Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial.

Ad CFTR, a replication-deficient adenovirus expressing the human cystic fibrosis transmembrane conductance regulator (CFTR), was administered by aerosolization in a single escalating dose to three pairs (cohorts) of cystic fibrosis (CF) patients. Buffer only was administered to the nose and lungs 9-14 days before nasal instillation of virus followed the day after by aerosolization of Ad CFTR to the lung. Nasal doses (defined in terms of viral plaque forming units, pfu) were 10(5), 10(7), and 4 x 10(8), whereas aerosolized doses were 10(7), 10(8), 5.4 x 10(8) for each cohort, respectively. No acute toxic effects were observed in the first 4 weeks after virus treatment. Shedding of infectious Ad CFTR was never detected, whereas detection of vector DNA sequences and CFTR expression demonstrated DNA transfer to the nose and airways of patients. No significant deviations in immunological and inflammatory parameters were observed in serum and in bronchoalveolar lavage (BAL). Importantly, for all patients, the serum anti-adenovirus antibody levels did not change significantly from baseline and no antibodies against adenovirus were found in BAL.

Diagnostic criteria for cystic fibrosis in men with congenital absence of the vas deferens.

The high frequency of cystic fibrosis (CF) mutations in males with absence of vas deferens supported the hypothesis of a primarily genital phenotype of CF disease. To consider the idea of an attenuated form of CF, we investigated 14 men with congenital bilateral aplasia of the vasa deferentia. All patients were consulting for infertility and none was known to have CF. The median age was 30.5 years (range, 20-38 yr). DNA analysis for 22 CF mutations showed at least 1 mutation in 10 patients (71%), whereas the CF carrier frequency is only 4% in the general population. Three compound heterozygotes were identified, all carriers of the R117H mutation. The sweat test was considered positive in 6 patients (43%), and a high frequency of radiologic evidence of sinus disease (8 patients) and of elevated antibodies to Pseudomonas (8 patients) was found. Only 2 patients were free of all these criteria for CF disease. This study strengthens the hypothesis that absence of vas deferens is an attenuated form of CF. We propose a combination of tests including DNA study, computerized tomographic scan of the paranasal sinuses, and testing of anti-Pseudomonas antibodies when the sweat test is inconclusive.

Biochemical assessment of the nutritional status of cystic fibrosis patients treated with pancreatic enzyme extracts.

We examined the protein and fat nutritional status of 65 cystic fibrosis patients aged 4-26 y (x +/- SD: 11.2 +/- 5.6 y). Patients were treated with pancreatic enzyme extracts to improve nutrient absorption; in addition, most patients were supplemented with vitamins A and E. Results were compared with those in a control group of 39 subjects aged 5-29 y (x: 14.3 +/- 5.6 y) with no digestive diseases or nutritional deficiencies. Protein determination showed low albumin concentrations in 42% of the cystic fibrosis patients and decreased blood concentrations of retinol binding protein in 12% of the patients. Lipoprotein components were characterized by decreased cholesterol concentrations in 25% of the cystic fibrosis group. Also, mean concentrations of apolipoprotein A-I were significantly lower in the cystic fibrosis group than in control subjects. The results of fatty acid status, expressed in relative (%) and absolute (mg/L) values, showed concentrations of essential fatty acids, represented by linoleic and arachidonic acids, to be significantly decreased in cystic fibrosis patients; this decrease was markedly significant for fatty acid status expressed in absolute values, especially in the cholesteryl ester subfraction. Serum retinol and alpha-tocopherol concentrations were lowered by 8% and 46% in cystic fibrosis patients and control subjects, respectively: retinol, 1.80 +/- 0.50 and 2.37 +/- 0.60 micromol/L, P < 0.001, and alpha-tocopherol, 18.1 +/- 8.7 and 25.7 +/- 5.0 micromol/L, P < 0.001. In conclusion, despite regular treatment with pancreatic enzyme replacements, neither protein nor fat malnutrition in cystic fibrosis patients was completely corrected.

Regional distribution of substance P binding sites in the brainstem of the human newborn.

The distribution of [3H]substance P ([3H]SP) binding sites in the brainstem of the human newborn was investigated in eleven cases (aged 1 h to 6 months) by in vitro quantitative receptor autoradiography. The binding of [3H]SP to newborn brainstem tissue was found to be saturable (for the eight cases examined, Kd and Bmax (M +/- S.E.M.) were 0.29 +/- 0.03 nM and 206 +/- 21 fmol/mg tissue, respectively). Competition studies showed unlabeled SP to be the most potent peptide for displacing [3H]SP binding from tissue sections. The desaturating effect of GTP on the specific binding of [3H]SP was also investigated, but was not found to be significant. Autoradiographic analysis showed that the neurokinin-1 (NK-1)/SP binding sites were widely but unevenly distributed, and that they varied with age. The highest densities of (NK-1)/SP binding sites were observed in the locus coeruleus, olivaris inferior nuclei, raphe magnus and obscurus nuclei, while low to moderate densities were observed in other brainstem structures. These findings support the idea that SP is involved in cardiovascular regulation, and that it may interact with the catecholaminergic and/or serotonergic system.

A case of the Rett syndrome.

This is a case report of the Rett syndrome in a girl with normal general and psychomotor development during the first 12 mos. Afterwards developmental stagnation and retrogression appeared which led within one yr to dementia, autism, loss of purposeful hand use, truncal ataxia and apraxia of gait. Characteristic stereotypic movements of the hands occurred, and, furthermore, rhythmic truncal balancing and episodic hyperpnea. At 2 yrs, neurological examination showed slight hypertonia and hyperreflexia of the legs without extensor plantar signs, there was relative microcephaly, and visceral examination was normal. The diagnosis was made on the basis of clinical signs: all laboratory investigations were negative except EEG which showed unspecific modifications. We didn't find hyperammonemia. No progression of the symptoms appeared in the 15 mos following the diagnosis.

Resveratrol and a novel tyrosinase in Carignan grape juice.

Polyphenol levels in wines are affected by the wine-making process. Resveratrol is one polyphenol which has been the subject of a commendable amount of recent research. In this work, we found that resveratrol is immediately degraded by tyrosinase. A novel tyrosinase was purified from Carignan grapes. The purification process included salting out and separation on a cation-exchange column, followed by gel filtration. Tyrosinase was purified in a homogeneous form by SDS-PAGE and was characterized: its specific activity toward 3-(3,4-dihydroxyphenyl)-L-alanine (DOPA) increased by a factor of 24 with an overall recovery of 3% of initial activity. The apparent molecular mass of the purified tyrosinase was 40 kDa as determined by SDS-PAGE, and 42 kDa as determined by gel filtration. Its activity was optimal at pH 6 and at 25 degrees C. The enzyme exhibited high activity toward phenylenediamine, epicatechin, pyrogallol, DOPA, and resveratrol. Tyrosinase activity was inhibited by KCN, thiourea, and SO(2). Resveratrol levels were stable following the removal of proteins from the juice, suggesting that early spraying of grapes with SO(2) is an important factor affecting the final amount of resveratrol in wine.

Clinical evaluation of a venotropic drug in man. Example of Daflon 500 mg.

Chronic venous insufficiency (CVI) of the lower limbs is a complex and fluctuating disease by its pathogenic mechanisms and its clinical symptoms. Although symptoms are subjective, they affect the quality of life and socio-professional activity of many patients. This is why convincing demonstration of therapeutic activity of a venotropic drug should be carried out according to strict methodology. Only randomized double-blind controlled trials versus placebo (no reference drugs being available) could demonstrate the activity on condition that they are set up in a protocol, the statistical design of which, is adapted and defined "a priori". Inclusion, non inclusion and judgement criteria must be rigorous, taking into account many exogenous and endogenous factors which could have influence on the severity or the change in CVI and on the comparability of groups at the beginning and at the end of the study. Thus, the main risk factors of CVI (heredity, obesity, obstetrical and gynecological history, estroprogestogen treatment, profession, environment, etc.) and the season when the patient is recruited should be taken into account. With respect to all these restraints on methodology, the venotrotopic activity of a flavonoid Daflon 500 mg (2 tablets daily) was demonstrated in 200 patients (174 women, 26 men) with organic CVI (n = 83) or functional CVI (n = 117) treated for two months in two double-blind randomized trials versus placebo. The venotropic activity of Daflon 500 mg, was shown by a significant reduction of CVI signs and symptoms, whether organic or functional, and a significant improvement in venous hemodynamics according to plethysmographic parameters. Good acceptability was observed after medium and long term trials.

[Chronic pulmonary heart disease during ventriculo-atrial shunts in children]. / Coeur pulmonaire chronique au cours des dérivations ventriculo-atriales chez l'enfant

This grave complication is a major cause of mortality in ventriculo-atrial shunts in children with hydrocephalus. It occurs at a much higher rate than with long-term indwelling intracavitary pacemakers, which suggests that the shunt procedure is responsible for either chronic infection or the introduction of cerebral thromboplastin.

[Pressure profile during exertion in subjects aged 70 years and older]. / Le profil tensionnel d'effort du sujet de 70 ans et plus.

One hundred and fifty-four patients from 70 to 85 years old (mean 74.5 +/- 4.5 years), including 105 men and 49 women, underwent a bicycle exercise test, in the upright position, with 3 minutes triangular levels (levels of 20 watts or more often 30 watts). Blood pressure (BP) was measured at rest and at the end of each level, using the auscultatory method and a mercury manometer. These 154 patients were divided in 59 "healthy" old people, 21 patients suffering from coronary insufficiency but with normal BP, 12 hypertensive patients and 62 patients receiving antihypertensive therapy. The results showed, as in younger people, a linear relation between BP and heart rate (HR). The slope of BP reported to HR determined the exercise BP of each subject. The mean value of "healthy" old people defined the normal exercise BP of people over 70 years old. Slope of systolic blood pressure (SBP) was higher in men than in women, but declined in both sexes in people over 80 years old. Slope of SBP was lower in the case of coronary insufficiency. In hypertensive patients, slope of SBP was the same as in normotensive patients, but was shifted upward. Finally mean exercise BP was lower in patients receiving antihypertensive therapy, compared to non-treaded patients with equal rest BP. The knowledge of exercise BP is useful for the right interpretation of exercise testing in old people suffering from coronary insufficiency or hypertension, as well as in presumed healthy old people.

MRI in Sturge-Weber syndrome.

Five children (3 girls, 2 boys, aged from 1 to 18 years) presenting with Sturge-Weber syndrome were explored by MRI with contrast injection in 2 cases. The respective positions of CT and MRI are discussed: CT is the method of choice to display leptomeningeal calcifications. MRI seems to be more accurate than CT to determine the location of the lesions and to demonstrate the enhancement of the angioma after contrast injection.

[Destombes-Rosai-Dorfman syndrome: 2 uncommon clinical forms]. / Syndrome de Destombes-Rosai-Dorfman: deux formes cliniques inhabituelles.

Two cases of Destombes Rosai Dorfman's syndrome are presented. Diagnosis was performed by superficial lymph node biopsy. The first case concerned a nine and half years old girl with cervical adenopathy who developed a compressive mediastinal adenopathy responsible for a right lower lobe atelectasis. Because of local lung suppuration a lobectomy had to be performed. The second case concerned a fourteen years old boy with recurrent fever, diffuse superficial lymph nodes and erythematous skin rash. The two patients showed clinical and biological inflammatory symptoms without any immunodeficiency. No aetiological agent could be identified. Antibiotics and corticoids had no effect but the two patients recovered (after 18 months follow up in case 2). These two particular cases confirm the clinical course heterogeneicity of the syndrome which requires histological diagnosis.

[Is male infertility caused by congenital bilateral atrophy of the vas deferens a clinical form of mucoviscidosis?]. / La stérilité masculine par atrophie congénitale bilatérale des canaux déférents est-elle une forme clinique de mucoviscidose?

We investigated clinical data, sweat electrolytes and cystic fibrosis (CF) mutations in twelve patients with congenital bilateral aplasia of vasa deferentia (CBAVD) to debate arguments for diagnosing CF. Sweat chloride concentration was definitely raised in four patients. Three patients are CF compound heterozygotes. Six patients are CF heterozygotes. This result reinforces the hypothesis that white males with CBAVD might have a mild form of CE.

[Pregnancy and cystic fibrosis. A case history]. / Grossesse et mucoviscidose. A propos d'une observation.

The authors report a case of pregnancy in a patient suffering from moderately severe cystic fibrosis (the syndrome consisted of diffused obstruction in respiratory function with a vital capacity of 79% and the lowered blood oxygen level with arterial blood gas estimations; oxygen saturation was 94%). The condition was marked by temporary worsening during the pregnancy in which infective bronchitis supervened). She also threatened to go into early labour and did in fact deliver at 36 1/2 weeks of an infant which was normal for the duration of the maturity. The authors review previous known facts about cystic fibrosis. A study of the literature has made it possible to be more accurate in describing methods of ante natal diagnosis of the condition and ways of following the pregnancy and the illness as well as the woman's fertility and her ability to breast feed.

[Mucoviscidosis: a genetic disease of adulthood]. / La mucoviscidose: une maladie génétique de l'âge adulte.

Mucoviscidosis (cystic fibrosis of the pancreas) is the most frequent lethal genetic disorder in the white race. It is an autosomal recessive transmission. In spite of its recent localisation on the 7th chromosome, the fundamental mechanism responsible for the symptoms remains unknown and it is still a syndrome more than a disease. It presents as a generalised seromucous exocrinopathy. The serous glands are functionally abnormal and have secretions too rich in chloride which allows for the sweat test (the only test of diagnostic value). The accumulation of abnormal mucous secretions is responsible for the clinical manifestations: intestinal troubles, bronchial and pulmonary disease, progressive pancreatic insufficiency and biliary cirrhosis. Mucoviscidosis is not longer a disease exclusively of children. The treatment which is solely symptomatic has profoundly changed the prognosis. Half of the children afflicted become adults. This fact and the better condition of diagnosis explain the appearance of a new symptomatology sometimes with a late presentation. On the basis of the genetic and prognostic implications one should consider the diagnosis at any age even if the general state is well conserved. The diagnosis rests on the association of suggestive symptoms and a disturbed sweat test. In the adult the presenting signs are always respiratory, more rarely digestive, and sometimes sterility. These associations are very suggestive. The current evolution requires a specific clinical management of new adult cases who, even if not in a very good clinical state, maintains a vital hope for several years with symptomatic treatment (and the hope perhaps that the discovery of the fundamental defect will lead to more specific therapy).

[Antibiotic therapy in cystic fibrosis: uncertainty and reality]. / Antibiothérapie dans la mucoviscidose: incertitudes et réalités.

Antibiotics inspite of certain contradictions remain an important part of the treatment of mucoviscidosis (MCV). Despite this the current practice of their extensive use does not always rest on firmly placed criteria. Before colonisation with pseudomonas (PA), the systemic prophylaxis of infection by Staphylococcus (SA), or Hemophilus (HI) is debatable. At the time of exacerbations, even if this may be caused by a virus, the prescription of antibiotics (ATB) active against SA and HI should often be continued for 2 or 3 weeks to maintain a durable clinical benefit. While awaiting the results of complimentary multi-centre trials at present underway it remains uncertain whether eradication of the germ at all costs remains indispensable. Systemic anti-PA antibiotic therapy given quarterly from the time of the implantation of the germ has not yet proved to have definitive advantages when compared to the treatment of exacerbations. An appreciation of the benefit of therapy should take count not only of survival curves but also of the quality of life. The indications for treatment should not neglect the possibility of therapeutic progress, sometimes unexpected. Intensive therapy may be justifiable in certain cases awaiting a lung transplant. ATB is only one part of treatment aimed strictly at the broncho-pulmonary system. Drainage and account of infectious agents other than classical bacterial infections or pathogenic mechanisms other than infections (nutritional problems, bronchial hyper-reactivity, immunological phenomenon, or primary or secondary inflammatory changes) should not be ignored.

[Azlocillin treatment of Pseudomonas aeruginosa bronchopulmonary infections in children with cystic fibrosis]. / Traitement par l'azlocilline des infections broncho-pulmonaires à pyocyanique chez les enfants atteints de mucoviscidose.

From April, 1980 to December, 1981 ten children aged from 2 to 14 years presenting with cystic fibrosis were admitted to hospital for exacerbation of their chronic bronchial infection. Mucous Pseudomonas aeruginosa was present in sputum. Seven of the 10 strains isolated were susceptible to azlocillin and 3 were classified as intermediate. Eight children were treated with azlocillin alone in doses of 200-300 mg/kg/day and two with combined azlocillin 300 mg/kg/day and amikacin 16 and 23 mg/kg/day respectively. In both groups the antibiotics were administered 8-hourly by short (30 min) intravenous infusions and the duration of treatment ranged from 8 to 21 days (mean 14 days). Both drugs were well tolerated. Antibacterial activity was assessed as "cure" when Pseudomonas could not be isolated in sputum for at least 2 weeks after the end of the treatment, as "relapse" when that organism reappeared in sputum within the same period of time, and as "failure" when it persisted in sputum. On this account, among the 8 children treated with azlocillin alone 3 were cured, one relapsed and 4 failed. One of the two children treated with the azlocillin-amikacin association was cured, the other failed. Clinical results correlated roughly with antibacterial activity. Five distinct improvements were observed: 2 were associated with bacteriological cure, 2 with transient eradication followed by relapse and 1 occurred although the responsible organism persisted in bronchial secretions. Two children showed poor clinical results; 2 with failure and 1 with bacteriological cure. In two other children treatment was ineffective both clinically and bacteriologically. This study confirms that high parenteral doses of azlocillin have a beneficial effect on exacerbations with Ps. aeruginosa of chronic bronchial infection in cystic fibrosis. Clinical improvement usually correlates with antibacterial activity when the organism is eliminated, even temporarily, from bronchial secretions. The synergistic azlocillin-aminoglycoside association should probably be recommended, at least to reduce the risk of emergence of resistant strains.

[Cystic fibrosis in adults]. / La mucoviscidose à l'âge adulte.

OBJECTIVES: At least half cystic fibrosis patients now reach adulthood. METHODS: We report a population of 61 patients above 18 years of age with the clinical pictures at time of diagnosis and the present clinical status. RESULTS: Thirty-five males and 26 females are aged from 18 to 47 years. Mean age at time of diagnosis was 5 years and 5 months, under 10 years in 80% of patients and above 15 years in 9 patients. Diagnosis was suspected because of pulmonary (2/3) or digestive (1/3) symptoms, insufficient height and weight (1/3) or past family history of cystic fibrosis (1/3). 37% of patients are homozygotes for delta F508 mutation. Adult patients had a normal height but half of them a body weight under 90% of expected weight. Recurrent pulmonary infections were observed in 95% of patients and 62% have chronically infected sputum with Pseudomonas aeruginosa. These patients had lower weight and a poorer radiological score than patients without pseudomonas. 25% of all patients had chronic respiratory insufficiency. 75% had pancreatic insufficiency and 6 patients diabetes mellitus. Thirteen patients had biological cholestasis and three a liver cirrhosis with portal hypertension. Four women underwent 6 normal pregnancies; semen analysis in five men revealed aspermia. Seven patients died during the last two years because of respiratory insufficiency (4), in the three months after pulmonary transplantation (2), and because of digestive haemorrhage (1). CONCLUSION: Treatment included daily bronchial drainage, adapted antibiotic treatment and pancreatic enzyme substitution.

[The prevention of neonatal herpes encephalitis: characteristics in a tropical area]. / Prevention de l'encephalite herpetique neonatale: particularites en zone tropicale.

Neonatal herpes infection virus is rare but of poor prognosis. The only way to prevent it, is to practice a prophylactic caesarean section. In medically undeveloped countries, indication of caesarean section should be very prudent because of subsequent risks of uterine rupture. After a short recall about herpes illness, a precise and simple behaviour is proposed.

[Cystic fibrosis: choices of treatment of respiratory manifestations (except Pseudomonas aeruginosa infections)]. / Mucoviscidose: abord du traitement des manifestations respiratoires (infections à Pseudomonas aeruginosa exceptées).

A knowledge of the natural history of cystic fibrosis is the basis for a treatment which, so far, has only been symptomatic. The three fundamental elements of our therapeutic possibilities are: prevention and treatment of bronchial obstruction, administration of antibiotics active against staphylococci and Haemophilus influenza (Pseudomonas aeruginosa infections will be dealt with in another article of this journal), and control of bronchial inflammatory processes. Some complications of cystic fibrosis regarded as serious are no longer beyond our resources. Many works of fundamental research are needed, concerning the local conditions that are necessary to the selective implantation and the development of Staphylococcus aureus in the lung, and the virus Staphylococcus and Staphylococcus-Pseudomonas relations. The real hope of an absolute treatment justifies the new, aggressive therapeutic approach but the precise indications of an antistaphylococcal treatment must still be evaluated carefully. Finally, the complexity of a treatment which must constantly be adjusted is one of the reasons for the existence of "specialized consultations", the organization of which is summarized.