Clinicopathological study of 13 cases of squamous cell carcinoma complicating hidradenitis suppurativa.

BACKGROUND: To the best of our knowledge, only 52 cases of squamous cell carcinoma (SCC) complicating hidradenitis suppurativa (HS) have been reported since 1958. We describe 13 new cases. METHODS: We propose a clinical and histological analysis of our cases. We include these results in a review of previously reported cases to analyze a total of 65 patients. In our series of 13 cases, we also investigate the presence of human papillomavirus (HPV) in tumor samples, by polymerase chain reaction (PCR) on paraffin-embedded material. RESULTS: Malignant transformation affects mainly men with a long-term history of genitoanal HS. Although our cases were 7 well-differentiated carcinomas and 6 verrucous carcinomas, lymphatic and visceral metastasis occurred in 2 and 3 cases, respectively. With PCR, we demonstrated presence of HPV in genitoanal tumoral lesions, principally HPV-16. CONCLUSION: SCC complicating HS evolves poorly, despite a good histological prognosis. Our results sustain the implication of HPV in the malignant transformation of HS.

[Intra- and interfamilial phenotype variation in Birt-Hogg-Dubé syndrome: Consequences for therapy]. / Variation phénotypique intra- et interfamiliale dans le syndrome de Birt-Hogg-Dubé : conséquences sur la prise en charge.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal-dominantly inherited genodermatosis that predisposes to the development of benign hair follicle tumours, lung cysts, kidney tumours, and possibly colonic cancers, due to mutations in the FLCN gene. We report cases involving a new mutation in three unrelated families. MATERIALS AND METHODS: Blood samples of three probands were submitted for a molecular diagnosis of BHDS. Following DNA extraction, FLCN gene sequencing was performed. The identified mutations were confirmed on a second sample. A cancer genetics consultation was organized and specific tests (dermatological examination, CT scan of chest and abdomen and colonoscopy) were proposed for each BHDS patient. RESULTS: FLCN gene-sequencing analysis revealed an identical complex harmful mutation in all three families. The first proband showed fibrofolliculomas (FF), a history of pneumothorax and colonic adenoma. The mutation was found in a brother and two sisters, who were asymptomatic, and in a niece with FF. The second proband showed FF. The mutation was found in her mother, who had FF. The third proband presented diffuse emphysema and very rare FF. DISCUSSION: This case report shows extremely wide intra- and interfamilial phenotype variation within individuals having a similar FLCN gene mutation. In large cohorts of BHDS patients, no genotype-phenotype correlation has been shown. This case emphasises the vital importance of presymptomatic diagnosis for each member of a BHDS family by means of a cancer genetics consultation, followed by a CT scan of the chest and abdomen, colonoscopy and annual kidney imaging.

[Swallowing disorders, pneumonia and respiratory tract infectious disease in the elderly]. / Troubles de la déglutition du sujet âgé et pneumopathies en 14 questions/réponses.

Swallowing disorders (or dysphagia) are common in the elderly and their prevalence is often underestimated. They may result in serious complications including dehydration, malnutrition, airway obstruction, aspiration pneumonia (infectious process) or pneumonitis (chemical injury caused by the inhalation of sterile gastric contents). Moreover the repercussions of dysphagia are not only physical but also emotional and social, leading to depression, altered quality of life, and social isolation. While some changes in swallowing may be a natural result of aging, dysphagia in the elderly is mainly due to central nervous system diseases such as stroke, parkinsonism, dementia, medications, local oral and oesophageal factors. To be effective, management requires a multidisciplinary team approach and a careful assessment of the patient's oropharyngeal anatomy and physiology, medical and nutritional status, cognition, language and behaviour. Clinical evaluation can be completed by a videofluoroscopic study which enables observation of bolus movement and movements of the oral cavity, pharynx and larynx throughout the swallow. The treatment depends on the underlying cause, extent of dysphagia and prognosis. Various categories of treatment are available, including compensatory strategies (postural changes and dietary modification), direct or indirect therapy techniques (swallow manoeuvres, medication and surgical procedures).

Frailty, osteoporosis and hip fracture: causes, consequences and therapeutic perspectives.

OBJECTIVE: The aim of this review of the literature is to report the factors which both contribute to the frailty syndrome and increase hip fracture risk in the elderly. This work is the fruit of common reflection by geriatricians, endocrinologists, gynecologists and rheumatologists, and seeks to stress the importance of detection and management of the various components of frailty in elderly subjects who are followed and treated for osteoporosis. It also sets out to heighten awareness of the need for management of osteoporosis in the frail elderly. DESIGN: The current literature on frailty and its links with hip fracture was reviewed and discussed by the group. RESULTS: The factors and mechanisms which are common to both osteoporosis and frailty (falls, weight loss, sarcopenia, low physical activity, cognitive decline, depression, hormones such as testosterone, estrogens, insulin-like growth factor-I (IGF-I), growth hormone (GH), vitamin D and pro-inflammatory cytokines) were identified. The obstacles to access to diagnosis and treatment of osteoporosis in the frail elderly population and common therapeutic pathways for osteoporosis and frailty were discussed. CONCLUSION: Future research including frail subjects would improve our understanding of how management of frailty can can contribute to lower the incidence of fractures. In parallel, more systematic management of osteoporosis should reduce the risk of becoming frail in the elderly population.

[Intravascular lymphoma revealed by generalized arborescent telangiectasia and repeated venous thrombosis]. / Thromboses veineuses récidivantes et télangiectasies arborescentes généralisées révélatrices d'un lymphome intravasculaire.

BACKGROUND: Intravascular lymphoma is a rare form of non-Hodgkin's lymphoma characterized by proliferation of lymphoid cells within the lumen of small veins, small arteries and capillaries. CASE REPORT: A 79-year-old man presented with repeated superficial venous thrombosis of the lower limbs associated with diffuse telangiectasia of the trunk, upper arms and thighs but with normal epidermis. Screening for thrombophilia and neoplasm were negative. The patient subsequently developed abdominal pain, lower-limb oedema, deterioration in performance status and rapidly increasing telangiectasia with the appearance of generalized oedematous cutaneous induration. Increased LDH and anaemia were observed without other blood count anomalies. Intravascular lymphoma was diagnosed on a skin biopsy with telangiectasia and oedema. After eight courses of treatment with rituximab-CHOP the outcome was good. DISCUSSION: A few telangiectasias associated with nodules or infiltrated plaques are often a clinical manifestation of intravascular lymphoma. The dermatological presentation described here is interesting for two reasons: on the one hand, telangiectasias were initially isolated in normal epidermis without any infiltration for more than one year and, on the other hand, the skin infiltration seen subsequently was very extensive and marked. Moreover, although microthrombi are frequent in small and medium-sized blood vessels, thrombosis of large vessels is rarely described in intravascular lymphoma.

Leptin a new biological marker for evaluating malnutrition in elderly patients.

BACKGROUND: There is no single universally accepted biochemical marker of nutritional status in the elderly. Many markers are affected by non-nutritional factors. OBJECTIVE: The purpose of this study was to determine the biological parameters best related to anthropometric markers of malnutrition in an elderly polypathological population, and determine cutoff values for these potential parameters to diagnose malnutrition. DESIGN: This prospective study enrolled 116 elderly hospitalized patients and 76 elderly outpatients. Nutritional status (albumin, transthyretin, body mass index (BMI), skinfold thickness) and biological parameters (leptin, insulin-like growth factor-1 (IGF-1), IGF binding protein-1 (IGFBP-1), IGFBP-3, C-reactive protein (CRP), orosomucoid) were assessed. We defined malnutrition according to the lowest quartile of BMI and skinfold thickness measured in a large healthy elderly French sample population. RESULTS: In this sample of elderly patients (age: 85+/-7 years old), leptin concentration was the only biological parameter significantly related to nutrition status. Independent correlations were found between leptin concentration and BMI, skinfold thickness and sex. The relationship between nutritional status and leptin concentration is significantly different in each sex: the more the patients are undernourished, the lower the leptin concentration in both sexes. The optimal leptin cutoff value for the diagnosis of malnutrition in this population was 4 microg/l in men (sensitivity 0.89, specificity 0.82) and 6.48 microg/l in women (sensitivity 0.90, specificity 0.83). CONCLUSION: Leptin concentration is highly correlated with anthropometric data whereas albumin or transthyretin are known to be also influenced by morbidity and inflammatory conditions. Serum leptin concentration could be used for nutritional assessment in elderly patients with acute diseases.

[Lung cancer in the elderly subject]. / Cancer bronchique du sujet âgé.

INTRODUCTION: In France, the average age for the diagnosis of bronchial carcinoma is 64. It is 76 in the population of over 70. In fact, its incidence increases with age linked intrinsic risk of developing a cancer and with general ageing of the population. Diagnosis tools are the same for elderlies than for younger patients, and positive diagnosis mainly depends on fibreoptic bronchoscopy, complications of which being comparable to those observed in younger patients. STATE OF THE ART: The assessment of dissemination has been modified in recent years by the availability of PET scanning which is increasingly becoming the examination of choice for preventing unnecessary surgical intervention, a fortiori in elderly subjects. Cerebral imaging by tomodensitometry and nuclear magnetic resonance should systematically be obtained before proposing chirurgical treatment. An assessment of the general state of health of the elderly subject is an essential step before the therapeutic decision is made. This depends on the concept of geriatric evaluation: Geriatric Multidimensional Assessment, and the Comprehensive Geriatric Assessment which concerns overall competence of the elderly. PERSPECTIVES: This is a global approach that allows precise definition and ranking of the patient's problems and their impact on daily life and social environment. Certain geriatric variables (IADL, BADL, MMSE, IMC etc) may be predictive of survival rates after chemotherapy or the incidence of complications following thoracic surgery. The main therapeutic principles for the management of bronchial carcinoma are applicable to the elderly subject; long term survival without relapse after surgical resection is independent of age. Whether the oncological strategy is curative or palliative, the elderly patient with bronchial carcinoma should receive supportive treatments. They should be integrated into a palliative programme if such is the case. In fact, age alone is not a factor that should detract from optimal oncological management. CONCLUSIONS: The development of an individual management programme for an elderly patient suffering from bronchial carcinoma should be based on the combination of oncological investigation and comprehensive geriatric assessment.

Subcorneal pustulosis and Pyoderma gangrenosum associated with a biclonal gammopathy.

Pyoderma gangrenosum and subcorneal pustulosis are two neutrophilic dermatoses. Their occurrence in the same patient is rare and may be related to an IgA dysglobulinemia. We report a case presenting these two conditions associated with a biclonal benign IgA and IgG gammopathy. A 67-year-old man exhibited typical pyoderma gangrenosum associated after three years duration with subcorneal pustulosis lesions, confirmed by cutaneous biopsy. Laboratory results showed a biclonal benign IgA and IgG kappa gammopathy. Therapeutic management was difficult: Pyoderma gangrenosum responded well to corticosteroids but subcorneal pustulosis management was harder and treatments were poorly effective.Pyoderma gangrenosum and subcorneal pustulosis are a part of the neutrophilic spectrum. Their association has been only reported in eleven patients. In eight cases, an IgA dysglobulinemia was associated suggesting its responsibility in the occurrence of both dermatoses. Treatments are various and not fully effective. If the Pyoderma gangrenosum usually responds to corticosteroids, the subcorneal pustulosis treatments are not well defined and often not efficient. Our case illustrates the dissociated evolution of these two dermatoses and their difficult global management. During the follow-up, a regular search for dysglobulinemia is required in order to detect malignant transformations.

Four common glomulin mutations cause two thirds of glomuvenous malformations ("familial glomangiomas"): evidence for a founder effect.

BACKGROUND: Glomuvenous malformation (GVM) ("familial glomangioma") is a localised cutaneous vascular lesion histologically characterised by abnormal smooth muscle-like "glomus cells" in the walls of distended endothelium lined channels. Inheritable GVM has been linked to chromosome 1p21-22 and is caused by truncating mutations in glomulin. A double hit mutation was identified in one lesion. This finding suggests that GVM results from complete localised loss of function and explains the paradominant mode of inheritance. OBJECTIVE: To report on the identification of a mutation in glomulin in 23 additional families with GVM. RESULTS: Three mutations are new; the others have been described previously. Among the 17 different inherited mutations in glomulin known up to now in 43 families, the 157delAAGAA mutation is the most common and was present in 21 families (48.8%). Mutation 108C-->A was found in five families (11.8%), and the mutations 554delA+556delCCT and 1179delCAA were present together in two families (4.7% each). Polymorphic markers suggested a founder effect for all four mutations. CONCLUSIONS: Screening for these mutations should lead to a genetic diagnosis in about 70% of patients with inherited GVM. So far, a mutation in glomulin has been found in all GVM families tested, thus demonstrating locus homogeneity.

[Evaluation of pulmonary function in the elderly. Intergroupe Pneumo Gériatrie SPLF-SFGG]. / Evaluation de la fonction respiratoire chez le sujet âgé. Intergroupe Pneumo Gériatrie SPLF-SFGG.

Aging is associated with a progressive decrease in lung function. As a consequence of aging, individual's reserve is diminished, but this decrease is heterogeneous between individual subjects. Many factors are involved in the overall decline in lung function. The prevalence of asthma in the elderly is estimated between 6 and 10%. Mortality due to COPD is increasing, especially among older subjects. Older subjects are at an increased risk of developing chronic diseases such as Parkinson's disease, which can have consequences for lung function. Under-nutrition is also common in the elderly and can produce sarcopenia and skeletal muscle dysfunction. The presentation of respiratory disorders may differ in the elderly, especially because of a lack of perception of symptoms such as dyspnea. The impact of bronchodilatators or corticosteroids on respiratory function has not been studied in the elderly. Drugs usually used for the treatment of hypertension or arrhythmias, which are often observed with aging, can have pulmonary toxicity. There is no difference between functional evaluation in younger and older subjects but it is more difficult to find predicted values for older patients. Performing pulmonary function tests in older patients is often difficult because of a higher prevalence of cognitive impairment and/or poor coordination. When assessing pulmonary function in the elderly, the choice of tests will be depend on the circumstances, with the use of voluntary manoeuvres dependent on the condition of the patient.

[Familial case of Parkes Weber syndrome]. / Syndrome de Parkes-Weber familial.

INTRODUCTION: Parkes-Weber syndrome is usually described as a sporadic form of osteohypertrophic angiodysplasia. However, family forms of Klippel-Trenaunay syndrome have been described. We report the first familial case of Parkes-Weber syndrome. OBSERVATION: A boy born at 27 weeks and 6 days of amenorrhea with extensive plane angioma of the right lower limb, right lower part of the back and abdomen. We also noted hypertrophy of this member with venous dilatations. Arterial Doppler ultrasound of the right lower limb showed an aneurysmal varix between the vein and the common femoral artery, confirming a diagnosis of Parkes-Weber syndrome. His maternal first cousin, 10 years his senior, also presented Parkes-Weber syndrome of the right upper limb. DISCUSSION: This is the first observation of a familial case of Parkes-Weber syndrome in first cousins. Vascular malformations are transmitted in autosomal dominant fashion in the majority of infected families but with incomplete penetrance and variable expressivity. Symptoms appeared to worsen from generation to generation. In each generation of this family, we noted the presence of hemangiomas or capillary malformations with aggravation in the third generation and onset of Parkes-Weber syndrome. Genetic investigation with linkage analysis for the various members in order to identify a predisposing locus yielded little of interest.

[Interstitial brachytherapy in management of primary cutaneous melanoma: 4 cases]. / Traitement par curiethérapie interstitielle du mélanome primitif cutané: 4 cas.

BACKGROUND: Traditionally melanoma has been considered as a radioresistant tumor. However, recent observations regarding radiobiology and clinical response of melanoma have prompted physicians to re-evaluate the role of radiotherapy in the management of melanoma. Indeed, radiotherapy is frequently used in the treatment of metastatic melanoma but the role of this therapeutic approach in the primary tumor management is unclear. We report 4 cases of thick primary melanoma treated by interstitial brachytherapy. CASE REPORTS: Four patients (3 men, 1 woman; age: 73, 74, 79, 84 years), three with lentigo maligna melanoma and one with nodular melanoma, were treated exclusively by interstitial brachytherapy. The thickness of the 4 tumors was more than 3 mm. This treatment was chosen either because of the impossibility of conservative surgery or because of a contraindication for general anesthesia. Median follow-up was 48 months [18 to 65 months] and we did not observe any local tumor relapse. The cosmetic and functional results of this therapy were excellent. DISCUSSION: These four cases illustrate the possibility of obtaining good local control of thick primary melanoma by interstitial brachytherapy where surgery is impossible, although without challenging the standard surgical therapy for primary melanoma. Before our study, this treatment was used only in one study to treat melanoma patients. In this case however, interstitial brachytherapy was accompanied by surgery. Therefore, the findings reported here are the first to demonstrate the efficacy of this treatment when used as the sole treatment for primary melanoma. In conclusion, where surgery is difficult or impossible, interstitial brachytherapy may be used to treat primary melanoma with excellent local tumor control and a good cosmetic outcome.

[Neonatal maculopapular exanthema revealing septicemia due to Klebsiella pneumoniae via maternofetal infection]. / Exanthème maculo-papuleux néonatal révélateur d'une septicémie à Klebsiella pneumoniaee par infection maternofoetale.

BACKGROUND: Neonatal exanthema of bacterial origin is caused very rarely by Gram-negative bacilli. We report a case of neonatal maculopapular exanthema evocative of Klebsiella pneumoniae septicemia resulting from maternofetal infection. OBSERVATION: On the fourth day of life, a newborn infant presented incipient morbilliform maculopapular exanthema on the face. During delivery, the mother had presented hyperthermia and meconium was found in the amniotic fluid. Clinical examination of the newborn was normal. No clinically obvious site of entry of infection was seen. Laboratory tests revealed major inflammatory syndrome. Blood cultures were positive for K. pneumoniae, which was also found in blood cultures from the mother. Screening for other causes of infection was negative. Parenteral antibiotics for 10 days yielded favorable results with simultaneous resolution of the exanthema, normalization of laboratory values and negative blood cultures. DISCUSSION: Exanthemas of infectious origin are not associated with any specific organism. The most common causative micro-organisms are Listeria monocytogenes, B streptococci, colibacilli, and more rarely, staphylococci. There have been reports of a number of cases of neonatal septicemia due to Gram-negative bacilli responsible for maculopapular exanthemas but the causative organism was not identified. To our knowledge, Klebsiella pneumoniae has never been incriminated in the appearance of this type of rash via maternofetal transmission. Consequently, the presence of neonatal exanthema should prompt screening for sepsis, even in the absence of other evocative signs, and in particular in settings of apyrexia.

[Invasive fungal dermatitis in extremely premature newborns: a specific clinical form of systemic candidiasis]. / La candidose cutanée invasive du grand prématuré, une forme clinique particulière de candidose systémique.

BACKGROUND: Fungal agents, chiefly Candida albicans, are the cause of rising morbidity and mortality in newborn infants weighing less than 1500 g. We studied the particular cutaneous effects during the course of these infections. PATIENTS AND METHODS: This was a retrospective 3-year study in premature infants weighing less than 1500 g and hospitalized in the neonatal department of the Lille University Teaching Hospital. The patients included in the study presented sepsis with isolation of Candida in blood and/or urine culture. RESULTS: Twelve infants were included (1.8%). The risk factors seen are those described in literature (broad-spectrum antibiotics, prolonged mechanical ventilation and parenteral nutrition, corticosteroids and central venous catheters). Infection occurred early (mean: D12) and affected extremely premature infants (mean: 25 weeks' amenorrhea) of low birth weight (mean: 758 g) generally born by vaginal delivery (9 of 12 infants). The sole fungal agent isolated was Candida albicans. In 10 of the 12 patients, a characteristic skin disorder was observed (erythema with erosion and desquamation). In 10 of the 12 patients, too, Candida was isolated from skin and/or mucosal samples. DISCUSSION: Although it is now universally accepted that antifungal treatment should be initiated without delay for candidemia in septic newborn infants at risk, diagnosis of systemic candidiasis remains delicate. However, a specific pattern of skin involvement is very commonly seen that is atypical for candidiasis, but which in addition to its diagnostic value indicates early colonization with Candida (first 2 weeks of life). In this setting of immaturity of the skin and immune system, colonization and proliferation in skin and/or mucosa appear to constitute the first stage of systemic infection and we may speak of invasive cutaneous-mucosal candidiasis in extremely premature infants and initiate treatment designed to prevent the disease becoming systemic..

[Skin diseases observed in the dermatology departments of three French university teaching hospitals]. / Activité de consultation de trois services de dermatologie hospitalo-universitaires français.

BACKGROUND: We recently carried out a study concerning consultations by French dermatologists in private practice. We evaluated consultations at the dermatology departments of 3 university teaching hospitals in France. MATERIALS AND METHODS: This was a 2-month prospective study conducted in 2003 at the dermatology departments of the university teaching hospitals of Amiens, Lille and Rouen. Each consultant completed a questionnaire covering the duration of the study. The following data were recorded: consultation date, function of the consultant, study centre, type of consultation, type of disease, and whether or not the patient was hospitalised after the consultation. RESULTS: 7296 files were examined during the study. 38% of the consultations were performed by part-time hospital consultants, 29% by dermatology interns, 18% by hospital practitioners, 9% by university professors and 6% by clinical heads or assistant heads. The most commonly encountered diseases were allergies (17%), cancer (16%), arteriovenous disease (15%) and infectious disease (11%). Three types of consultation were identified: emergency consultations without an appointment, consultations by appointment for a specific problem and consultations by appointment without a specific problem. The number of resulting hospital admissions ranged from 2 to 10% of consultations, depending on the type of consultation and the role of the consultant in question. DISCUSSION: This study shows that in France, consultations at hospital dermatology departments differ greatly from those of dermatologists in private practice. The main diseases seen (cancer, arteriovenous disease, allergy, infectious dermatosis) accounted for the majority of hospitalisations in these departments. The organisation of hospital consultations is increasingly tending both towards treatment of highly specialised diseases through specifically oriented consultations and also towards the emergency treatment of certain forms of acute dermatosis.

Hemodynamic determinants of exercise ST-segment depression in coronary patients.

Eight patients with coronary heart disease were studied during two periods of exercise separated by 30 min of rest; workload was increased in a stepwise fashion every minute of exercise up to a level that produced limiting symptoms of angina, fatigue, or dyspnea. The magnitude of ST-segment depression and the central aortic pressure were measured during exercise and recovery periods, and myocardial oxygen requirements were estimated by the pressure-time index (systolic aortic pressure x heart rate x ejection time). Seven of the eight patients exhibited a close relationship (r ranged from 0.74 to 0.98) between magnitude of exercise ST-segment depression and indices expressing myocardial oxygen requirements; heart rate, blood pressure, and ejection time were also related to magnitude of exercise ST-segment depression. These relationships were reproducible during two consecutive exercises. Like onset of angina, magnitude of exercise ST-segment depression is usually related to hemodynamic factors influencing myocardial oxygen needs. Consequently, comparisons of exercise-induced ST depression before and after therapy (drugs, physical training, and surgery) are valid only if ECG findings are compared at the same level of myocardial oxygen requirements. In contrast, absence of such a relationship during recovery suggests an important difference in mechanisms of the post-exercise electrocardiogram.

Analysing Time to Event Data in Dementia Prevention Trials: The Example of the GuidAge Study of EGb761.

Time-to-event analysis is frequently used in medical research to investigate potential disease-modifying treatments in neurodegenerative diseases. Potential treatment effects are generally evaluated using the logrank test, which has optimal power and sensitivity when the treatment effect (hazard ratio) is constant over time. However, there is generally no prior information as to how the hazard ratio for the event of interest actually evolves. In these cases, the logrank test is not necessarily the most appropriate to use. When the hazard ratio is expected to decrease or increase over time, alternative statistical tests such as the Fleming-Harrington test, provide a better sensitivity. An example of this comes from a large, five-year randomised, placebo-controlled prevention trial (GuidAge) in 2854 community-based subjects making spontaneous memory complaints to their family physicians, which evaluated whether treatment with EGb761 can modify the risk of developing AD. The primary outcome measure was the time to conversion from memory complaint to Alzheimer's type dementia. Although there was no significant difference in the hazard function of conversion between the two treatment groups according to the preplanned logrank test, a significant treatment-by-time interaction for the incidence of AD was observed in a protocol-specified subgroup analysis, suggesting that the hazard ratio is not constant over time. For this reason, additional post hoc analyses were performed using the Fleming-Harrington test to evaluate whether there was a signal of a late effect of EGb761. Applying the Fleming-Harrington test, the hazard function for conversion to dementia in the placebo group was significantly different from that in the EGb761 treatment group (p = 0.0054), suggesting a late effect of EGb761. Since this was a post hoc analysis, no definitive conclusions can be drawn as to the effectiveness of the treatment. This post hoc analysis illustrates the interest of performing another randomised clinical trial of EGb761 explicitly testing the hypothesis of a late treatment effect, as well as of using of better adapted statistical approaches for long term preventive trials when it is expected that prevention cannot have an immediate effect but rather a delayed effect that increases over time.

NAT2 genotyping and efficacy of sulfasalazine in patients with chronic discoid lupus erythematosus.

Sulfasalazine is an effective agent for chronic discoid lupus erythematosus (CDLE) but the response to treatment is considerably variable between patients and is also unpredictable. The reason for this might relate to differences in metabolism of the drug which is extensively acetylated by the polymorphic enzyme N-acetyltransferase 2 (NAT2). To test this possibility, the N-acetylation phenotype of eleven patients with CDLE and treated by standard doses of sulfasalazine was retrospectively determined by genotyping. A clear-cut difference in the outcome of treatment was observed according to whether the patients were slow acetylators (SA) or rapid acetylators (RA). Eight out of 11 patients responded to treatment with a complete or marked remission of the disease. Seven of them were RA. The three other patients who did not respond at all to the drug were SA. In addition, SA seem to be more prone to toxic events. These findings strongly suggest that the genetic polymorphism of NAT2 is responsible for differences in the response to sulfasalazine in patients with CDLE. Therefore, candidates for sulfasalazine therapy should be genotyped to identify those patients who might benefit from the drug.

Modeling the relation between neurofibrillary tangles and intellectual status.

The relationship between the neurofibrillary tangles and the intellectual deficit observed in senile dementia of the Alzheimer type was studied in 27 patients over the age of 75. The presence and density of tau positive tangles were assessed in six areas including limbic, paralimbic, and isocortical cortices. In the isocortical areas, the presence [1] or absence [0] of neurofibrillary tangles was better correlated with the Blessed test score than the density of the neurofibrillary tangles profiles. Multivariate analysis showed that the number of areas containing at least one neurofibrillary tangle was the best explanatory variable of the intellectual status. The cortical areas were ranked according to the prevalence of their involvement. The presence of tangles in an area of a given rank took place only if the areas of lower ranks were also involved. It is proposed that the presence of tangles in a given area is a more significant information than the value of their density. These data may lead to new diagnostic procedures.

Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer's disease.

Cholinergic neurons were studied by immunohistochemistry, with an antiserum against choline acetyltransferase (ChAT), in the basal forebrain (Ch1 to Ch4) of four patients with Alzheimer's disease (AD) and four control subjects. ChAT-positive cell bodies were mapped and counted in Ch1 (medial septal nucleus), Ch2 (vertical nucleus of the diagonal band), Ch3 (horizontal nucleus of the diagonal band) and Ch4 (nucleus basalis of Meynert). Compared to controls, the number of cholinergic neurons in AD patients was reduced by 50% on average. The interindividual variations in cholinergic cell loss were high, neuronal loss ranging from moderate (27%) to severe (63%). Despite the small number of brains studied, a significant correlation was found between the cholinergic cell loss and the degree of intellectual impairment. To determine the selectivity of cholinergic neuronal loss in the basal forebrain of AD patients, NPY-immunoreactive neurons were also investigated. The number of NPY-positive cell bodies was the same in controls and AD patients. The results (1) confirm cholinergic neuron degeneration in the basal forebrain in AD and the relative sparing of these neurons in some patients, (2) indicate that degeneration of cholinergic neurons in the basal forebrain contributes to intellectual decline, and (3) show that, in AD, such cholinergic cell loss is selective, since NPY-positive neurons are preserved in the basal forebrain.