3 others, myelination improved. In a seventh patient, myelination is progressing at a normal rate. These results suggest a fundamental role of DHA in the pathogenesis of Zellweger syndrome. DHA therapy is thus strongly recommended, not only to alleviate symptoms in patients with life-threatening diseases, but also to clarify remaining questions regarding the role of DHA in health and disease.

Smoking and Parkinson's disease. An age-dependent risk effect? The EUROPARKINSON Study Group.

We studied the association between smoking and Parkinson's disease (PD) through a case-control study. Several studies have shown an inverse association between smoking and PD. This association has been interpreted as spurious by some investigators, and as real and causal by others. Several other studies did not confirm the inverse association. We included 193 prevalent cases of PD ascertained in five European prevalence surveys that followed a two-phase design of screening and clinical examination. Each case was matched by center, age (+/- 2 years), and gender to three control subjects drawn from the same populations (N = 579). Information on smoking was obtained through direct or proxy interview. Overall, there was no association between ever smoking and PD (odds ratio = 1.1; p = 0.6). Analyses stratified by age showed that ever smoking was associated with a decreased risk of PD in the younger individuals (odds ratio = 0.4; p = 0.03) and with a significant trend of increasing risk with advancing age (p = 0.003). The risk of PD in relation to smoking is strongly modified by age; smoking may be protective in the younger cases but not in the older cases. This finding may explain the conflicting results from previous studies.

Familial aggregation of Parkinson's disease: a population-based case-control study in Europe. EUROPARKINSON Study Group.

OBJECTIVE: To investigate the familial aggregation of PD in a large collaborative population-based case-control study. BACKGROUND: Most previous case-control studies of the familial aggregation of PD have been hospital- or clinic-based. METHODS: We included 219 prevalent cases ascertained in three European populations (centers), using a two-phase design consisting of screening and examination by a neurologist. Each case was matched by age, sex, and center to three controls drawn from the same populations (n = 657). Presence of PD among first-degree relatives (parents and siblings) was determined using the family history approach for 175 cases and 481 controls. RESULTS: Overall, a positive family history (at least one parent or sibling affected by PD) was reported in 10.3% of patients and 3.5% of controls (odds ratio [OR] = 3.2; 95% confidence interval [CI] = 1.6 to 6.6). A similar association was observed when analyses were restricted to nondemented patients and controls (OR = 3.9; 95% CI = 1.7 to 8.7) or to newly diagnosed patients (OR = 3.3; 95% CI = 0.9 to 11.9). We found a significant trend of increasing risk with increasing number of affected relatives (p = 0.003). Analyses stratified by age showed a stronger association for younger PD patients (OR = 7.6; 95% CI = 1.5 to 38.9) than for older patients (OR = 2.5; 95% CI = 1.1 to 5.7). CONCLUSIONS: In this large sample of prevalent PD patients and population-matched controls, PD significantly aggregates in families, with the strength of the association being age-dependent. Therefore, familial factors, which can be genetic, environmental, or both, play a role in PD.

Parkinson's disease, smoking, and family history. EUROPARKINSON Study Group.

There is growing evidence that both genetic and environmental factors play a role in the etiology of Parkinson's disease (PD). The hypothesis of an interaction between genetic and environmental risk factors has been little explored, and never using a population-based case-control study design. Our objective was to investigate the possible interaction between smoking and family history in the etiology of PD, as part of a collaborative population-based case-control study. We included 149 nondemented PD patients ascertained in three European prevalence surveys using a two-phase design. Each patient was matched by age (+/-2 years), gender, and center to three controls drawn from the same populations (n=375). Presence of PD among first-degree relatives and smoking history were assessed through an interview for 127 cases and 306 controls. In the overall sample we found suggestive evidence that family history and ever-smoking interact in determining the risk of PD (P=0.09), with individuals exposed to both risk factors having the highest risk (OR=10.0; 95% CI=2.0-49.6). Analyses were repeated after stratification into two age-groups (cutoff: 75 years). In older patients, the joint exposure to both risk factors was associated with a significant increase in the risk of PD (OR=17.6; 95% CI=1.9-160.5). Among younger subjects, the OR for joint exposure was not significant. In conclusion, our findings suggest that smoking and family history interact synergistically on a multiplicative scale in determining the risk of PD in individuals older than 75 years.

CCR5 genotype and HIV-1 infection in perinatally-exposed infants.

The CCR5 chemokine receptor is required by non-syncytium HIV-1 strains to infect target cells. A 32 base pair deletion (delta32) in the CCR5 gene causes a structural CCR5 modification that does not permit HIV-1 entry into cells. The rate of the CCR5 delta32 was investigated in 137 children born from HIV-infected mothers. Overall, five (10.6%) of 47 HIV-infected infants showed the defect in heterozygosis vs. eight (8.9%) of 90 uninfected children. No CCR5 delta32 homozygotes were found. Interestingly, among infected children, five (21.7%) of 23 showing a slow disease progression were heterozygous for the CCR5 delta32, meanwhile none of the 24 infants with rapid disease course had the deletion (P = 0.022). In conclusion, the CCR5 delta32 defect does not protect against vertical HIV-1 transmission, but is associated with a delayed disease progression in HIV-infected children.

Evolution of immunological abnormalities in HIV infection by vertical transmission.

Forty-four children infected through vertical transmission, from a total of 146 born to HIV-positive mothers, were studied. Immunological data were analysed and compared with those of the noninfected children. Two transmission patterns emerge from the clinical and immunological characteristics: (i) infants infected during pregnancy with severe immunodeficiency and clinical manifestations before the age of 1 year, and (ii) children probably infected perinatally, who have better clinical outcome. Immunological data are important for prognosis and early therapeutic protocols to be established.

[Long term outcome of phonatory fistulae]. / Resultados a largo plazo de las fístulas fonatorias.

Since January 1983 to January 1990 we have operated 84 Phonatory fistuloplasties (P.F.). The aim of this paper is an intend to know the long term results, farther than 3 years follow-up. We have practiced 70 primary P.F. and 14 secondary. The technique used have been plain puncture and Algaba's procedure. Myotomy of the cricopharyngeus muscle and Herrmann' flap (skin-platysma-fascia) was sometimes associated. The early success of the primary P.F. has been 95 percent and the late one 48 percent. In the secondary P.F. 54 percent and 29 percent, respectively. The most frequent causes of failure have been: enlargement, accidental loss of the prothesis and spontaneous closure and unhappy patient and fibrosis periprosthesis as well. Two factors have to be taken into account in late failures; the immediate postoperative positive psychological feeling and the fact that every patient uses the esophageal voice satisfactorily.

[Orbital complications of sinusitis. Study of 40 cases]. / Complicaciones orbitarias de las sinusitis. Estudio de 40 casos.

During the past few years we have seen an increasing number of orbital complications of sinusitis. In the whole there are summarized 40 complications: 34 cellulitis, 4 exophthalmos and 2 neuritis of the optic nerve. In our opinion the complications were due to the wrongly use of the antibiotics as well as to erroneous indications for surgery. After the survey of diagnosis and managements, the AA. believe the TAC technique is unavoidable for ranging the cellulitis cases in one of the 5 groups established by Chandler and accordingly to treat them medically (antibiotics through the vein) or by surgery (external ethmoidectomy, Caldwell-Luc or osteoplasty of the frontal sinus).

[Results of surgery of the endolymphatic sac]. / Resultados de la cirugía del saco endolinfático.

Surgery of the endolymphatic sac is controversial. Some consider it a placebo and others consider it the surgical treatment of choice in Ménière's disease. We studied the medical records of 87 patients who underwent surgery between 1978 and 1996. Simple decompression was practiced in 89% and a House shunt in 27.6%. The 1-year results were improvement or recovery from vertigo in 65.4%, no improvement in 25%, and reoperation in 9.5%. Tinnitus improved in only 11.9% and hearing loss improved in 9.5% and worsened in 19%. We reviewed the cases of 50 patients with a 5-year follow-up(60%). Vertigo improved in 72%,hearing loss worsened in 72%, and tinnitus remained unchanged in 78%. In view of the good results, scant complications and simplicity of the surgical procedure, we consider endolymphatic saccule surgery to be the first choice in Ménière's disease that is unresponsive to medical treatment.

[New treatments in dementia]. / Nuevos tratamientos en demencia.

The advances in the treatment of Alzheimer's disease, mainly related to anticholinesterase drugs (tacrine, donepezil, metriphonate and rivastigmine) and the methodology of their application in clinical studies and in everyday neurologic practice are reviewed. Recent discoveries with the immunization with Abeta-42 of transgenic rats expressing a mutation related to Alzheimer's disease may lead to new possibilities of etiopathogenic treatments.

[Common variable immunodeficiency in children]. / Inmunodeficiencia común variable en la edad pediátrica.

UNLABELLED: Common variable immunodeficiency (CVID) is one of the more frequent primary immunodeficiencies (PID), after IgA deficiency, and affects a heterogeneous group of patients of various ages and with autosomal recessive inheritance. Our objective is to present the group of children diagnosed with CVID treated in our Hospital Infantil Vall d'Hebron and comment on the diagnostic problems that can arise. Sixteen boys and girls were diagnosed between the ages of 7 months and 15 years. The diagnosis is based on low immunoglobulins and a clinical picture of infection. Differential diagnosis in the paediatric age must consider mainly other PIDs: transient hypogammaglobulinaemia of infancy, X chromosome-linked agammaglobulinaemia (XLA), X chromosome-linked hyper IgM syndrome (X-HIM), IgG subclass deficiency and IgA deficiency (IgAD). Other processes that evolve with recurrent respiratory infections, such as cystic fibrosis, must also be discarded. CONCLUSIONS: These patients present a high incidence of respiratory infections and bronchiectasias. We also observe associated allergic and autoimmune processes. Early diagnosis is indispensable to initiate suitable treatment and avoid the consequences of both respiratory and digestive infections.

Hypogammaglobulinaemia and negative anti-HIV antibodies in AIDS.

Repeated bacterial infections are frequent in children with AIDS owing to the B cell abnormalities produced by HIV infection. We report on two infants who presented with hypogammaglobulinaemia and with no HIV antibodies, but with epidemiological, immunological, and clinical features of AIDS.

Very late presentation of vertically transmitted HIV-1 infection.

We describe a 13-year-old boy with a very late presentation of vertically transmitted HIV-1 infection. The mother, an intravenous drug user before pregnancy, was diagnosed with AIDS in 1987 when the boy was 6 years old. HIV infection in her son was never suspected or investigated. No other risk factors for this infection can be attributed to the boy. On diagnosis of the infection the boy had moderately severe respiratory symptoms, as classified in category B2 of the 1994 paediatric HIV infection definition, and virological replicative kinetics and the phenotype have been determined. Standard AZT therapy has improved the clinical symptoms, with negativization of plasma p24 Ag and HIV RNA. Clinicians should be aware of this form of presentation of HIV-1 infection to avoid further delay of proper therapy.

Development of a common variable immunodeficiency in IgA-deficient patients.

IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) are two primary immunodeficiencies that share clinical features. Occasionally, both diseases have been diagnosed in the same family, which suggests the existence of some common pathogenic mechanism, but progression from IgA-D to CVID has rarely been documented. We report three cases of CVID diagnosed 1 to 12 years after IgA-D was detected. Two of these patients presented autoimmune diseases followed by a progressive decline in IgG levels. They are currently on intravenous immunoglobulin therapy with complete remission of their autoimmune and infectious symptoms.

[Diagnostic clinical and immunologic characteristics of infection by the human immunodeficiency virus in infants]. / Características clínicas e inmunológicas diagnósticas de la infección por el virus de la inmunodeficiencia humana en el lactante.

Acquired immunodeficiency syndrome (AIDS) in infants has different clinical and immunological characteristics from adult AIDS because of immunological immaturity of the fetus and newborn when infection is produced. Differential diagnosis with primary immunodeficiency diseases, mainly with severe combined immunodeficiency and hypogammaglobulinemia is often difficult, but clinical, epidemiological and immunological data aid in establishing diagnosis. Repeated bacterial infections and abnormal antibody production are common in such children and gammaglobulin therapy is indicated to prevent them and avoid continuous immunological stimulation that viral replication and disease progression.

[Bile peritonitis caused by idiopathic perforation of a choledochal cyst]. / Cholépéritoine par perforation idiopathique d'un kyste du cholédoque.

The case of a 8 month-old infant presenting with biliary peritonitis, mild icterus and slowly progressive ascites is reported. Diagnosis was made through paracentesis showing higher bilirubin levels in the ascitic fluid (18 mg/100 ml) than in serum, and abdominal ultrasonography which showed pictures suggestive of choledochal cyst. A perforated choledochal cyst was surgically removed. The biliary duct was reconstructed by means of a hepatic Roux-en-Y jejunostomy. Postoperative course was satisfactory.

Vertical HIV-1 transmission correlates with a high maternal viral load at delivery.

Transmission of HIV-1 from an infected mother to her child occurs in around 20% of cases. Although maternal, immunological, and virological factors have been implicated in transmission, clear association is not yet well defined. For this reason, we have conducted a study to determine the relative contribution of the above-mentioned factors with special emphasis on quantitative viral load. We studied 67 HIV-1-infected mothers during pregnancy and labor and their 69 newborns (two sets of twins) from two university hospitals in Barcelona. Plasma and cell samples were collected at delivery between January 1992 and May 1994, and HIV-1 RNA and p24 in plasma, CD4 cell counts, and tissue culture infectious doses (TCID) were measured. Diagnosis of infection in children was based on persistence of anti-HIV-1 antibodies at 18 months of age, a positive HIV-1 culture or polymerase chain reaction in two separate samples, or presence of signs or symptoms of AIDS before 18 months of age. Results showed a very high relationship between > 10(5)/ml viral RNA copies (odds ratio [OR] 22, 95% confidence interval [CI] 4.4-119.2, p < 0.00001), > 0.5 TCID (OR 17, 95% CI 2.1-139.7, p = 0.001), CDC B + C (OR 3.5, 95% CI 0.98-12.5, p = 0.055), < 400 CD4 cells (OR 4.1; 95% CL 1.1-15.4, p = 0.01) and transmission of HIV-1. In this study, a strong association between mother-to-child transmission of HIV-1 and a high maternal viral RNA load in plasma at delivery is demonstrated. Viral load, which is related to clinical and immunological status in the mother, is the main contributing factor for HIV-1 vertical transmission, and these findings may have global and even individual therapeutic implications.