Analysis of antibodies against components of the autonomic nervous system in diabetes mellitus

Antibodies to autonomic nervous system structures have previously been detected using a complement fixation immunofluorescence test in the sera of patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM). These antibodies might play a role in the aetiology of autonomic neuropathy. Sera from 45 IDDM, 40 NIDDM and 52 control subjects were tested by immunofluorescence for antibodies to human sympathetic ganglia, human adrenal medulla and rabbit vagus nerve. The use of human sympathetic ganglia was compared with rabbit tissue for the detection of sympathetic ganglia antibodies; the results for these autonomic nervous system antibodies were also compared with results using an ELISA. There was no relationship between the presence of antibodies detected by ELISA and those detected by immunofluorescence, but of 14 IDDM patients with thyroid antibodies, 12 had autonomic nervous system antibodies detected by either immunofluorescence or ELISA (p < 0.005 compared to patients without thyroid antibodies). To further characterize the autoantigen(s), immunoblotting was performed. An adrenal antigen corresponding to 74 kDa was detected in sera from three patients, only one of whom had antibodies detectable by ELISA and immunofluorescence. One IDDM serum showed specific binding to a vagus nerve antigen corresponding to 33 kDa. No specific binding to sympathetic ganglia antigen was demonstrated. Antibodies against autonomic nervous system antigens are an inconsistent feature of diabetes, and appear more associated with coincidental autoimmunity against other organs such as the thyroid.      

Assessing diagnosis in heart failure: which features are any use?

We assessed the value of symptoms, past history, medications and signs in the evaluation of patients who might have heart failure secondary to left ventricular systolic dysfunction. An open-access echocardiography service was set up to help identify patients with left ventricular systolic dysfunction who might benefit from treatment with an angiotensin-converting-enzyme inhibitor. History and examination were recorded for each of these patients. The patients were divided into groups according to whether left ventricular systolic function was preserved or not and whether various clinical features were present or not. Of 259 consecutive patients studied, 41 had impairment of left ventricular systolic function as assessed by echocardiography. Past history of myocardial infarction and displaced apex beat were the best single predictors of left ventricular systolic dysfunction as assessed by echocardiography. The combination of past history of myocardial infarction and displaced apex had the best positive predictive value of all. Patients with such clinical features or combinations of clinical features may not need echocardiography, and where access to this resource is limited, it could be reserved for patients without such diagnostic features.      

Impact of intra-operative ultrasonography in liver surgery.

BACKGROUND/OBJECTIVE: Intra-operative ultra-sonography (IOUS) during surgery for primary and metastatic hepatic tumors identifies additional lesions and helps in determining the most optimal surgical strategy. We assessed the impact of IOUS in liver surgery at our hospital, a tertiary-care cancer center. METHODS: Patients with potentially resectable hepatic tumors underwent surgical exploration. The relationship of the tumor with regard to the intrahepatic vasculature was determined by IOUS. A search was also made for additional lesions not detected by pre-operative imaging modalities. In appropriate cases, IOUS was also used to assist resection and radiofrequency ablation/ethanol injection. RESULTS: Between January 2003 and January 2005, 52 patients underwent surgery for primary or secondary hepatic tumors. IOUS was performed in 48 of these patients. It detected additional hepatic lesions in 14 patients (29.2%). IOUS contributed to changing the operative plan in 21 patients (43.8%). It was directly responsible for avoiding resection or ablation in 7 patients (14.6%), 5 of whom had multiple bilobar lesions, 1 had IOUS-guided biopsy that revealed caseating granuloma on frozen section, and 1 patient had no lesion on IOUS. Three patients had extent of resection changed based on IOUS findings. IOUS also guided radiofrequency ablation in 8 patients and ethanol injection in one patient. CONCLUSION: IOUS is an essential tool in surgery for hepatic tumors. In addition to accurate staging, it also aids in safe resection and radiofrequency ablation in appropriate cases.     

Whither bedside teaching? A focus-group study of clinical teachers.

PURPOSE: Previous reports document diminishing time spent on bedside teaching, with a shift towards conference rooms and corridors. This study explored faculty's perceptions of the barriers to and their strategies for increasing and improving bedside teaching. METHOD: Four focus groups consisting of (1) chief residents, (2) residency program directors, (3) skilled bedside teachers, and (4) a convenience group of other Department of Medicine faculty from the Boston University School of Medicine's affiliated hospitals were held in May 1998. Each session lasted 60-90 minutes. Sessions were audiotaped, transcribed, and analyzed using qualitative methods. RESULTS: The most significant barriers reported were (1) declining bedside teaching skills; (2) the aura of bedside teaching, a belief that bedside teachers should possess an almost unattainable level of diagnostic skill that creates intense performance pressure; (3) that teaching is not valued; and (4) erosion of teaching ethic. Focus-group participants suggested the following strategies for addressing these barriers: improve bedside teaching skills through faculty training in clinical skills and teaching methods; reassure clinical faculty that they possess more than adequate bedside skills to educate trainees; establish a learning climate that allows teachers to admit their limitations; and address the undervaluing of teaching on a department level with adequate recognition and rewards for teaching efforts. Skilled teachers, in particular, stated that a bedside teaching ethic could be reestablished by emphasizing its importance and challenging learners to think clinically. CONCLUSIONS: Bedside teaching is regarded as valuable. Some barriers may be overcome by setting realistic faculty expectations, providing incentives for teaching faculty, and establishing ongoing faculty development programs.     

Autoimmunity as an aetiological factor in vitiligo

Vitiligo is a common dermatological disorder characterized by the presence on the skin of depigmented macules resulting from the destruction of cutaneous melanocytes. Autoimmunity is an important hypothesis with regard to vitiligo aetiology and the evidence for autoimmune responses being involved in the pathogenesis of this disorder will be discussed in the present review. All immune system compartments, including innate and adaptive immunity have been implicated in vitiligo development. Particularly relevant are autoantibodies and autoreactive T cells in vitiligo patients that have cytotoxic effects upon pigment cells. Furthermore, predisposition to vitiligo appears to be associated with certain alleles of the major histocompatibility complex class II antigens as well as with other autoimmune-susceptibility genes. Moreover, the association of vitiligo with autoimmune disorders, the animal models of the disease, and the positive response to immunosuppressive therapeutic agents emphasize the role of autoimmunity in the development of this disorder.     

Balance of pro‐ versus anti‐angiogenic splice isoforms of vascular endothelial growth factor as a regulator of neuroblastoma growth

Neuroblastoma (NB) is the second most common extracranial tumour of childhood. Angiogenesis plays a crucial role in the growth and development of NB and vascular endothelial growth factor (VEGF), one of the most potent stimuli of angiogenesis, has been studied extensively in vitro. VEGF₁₆₅ has been shown to be the predominant angiogenic isoform expressed in NB cell lines and tumours. In this study, we investigated the anti‐angiogenic isoform of VEGF‐A, generated from distal splice site selection in the terminal exon of VEGF (VEGF₁₆₅b) and shown to be down‐regulated in epithelial malignancies. The expression of both the pro‐ (VEGF_xxx) and the anti‐angiogenic (VEGF_xxxb) isoforms was compared in a range of NB and ganglioneuroma (GN) tumours. Whereas VEGF_xxxb and VEGF_xxx were both expressed in GN, specific up‐regulation of the VEGF_xxx isoforms was seen in NB at RNA and protein levels. Highly tumourigenic NB cell lines also showed up‐regulation of the angiogenic isoforms relative to VEGF_xxxb compared to less tumourigenic cell lines, and the isoforms were differentially secreted. These results indicate that VEGF₁₆₅ is up‐regulated in NB and that there is a difference in the balance of isoform expression from anti‐angiogenic VEGF₁₆₅b to angiogenic VEGF₁₆₅. Treatment with recombinant human VEGF₁₆₅b significantly reduced the growth rate of established xenografts of SK‐N‐BE(2)‐C cells (4.24 ± 1.01 fold increase in volume) compared with those treated with saline (9.76 ± 3.58, p < 0.01). Microvascular density (MVD) was significantly decreased in rhVEGF₁₆₅b‐treated tumours (19.4 ± 1.9 vessels/mm³) in contrast to the saline‐treated tumours (45.5 ± 8.6 vessels/mm³). VEGF₁₆₅b had no significant effect on the proliferative or apoptotic activity, viability or cytotoxicity of SK‐N‐BE(2)‐C cells after 48 h. In conclusion, VEGF₁₆₅b is an effective inhibitor of NB growth. These findings provide the rationale for further investigation of VEGF₁₆₅b in NB and other paediatric malignancies. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The changing clinical pattern of Reye's syndrome 1982-1990

OBJECTIVE: To describe trends in the clinical pattern of Reye's syndrome in the British Isles between 1982 and 1990; and to determine the relation between any changes and the June 1986 warnings against the use of aspirin in children. DESIGN: Development, and application to reported cases, of a scoring system designed such that patients showing the typical clinical and pathological features of 'classical' Reye's syndrome scored highly. The relations between 'Reye scores' and a number of explanatory variables were explored using multivariable analysis. SETTING: British Isles. SUBJECTS: 445 cases fulfilling the Reye's syndrome case definition reported to the surveillance scheme between January 1982 and December 1990. MAIN OUTCOME MEASURE: Individual 'Reye score'. RESULTS: Cases with high scores were more likely to have occurred in the 4 1/2 year period before June 1986 compared with the subsequent period (p < 0.006). Numbers of cases in the low and intermediate score categories declined by about 50% after June 1986, whereas those in the high category fell by 79%. High scorers were more likely to have received aspirin (p < 0.0001) and were older than intermediate and low scorers (p < 0.008). No relation was identified between score and season of onset. CONCLUSIONS: The decline in Reye's syndrome after the aspirin warnings cannot be explained entirely, as has been proposed, by improved diagnosis of 'Reye-like' inherited metabolic and other disorders: this would not account for the greater decline of the high scoring subgroup which also contained those cases most likely to resemble 'classical' Reye's syndrome and to have received aspirin. This study provides further evidence for the role of aspirin in a subset of cases meeting the standard diagnostic criteria for Reye's syndrome and supports the need to consider this disorder as a heterogeneous group of conditions including Reye-like inherited metabolic disorders.     

Expression of the stem cell factor receptor c-kit in normal and diseased pediatric liver: identification of a human hepatic progenitor cell?

The stem cell factor (SCF)/c-kit ligand/receptor system has been implicated in stem (oval) cell activation following liver injury in the rat. The aim of this study was to determine the role of the SCF/c-kit system in pediatric human liver during acute and chronic liver injury. Tissue was obtained from hepatectomy specimens of patients undergoing liver transplantation for extrahepatic biliary atresia (EHBA) and fulminant hepatic failure (FHF). Specific expression of mRNA for c-kit and beta-actin was measured by ribonuclease protection and by immunohistochemistry to localize c-kit in tissue sections. Expression of c-kit was detected at relatively consistent levels in normal and cirrhotic (EHBA) livers. However, in FHF, c-kit mRNA levels were elevated in 3 of 6 specimens. Immunolocalization highlighted the presence of small numbers of c-kit-positive cells in the portal tracts of normal livers with increased numbers in cirrhotic livers. The highest c-kit staining, however, was observed in FHF, in which, in addition to the cells in the portal tracts, discrete c-kit-positive cells were also found integrated into bile ducts. Colocalization studies demonstrated some of the c-kit-positive cells to be of mast cell, leukocyte, and hematopoietic cell origin. However, there remained a subset that was also negative for these markers. The up-regulation of c-kit receptor expression in diseased livers suggests an involvement of this receptor/ligand system in hepatic repair mechanisms, and we speculate that c-kit-positive cells may represent a hepatic progenitor cell population. The origin and growth/differentiation potential of these c-kit-positive cells is under investigation.     

Periosteal chondrosarcoma of metacarpal bone: Report of a rare entity

Chondrosarcomas of the hand are very rare, constituting less than 0.5% of all chondrosarcomas. Metacarpal involvement and juxtacortical location are still rarer. We report a case of periosteal chondrosarcoma of metacarpal bone in a 38-year-old man, who presented with swelling of the left hand. He underwent extended ray amputation with removal of the entire left third metacarpal bone. Histopathological and radiological features of the tumour are described. Recognition of periosteal chondrosarcoma and its differentiation from other surface bone tumours is very important because the prognosis is excellent after adequate local surgery.