Expression of p170 protein in multiple myeloma: a clinical study.

The expression of the p170 multidrug resistance protein by bone marrow plasma cells (BMPC) was assessed at clinical presentation in 53 patients with multiple myeloma (MM) using the C219 monoclonal antibody. Twenty-two of the 53 (41 per cent) patients had variable aliquots (1-60 per cent, median = 6 per cent) of p170+ BMPC by immunocytochemistry. Five of 10 patients studied using bivariate flow cytometry had both diploid and hyperdiploid (DNA index ranged from 1.2 to 1.5) BMPC with hyperdiploid clones having significantly greater p170 expression than diploid ones. Of the 37 patients evaluated for a response, 20 (54 per cent) had responded to induction chemotherapy. The presence of p170+ BMPC was a negative indicator for achieving response. The response rate was 75 per cent for p170- and 25 per cent for p170+ cases (p < 0.01), with no difference on the basis of treatment schedule (melphalan and prednisone, 24 patients; peptichemio, vincristine and prednisone, 13 patients). No difference in response and survival duration was found between p170+ and p170- patients. In six of nine patients studied both at diagnosis and following induction chemotherapy the p170+ BMPC% increased irrespective of the type of treatment or outcome.     

Epilepsy and family expressed emotion: results of a prospective study.

PURPOSE: To verify the emotional components expressed by the relatives of adult patients with a diagnosis of epilepsy, and whether they are related to adjustment to the illness and the course of the illness over time. METHODS: We studied a consecutive sample of 43 outpatients suffering from epilepsy and 43 key relatives using the Camberwell Family Interview (CFI), with the expressed emotion (EE) of the relatives being rated at baseline (T0). EE refers to a construct representing some key aspects of interpersonal relationships: the relatives were assigned to the high-EE group if they scored 3 or more on the emotional over involvement (EOI) scale, or showed hostility, or made 6 or more critical comments. The patients were clinically evaluated at baseline and for 1 year of appropriate treatment by an epileptologist who was blinded to the EE ratings. They also completed STAI XI, STAI X2 and Beck's Depression Inventory at baseline. RESULTS: Twenty-six relatives (60%) were rated as showing a high degree of EE. In the 12-month follow-up study, high EE and high EOI were found to be associated with a significantly higher seizure frequency than that recorded for the patients living in low-EE households (p<0.05). The patients from households assessed as reflecting a high degree of criticism showed poor drug compliance (p<0.01), whereas those with relatives assessed as having a high degree of warmth showed better clinical and pharmacological compliance (p<0.01). High family criticism scores also correlated with higher study entry levels of depression (p<0.05) and trait and state anxiety (p<0.05) among the patients. CONCLUSIONS: The study findings highlight the impact of particular components of the family emotional climate on the clinical course and psychological adjustment of patients with epilepsy.     

Genes and (auto)immunity in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strengthens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed.     

The enigma of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease characterized by a striking predominance in female patients (with most cases diagnosed between ages 40 and 60 yr) as well as serum auto-antibodies to mitochondrial antigens, elevated serum immunoglobulin M, progressive destruction of intrahepatic bile ducts, and, ultimately, liver cirrhosis and failure (1). The precise mechanisms leading to selective destruction of biliary epithelial cells lining intrahepatic bile ducts are still unknown, although numerous immunomediated pathways have been proposed. Genetic background appears to be important in determining susceptibility to the disease (2), but no clear association with alleles in the major histocompatibility complex has been identified. Molecular mimicry either by infections (3) or xenobiotics (4) has been proposed to be capable of breaking tolerance in genetically predisposed individuals, thus leading to onset of PBC. This article describes and discusses the available data regarding the immunomediated pathogenesis of PBC (with particular attention to auto-antibodies and autoreactive T-cells) and presents the recent evidence indicating a role for either xenobiotic chemicals or novel infectious agents in the induction of the disease.     

High-degree abnormalities of nuclear DNA distribution in SIg negative acute lymphoblastic leukemia with vacuolated blasts

Among 65 consecutive patients with untreated adult acute lymphoblastic leukemia (ALL), six had peculiar clinical and cytologic features. Bone marrow and circulating blasts were large and showed prominent vacuolization, with variable degree of granular periodic acid-Schiff positivity in the cytoplasm. All patients had marked spleen and liver enlargement with cholestasis and without either lymph node or central nervous system disease. They achieved complete response to chemotherapy, and their median survival was longer than 12 months. Blast cells were studied for immunologic markers, propidium iodide flow cytofluorometric DNA content, and in vitro tritiated thymidine labeling index (3H-TdR LI). These showed a "null" phenotype in two cases, contained intracytoplasmic immunoglobulins (Cy mu) in two and were positive for CALL and Ia antigens in two others (one of which also contained Cy mu). Surface immunoglobulins (SIg) were found on less than 12% of cells, and T-cell markers were absent. In five cases, one or two stem lines with highly abnormal modal DNA content were found to coexist with diploid blasts. The 3H-TdR LI was high (8.5%-15.5%). Abnormal cell lines, after being cleared by chemotherapy, were found again at relapse. Additional cell lines appeared during the course of the disease in one patient, having different sensitivity to cytostatics. These cases of ALL apparently derive from B-cells not yet expressing SIg and have an exceptionally high incidence of aneuploid cell lines.     

The Senning operation for transposition of the great arteries

The original Senning technique of interatrial transposition of venous return was selectively employed for physiological correction in 24 patients with transposition of the great arteries (TGA) ranging in age from 74 days to 26 months (median 7 months). Twenty-three had intact ventricular septum and one had a large ventricular septal defect and diaphragmatic subpulmonary stenosis. There were no hospital or late deaths, and at follow-up examination 1.5 to 12 months postoperatively, each patient was asymptomatic, in normal sinus rhythm, and had no clinical evidence of caval or pulmonary venous obstruction. Nine patients underwent cardiac catheterization and angiocardiographic studies between 1.3 and 9 months postoperatively which demonstrated widely patent venous pathways and effective "left" and "right" atrial contraction. This experience lends support to the continued use of the Senning technique for interatrial transposition of venous return.     

Management of papillary microcarcinoma of the thyroid gland

DESIGN: To investigate the frequency, treatment and clinical behaviour of differentiated microcarcinoma of the thyroid gland (PTMC). PATIENTS AND METHODS: Out of 376 patients submitted to surgical treatment for differentiated thyroid cancer from June 1980 to October 2003, 77 had been identified has having a PTMC (63 females, 14 males; mean age 43+/-13 years). Sixty-seven patients (87%) met the AMES risk definition for low (group I) and 10 (13%) for high-risk (group II) definition. The surgical procedures were lobo-isthmusectomy (n=14) or subtotal thyroidectomy (n=20) and total thyroidectomy (n=43) with node dissection in 15 cases. Follow-up ranging from 9 to 274 months (mean 124+/-84). RESULTS: Overall patient survival rates were 100 and 94% at 20 years in groups I and II, respectively (p=ns). There were no significant differences in surgical complications and in survival in patients submitted to total thyroidectomy when compared to partial thyroid resection. The presence of cervical node metastasis did not affect patient survival (p=0.8). The overall mean survival time was 266 months. CONCLUSIONS: Despite the overall excellent prognosis, PTMC was associated with a 1% disease-related mortality, a 2.5% local recurrence rate, 1% lymph-node recurrence rate, and 1% distant metastasis rate. We recommend total thyroidectomy accompanied by modified neck dissection if enlarged nodes are diagnosed.     

Infectome: A platform to trace infectious triggers of autoimmunity

The “exposome” is a term recently used to describe all environmental factors, both exogenous and endogenous, which we are exposed to in a lifetime. It represents an important tool in the study of autoimmunity, complementing classical immunological research tools and cutting-edge genome wide association studies (GWAS). Recently, environmental wide association studies (EWAS) investigated the effect of environment in the development of diseases. Environmental triggers are largely subdivided into infectious and non-infectious agents. In this review, we introduce the concept of the “infectome”, which is the part of the exposome referring to the collection of an individual's exposures to infectious agents. The infectome directly relates to geoepidemiological, serological and molecular evidence of the co-occurrence of several infectious agents associated with autoimmune diseases that may provide hints for the triggering factors responsible for the pathogenesis of autoimmunity. We discuss the implications that the investigation of the infectome may have for the understanding of microbial/host interactions in autoimmune diseases with long, pre-clinical phases. It may also contribute to the concept of the human body as a superorganism where the microbiome is part of the whole organism, as can be seen with mitochondria which existed as microbes prior to becoming organelles in eukaryotic cells of multicellular organisms over time. A similar argument can now be made in regard to normal intestinal flora, living in symbiosis within the host. We also provide practical examples as to how we can characterise and measure the totality of a disease-specific infectome, based on the experimental approaches employed from the “immunome” and “microbiome” projects.     

How many forms of perseveration? Evidence from cancellation tasks in right hemisphere patients

Neglect patients' performance during cancellation tasks is characterized by left sided omissions and, in many cases, by the production of inappropriate material of various kinds in the ipsilesional space, e.g. additional marks over already cancelled targets, marks drawn away from targets, scribbles, irrelevant drawings. It is unclear whether these behaviours, which have collectively been called perseverative, are functionally and anatomically connected and whether they correlate with the severity of neglect. Here we report a retrospective study on 33 right brain damaged patients with neglect after right hemisphere lesions in whom we measured the intensity of perseveration of the three following kinds: (1) ‘additional marks' (AM) perseveration where patients cancelled a target with two or more well separated marks; (2) ‘scribble’ perseveration, where patients, instead of cancelling the target with a single pen stroke as required by the task, performed multiple pen strokes without breaking the pen-to-paper contact, with the final product being a scribble; (3) ‘flying marks’ (FM) perseveration where patients produced cancellation marks well away from the targets. We found that AM and FM perseveration correlated with neglect severity, while ‘scribble’ perseveration did not. The lesion-symptom mapping showed three separate anatomical areas in the right hemisphere: ‘scribble’ perseveration was associated with lesions of the orbitofrontal cortex and caudate nucleus; AM perseveration was associated with damage to the rolandic operculum, superior temporal gyrus and inferior frontal gyrus; FM perseveration was associated with damage to the dorsal premotor cortex and the temporal pole. Neglect severity followed damage to a region which grossly corresponds to the sum of the regions associated with AM and FM perseveration respectively. This complex behavioural and anatomical pattern is interpreted in terms of a three-factor model, in which AM perseveration is caused by a deficit of disengagement of attention from the right side (also causing omissions), FM perseveration is caused by directional hypokinesia (also causing left-side omissions), and ‘scribble’ perseveration is the consequence of a failure to inhibit an initiated motor act, which is completely separate (both anatomically and functionally) from the disorder inducing omissions.