Genotype-phenotype and OCT correlations in Autosomal Dominant Optic Atrophy related to OPA1 gene mutations: Report of 13 Italian families.

Mutations in OPA1 are responsible of 32-89% cases of Autosomal Dominant Optic Atrophy (ADOA). OPA1 ADOA usually presents in childhood with bilateral, progressive visual loss due to retinal ganglion cells neurodegeneration, but environmental factors are supposed to influence onset and phenotype. Sixty Italian OPA1 mutations carriers (fifty-two symptomatic), belonging to thirteen families, underwent neuro-ophthalmologic evaluation. Visual acuity (n=60) and Optical Coherence Tomography (OCT) (n=12) were compared in missense mutations (OPA-M) versus haploinsufficiency-inducing mutations (OPA-H) and correlated with age. Presence of plus phenotypes was investigated. We found four known mutations, the most common being missense c.1034G>A, and a new missense mutation, c1193A>C, the latter in a 54-yrs old female with late-onset phenotype. Visual acuity, colour sensitivity, and optic disc atrophy were sensitive indicators of disease. OCT RNFL thickness was reduced in OPA1 compared to controls. OPA-M showed worst visual acuity than OPA-H, but not more frequent plus-phenotype, observed only in four OPA-H patients. In both groups, visual acuity worsened with age. Our data confirm worst vision in OPA-M, but not increased plus-phenotype. Since most patients belonged to nine families from south-eastern Sicily (a famous region for the cult of St. Lucy, patron of the blinds) local genetic and environmental factors might have accounted for the low occurrence of plus-phenotypes.

Polyneuropathy in cerebrotendinous xanthomatosis and response to treatment with chenodeoxycholic acid.

Polyneuropathy has been reported in cerebrotendinous xanthomatosis (CTX), although its nature and possible association with certain genotypes and phenotypes are unclear. The effect of chronic administration of chenodeoxycholic acid (CDCA) on peripheral nerve conduction parameters is still debated. We report clinical, laboratory, and electrophysiological findings in 35 CTX patients. Twenty-six subjects (74.2 %) showed peripheral nerve abnormalities. Polyneuropathy was predominantly axonal (76.9 % of patients) and generally mild. No correlation was found between its presence and clinical or biochemical data. In polyneuropathic patients, CDCA treatment improved electrophysiological conduction parameters, irrespective of the duration of therapy. Improvement mainly concerned nerve conduction velocities, whereas most nerve amplitudes remained unchanged. This means that CDCA treatment did not influence the number of axons activated by maximum electrical stimulation but increased the conduction of the still-excitable fibers. Our findings may suggest that CDCA treatment promotes myelin synthesis in nerve fibers with residual unaffected axons. The effect of therapy may therefore depend largely on the extent of irreversible structural damage to axons.

High frequency of OPA1 mutations causing high ADOA prevalence in south-eastern Sicily, Italy.

Optic atrophy type 1 (OPA1) gene mutation causes autosomal dominant optic atrophy (ADOA, MIM #165500). Prevalence of ADOA ranges from 1:50,000 in most populations to 1:12,000 in Denmark. Seventy members of nine families were analysed for the presence of OPA1 gene mutations by polymerase chain reaction (PCR) and direct sequencing. We identified three OPA1 gene mutations in 48 patients with variable signs of optic atrophy. Two mutations, c.784-21_784-22insAluYb8 and c.876_878delTGT, were found in two different families. The third mutation, c.869G>A, was found in 28 patients from seven families. The haplotype analysis data suggested that the c.869G>A mutation is a founder mutation. Our main result suggests a higher ADOA prevalence in south-eastern Sicily than previously found in Denmark. This is because of not only the founder effect but also to the presence of three different mutations in the geographical area of the study. Our hypothesis is that a combination of social pressure because of blindness and migration factors is involved. In fact, in Siracusa, a provincial capital in south-eastern Sicily, St. Lucy, the patron saint of the blind was born and died.

Clinical relevance and neurophysiological correlates of spasticity in cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease due to defective activity of sterol 27-hydroxylase, with plasma and tissue cholestanol storage. Clinical phenotype is characterized by both systemic manifestations and neurological signs. Therapy with chenodeoxycholic acid (CDCA) suppresses abnormal bile acid synthesis. The purpose of the study was to assess the frequency and clinical relevance of spasticity in the CTX phenotype and to study the usefulness of transcranial magnetic stimulation (TMS) in detecting corticospinal tract damage and monitoring the effects of replacement therapy. Twenty-four CTX patients underwent clinical evaluation including general disability scores, pyramidal and cerebellar function scales, assessment of serum cholestanol and TMS. Nine patients who started CDCA therapy at baseline received clinical and neurophysiological follow up. All patients showed signs of pyramidal damage which were relevant for clinical disability in 18 out of 24 cases (75%), resulting in spastic paraparesis. TMS revealed corticospinal alterations even in subjects with mild clinical signs of corticospinal tract involvement. After CDCA treatment, serum cholestanol decreased to normal concentrations in all patients. Clinical picture was unchanged in seven out of nine cases; in two others pyramidal signs disappeared. A reduction in abnormal neurophysiological parameters was found. Spastic paraparesis is the most frequent and relevant neurological feature in CTX patients. Replacement treatment with CDCA can prevent the progression of pyramidal damage, especially if started early in the course of the disease. TMS represents a sensitive indicator of corticospinal tract dysfunction and subclinical improvements in pyramidal function after CDCA therapy.

Four novel CYP27A1 mutations in seven Italian patients with CTX.

BACKGROUND AND PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, because of sterol 27-hydroxylase deficiency. Clinical manifestations of CTX are tendon xanthomas, juvenile cataracts, osteoporosis, diarrhoea and multiple progressive neurological dysfunctions. More than 300 patients with CTX have been reported to date worldwide and about fifty different mutations identified in CYP27A1 gene. This study describes the clinical and laboratory findings of seven new patients. METHODS: We report the molecular and clinical characterization of seven new Italian patients with CTX carrying four novel mutations. RESULTS: We identified four novel mutations located in different exons, in particular in the region of exons 2-5 of the CYP27A1 gene. Phenotypical expression did not differ from classical CTX presentation except for absence of tendon xanthomas in two patients.

Chronic progressive external ophthalmoplegia: a new heteroplasmic tRNA(Leu(CUN)) mutation of mitochondrial DNA.

We sequenced all genes of mitochondrial tRNAs of a patient with chronic progressive external ophthalmoplegia with 5% ragged red fibres and 15% COX-negative fibres but without macrorearrangements of mitochondrial DNA (mtDNA). Direct sequencing showed a novel heteroplasmic G>A substitution in position 12316 of tRNA(Leu(CUN)) gene. This change destroys a highly conserved G-C base coupling in tRNA TpsiC branch. By RFLP analysis we could demonstrate different degrees of heteroplasmy in different patient's tissues. This alteration, absent in a population of 110 patients with different encephalomyopathies, can be considered pathogenic: it is the tenth tRNA(Leu(CUN)) pathogenic mutation described up to date.

Questioning the utility of pooling samples in microarray experiments with cell lines.

We describe a microarray experiment using the MCF-7 breast cancer cell line in two different experimental conditions for which the same number of independent pools as the number of individual samples was hybridized on Affymetrix GeneChips. Unexpectedly, when using individual samples, the number of probe sets found to be differentially expressed between treated and untreated cells was about three times greater than that found using pools. These findings indicate that pooling samples in microarray experiments where the biological variability is expected to be small might not be helpful and could even decrease one's ability to identify differentially expressed genes.

Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease due to defective activity of the mitochondrial enzyme sterol 27-hydroxylase. In 1991, sterol 27-hydroxylase gene (CYP27A1) was localised on the long arm of chromosome 2 [1]. Clinical characteristics of CTX are diarrhoea, cataracts, tendon xanthomas and neurological manifestations including dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures. More than 300 patients with CTX have been reported to date worldwide and about 50 different mutations identified in the CYP27A1 gene. Almost all mutations lead to the absence or inactive form of the sterol 27-hydroxylase. In this review, according with the aims of this section of the journal, we describe the different pathogenetic mutations in the CYP27A1 gene and the main clinical and pathogenetic aspects that may help clinical neurologists in the diagnosis of CTX.

Monitoring surgical and medical outcomes: the Bernoulli cumulative SUM chart. A novel application to assess clinical interventions.

BACKGROUND: Monitoring clinical interventions is an increasing requirement in current clinical practice. The standard CUSUM (cumulative sum) charts are used for this purpose. However, they are difficult to use in terms of identifying the point at which outcomes begin to be outside recommended limits. OBJECTIVE: To assess the Bernoulli CUSUM chart that permits not only a 100% inspection rate, but also the setting of average expected outcomes, maximum deviations from these, and false positive rates for the alarm signal to trigger. METHODS: As a working example this study used 674 consecutive first liver transplant recipients. The expected one year mortality set at 24% from the European Liver Transplant Registry average. A standard CUSUM was compared with Bernoulli CUSUM: the control value mortality was therefore 24%, maximum accepted mortality 30%, and average number of observations to signal was 500-that is, likelihood of false positive alarm was 1:500. RESULTS: The standard CUSUM showed an initial descending curve (nadir at patient 215) then progressively ascended indicating better performance. The Bernoulli CUSUM gave three alarm signals initially, with easily recognised breaks in the curve. There were no alarms signals after patient 143 indicating satisfactory performance within the criteria set. CONCLUSIONS: The Bernoulli CUSUM is more easily interpretable graphically and is more suitable for monitoring outcomes than the standard CUSUM chart. It only requires three parameters to be set to monitor any clinical. INTERVENTION: the average expected outcome, the maximum deviation from this, and the rate of false positive alarm triggers.

Systolic and pulse blood pressures (but not diastolic blood pressure and serum cholesterol) are associated with alterations in carotid intima-media thickness in the moderately hypercholesterolaemic hypertensive patients of the Plaque Hypertension Lipid Lowering Italian Study. PHYLLIS study group.

OBJECTIVE: The Plaque Hypertension Lipid Lowering Italian Study (PHYLLIS), is the first study in patients with hypertension (diastolic blood pressure (DBP) 95-115 mmHg; systolic blood pressure (SBP) 150-210 mmHg), moderate hypercholesterolaemia (LDL-cholesterol 4.14-5.17 mmol/l (160-200 mg/dl) and initial carotid artery alterations (maximum intima-media thickness (IMT) Tmax > or = 1.3 mm). The primary objective of PHYLLIS is investigating whether in these patients administration of an angiotensin converting enzyme inhibitor, fosinopril, and a statin, pravastatin, is more effective than administration of a diuretic and a lipid-lowering diet in retarding or regressing alterations in carotid IMT. While the study is in progress, baseline data are here reported to clarify the association of various risk factors with carotid IMT in these medium-high risk hypertensive patients. METHODS: Patients numbering 508 have been randomized to PHYLLIS by 13 peripheral units, in Italy. Age was (mean +/- SD) 58.4 +/- 6.7 years, males were 40.2%, current smokers 16.5%, means +/- SD of serum total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol and triglycerides concentrations were 6.79 +/- 0.67, 4.69 +/- 0.51, 1.37 +/- 0.38, 1.59 +/- 0.64 mmol/l (262.4 +/- 25.8, 181.3 +/- 19.8, 53.0 +/- 14.6, 141.0 +/- 56.7 mg/ dl). Means +/- SD of clinic sitting SBP/DBP were 159.8 +/- 9.0/98.3 +/- 4.2 mmHg. 483 of the 508 patients also had 24 h ambulatory BP monitoring, edited and read at a centralized unit (mean +/- SD 24 h SBP/DBP averages 136.3 +/- 14.1/84.0 +/- 10.0 mmHg). Quantitative B-mode ultrasound (Biosound 2000 II 5A, Biosound, Indianapolis, Indiana, USA) recordings of carotid arteries were taken by certified sonographers in the peripheral units and tracings were all read at a central unit. CBMmax (mean IMT of eight sites at common carotids and bifurcations) was 1.21 +/- 0.17; Mmax (mean of 12 sites also including internal carotids) 1.16 +/- 0.17, and Tmax (single maximum) 1.85 +/- 0.48 mm. RESULTS: Ambulatory SBP and pulse pressure (PP) (24 h, daytime, night-time averages) and their variability indices (24 h SD) were always significantly correlated with CBMmax and Mmax (P0.01 -0.001), and the correlations remained significant after adjustment for age, gender and smoking. No measurement of DBP was ever associated with any IMT measurement. Likewise, no lipid variable was found associated with any IMT measurement. CONCLUSIONS: Baseline data from PHYLLIS indicate that in this population of hypertensive patients with moderate hypercholesterolaemia, SBP and PP are with age among the most significant factors associated with carotid artery alterations. However, the narrow range of inclusion LDL-cholesterol and DBP values may have obscured an additional role of these variables.

Intima-media thickness after pravastatin stabilizes also in patients with moderate to no reduction in LDL-cholesterol levels: the carotid atherosclerosis Italian ultrasound study.

The Carotid Atherosclerosis Italian Ultrasound study (CAIUS), a multicenter, double-blind clinical trial, performed in 305 asymptomatic, moderately hypercholesterolemic patients, clearly demonstrated beneficial effects of pravastatin on the carotid intima-media thickness (IMT) progression. The database of the CAIUS study was examined in order to investigate the presence of a relationship, if any, between the activity of pravastatin on IMT progression rate and its hypocholesterolemic effect. Quantitative B-mode ultrasound imaging was used to quantify the individual mean maximum IMT progression rate in 3 years. In the overall group of patients (placebo and pravastatin) covariance analysis showed that while the variable 'treatment' (0 = placebo, 1 = pravastatin) was significantly related to the reduction of IMT progression (F= 6.6, P = 0.01), the IMT progression did not correlate with the extent of LDL-C lowering (F= 0.00, P = 0.98). To further investigate this issue. the pravastatin treated group was stratified into quartiles of LDL-C reduction. In contrast to what was observed in the placebo group, in which a positive mean IMT progression rate was observed, independent of the extent of LDL-C reduction, no IMT progressionwas observed in any subgroup treated with pravastatin. No significant difference was found among quartiles and no trend could be identified. In conclusion, the effect of pravastatin treatment on carotid IMT progression rate is beneficial; however the CAIUS study demonstrated that lowering LDL-C by itself, does not explain the variability of beneficial changes in IMT.

Low prevalence of islet autoimmunity in adult diabetes and low predictive value of islet autoantibodies in the general adult population of northern Italy.

AIMS/HYPOTHESIS: To assess the prevalence of islet autoimmunity in adult-onset diabetes mellitus and the predictive value of islet autoantibodies in the general adult population of northern Italy. METHODS: A sample of 2076 people aged 40 years or more participating in the population-based Cremona Study and classified in 1990 as having diabetes mellitus, impaired and normal glucose tolerance according to WHO criteria after an oral glucose tolerance test, were tested for antibodies to glutamic acid decarboxylase and IA-2. RESULTS: Increased concentrations of glutamic acid decarboxylase antibodies were found in 4 (2.8 %) of 143 participants with known diabetes and none of 50 with previously unknown diabetes, 1 (0.65%) of 153 with impaired and 18 (1.0%) of 1718 with normal glucose tolerance. The increased prevalence of these antibodies in subjects with known diabetes was not statistically significant. Protein tyrosine phosphatase IA-2-antibodies were found in only four subjects, two of whom also had glutamic acid decarboxylase antibodies, all with normal glucose tolerance. After 8 years of follow-up, none of 21 non-diabetic subjects with either glutamic acid decarboxylase or IA-2-antibodies had developed diabetes and only a slight deterioration from normal to impaired fasting glucose was observed in 3 of 15 subjects with previous normal glucose tolerance. CONCLUSION/INTERPRETATION: This study has shown that in northern Italy the prevalence of adult autoimmune diabetes in the general adult population is 0.19% (95 % CI 0.05-0.5); that autoimmune diabetes represents only a minority of all cases of adult diabetes; and that islet autoantibodies are not a high-risk factor for diabetes development in adults with normal glucose tolerance over 8 years of follow-up.

Factors related to glycemic control in IDDM and insulin-treated NIDDM patients in current practice. A comparison of care policies. SIEMTIC Group. Studio Italiano Epidemiologico Multicentrico su Terapia Insulin e Controllo Metabolico.

OBJECTIVE: To evaluate, under routine conditions, the relation between different diabetes care policies and glycemic control through a by-center analysis procedure aimed at reducing some drawbacks of cross-sectional data. RESEARCH DESIGN AND METHODS: A survey on insulin-treated diabetes care management (IDDM and NIDDM) involved 16 Italian randomly selected diabetes outpatient clinics. A total of 2,142 representative patients were investigated. The standardized HbA1c average value of each center was related, by regression models, to some indicators of center care policy (average number of injections, average BMI, proportion of cases with recent fundus oculi examinations, or frequent visits) as well as to patients' average social levels (employment type). Homogeneity in patient admission criteria is assumed among the investigated centers as a basic condition for the procedure validity. Some known imbalance were controlled for both design and analysis. RESULTS: HbA1c showed a univariate inverse relation with daily number of injections in IDDM (P = 0.0009, r2 = 0.56) but not in NIDDM (P = 0.33). It was inversely related to both fundus examination (IDDM P = 0.04; NIDDM P = 0.099) and qualified employment (IDDM P = 0.06; NIDDM P = 0.026). A stepwise regression analysis left in the model insulin injections (P = 0.0002) in IDDM (total r2 = 0.68) and qualified employment (P = 0.016) and fundus examination (P = 0.14) in NIDDM (total r2 = 0.53), after controlling for age, sex, disease duration, insulin therapy starting delay, and insulin dose per kilogram. CONCLUSIONS: These results suggest that the confirmed benefits of a multiple-injection regimen in IDDM cannot be simply extrapolated to NIDDM, where patients' awareness and medical attention to complications proved to be the most important factors in current practice.

Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic mediterranean population: the Carotid Atherosclerosis Italian Ultrasound Study.

PURPOSE: The Carotid Atherosclerosis Italian Ultrasound Study (CAIUS) was performed to test the effects of lipid lowering on the progression of carotid intima-media thickness (IMT) in 305 asymptomatic patients from a Mediterranean country. PATIENTS AND METHODS: Eligibility included hypercholesterolemia (baseline means: low-density lipoprotein [LDL] = 4.68 mmol/L, high-density lipoprotein [HDL] = 1.37 mmol/L), and at least one 1.3 < IMT < 3.5 mm in the carotid arteries. Patients (mean age 55 years, 53% male) were assigned to pravastatin (40 mg/day, n = 151) or placebo (n not equal to 154). Ultrasound imaging was used to quantify IMT at baseline, and semiannually thereafter for up to 3 years. The mean of the 12 maximum IMTs (MMaxIMT), was calculated for each patient visit, and used to determine each patient's longitudinal progression slope. The intention-to-treat group difference in the MMaxIMT progression was chosen a priori as the primary end point. RESULTS: Five serious cardiovascular events (1 fatal myocardial infarction), and 7 drop-outs for cancer were registered. In the pravastatin group, LDL decreased -0.22 after 3 months versus -0.01 in the placebo group, and remained substantially unchanged afterward (-0.23 versus +0.01 at 36 months, respectively). Progression of the MMaxIMT was 0.009 +/- 0.0027 versus -0.0043 +/- 0.0028 mm/year (mean +/- SE, P < 0.0007) in the placebo and pravastatin groups, respectively. IMT progression slopes diverged after 6 months of treatment. CONCLUSIONS: Pravastatin stops the progression of carotid IMT in asymptomatic, moderately hypercholesterolemic men and women. This finding extends the beneficial effects of cholesterol lowering to the primary prevention of atherosclerosis in a population with relatively low cardiovascular event rates, and suggests that this benefit is mediated by specific morphological effects on early stages of plaque development.

Age-specific incidence and duration of known diabetes. The Cremona Study.

OBJECTIVE: To estimate the overall and age-specific incidence of known diabetes and its total duration through prevalence data and to assess the consistency of the results by mortality analysis of the same cohort. RESEARCH DESIGN AND METHODS: Two different sources were used. The first was a representative sample of 2,274 prevalent known-diabetic subjects. These data provided overall and age-specific incidence estimates by fitting a logistic model to the partial incidence rates for different diagnosis cohorts and to the disease duration. The age at diagnosis structure was built from the age-specific estimates. Prevalence data also provided total duration estimates by converting the prevalent duration-to-date structure into an incident total duration structure. The second source was 145 deceased subjects who were taken from the 6-year follow-up sample of 1,132 prevalent subjects. The age at diagnosis and estimates of total disease duration were provided for these subjects, who paralleled the characteristics of the incident cohort. RESULTS: The two independent estimates of total disease duration were similar (prevalent subjects, 15.7 years; deceased subjects, 14.1 years): the average duration was 14.9 years. The ratio between prevalence and total duration yielded an independent yearly incidence estimate of 2.2 per 1,000 person-years (men, 2.0; women, 2.4), which was close to the value given by the model of 2.1 per 1,000 person-years (men, 1.9; women, 2.3). Also, the independently determined age structures overlapped, and their average was used to calculate the age-specific incidence. Incidence was negligible for individuals < 30 years of age, and it was about 6.0 per 1,000 person-years for individuals > 50 years of age. CONCLUSIONS: This study provided reliable estimates of NIDDM age-specific incidence rates and total disease duration, data that are seldom investigated in this type of disease.

Otitis media with effusion and S-carboxymethylcysteine and/or its lysine salt: a critical overview.

An overview of the placebo-comparative articles retrieved by a literature search on Medline - Embase - Biosis data banks from 1972 to 1993 was performed to evaluate the therapeutic relevance of the medical treatment with S-carboxymethylcysteine (SCMC) and its monohydrate lysine salt (SCMC-LYS) in patients with otitis media with effusion (OME). Ten original published studies were reviewed by an independent physician who assessed their quality by standard nine-items methodology. A meta-analytical approach was used to compare outcomes across all qualifying studies. Because of the heterogeneity of clinical endpoints, a new outcome measure was defined, i.e. overall clinical improvement, which consisted of the number of patients with complete resolution of clinical signs and symptoms and no need for surgical intervention. The objective evaluation criteria of normalisation of tympanogram was an additional end-point. Potential confounding variables such as eligibility criteria, treatment protocol and study design of the six methodologically complying studies were statistically homogeneous. No association was found between treatment effect-size and publication date or patients' age. Outpatients with disease duration of < 6 months, not previously treated, with bilateral ear involvement were included in the studies; half of them presented hyperplasia or hypertrophy of the pharyngeal or the adenoid tissue. Out of 483 patients, 430 (89%) terminated studies and were evaluable. Results from this meta-analysis indicate that patients with OME receiving oral SCMC/-lys benefit from the medical treatment to the extent of avoiding surgical intervention approximately 2.31 times more often than similar patients receiving placebo (ratio of active drug to placebo-effect on overall clinical improvement: 2.31; C.I. 1.28-4.20, P < 0.01) and attain reversion to normal of the tympanogram at an extent close to statistical significance (odds ratio: 2.25, C.I. 0.97-5.22, P = 0.058). In conclusion, the use of this new methodology for the evaluation of the mucoactive drug effect in OME has shed light into methodological pitfalls of clinical trials to date and underlines the need for agreed outcome measures, which may modify medical policy, which addresses more and more often to symptomatic treatment.

Neoadjuvant combined microwave induced local hyperthermia and topical chemotherapy versus chemotherapy alone for superficial bladder cancer.

PURPOSE: We evaluated the effectiveness of local bladder hyperthermia and intravesical chemotherapy compared to intravesical chemotherapy alone in the treatment of superficial transitional cell carcinoma. MATERIALS AND METHODS: A new system designed to deliver simultaneously local bladder hyperthermia and intravesical chemotherapy has been developed at our institute. The system consists of a computerized 915 MHz. microwave source that directly heats the bladder walls (within a temperature range of 42.5 to 45.5C) using a transurethral catheter. From February 1989 to December 1993, 52 patients 44 to 81 years old (mean age 64.3) with superficial stages Ta to T1, grades 1 to 3 transitional cell carcinoma of the bladder were selected for neoadjuvant intracavitary treatment. Tumors were left intact as marker lesions. Of the patients 29 were randomly assigned to receive combined neoadjuvant intravesical chemotherapy and local hyperthermia (group 1), while 23 received intravesical chemotherapy alone (group 2). The treatment protocol included multiple sessions performed on an outpatient basis. Mitomycin C (40 mg. in 50 cc distilled water) was used for intravesical chemotherapy in both groups. All patients underwent transurethral resection of residual tumors and of all suspicious areas 7 to 10 days after completion of treatment. Only a complete response was considered for statistical analysis. RESULTS: A pathological complete response was documented in 19 cases (66%) in group 1 and 5 (22%) in group 2 (chi-square p< 0.01). CONCLUSIONS: According to these preliminary data, microwave induced hyperthermia combined with local intravesical chemotherapy seems to be a feasible, safe and promising approach for neoadjuvant and minimally invasive treatment of superficial bladder cancer.

The effect of cigarette-smoking on cardiovascular risk factors: a study of monozygotic twins discordant for smoking.

The association of cigarette smoking with the development of occlusive vascular disease is firmly established. Unfavourable changes in a series of variables held independent risk factors for the development of vascular lesions (HDL-cholesterol, haematocrit, white blood cell count, fibrinogen and plasminogen activator inhibitor-1 (PAI-1)) are thought to be directly influenced by cigarette smoking. However, the role played by the genotype in the effect of smoking on the above parameters has not been investigated. To control the genotype, we studied the relationship between cigarette smoking and a series of cardiovascular risk factors in 27 monozygotic twin pairs (7 male and 20 female pairs, mean age +/- SD: 47.4 +/- 12.9 yrs) with a life-long discordance for smoking. Smoking twins had a life-long dose of smoking (Brickman index) of 287.3 +/- 241.5. Body mass index, blood pressure, haematocrit, haemoglobin and red blood cell counts, total cholesterol levels and the acute phase reactants alpha 1-acid glycoprotein and C-reactive protein were similar in smokers and non-smokers. Triglyceride was higher by 12.6% (9.5-35%, 95% confidence interval, p = 0.02) and HDL-cholesterol lower by 7.5% (0.2-15%, p = 0.04) in the smoking co-twins, who also had 8.4% (-0.2-17%, p = 0.06) higher white blood cell counts and 4.1% (1.2-7%, p < 0.01) larger mean platelet volume. There was no significant difference in clottable fibrinogen (by two methods) or in the activity of plasminogen activator inhibitor-1 between the two groups, nor was the within-pair difference in these parameters related to the smoking dose. Echo-doppler examination of the carotid arteries of 24 twin pairs showed mostly minor atherosclerotic lesions in 46% and 42% of the smoking and non-smoking co-twins. After adjustment for age, systolic blood pressure and platelet count and volume were the only variables significantly associated to the presence of vascular lesions. Cigarette smoking is associated with an atherogenic lipid profile and with changes in platelets and white cells potentially reflecting endothelial cell damage. When controlling the genotype, fibrinogen and PAI-1 activity levels did not seem directly influenced by cigarette smoking.