Prediagnostic transcriptomic markers of Chronic lymphocytic leukemia reveal perturbations 10 years before diagnosis.

BACKGROUND: B-cell lymphomas are a diverse group of hematological neoplasms with differential etiology and clinical trajectories. Increased insights in the etiology and the discovery of prediagnostic markers have the potential to improve the clinical course of these neoplasms. METHODS: We investigated in a prospective study global gene expression in peripheral blood mononuclear cells of 263 incident B-cell lymphoma cases, diagnosed between 1 and 17 years after blood sample collection, and 439 controls, nested within two European cohorts. RESULTS: Our analyses identified only transcriptomic markers for specific lymphoma subtypes; few markers of multiple myeloma (N = 3), and 745 differentially expressed genes in relation to future risk of chronic lymphocytic leukemia (CLL). The strongest of these associations were consistently found in both cohorts and were related to (B-) cell signaling networks and immune system regulation pathways. CLL markers exhibited very high predictive abilities of disease onset even in cases diagnosed more than 10 years after blood collection. CONCLUSIONS: This is the first investigation on blood cell global gene expression and future risk of B-cell lymphomas. We mainly identified genes in relation to future risk of CLL that are involved in biological pathways, which appear to be mechanistically involved in CLL pathogenesis. Many but not all of the top hits we identified have been reported previously in studies based on tumor tissues, therefore suggesting that a mixture of preclinical and early disease markers can be detected several years before CLL clinical diagnosis.

Enterolith causing acute afferent loop syndrome after Billroth II gastrectomy: a case report.

Enterolith is a rare cause of afferent loop obstruction following Billroth II gastrectomy. We report a case of acute afferent loop syndrome (ALS) due to a huge enterolith, necessitating prompt surgery. The clinical pattern may mimic acute cholangitis and/or pancreatitis. Delayed diagnosis may result in severe complications such as bowel ischemia or perforation. Only 14 reported cases of enterolith causing afferent loop obstruction were found in the English literature.

A methodological and functional proteomic approach of human follicular fluid en route for oocyte quality evaluation.

Human follicular fluid (HFF) has been proven to contain biologically active molecules and proteins that may affect follicle growth and oocyte fertilization. Based on this concept, HFF proteomic characterization is having a significant impact in the delineation of a biomarkers' profile for oocyte quality estimation and, maybe, for in vitro fertilization (IVF) success improvement. Follicular fluid is characterized by a vast protein complexity and a broad dynamic range of protein abundances that hinder its analysis. In this study we determined a proper solubilization and resolution method of HFF in 2-DE, minimizing sample manipulation, protein loss, and experimental artifacts. According to our methodology some low-abundance proteins were detected and identified by MS. Identified proteins were then functionally cross-linked by a pathway analysis. The generated path highlighted the occurrence in HFF of a tight functional-network in which effectors and inhibitors control and balance a space- and time-dependent induction/inhibition of inflammation, coagulation, and ECM degradation/remodeling. Such fine modulation of enzymatic activities exerts a fundamental role in follicle development and in oocyte competence acquiring. Alpha-1-antitrypsin resulted in the core protein of the delineated net and we interestingly detected its differential incidence in FF and serum from two small cohorts of patients who underwent IVF. BIOLOGICAL SIGNIFICANCE: Human ovarian follicular fluid (HFF) is the in vivo microenvironment for oocyte during folliculogenesis. It contains biologically active molecules that may affect oocyte quality, fertilization, and embryo development. HFF is also one of the most abundant "waste product" in assisted reproduction. This makes HFF a readily accessible source of biomolecules for competence evaluation of collected oocytes. The methodological improvement we obtained in proteomics characterization of HFF lead to a wide overview on the functional correlation existing between several fluid components and on how their aberrant occurrence/activity may affect oocyte quality and ovulation.

Female reproductive dysfunction during ageing: role of methylglyoxal in the formation of advanced glycation endproducts in ovaries of reproductively-aged mice.

Reproductive dysfunction with ageing has been so far extensively characterized in terms of depletion of ovarian follicles and reduced ability to produce gametes competent for fertilization. Nevertheless, molecular mechanisms underlying this process are still poorly understood. In the present study we addressed the hypothesis that methylglyoxal (MG), a major precursor of Advanced Glycation Endproducts (AGE), may contribute to molecular damage occurring during ovarian ageing. Our results showed that the biochemical activity of glyoxalase 1, the main component of the MG scavenging system, is significantly decreased in ovaries from reproductively-aged mice in comparison with the young group. This effect was associated with decreased expression at protein and RNA level of this enzyme and increased intraovarian level of MG. MG-arginine adducts argpyrimidine as detected with a specific antibody was found to accumulate with ageing in specific ovarian compartments. Separation of ovarian proteins by 2D gels and Western blotting revealed an approximate 30-fold increase in the extent of protein glycation in aged ovaries along with the appearance of eight argpyrimidine modified proteins exclusive for the aged group. In conclusion, the present results show that impaired MG detoxification causing relevant damage to the ovarian proteome might be one of the mechanisms underlying reproductive ageing and/or ageing-like ovarian diseases.

[Association of antioxidants and natural immune activators in the treatment of astheno-teratospermia and abacterial leukocytosis]. / Ruolo di un'associazione tra antiossidanti e stiomlanti immunitari naturali nel trattamento dell'astenoteratospermia con leucocitosi.

AIM: Leukocytes are often present in human seminal plasma and more frequently in infertile men. Leukocytospermia is associated with sperm morphological and functional alterations. Immune cell activation leads to an increase of free radical production, without any antioxidant defence activation. Leukocyte presence during sperm maturation and migration through male genital tract and consequently exposure to reactive oxygen species led to sperm alteration: axonemal, acrosomal and nuclear structure damage, associated with necrosis. In order to evaluate the immune-modulating and antioxidative activity of beta-glucan, fermented papaya and lactoferrin associated with vitamins C and E, we analysed sperm characteristics of selected infertile male with astheno-teratospermia and abacterial leukocytosis. METHODS: We selected 20 patients referred to our Sterility Centre for semen analysis with leukocyte concentration higher than 1x106 cell/mL. Seminal quality evaluation was performed according to WHO guidelines (1999) using Papanicolau and eosin staining, before and after three months of treatment with beta-glucan, papaya, lactoferrin, vitamin C and E. RESULTS: After therapy, seminal analysis showed a significant reduction of leukocyte concentration and an increase of sperm motility and normal sperm morphology. CONCLUSION: Our results suggest that a combined immunomodulating and antioxidant treatment protect sperm cells during maturation and migration through the male genital tract, resulting in a functional rescue demonstrated by the improvement of semen quality.

Clinical presentation and treatment of Wilson's disease: a single-centre experience.

Thirty patients with Wilson's disease (WD) were observed at a movement disorder clinic between 1970 and 2000. Disease onset was at the mean age (SD) of 14.5 (+/-5.9) years. Presentation with hepatic disease occurred in 12 of 30 patients and with neurologic disease in 15. Three patients were asymptomatic at the time of diagnosis. The mean (SD) delay to diagnosis was 5.9 (+/-5.7) years. Five patients diagnosed in an advanced stage of disease died before initiating treatment. Eighteen patients were followed and treated with D-penicillamine alone or in combination with zinc sulphate. Treatment improved most of neurological symptoms. Dystonic postures, behavioural disturbances and dysarthria were the most resistant neurological signs. 'Pseudo-sclerotic' neurologic involvement predicted a good outcome, whereas hepatic onset and 'classic' neurologic involvement were associated with a poorer prognosis. Two of the 18 treated patients died of hepatic failure due to voluntary discontinuation of therapy. Both D-penicillamine and zinc sulphate were well tolerated. No teratogenic effect of D-penicillamine was observed throughout 5 pregnancies. Our results suggest that D-penicillamine or a combination of D-penicillamine and zinc sulphate is a safe and effective long-term treatment in patients with WD.

Excitatory and inhibitory mechanisms in Wilson's disease: investigation with magnetic motor cortex stimulation.

We have evaluated cortical excitability in nine patients affected by Wilson's disease (WD) using transcranial magnetic (TMS) and electric (TES) cortical stimulation and central silent period (CSP) data. A clinical score was derived from the sum of scores assigned to extrapyramidal, pyramidal and cerebellar signs. All patients underwent TMS. Motor evoked potentials (MEPs) from abductor pollicis brevis (APB) and tibialis anterior (TA) muscles were recorded. MEP threshold and amplitude, central motor conduction time (CMCT), CSP threshold, CSP and peripheral silent period (PSP) duration were measured. Three patients also underwent transcranial bifocal electric cortical stimulation (TES) and MEPs were recorded from the APB muscle, and CMCT, MEP threshold and amplitude were measured. TMS MEPs were absent from relaxed muscles in six patients and from contracted muscles in three. CMCT was prolonged in six patients. APB CMCT correlated with clinical score. In three patients in whom TMS revealed abnormal or no MEP, TES MEPs were of normal threshold and amplitude. The CSP threshold was increased in seven patients, and CSP was absent in one. These results suggest an intracortical presynaptic motor dysfunction in WD.

Takayasu's arteritis and Crohn's disease: an unusual association. Report on two cases.

Two cases of Takayasu's arteritis associated with Crohn's disease of the colon are described, both of which occurring in young female patients. In the first case, the vasculitic process was widespread, involving the aortic arch, the abdominal aorta, the renal arteries and the left iliac artery, similar to the angiographic "Indian" pattern. The second case presented a typical "Japanese" aortic arch involvement. In the first patient, Crohn's disease appeared to have been present prior to Takayasu's arteritis, vice versa in the second case; steroid treatment, assigned for both diseases might, however, have modified their natural evolution. The association is rare. Moreover, the coexistence of two immune-mediated diseases in the same subject is unusual as they are generally considered to be independent. Hypotheses concerning their possible inter-relationship are advanced.

Takayasu's arteritis associated with Crohn's disease. Report of a case.

The authors report a rare case of Takayasu's arteritis with aortic arch and abdominal aorta involvement associated with Crohn's disease of the colon which both occurred in a young female patient. The coexistence of two immune mediated diseases in the same subject is unusual for they are generally considered to be independent of each other, however a hypothesis of their possible interrelationship is put forward.

Effect of diabetes on some primitive reflexes.

Primitive reflexes (PRs) are present in newborns; they disappear as the brain matures and increase in frequency in healthy elderly individuals. Primitive reflexes are more frequent in some neurological disorders than in age-matched controls. The aim of this study was to investigate the effect of diabetes on some PRs. We examined three PRs (glabellar tap, snout and palmomental reflexes) in 376 subjects: 111 normal age-matched controls, 60 patients with cerebrovascular disease (CVD) and 205 patients with type 2 diabetes mellitus. The latter patients were divided into three groups: (1) diabetics without neurological complications (D); (2) diabetics with cerebrovascular disease (D-CVD); and (3) diabetics with polyneuropathy (D-PN). The frequency of PRs was increased in CVD, unchanged in D-CVD (except palmomental) and greatly reduced in D and D-PN. It is possible that the vascular lesions in perforating arteries of the pons in diabetic subjects, previously studied in some pathological reports, can account for the reduced occurrence of primitive reflex responses.

[Takayasu's arteritis]. / L'arterite di Takayasu.

A brief review of Takayasu's Arteritis (TA), a chronic granulomatous arteritis that mainly affects the aorta and its major branches, is made. The various ethiopathogenetic mechanisms which may give origin to the vascular damage and its pathologic pattern are described. TA is a more widespread disease than previously stated, it is not exclusive of young women of Japanese origin but it is actually present worldwide irrespective of age and with variegated patterns of clinical and angiographic presentation. However, two main forms may be identified: the Japanese form in which prevails the aortic arch involvement and the Indian form in which vasculitis is present in abdominal aorta and its branches (above all the renal arteries) with an upright extension to the thoracic aorta and a protean clinical picture with a more systemic spectrum. The new clinical and angiographic criteria for TA definition are reviewed and stressed.

A case of neurofibromatosis type 1 with an aldosterone-producing adenoma of the adrenal.

Neurofibromatosis type 1 is a phacomatosis. Neurofibromas are the most common tumours associated with the disease, and along with other tumours, make neurofibromatosis type 1 the most common tumour predisposing syndrome in humans. Hypertension may be coincidental, but at least two specific neurofibromatosis related causes must be considered, namely neurofibromatous involvement of the renal artery and pheochromocytoma. We have described the first known case of a patient with neurofibromatosis type 1 who developed hypertension due to an aldosterone-producing adenoma of the adrenal. The question of whether this association was coincidental or due to the tumour predisposition of neurofibromatosis type 1 was debated.

[Tularemia: considerations on a new case in the Monte Amiata]. / Tularemia: considerazioni su un nuovo caso sul Monte Amiata.

One sporadic case of tularemia induced by direct contact with an infected hare is described. Human epidemiological data of the last ten years in Tuscany, emphasize that this infection, although at low incidence, shows the presence and persistence of Francisella tularensis in the animals and the ensuing transmission to humans so that it continues to be responsible for significant morbididy in "at risk" territories. Difficulties in the differential diagnosis, above all for glandular and pharyngeal forms, are reviewed.

Long-term effect of a single dose of flunarizine in Huntington's disease.

We report a preliminary pilot study on the clinical efficacy of flunarizine (FNZ), a calcium-entry blocker that causes extrapyramidal side-effects, in 10 patients with Huntington's disease (HD). FNZ (20 mg) administered by the sublingual route resulted in a decrease in choreic movements and improved dexterity in performing several tests. These effects lasted for at least 7 days after a single dose. Therefore, FNZ seems to exert the same effect as a long-acting neuroleptic agent in our HD patients.Copyright Lippincott-Raven Publishers

Reliability of ultrasounds in detecting common bile duct stones before biliary surgery. A retrospective analysis.

UNLABELLED: The aim of this study is to evaluate the diagnostic benefit of US in the preoperative screening for CBD stones in patients submitted to surgery for biliary lithiasis. MATERIALS AND METHODS: We analyzed the data of 135 patients admitted for biliary lithiasis, jaundice or biliary pancreatitis in the last three years. Mean age was 63 years (54.8% females), 48% of the cases had an urgent admission. US of the liver and biliary ducts was the first examination performed and the patients were divided in 2 groups on the bases of the results: those with the diameter of the CBD < 1 cm (101 pts-group A) and those with a diameter > 1 cm (34 pts-group B). RESULTS: In group A were subsequently performed: 35 IV cholangiographies (6 showed CBD stones, 1 was a false negative for CBD stones), 15 intraoperative (I.O.) cholangiographies (1 positive for CBD stones), 9 ERCP for jaundice or pancreatitis (2 positive for CBD stones). The incidence of CBD stones was 8.9% in this group. In group B were performed: 7 IV cholangiographies (2 showed CBD stones), 12 I.O. cholangiographies (6 showed CBD stones), 10 ERCP for jaundice or pancreatitis (7 showed CBD stones). The incidence of CBD stones was 44% in this group. CBD stones were detected by US in 2 cases (22%) in group A and in 6 cases (40%) in group B. CONCLUSIONS: In our patients there is a relatively high incidence of CBD stones (8.9%) in spite of a normal CBD at US. Considering that the minimally invasive approach for the gallbladder stones is becoming the "gold standard" and the laparoscopic treatment of the CBD stones is not widely diffused, it is important to know the presence of CBD stones before surgery. With this in mind US does not seem to be a reliable diagnostic tool and we suggest that before surgery an IV cholangiography (sensitivity > 95% in our experience) should be performed together with US and ERCP in selected cases. Moreover this could reduce the number of preoperative ERCP leaving the possibility to treat more selectively by endoscopic papillosphincterotomy the patients with CBD stones before laparoscopic cholecystectomy.

May age onset be relevant in the occurrence of left ventricular hypertrophy in Friedreich's ataxia?

BACKGROUND: Although heart involvement has been widely reported in Friedreich's ataxia (FA), which is the most prevalent of the spino-cerebellar degenerative diseases, the reason that cardiac abnormalities develop has not been yet established. HYPOTHESIS: The investigation was undertaken to study the prevalence and characteristics of cardiac abnormalities in patients with FA and to evaluate whether the presence of left ventricular hypertrophy could be predicted. METHODS: In all, 75 patients with FA and 16 patients with late onset FA (LOFA) disease were investigated for cardiac abnormalities using noninvasive methods. RESULTS: A significant (p < 0.01) difference in the age onset (9.8 +/- 3.9 years) was found in 31 of the 75 patients with FA (41%) who showed left ventricular hypertrophy (LVH) at echocardiographic examination compared with the remaining 44 patients with FA without LVH (12.6 +/- 4.3 years). Moreover, none of the 16 patients with LOFA (age onset 26.5 +/- 4.2 years) showed abnormalities at echocardiographic examination. A significant (p < 0.01) concordance in the familial distribution of hypertrophy was also found. CONCLUSION: These data suggest that the earlier the disease develops the more frequently LVH occurs.

International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology.

Despite the involvement of cerebellar ataxia in a large variety of conditions and its frequent association with other neurological symptoms, the quantification of the specific core of the cerebellar syndrome is possible and useful in Neurology. Recent studies have shown that cerebellar ataxia might be sensitive to various types of pharmacological agents, but the scales used for assessment were all different. With the long-term goal of double-blind controlled trials-multicentric and international-an ad hoc Committee of the World Federation of Neurology has worked to propose a one-hundred-point semi-quantitative International Cooperative Ataxia Rating Scale (ICARS). The scale proposed involves a compartimentalized quantification of postural and stance disorders, limb ataxia, dysarthria and oculomotor disorders, in order that a subscore concerning these symptoms may be separately studied. The weight of each symptomatologic compartment has been carefully designed. The members of the Committee agreed upon precise definitions of the tests, to minimize interobserver variations. The validation of this scale is in progress.

Transglutaminase activity is related to CAG repeat length in patients with Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder associated with CAG repeat expansion. We measured transglutaminase (TGase) activity in lymphocytes from 35 HD patients and from healthy individuals to ascertain whether it was altered in this condition. TGase activity was above maximum control levels in 25% of HD patients; it was correlated with the age of the patient and inversely correlated with the CAG repeat length. These results suggest that: (1) HD could be biochemically heterogeneous, and (2) the length of the CAG repeat expansion/TGase ratio could be important in the manifestation of HD.

Age of onset, sex, and cardiomyopathy as predictors of disability and survival in Friedreich's disease: a retrospective study on 119 patients.

We performed a retrospective study on a series of 119 of our patients who have Friedreich's disease to assess the predictive value of age at onset, gender, and left ventricular hypertrophy in regard to disease progression. Outcome variables were survival, time to loss of independent gait, and time to confinement in a wheelchair. Diabetes was considered to be an outcome variable when defining time to diabetes and an explanatory variable when testing its effect on survival. Eleven patients died. The median estimated survival from onset was 36 years, and the median time to loss of independent gait was 8 years and to confinement in a wheelchair was 15 years from onset. Nineteen patients developed diabetes after a median time of 16 years. The presence of left ventricular hypertrophy or diabetes significantly reduced survival based on univariate analysis. Onset at the age of < or = 20 years and the presence of left ventricular hypertrophy predicted a faster rate of progression of the disease.