Search

Mini-Mental State Examination (MMSE) lacks of sensitivity in detecting cognitive deficits associated with subcortical damage. The HIV-Dementia Scale (HDS), a screening tool originally created for detecting cognitive impairment due to subcortical damage in HIV + patients, has proved to be useful in other neurological diseases. Until now, an Italian version of the HDS is not available. We aimed at: (1) validating the HDS Italian version (HDS-IT) in a cohort of cognitively healthy subjects (CN); (2) exploring the suitability of HDS-IT in detecting cognitive impairment due to subcortical damage (scCI). The psychometric properties of the HDS-IT were assessed in 180 CN (mean age 67.6 ± 8.3, range 41–84) with regard to item-total correlation, test–retest reliability and convergent validity with MMSE. Item-total correlations ranged 0.44–0.72. Test–retest reliability was 0.70 (p p scCI subjects (mean age 64.9 ± 10.6, range 41–84). Mean HDS-IT total score was close to the original version and significantly lower in the scCI group compared to CN (8.6 ± 3.6 vs. 12.6 ± 2.5, p p

For the first time in the literature, a case of Sars-Cov-2 infection after lung Transplantation has been described. This case, particularly rare, brought attention on the in-depth screening for Sars-CoV-2 on lung donor. In addition to infectious problems, it is important to focus attention on medico-legal issues related to this case. In fact, from the point of view of professional responsibility, in theory, there could be criteria for identifying professional responsibility. The author analyzes the possible presence of medical liability in this specific case.

The article's author has sought to summarize the regulatory and legal evolution of accidental criminal liability of doctors starting from earliest positions up until the enactment of the Gelli-Bianco law. An in-depth analysis is laid out based on the Italian Supreme Court Joint Sections ruling n. 8770/2018 (so-called Mariotti decision). The author has also elaborated upon the notion of varying degrees of guilt, which was taken out of the law's wording, to be later reintroduced as a concept by judicial interpretation. It is worth noting that Article 3 of the Balduzzi decree, article 590 sexies of the Italian Criminal Code and the reference to article 2236 of the Civil Code reflect an awareness on the part of legislators that medical liability needs to be limited. Clearly, the approach based on lawfulness alone, which protects from liability physicians that have adhered to guidelines, has been dismissed, superseded by the notion of minor fault. Nonetheless, the new legislation, in the author's estimation, constitutes a standard particularly ill-suited to modern medical practice, which has a high degree of complexity. The author concludes that it might be worth considering a more balanced alternative: getting back to the notion of fault, considering minor fault relevant, rather than major fault.

The authors have sought to expound upon and shed a light on the rise of nootropics, which have gradually taken on a more and more relevant role in workplaces and academic settings.Multidisciplinary databases have been delved into by entering the following keys: "nootropics", "cognitive enhancement", "workplace", "productivity", "ethics", "bioengineering". In addition, a broad-ranging search has been undertaken on institutional websites in order to identify relevant analysis and recommendations issued by international institutions and agencies. Papers and reports have been independently pored over by each author. This search strategy has led to the identification of 988 sources but only 64 were considered appropriate for the purposes of the paper after being selected by at least 3 of the authors, independently.The notion of an artificially enhanced work performance - carried out by the 'superworker' - is particularly noteworthy and resonates with the conception of contemporary work on so many different levels: the rising need and demands for higher degrees of flexibility and productivity on the job, the implications of a '24/7' society, where more and more services are available at any time, the ever greater emphasis on entrepreneurial spirit, individual self-reliance and self-improvement, and last but not least, the impact of an ageing society on economic standards and performance.Moreover, it is worth mentioning that human enhancement technologies will predictably and increasingly go hand in hand with gene editing, bioengineering, cybernetics and nanotechnology. Applications are virtually boundless, and may ultimately affect all human traits (physical strength, endurance, vision, intelligence and even personality and mood).

Extensive scientific evidence shows that there is a broad spectrum of substances used as adulterants, whose effects on the user's health may be extremely harmful. The degree of purity of the drugs most commonly abused is highly variable depending on the region or epidemiological context. Practices of drug adulteration have been substantially evolving over the years: a significant trend has been observed in the last decade indicating a decline in the average purity of most drugs. Although the most frequent adulterants of common street drugs have long been well known, the rise of synthetic opioids has inevitably entailed gaps in knowledge in terms of the substances being used and their composition, which constitutes an even greater threat to public health.

The present letter is meant as a response to the commentary titled "Medically-assisted procreation and the rise of off-center, new types of "parenthood": it is incumbent upon lawmakers to intervene", which was published in issue 4, 2019, of the La Clinica Terapeutica journal. Newly available reproductive techniques have given rise to new opportunities to fulfill one's wishes for parenthood. Such developments have caused procreation to be perceived as a right, intended as the right to «artificial» procreation. Not only do such trends impact those couples who travel abroad in order to have children through heterologous fertilization and surrogacy: singles and same-sex couples pursue those avenues as well in order to become parents. In the article which we are commenting upon, the author has perused the evolving jurisprudence on that subject, pointing out how necessary it is for lawmakers to step in and clearly define the rights of all parties involved, minors in particular.

Background The study aimed to investigate whether HLA-G antigen is expressed in the kidneys of patients affected by lupus nephritis (LN) and whether its detection in renal biopsies could be adopted as a marker of treatment response and prognosis. Methods Thirty renal biopsies from patients with LN were selected and analyzed through immunohistochemistry. Laboratory and clinical data were retrospectively collected at baseline, 6 and 12 months and at the latest clinical appointment. A number of patients (63.3%) were treated with rituximab (RTX) +/− methylprednisolone in the induction phase. The expression of HLA-G in glomeruli, tubules and infiltrating cells was examined and compared between lupus patients who achieved either complete or partial renal response and those who did not respond to treatment. Results HLA-G staining was observed in the glomeruli of 20 of 30 samples from patients with LN. The expression of the antigen was detected in podocytes, along glomerular capillary walls, on parietal glomerular epithelial cells and within the juxtaglomerular apparatus. Seventy per cent of patients whose glomeruli expressed HLA-G achieved partial or complete response at 6 months and 75% at the latest available follow up compared with 30% and 40%, respectively, of those who did not show any expression. The pattern of staining in tubules and infiltrating cells was highly variable precluding any clinical correlation. Conclusion This study demonstrates that HLA-G is expressed in renal tissue in LN. Our retrospective data suggest that its expression could correlate with response to treatment.

We present a 47-year-old, South-African origin, woman with a background of stable monoclonal gammopathy of unknown significance (MGUS) who attended A&E with a history of coryzal symptoms associated with persistent fever, lymphadenopathy and a new onset of rash, not responding to antibiotics and paracetamol. A trial of high-dose steroids resolved symptoms. Bone marrow biopsy confirmed a progression of MGUS into multiple myeloma and her axillary lymph node biopsy analysis supported a diagnosis of Kikuchi-Fujimoto disease (KFD). This is an unusual presentation where KFD has been noted alongside MGUS progression to multiple myeloma. Haematology follow-up is underway.

Our objective was to describe incidence and clinical features of ALS from a prospective population-based study in Emilia Romagna Region (ERR). From 2009 onwards, a prospective registry recorded all incident cases of ALS among residents in the ERR (population, 4.4 million inhabitants), involving 17 neurological departments. For each patient, detailed demographic and clinical information was collected by caring physicians. Results showed that from 1 January 2009 to 31 December 2011, 347 patients received a new diagnosis of ALS with a crude incidence rate of 2.63/100,000/year. There was micro-geographic heterogeneity throughout ERR, with higher incidence rates in the low density population (3.27/100,000) (p < 0.01). ALS patients have been more frequently employed in agriculture than the general ERR population (8.64\% vs. 4.6\%, p < 0.01). Clinical features were similar to those described in previous population based studies. In conclusion, we report incidence rates similar to those reported by European registries, reflecting good accuracy of our prospective study. We confirmed previous studies reporting higher incidence rates in rural areas and among agricultural workers. Although genetics has been gaining increasing importance in ALS aetiology, some epidemiological data are still unexplained. Identifying geographical areas or populations with high incidence rates can be a starting point for identifying environmental risk factors. Further studies having this specific aim can shed light on these topics.

Background: Clinical and molecular factors are essential to define the prognosis in patients with glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status, age, Karnofsky Performance Status (KPS), and extent of surgical resection are the most relevant prognostic factors. Our investigation of the role of gender in predicting prognosis shows a slight survival advantage for female patients. Methods: We performed a prospective evaluation of the Project of Emilia Romagna on Neuro-Oncology (PERNO) registry to identify prognostic factors in patients with GBM who received standard treatment. Results: A total of 169 patients (99 males [58.6%] and 70 females [41.4%]) were evaluated prospectively. MGMT methylation was evaluable in 140 patients. Among the male patients, 36 were MGMT methylated (25.7%) and 47 were unmethylated (33.6%); among the female patients, 32 were methylated (22.9%) and 25 were unmethylated (17.9%). Survival was longer in the methylated females compared with the methylated males (P = 0.028) but was not significantly different between the unmethylated females and the unmethylated males (P = 0.395). In multivariate analysis, gender and MGMT methylation status considered together (methylated females vs. methylated males; hazard ratio [HR], 0.459; 95% confidence interval [CI], 0.242-0.827; P = 0.017), age (HR, 1.025; 95% CI, 1.002-1.049; P = 0.032), and KPS (HR, 0.965; 95% CI, 0.948-0.982; P < 0.001) were significantly correlated with survival. Conclusions: Survival was consistently longer among MGMT methylated females compared with males. Gender can be considered as a further prognostic factor.

Congenital muscular dystrophies due to defects in genes encoding proteins involved in α-dystroglycan (α-DG) glycosylation are a heterogeneous group of muscle disorders variably associated with central nervous system and eye abnormalities. One of the more severe is muscle-eye-brain disease (MEB). Mutations in genes coding for proven or putative glycosyltransferases (POMT1, POMT2, POMGnT1, fukutin, FKRP, and LARGE), the DPM3 gene encoding a DOL-P-Man synthase subunit, and the DAG1 gene encoding α-dystroglycan, have been associated with altered α-DG glycosylation. We report new POMGnT1 mutations and evaluate protein expression in 3 patients and 2 foetuses with variably severe MEB features. We identify two new point mutations (c.643 C > T, c.1863delC), one new intragenic rearrangement (deletion of exons 2–8), and a new intron retention (between exons 21 and 22) resulting from a known point mutation c.1895 + 1 G > T. Our study provides further evidence that rearrangements of the POMGnT1 gene are relatively common. Importantly, if heterozygous, they can be missed on standard genomic DNA sequencing. POMGNT1 protein analysis in 3 patients showed that the severity of the phenotype does not correlate with protein expression. Cerebral MRI is important for identifying MEB and α-dystroglycanopathy phenotypes in children and foetuses, and hence for directing the genetic analysis.

Janus-activated kinase 2 (JAK2) mutations are common in myeloproliferative disorders; however, although they are detected in virtually all polycythemia vera patients, they are found in ∼50% of essential thrombocythemia (ET) patients, suggesting that converging pathways/abnormalities underlie the onset of ET. Recently, the chromosomal translocation 3;21, leading to the fusion gene AML1/MDS1/EVI1 (AME), was observed in an ET patient. After we forced the expression of AME in the bone marrow (BM) of C57BL/6J mice, all the reconstituted mice died of a disease with symptoms similar to ET with a latency of 8 to 16 months. Peripheral blood smears consistently showed an elevated number of dysplastic platelets with anisocytosis, degranulation, and giant size. Although the AME-positive mice did not harbor Jak2 mutations, the BM of most of them had significantly higher levels of activated Stat3 than the controls. With combined biochemical and biological assays we found that AME binds to the Stat3 promoter leading to its up-regulation. Signal transducers and activators of transcription 3 (STAT3) analysis of a small group of ET patients shows that in about half of the patients, there is STAT3 hyperactivation independently of JAK2 mutations, suggesting that the hyperactivation of STAT3 by JAK2 mutations or promoter activation may be a critical step in development of ET. [Cancer Res 2009;69(1):262–71]

A letter to the editor is presented related to the case where GATA1 is overexpressed in patients with essential thrombocythemia and polycythemia vera, but not in patients with primary myelofibrosis or chronic myelogenous leukemia.

Recurring chromosomal translocations observed in human leukemia often result in the expression of fusion proteins that are DNA-binding transcription factors. These altered proteins acquire new dimerization properties that result in the assembly of inappropriate multimeric transcription complexes that deregulate hematopoietic programs and induce leukemogenesis. Recently, we reported that the fusion protein AML1/MDS1/EVI1 (AME), a product of a t(3;21)(q26;q22) associated with chronic myelogenous leukemia and acute myelogenous leukemia, displays a complex pattern of self-interaction. Here, we show that the 8th zinc finger motif of MDS1/EVI1 is an oligomerization domain involved not only in interaction of AME with itself but also in interactions with the parental proteins, RUNX1 and MDS1/EVI1, from which AME is generated. Because the 8th zinc finger motif is also present in the oncoprotein EVI1, we have evaluated the effects of the interaction between RUNX1 and EVI1 in vitro and in vivo. We found that in vitro, this interaction alters the ability of RUNX1 to bind to DNA and to regulate a reporter gene, whereas in vivo, the expression of the isolated 8th zinc finger motif of EVI1 is sufficient to block the granulocyte colony-stimulating factor–induced differentiation of 32Dcl3 cells, leading to cell death. As EVI1 is not detected in normal bone marrow cells, these data suggest that its inappropriate expression could contribute to hematopoietic transformation in part by a new mechanism that involves EVI1 association with key hematopoietic regulators, leading to their functional impairment. [Cancer Res 2007;67(12):5658–66]

EVI1 is an aggressive nuclear oncoprotein deregulated by recurring chromosomal abnormalities in myelodysplastic syndrome (MDS). The expression of the corresponding gene is a very poor prognostic marker for MDS patients and is associated with severe defects of the erythroid lineage. We have recently shown that the constitutive expression of EVI1 in murine bone marrow results in a fatal disease with features characteristic of MDS, including anemia, dyserythropoiesis, and dysmegakaryopoiesis. These lineages are regulated by the DNA-binding transcription factor GATA1. EVI1 has two zinc finger domains containing seven motifs at the N terminus and three motifs at the C terminus. Supported by results of assays utilizing synthetic DNA promoters, it was earlier proposed that erythroid-lineage repression by EVI1 is based on the ability of this protein to compete with GATA1 for DNA-binding sites, resulting in repression of gene activation by GATA1. Here, however, we show that EVI1 is unable to bind to classic GATA1 sites. To understand the mechanism utilized by EVI1 to repress erythropoiesis, we used a combination of biochemical assays, mutation analyses, and in vitro bone marrow differentiation. The results indicate that EVI1 interacts directly with the GATA1 protein rather than the DNA sequence. We further show that this protein-protein interaction blocks efficient recognition or binding to DNA by GATA1. Point mutations that disrupt the geometry of two zinc fingers of EVI1 abolish the protein-protein interaction, leading to normal erythroid differentiation of normal murine bone marrow in vitro.

Background: Cytotoxic regimens used in induction treatments for acute myeloid leukemia (AML) almost always include standard or high-dose cytarabine (Ara-C). During or soon after induction therapy, leukemic patients frequently develop gastroenteric complications, characterized by abdominal pain and diarrhea. The association ofthese symptoms with f and melena is typical ofnecrotizing enterocolitis (NE), a life-threathening condition that can be documented by ultrasound abdominal scan. Patients and methods: We analyzed retrospectively the clinical course of169 adult patients with AML treated by standard dose Ara-C-containing induction regimens, either by continuous venous infusion (group 1) or subcutaneous injection (group 2). Ultrasonography was employed as early diagnostic tool in a majority ofpatients with gastroenteric complications. Bowel wall thickening was accurately measured and used to confirm the diagnosis of necrotizing enterocolitis. Results: In the first group of 115 patients (median age, 51 years), gastroenteric complications were observed in 55 patients (48%), and 10 patients (9%) received diagnosis ofNE, which was fatal in four. Patients with NE had a median age older than that of patients without gastroenteric symptoms, and a more prolonged neutropenia. In the second group of54 patients (median age, 60 years), gastroenteric events were observed in 14 patients (26%), and no case of NE was recorded. Conclusions: This retrospective analysis shows that NE is a serious complication occurring mainly in patients treated by Ara-C administered as continuous i.v. infusion. The Hematology Journal (2003) 4, 346–350. doi:10.1038/sj.thj.6200304

Reduction strategies of blood pressure, as a modifiable cardiovascular risk, are currently based on office assessment of brachial artery blood pressure. However, antihypertensive treatment based on brachial BP values reduces cardiovascular risk but cannot completely reverse the hypertension-induced risk of morbidity events. As is well known, BP varies in different arterial systems and invasive and non-invasive studies have demonstrated that brachial BP does not necessarily reflect central aortic BP. Emerging evidences now suggest that central pressure may predict cardiovascular diseases better than brachial BP; moreover, it may differently respond to certain antihypertensive drugs. The potential effects beyond peripheral BP control may be due to specific protective properties of different antihypertensive drugs in affecting central aortic pressure and arterial stiffness. Although data on direct cardiovascular benefit impact of central blood pressure treatment in randomized clinical trials are still lacking, it is likely that the improvement of quality of care and the individualized assessment of the hypertension-associated cardiovascular risk are achievable with the use of central hemodynamics. Therefore, basing antihypertensive treatment guidance on central pressures rather than on peripheral blood pressure may be the key for future antihypertensive strategies.

To propose a test to evaluate endothelial function, based on VO(2) on-transition kinetics in sub-anaerobic threshold (AT) constant load exercise, we tested healthy subjects and patients with ischemic-hypertensive cardiopathy by two cardiopulmonary tests on a cycle ergometer endowed with an electric motor to overcome initial inertia: a pre-test and, after at least 24 h, one 6 min constant load exercise at 90 % AT. We measured net phase 3 VO(2)-on kinetics and, by phase 2 time constant (tau), valued endothelial dysfunction. We found shorter tau in repeated tests, shorter time between first and second test, by persisting endothelium-dependent arteriolar vasodilatation and/or several other mechanisms. Reducing load to 80 % and 90 % AT did not produce significant changes in tau of healthy volunteers, while in heart patients an AT load of 70 %, compared to 80 % AT, shortened tau (delta=4.38+/-1.65 s, p=0.013). In heart patients, no correlation was found between NYHA class, ejection fraction (EF), and the two variables derived from incremental cycle cardio-pulmonary exercise, as well as between EF and tau; while NYHA class groups were well correlated with tau duration (r=0.92, p=0.0001). Doxazosin and tadalafil also significantly reduced tau. In conclusion, the O(2) consumption kinetics during the on-transition of constant load exercise below the anaerobic threshold are highly sensitive to endothelial function in muscular microcirculation, and constitute a marker for the evaluation of endothelial dysfunction.

Although the clinical relevance of brachial blood pressure (BP) measurement for cardiovascular (CV) risk stratification is nowadays widely accepted, this approach can nevertheless present several limitations. Pulse pressure (PP) amplification accounts for the notable increase in PP from central to peripheral arterial sites. Target organs are more greatly exposed to central hemodynamic changes than peripheral organs. The pathophysiological significance of local BP pulsatility, which has a role in the pathogenesis of target organ damage in both the macro- and the microcirculation, may therefore not be accurately captured by brachial BP as traditionally evaluated with cuff measurements. The predictive value of central systolic BP and PP over brachial BP for major clinical outcomes has been demonstrated in the general population, in elderly adults and in patients at high CV risk, irrespective of the invasive or non-invasive methods used to assess central BP. Aortic stiffness, timing and intensity of wave reflections, and cardiac performance appear as major factors influencing central PP. Great emphasis has been placed on the role of aortic stiffness, disturbed arterial wave reflections and their intercorrelation in the pathophysiological mechanisms of CV diseases as well as on their capacity to predict target organ damage and clinical events. Comorbidities and age-related changes, together with gender-related specificities of arterial and cardiac parameters, are known to affect the predictive ability of central hemodynamics on individual CV risk.

Mental retardation, facial dysmorphisms, seizures, and brain abnormalities are features of 6q terminal deletions. We have ascertained five patients with 6q subtelomere deletions (four de novo, one as a result of an unbalanced translocation) and determined the size of the deletion ranging from 3 to 13 Mb. Our patients showed a recognizable phenotype including mental retardation, characteristic facial appearance, and a distinctive clinico-neuroradiological picture. Focal epilepsy with consistent electroencephalographic features and with certain brain anomalies on neuroimaging studies should suggest 6q terminal deletion. The awareness of the distinctive clinical picture will help in the diagnosis of this chromosomal abnormality.

The Burkholderia cepacia complex (Bcc) is a group of phenotypically similar, genetically distinct, motile, freeliving, glucose-non-fermentative, gram-negative bacilli that can be found in soil or water, and it has emerged as an important lung pathogen for patients with cystic fibrosis [1]. Many strains of Bcc are transmissible. Although it is capable of occasionally contaminating hospital environments [1], Bcc rarely causes community-acquired infections in immunocompetent patients. The prospective study described here investigated the nasal microbiology of 48 patients with sinonasal polyposis and 24 patients with chronic sinusitis who consecutively underwent functional endoscopic sinus surgery (FESS). The nasal microbiology of a control group of ten patients without rhinologic abnormalities was also considered. The significant rate of Bcc isolation in our sinonasal polyposis group is discussed. The records of 72 consecutive patients with chronic sinonasal disease treated with FESS at the Section of Otolaryngology of Padova University, a tertiary referral academic hospital, were reviewed. None of the patients had immunosuppression or cystic fibrosis in their medical history, but one had diabetes mellitus. All patients considered for inclusion in the study were admitted on the day of surgical intervention. Nasal swabs were obtained in the operating room before the administration of local nasal anesthesia; a second nasal swab was performed on an outpatient basis 1 month after FESS, during follow-up nasal endoscopy. One nasal middle meatal bacterial swab was taken from each patient under rigid endoscope control. Postoperatively, intravenous antibiotic treatment (ampicillin/sulbactam 1.5 g four times a day in 50 patients; cefazolin 1 g three times a day in 14 patients) was administered for 2–3 days in 64 patients, and oral antibiotic treatment (levofloxacin 500 mg once a day) was administered in eight patients. After discharge, the patients received a 7-day course of antibiotic treatment, consisting of oral amoxicillin-clavulanate (1 g three times per day) in 58 cases, levofloxacin (500 mg once a day) in seven cases, or ceftibuten (400 mg twice a day) in seven cases. Nasal irrigation with either sulphurous-arsenical-ferruginous thermal water (Levico Terme, Trento, Italy) (40 cases) or isotonic sodium chloride solution (32 cases) was performed for at least 1 month after surgery. Histological evaluation of surgical specimens confirmed the diagnosis of sinonasal polyposis in 48 of 72 patients. In the clinical history of these patients, allergy was present in 15 cases, asthma in eight and acetylsalicylic acid intolerance in five. A control group of ten patients without rhinologic abnormalities ruled out by rigid nasal endoscopy also underwent nasal swabbing. Nasal swabs were plated onto sheep blood agar (COS; bioMerieux, Marcy l’Etoile, France) and chocolate agar with PolyVitex (bioMerieux). Plates were incubated for 24 and 48 h. Gram staining was performed. The isolates were Eur J Clin Microbiol Infect Dis (2007) 26:73–75 DOI 10.1007/s10096-006-0233-9

OBJECTIVE: To determine whether a multisystemic bioenergetic deficit is an underlying feature of familial hypobetalipoproteinaemia. METHODS: Brain and skeletal muscle bioenergetics were studied by in vivo phosphorus MR spectroscopy (31P-MRS) in two neurologically affected members (mother and son) and in one asymptomatic member (daughter) of a kindred with familial hypobetalipoproteinaemia. Plasma concentrations of vitamin E and coenzyme Q10 (CoQ10) were also assessed. RESULTS: Brain 31P-MRS disclosed in all patients a reduced phosphocreatine (PCr) concentration whereas the calculated ADP concentration was increased. Brain phosphorylation potential was reduced in the members by about 40%. Skeletal muscle was studied at rest in the three members and during aerobic exercise and recovery in the son and daughter. Only the mother showed an impaired mitochondrial function at rest. Both son and daughter showed an increased end exercise ADP concentration whereas the rates of postexercise recovery of PCr and ADP were slow in the daughter. The rate of inorganic phosphate recovery was reduced in both cases. Plasma concentration of vitamin E and CoQ10 was below the normal range in all members. CONCLUSIONS: Structural changes in mitochondrial membranes and deficit of vitamin E together with reduced availability of CoQ10 can be responsible for the multisystemic bioenergetic deficit. Present findings suggest that CoQ10 supplementation may be important in familial hypobetalipoproteinaemia.

Ultrasound-guided ethanol injection (PEI) is an effective treatment of autonomously functioning thyroid nodules (AFTN) but little is known about the tissue lesions induced by alcohol. We report morphological changes of an AFTN which was removed after successful PEI treatment. At histological evaluation, the adenoma showed multiple areas of coagulative necrosis with eosinophilic ghost follicles, hemorrhages, small vessel thrombosis and a wedge-shaped hemorrhagic infarction. The peripheral adenomatous tissue and the surrounding thyroid parenchyma were free of regressive changes and/or lympho-monocytic inflammatory reactions. Enzyme histochemistry confirmed the hyperfunctioning character of the lesion and showed reduction of succinic dehydrogenase and cytochrome-c-oxydase activity in the viable tissue surrounding the central necrotic areas. By electron microscopy, the hyperfunctioning follicular epithelium showed submicroscopical alterations of the adenomatous cells surrounding the areas of coagulative necrosis. These results suggest that control of hyperthyroidism, after PEI, is due to: a) directly induced, irreversible damage (coagulative necrosis and vascular thrombosis with hemorrhagic infarction) in the central areas of the lesion; b) potentially reversible damage (reduction of intracellular enzyme activity and ultrastructural changes) in the peripheral areas.

Objective: Recently, fine needle cytology (FNC) of the thyroid has been combined with biomolecular analysis. In particular, there has been detailed study of the V600E-BRAF mutation. The aim of our study is to demonstrate that with a single thyroid sample it is possible to obtain enough cellular material for both cytological diagnosis and a V600E-BRAF molecular test. Study Design: FNC was carried out under ultrasound guidance aided by an echographist and cytopathologist. We acquired one biopsy for each nodule with a 23-gauge needle without suction. The preparations were smeared by the pathologist onto one glass slide, air dried and stained with Diff-Quick. Cell adequacy was evaluated for each patient. The needle was washed by aspirating 2 ml of physiologic solution which was collected into a tube. The material was collected for molecular testing. Results: The following cytological diagnoses were made: not neoplastic, Tir2 (n = 227); indeterminate, Tir3 (n = 15); suspicious, Tir4 (n = 4), and malignancy, Tir5 (n = 12). The V600E-BRAF mutation was found in 0 of 227 Tir2 specimens, 2 of 15 (13.3%) Tir3 specimens, 2 of 4 (50%) Tir4 specimens and 9 of 12 (75%) Tir5 specimens. Conclusions: Our data showed that, in a routine clinical setting, FNC specimens can be handled properly to provide both morphological and molecular information. In fact, our tests show that with a single specimen it is possible to set up a slide for the cytological diagnosis and to obtain enough residual cellular material for DNA extraction (>70 ng) and for the identification of the V600E-BRAF mutation.

Background: Patellar tumors are rare; only a few series have been described in the literature and radiographic diagnosis can be challenging. We reviewed all patellar tumors at one institution and reviewed the literature. Materials and methods: In an evaluation of the database at one institution from 1916 to 2009, 23,000 bone tumors were found. Of these, 41 involved the patella. All had imaging studies and microscopic diagnostic confirmation. All medical records, imaging studies, and pathology were reviewed. Results: There were 15 females and 26 males, ranging from 8 to 68 years old (average 30). There were 30 benign tumors; eight giant cell tumors, eight chondroblastomas, seven osteoid osteomas, two aneurysmal bone cysts, two ganglions, one each of chondroma, exostosis, and hemangioma. There were 11 malignant tumors: five hemangioendotheliomas, three metastases, one lymphoma, one plasmacytoma, and one angiosarcoma. Conclusion: Patellar tumors are rare and usually benign. As the patella is an apophysis, the most frequent lesions are giant cell tumor in the adult and chondroblastoma in children. Osteoid osteomas were frequent in our series and easily diagnosed. Metastases are the most frequent malignant diagnoses in the literature; in our series malignant vascular tumors were more common. These lesions are often easily analyzed on radiographs. CT and MR define better the cortex, soft tissue extension, and fluid levels. This study presents the imaging patterns of the more common patellar tumors in order to help the radiologist when confronted with a lesion in this location. © 2011 Elsevier Ireland Ltd. All rights reserved.

Item does not contain fulltext BACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Cushing's syndrome may remain unrecognized among patients referred for metabolic syndrome; thus, a proactive screening has been suggested in certain patient populations with features of the disorder. However, conflicting data have been reported on the prevalence of Cushing's syndrome in patients with type 2 diabetes.Our aim was to evaluate the prevalence of unsuspected Cushing's syndrome among outpatients with type 2 diabetes.This was a cross-sectional prospective study in 24 diabetes clinics across Italy.Between June 2006 and April 2008, 813 patients with known type 2 diabetes without clinically overt hypercortisolism were evaluated. Follow-up of the study was closed in September 2010. Patients were not selected for characteristics conferring a higher pretest probability of hypercortisolism. Patients underwent a first screening step with the 1-mg overnight dexamethasone suppression test.Forty patients failed to suppress serum cortisol less than 5.0 μg/dl (138 nmol/liter) and underwent a standard 2-d, 2-mg dexamethasone suppression test, after which six patients (0.6% of the overall series) failed to suppress cortisol less than 1.8 μg/dl (50 nmol/liter), receiving a definitive diagnosis of Cushing's syndrome that was adrenal dependent in five patients. Four patients were cured, being able to discontinue, or reduce, the glucose-lowering agents.The present data do not support widespread screening of patients with type 2 diabetes for Cushing's syndrome; however, the disorder is less rare than previously thought when considering epidemiology of type 2 diabetes. Our results support a case-finding approach in patients with uncontrolled diabetes and hypertension despite appropriate treatment.

International audience; Transformation to acute myeloid leukemia (AML) is a known complication of myeloproliferative neoplasia (MPN). Recent studies reported the high incidence (53%) of JAK2 negative blasts from transformed JAK2V617F-MPN. We collected, by cell sorting, blast cells and mature cells (GRA) from total bone marrow (BM) of 34 patients newly diagnosed of secondary AML. At MPN diagnosis (PMF n = 18; PV n = 9; ET n = 7), JAK2 was mutated in 22 of 34 patients. Twenty of 22 JAK2V617F-MPN (91%) maintained the mutation in blasts and GRA after leukemic switch, while in 2 of 22 patients the selected compartments lost the mutation. Surprisingly we also found the first case of JAK2V617F-AML from a wild type (WT)-MPN. In contrast to the previous study, we conclude that JAK2V617F-MPN yields rarely (9%) a JAK2WT-AML and any JAK2-status modification/persistence involves always the entire BM during leukemic transformation.

The involvement of the small bowel in systemic forms of amyloidosis may be diffuse or very rarely focal.? Some cases of focal amyloidomas of the duodenum and jejunum without extraintestinal manifestations have been reported. The focal amyloidomas consisted of extensive amyloid infiltration of the entire intestinal wall thickness. Radiological barium studies, ultrasound and computed tomography (CT) patterns of diffuse small bowel amyloidosis have been described: the signs are non-specific and may include small-bowel dilatation, symmetric bowel wall thickening, mesenteric infiltration, and mesenteric adenopathy. No data are available about the positron emission tomography (PET)/CT and magnetic resonance imaging (MRI) patterns of intestinal amyloidosis. We report two cases of small bowel amyloidosis: the former characterized by focal deposition of amyloid proteins exclusively within blood vessel walls of the terminal ileum, the latter characterized by diffuse intestinal involvement observed on MRI and PET/CT studies.

EVI1 is an oncogene inappropriately expressed in the bone marrow (BM) of ∼10% of myelodysplastic syndrome (MDS) patients. This disease is characterized by severe anemia and multilineage myeloid dysplasia that are thought to be a major cause of mortality in MDS patients. We earlier reported on a mouse model that constitutive expression of EVI1 in the BM led to fatal anemia and myeloid dysplasia, as observed in MDS patients, and we subsequently showed that EVI1 interaction with GATA1 blocks proper erythropoiesis. Whereas this interaction could provide the basis for the erythroid defects in EVI1-positive MDS, it does not explain the alteration of myeloid differentiation. Here, we have examined the expression of several genes activated during terminal myelopoiesis in BM cells and identified a group of them that are altered by EVI1. A common feature of these genes is their regulation by the transcription factor PU.1. We report here that EVI1 interacts with PU.1 and represses the PU.1-dependent activation of a myeloid promoter. EVI1 does not seem to inhibit PU.1 binding to DNA, but rather to block its association with the coactivator c-Jun. After mapping the PU.1-EVI1 interaction sites, we show that an EVI1 point mutant, unable to bind PU.1, restores the activation of PU.1-regulated genes and allows a normal differentiation of BM progenitors in vitro. [Cancer Res 2009;69(4):1633–42]

High performance liquid chromatography (HPLC) with electrochemical detection proves to be a reliable method for determination of plasma catecholamines (CA) to assess the possible role of the sympathetic nervous system (SNS) in essential hypertension (EH). The present investigation in a group of 15 normotensive (N) and 13 stable EH patients, homogeneous for age and duration of hypertension, was carried out without treatment in the supine position, up-right position and during a personalized bicycle exercise. Mean blood pressure, mean heart rate, plasma renin activity and plasma aldosterone were also evaluated at the various exertion phases. Norepinephrine (NE) and epinephrine (E) showed a progressive increase in N and in EH patients, reaching the highest values at maximum effort. However, EH patients showed higher E plasma levels than N before maximum effort. Dopamine (DA) reached the highest values in N at maximum effort and in EH patients at recovery time. These findings allow us to foresee the possibility of a better characterization of the SNS role in EH.

RUNX1 (AML1, CBFalpha2, PEBP2alphaB) is a transcription factor essential for the establishment of the hematopoietic stem cell. It is generally thought that RUNX1 exists as a monomer that regulates hematopoietic differentiation by interacting with tissue-specific factors and its DNA consensus through its N terminus. RUNX1 is frequently altered in human leukemia by gene fusions or point mutations. In general, these alterations do not affect the N terminus of the protein, and it is unclear how they consistently lead to hematopoietic transformation and leukemia. Here we report that RUNX1 homodimerizes through a mechanism involving C terminus-C terminus interaction. This RUNX1-RUNX1 interaction regulates the activity of the protein in reporter gene assays and modulates its ability to induce hematopoietic differentiation of hematopoietic cell lines. The promoters of genes regulated by RUNX1 often contain multiple RUNX1 binding sites. This arrangement suggests that RUNX1 could homodimerize to bring and hold together distant chromatin sites and factors and that if the dimerization region is removed by gene fusions or is altered by point mutations, as observed in leukemia, the ability of RUNX1 to regulate differentiation could be impaired.

Our retrospective experience underscores the ability of Doppler echocardiography to detect the cardiotoxicity of chemotherapy (functional and pericardial abnormalities, heart involvement) and points out the need for an accurate echocardiographic follow-up of hematologic patients.

To establish the role of percutaneous ethanol injection (PEI) treatment in benign thyroid lesions by evaluating: (1) the long-term efficacy and side effects of the treatment, (2) the factors predictive of efficacy of PEI, and (3) the cost effectiveness of the procedure.Fifty-eight recurrent cystic nodules, 95 autonomously functioning nodules (AFTN), and 17 hyperfunctioning nodules causing thyrotoxicosis (toxic nodules) were treated by PEI from 1990 to 1996 in our center. Ultrasound (US) and color flow doppler (CFD) examinations were carried out before and after each treatment. In patients with AFTN, serum thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb) levels were tested before and after PEI. All patients were independently reexamined by two external reviewers after a minimum follow-up of 5 years (median, 6.9 years).The median number of treatments was 2.0 (range, 1.0-4.0) for cystic nodules, 4 (range, 2.0-6.0) for AFTN, and 5 (range, 3.0-7.0) for toxic nodules. At the 5-year evaluation cystic nodules showed a volume reduction greater than 75% versus baseline in 86.2% of cases and an improvement of local symptoms in 91.4% of cases. AFTN presented serum TSH within normal limits in 60.0% of patients. Toxic nodules showed a detectable serum TSH and normal FT3 and FT4 values in 35.3% of cases. Two cases of transient dysphonia were observed. In cystic lesions no significant correlation was found between the baseline and the final volume (r2 = 0.17) and no significant predictor of treatment efficacy was found. However, unilocularity was associated with a lower number of treatments than multilocularity (median, 2.0 vs. 3.0). Independent predictors of clinical efficacy in both AFTN and toxic nodules were a baseline volume less than 5.0 mL and a fluid component greater than 30% (odds ratio [OR] = 6.1 and 3.3, respectively).Most recurrent cystic lesions of the thyroid can be cured by PEI, which should become the first line of treatment. The majority of AFTN and toxic nodules with volume less than 5.0 mL presented a marked volume decrease and normal serum TSH levels when treated by PEI, which seems a valid alternative to clinical follow-up alone in patients refusing 131I. PEI is not indicated in large or toxic nodules, for which 131I is the treatment of choice.

The Authors describe a cutaneous recurrence of a thyroid follicular cancer, immediately above the thyroid nodule, in a 76-year-old woman with advanced multiple myeloma, 8 mo after a fine-needle axpiration biopsy performed with 22-gauge needles. © 1994 Wiley-Liss, Inc.

To evaluate if chronic viral hepatitis may be a protective factor for atherosclerosis.Echo-doppler of the carotid and femoral arteries and the abdominal aorta was used to examine 48 patients with a histological diagnosis of chronic viral hepatitis (42 hepatitis C virus-related, 6 hepatitis B virus-related), with a low degree of activity and preserved hepatic function, and 50 controls matched for age, sex and exposure to the main risk factors of atherosclerosis.The prevalence of atherosclerosis in patients was clearly lower than in controls in all investigated sites, although the difference was statistically significant only for the carotid arteries. The percentage of patients with carotid atherosclerosis was 27% in patients with liver disease and 56% in controls (P0.005). Furthermore, and again at the carotid level, the patients with liver disease had fewer atheromatous lesions (16 plaques vs. 59; P0.001) than controls as well as a lower degree of vessel stenosis. None of the liver disease patients presented with vessel stenosis above 30% vs. 8% of control subjects.Chronic viral hepatitis may help prevent from atherosclerosis.

The aim of the study was to correlate the sonographic [ultrasound (US)] and color-Doppler (CFD) findings with the results of US-guided fine needle aspiration biopsy (FNA) and of pathologic staging of resected carcinomas to establish: 1) the relative importance of US features as risk factors of malignancy; and 2) a cost-effective management of nonpalpable thyroid nodules. Four hundred ninety-four consecutive patients with nonpalpable thyroid nodules (8-15 mm) were evaluated by US, CFD, and US-FNA. Ninety-two patients with inadequate cytology were excluded from the study. All patients with suspicious or malignant cytology underwent surgery, whereas subjects with benign cytology had clinical and US control 6 months later. Thyroid malignancies were observed in 18 of 195 (9.2%) solitary thyroid nodules and in 13 of 207 (6.3%) multinodular goiters. Cancer prevalence was similar in nodules greater or smaller than 10 mm (9.1 vs. 7.0%). Extracapsular growth (pT(4)) was present in 35.5%, and nodal involvement in 19.4% of neoplastic lesions, with no significant differences between tumors greater or smaller than 10 mm. At US cancers presented a solid hypoechoic appearance in 87% of cases, irregular or blurred margins in 77.4%, an intranodular vascular pattern in 74.2%, and microcalcifications in 29.0%. Irregular margins (RR 16.83), intranodular vascular spots (RR 14.29), and microcalcifications (RR 4.97) were independent risk factors of malignancy. FNA performed on hypoechoic nodules with at least one risk factor was able to identify 87% of the cancers at the expence of cytological evaluation of 38.4% of nonpalpable lesions. The majority of nonpalpable thyroid tumors can be identified by cytological evaluation of lesions presenting hypoechoic appearance in conjunction with one independent risk factor. Due to the nonnegligible prevalence of extracapsular growth and nodal metastasis, US-FNA should be performed on all 8-15 mm hypoechoic nodules with irregular margins, intranodular vascular spots or microcalcifications. Nonpalpable lesions of the thyroid without risk factors should be followed by means of clinical and US evaluation.

Tachykinins (TKs) have been shown to be involved in the excitatory enteric motor pathway. This study aimed to examine the direct and nerve-mediated effect of specific NK1, NK2 and NK3 receptor agonists and antagonists in colonic preparations from control subjects and patients with idiopathic chronic constipation (ICC).Cumulative concentrations of Sar9Met(O2)11 substance P (selective NK1 receptor agonist), [Ala5,beta-Ala8]-neurokinin A (4-10) (selective NK2 receptor agonist) and [MePhe7]-neurokinin B (selective NK3 receptor agonist) were tested on colonic circular muscle strips to evaluate the direct drug effects. In addition, in the presence of atropine, the role of TKs in the off-contraction that follows the typical inhibitory response evoked by low frequencies of electrical field stimulation (0.5--10 Hz, 20 V, 1 ms pulse trains lasting 1 min) was investigated.In control preparations, the rank order of potency was: NK2 receptor-selective agonistNK3 receptor-selective agonistNK1 receptor-selective agonist. The off-contraction was found to be reduced by about 30--40% in colonic circular muscle from ICC patients with respect to controls. Incubation with the NK1 receptor agonist did not modify the off-contraction measurements in either control or ICC preparations. Conversely, both NK2 and NK3 receptor agonists significantly (P0.01) increased the off-contraction in ICC preparations only. This increased response was fully antagonized by MEN-10627, a NK2 and NK3 receptor antagonist depending on the dose.We may conclude that ICC is hyporesponsive to TKs and that the contractile reflex to distension is greatly reduced in ICC disease, but can be restored by incubation with NK2 and NK3 receptor agonists.

Impaired gastrointestinal function outside the esophagus has been found in achalasic patients. Moreover, achalasia may occur in diseases in which a systemic dysautonomia is evident. These findings raise the question of whether a generalized subclinical alteration of autonomic control is also present in primary achalasia. Cardiovascular reflex tests and power spectral analysis of heart rate variability were studied in patients with primary achalasia to establish whether autonomic nervous system changes are present in districts other than the gastrointestinal tract. Nineteen normotensive patients with untreated primary achalasia and with no history of cardiac, renal, or endocrinological diseases were examined. Cardiovascular reflex tests included: the tilt test (10 min at 65 degrees), Valsalva maneuver (40 mm Hg for 15 sec), deep breathing (6 breaths/min), and sustained handgrip (30% of maximal effort for 5 min). The parameters evaluated were systolic and diastolic blood pressure (continuously recorded), ECG, oronasal and thoracic respiration, tachogram, and plethysmogram. To evaluate the balance between parasympathetic and sympathetic functions, power spectral analysis of the heart rate variability was carried out. Each patient was paired with two sex- and age-matched healthy controls. In achalasic patients the head-up tilt test, Valsalva maneuver, deep breathing test, and sustained handgrip did not show significant differences from the control group. Low-frequency (LF) and high-frequency (HF) spectral powers and the ratio of LF to HF did not differ in both groups. This study failed to disclose impaired cardiovascular autonomic control in achalasic patients. We suggest that in primary achalasia the defect is limited to the gastrointestinal tract.

Erythromycin has been shown to have profound prokinetic effects on the gastrointestinal tract of humans and animals, probably through its action on endogenous motilin receptors. The purpose of this study was to determine both the direct and indirect effects ('off contraction') of erythromycin and motilin on ex vivo circular muscle strips of the distal colon from patients with or without idiopathic chronic constipation (ICC).Cumulative concentrations of erythromycin (1-20 microM) and motilin (0.05-1 microM) were tested in both control and ICC preparations in order to evaluate the direct drugs effect. A range doses of both erythromycin (0.5-10 microM) and motilin (0.05-0.5 microM) were tested on their ability to affect the off-contraction that follows the typical inhibitory response evoked by low frequencies of Electrical Field Stimulation (EFS) (1-5 Hz, 20 V, 1 msec pulse trains lasting 1 min).The direct effect of both erythromycin and motilin was a slight increase (less than 10% of the maximal ACh-induced contraction) in the basal tension, with no dose-response relationship. The off-contraction, evoked by EFS, was not affected by drugs pretreament in control preparations. Conversely, in ICC preparations both drugs significantly increased the off-contraction (about 30%).Erythromycin causes mainly an indirect contractile effect in circular muscle strips from ICC patients. This effect may be related to the activation of inhibitory neuronal motilin receptors. This activation might potentiate NANC relaxation, proportionally increasing the circumferential reflex contraction that follows the EFS-induced relaxation.

Liver metastases from differentiated thyroid tumors are unusual clinical findings, and are only rarely hyperfunctioning. We report a case of thyrotoxicosis caused by a huge and surgically unresectable liver metastasis from follicular thyroid cancer, unresponsive to treatment with large doses of thionamides. To avoid the hazardous side effects of (131)I treatment in a severely thyrotoxic patient, a preliminary debulking of the liver mass was performed by means of percutaneous interstitial laser photocoagulation. Three treatments (total energy delivery: 7200 J) were performed under ultrasound guidance, with no serious complications, during a 2-week period. One month later, serum thyroid hormones had decreased, general condition was improved, and magnetic resonance evaluation revealed large and well-defined areas of necrosis of metastatic tissue. During the following 10 months, the patient underwent 3 radioiodine treatments. Eighteen months after diagnosis, thyroid hormones were within normal levels, liver mass decreased, and the clinical condition markedly improved. The combination of percutaneous interstitial laser photocoagulation treatment and radioiodine therapy made possible the effective management of a hyperfunctioning and surgically untreatable liver metastasis from thyroid follicular carcinoma, avoiding the side effects of (131)I therapy in a thyrotoxic patient and increasing the effectiveness of radioiodine-induced neoplastic tissue ablation.

We performed chromosome microdissection in order to define the "de novo" rearrangement observed in a female patient affected by: frontal microgyria, mild psychomotor retardation, thoracic scoliosis, XIIth rib asymmetry and facial dysmorphisms. Through the use of the micro-FISH we evidenced a deletion of the 3p25pter region and a 4p16.1 duplication. We performed a karyotype-phenotype correlation in our patient and in the ones previously reported in literature which had a 3p25pter deletion or the 4p16 duplication.

The aim of our study was to further investigate the pathophysiological mechanism underlying idiopathic chronic constipation (ICC), a disorder of colonic motility. A possible alteration of excitatory and inhibitory neurotransmission and also the role of inhibitory neurotransmitters such as nitric oxide (NO), 5'-adenosine triphosphate (ATP), and vasoactive intestinal peptide (VIP) has been evaluated on preparations of distal colon from patients with or without ICC. The isometric tension was recorded from isolated circular muscle strips of both experimental groups during pharmacological and electrical field stimulation (EFS). The contractile response obtained by acetylcholine (ACh 20 microM), EFS (20 Hz, 20 V, 1 msec, pulse trains lasting 1 min) and substance P (SP 1 microM) was significantly lower in ICC than in control preparations. The effect of inhibitory nonadrenergic, noncholinergic innervation was evaluated using EFS at low frequencies (0.5-8 Hz), after cholinergic and sympathetic blockade with atropine (3 microM) and guanethidine (3 microM). The maximum relaxation value expressed as percentage of inhibition of SP-induced contraction was significantly higher in ICC than in control preparations (87+/-2.4 and 67+/-6.3, respectively; P0.05). Experiments with substances that antagonize or reduce the effect of putative inhibitory mediators (VIP 6-28, apamin and N(G)-nitro-L-arginine) suggest that an alteration in NO and ATP release is present in ICC preparations. In particular at a higher inhibitory frequency NO-mediated relaxation is enhanced in ICC vs control, supporting the hypothesis that excessive NO production may be involved in pathophysiological mechanism of constipation.

We studied for 5 yr a homogeneous group of 83 patients randomly assigned to a levothyroxine (L-T4) suppressive therapy or to a control group to evaluate changes in nodule or thyroid size, appearance of new nodules, and correlations with clinical parameters. In the control group, mean nodule volume increased significantly after 5 yr (2.12 +/- 1.46 vs. 1.46 +/- 0.77 mL), whereas in the treatment group it decreased, although not significantly (1.45 +/- 1.17 mL vs. 1.53 +/- 0.61 mL). Baseline nodule volume was not different in the two groups, but a significant difference was observed at 5 yr. After 5 yr, sonograms detected 12 new nodules in the control group (28.5%) and 3 (7.5%) in the treatment group. Nodule shrinkage was more frequent in patients with complete TSH suppression, but no correlation was found with other parameters. A significant increase in thyroid size was observed in the control group. In conclusion, long term TSH suppression induced volume reduction in only a subgroup of thyroid nodules, but effectively prevented the appearance of new lesions and increases in nodule and thyroid volume. As the changes in the natural history of nodular goiter are related to prolonged TSH suppression, which can induce unfavorable side-effects, L-T4 suppressive therapy should be reserved for small nodules in younger patients.

SUMMARY. In chronic hepatitis C (HCV) infection, treatment with interferon is associated with a rather low rate of sustained response and many treated patients do not achieve significant benefit. Efforts have therefore been made to identify non-responders as early as possible to avoid unjustified costs and side-effects. We treated 106 cases of HCV with an algorithm based on the results of sequential alanine aminotransferase (ALT) and HCV RNA determinations, using an initial dose of 6 MU thrice weekly for 4 months, and modified the subsequent treatment according to the biochemical and virological profile. Thirty-three out of 48 patients (68.7%) who were HCV RNA negative with normal ALT at 4 months after initiation of treatment were sustained responders when treated for an additional 4-month period with a reduced 3 MU dose, while sustained response was achieved in 12.5% of HCV RNA positive patients treated with a higher dosage and for a more prolonged period of time. Our findings indicate that HCV RNA monitoring during interferon therapy may be useful in modifying of the treatment schedule for the individual patient.

AIMS: To determine cell proliferation in infiltrating breast carcinomas. METHODS: Using the MIB-1 monoclonal antibody, the proliferation index was measured in paraffin wax sections of 871 breast cancers. The MIB-1 proliferation index was compared with other markers of disease progression: size, lymph node status, histotype, oestrogen and progesterone receptor status, expression of p53 and Neu, and DNA ploidy. All parameters were measured using image analysis. In 347 tumours, the MIB-1 and Ki-67 proliferation indexes were compared. Follow up data were available for 170 cases (median 66.5 months). RESULTS: Of the tumours, 314 (36%) had a high proliferation index. The MIB-1 proliferation index was correlated directly with size, nodal status, overexpression of p53 and Neu, and the DNA index; and inversely with oestrogen and progesterone receptor status. The correlation between MIB-1 and Ki-67 proliferation indexes was statistically significant. In patients with pT1 tumours, a low proliferation index correlated with a longer relapse-free interval and overall survival; node negative patients with a low proliferation index had a longer overall survival. CONCLUSIONS: The MIB-1 proliferation index is a reliable, practical and useful method of measuring proliferative activity and is an important predictor of clinical behaviour.