Synchronous Ventricular Pacing without Crossing the Tricuspid Valve or Entering the Coronary Sinus—Preliminary Results

Background: Right ventricular apical (RVA) pacing promotes tricuspid regurgitation (TR), electromechanical dyssynchrony, and ventricular dysfunction. We tested a novel intramyocardial bipolar lead to assess whether stimulation of the atrioventricular septum (AVS) produces synchronous ventricular activation without crossing the tricuspid valve (TV). Methods: A lead with an active external helix and central pin was placed on the AVS and the RVA in three dogs. High‐density electroanatomic (EA) mapping was performed of both ventricles endocardially and epicardially. Intracardiac echocardiography was used to access ventricular synchrony. Results: The lead was successfully deployed into the AVS in all cases with consistent capture of the ventricular myocardium without atrial capture or sensing. The QRS duration was less with AVS compared with RVA pacing (89 ± 4 ms vs. 100 ± 11 ms [P < 0.0001, GEE P = 0.03]). There was decreased delay between color Doppler M‐mode visualized peak contraction of the septum and the mid left ventricular free wall with AVS compared with RVA pacing (89 ± 91 ms vs. 250 ± 11 ms [P < 0.0001, GEE P = 0.006]). Activation time between the mid septum and mid free wall was shorter with AVS versus RVA pacing (20.4 ± 7.7 vs. 30.8 ± 11.6 [P = 0.01, GEE P = 0.07]). The interval between QRS onset to earliest free wall activation was shorter with AVS vs. RVA pacing (19.2 ± 6.4 ms vs. 31.1 ± 11.7 ms [P = 0.005, GEE P = 0.02]). Conclusion: The AVS was successfully paced in three dogs resulting in synchronous ventricular activation without crossing the TV.     

Differences in immune recognition of cytochrome P4502D6 by liver kidney microsomal (LKM) antibody in autoimmune hepatitis and chronic hepatitis C virus infection

LKM-1 antibody, which characterizes a subtype of autoimmune hepatitis (AIH), is also found in some patients with chronic hepatitis C virus (HCV) infection. It has been suggested that HCV initiates autoimmunity through molecular mimicry, because there is partial identity between HCV and cytochrome P4502D6 (CYP2D6), the putative target of LKM-1. Whether CYP2D6 is the target of LKM-1 in HCV-related liver disease, however, is controversial. To clarify this issue, we have studied by phage plaque assay and Western blot the reactivity to recombinant CYP2D6, isolated from a human liver cDNA library, in 55 patients with LKM-1, 18 (14 females, median age 12 years) anti-HCV-negative, with classical AIH, and 37 (27 females, median age 52 years) anti-HCV-positive. Reactivity to CYP2D6 was found in 72% of the anti-HCV-negative, but only in 27% of the anti-HCV-positive patients (P < 0.001), although immunofluorescence LKM-1 titres were similar in the two groups. In addition, to investigate whether the antibody responsible for the LKM-1 fluorescent pattern also reacts with CYP2D6, we have determined the specificity of LKM-1 antibodies present in the supernatant of lymphoblastoid B cell lines obtained from two patients with LKM-1-positive AIH. An oligo/monoclonal antibody thus generated gave both the typical fluorescent pattern and reacted with CYP2D6. Our results show that whilst antibodies producing the characteristic LKM-1 fluorescent pattern can react with CYP2D6, not all LKM-1-positive sera do so, particularly if obtained from patients with chronic HCV infection. This suggests that LKM-1 in HCV infection recognizes epitopes or antigens different from those targeted in AIH.     

PROGNOSTIC VALUE OF ANGIOGENESIS IN OPERABLE NON-SMALL CELL LUNG CANCER

Tumour angiogenesis is an important factor for tumour growth and metastasis. Although some recent reports suggest that microvessel counts in non-small cell lung cancer are related to a poor disease outcome, the results were not conclusive and were not compared with other molecular prognostic markers. In the present study, the vascular grade was assessed in 107 (T1,2–N0,1) operable non-small cell lung carcinomas, using the JC70 monoclonal antibody to CD31. Three vascular grades were defined with appraisal by eye and by Chalkley counting: high (Chalkley score 7–12), medium (5–6), and low (2–4). There was a significant correlation between eye appraisal and Chalkley counting ( P <0·0001). Vascular grade was not related to histology, grade, proliferation index (Ki67), or EGFR or p53 expression. Tumours from younger patients had a higher grade of angiogenesis ( P =0·05). Apart from the vascular grade, none of the other factors examined was statistically related to lymph node metastasis ( P <0·0001). A univariate analysis of survival showed that vascular grade was the most significant prognostic factor ( P =0·0004), followed by N-stage ( P =0·001). In a multivariate analysis, N-stage and vascular grade were not found to be independent prognostic factors, since they were strongly related to each other. Excluding N-stage, vascular grade was the only independent prognostic factor ( P =0·007). Kaplan–Meier survival curves showed a statistically significant worse prognosis for patients with high vascular grade, but no difference was observed between low and medium vascular grade. These data suggest that angiogenesis in operable non-small cell lung cancer is a major prognostic factor for survival and, among the parameters tested, is the only factor related to cancer cell migration to lymph nodes. The integration of vascular grading in clinical trials on adjuvant chemotherapy and/or radiotherapy could substantially contribute in defining groups of operable patients who might benefit from cytotoxic treatment.     

TINEA VERSICOLOR: HISTOLOGIC AND ULTRASTRUCTURAL INVESTIGATION OF PIGMENTARY CHANGES

A comparative histopathologic study is made between the hypopigmented and hyperpigmented skin lesions of pityriasis versicolor and normal skin areas utilizing histochemical stains and electron microscopy. There were no differences found between the population of Dopa-positive melanocytes within the hypopigmented and hyperpigmented lesions and the normal skin areas. The total epidermal pigmentation was diminished in hypopigmented lesions. The keratin layer was found to be significantly thicker in hyperpigmented lesions and contained more organisms. In hypopigmented lesions, melanocytes contained fewer and smaller melanosomes and exhibited signs of degenerative cellular changes.     

Importance of mechanical damage to urinary red blood cells by the glomerular basement membrane

The reasons for morphological changes of urinary red blood cells (RBC) in patients with glomerulonephritis are still controversial. In order to evaluate the importance of mechanical damage by the glomerular basement membrane (GBM), we examined urinary RBC taken from the patients with two different diseases which have characteristic GBM changes. Urinary RBC taken from 20 patients with Alport syndrome and nine with thin GBM disease were examined using a scanning electron microscope. Nineteen out of the 20 patients (95.0%) with Alport syndrome showed ‘glomerular type’, while five of the nine patients (55.6%) with thin GBM disease showed ‘glomerular type’. These results suggest that more complicated GBM abnormalities cause more severe RBC distortion. Therefore, we conclude that mechanical damage by the GBM may be the major factor in dysmorphism of urinary RBC.     

Vasoactive intestinal peptide immunoreactive nerve fibres are deficient in intestinal and nasal mucosa affected by cystic fibrosis

Cystic fibrosis (CF) is the most common lethal or debilitating inherited disease amongst Caucasians, with estimates of its frequency of occurrence in this population ranging from 1: 2000 to 1: 15 000 live births. It is characterized by disorders of exocrine secretions, primarily of the skin, respiratory tract and digestive system. The secretory processes of these tissues are influenced by autonomic nerve fibres, many of which contain regulatory peptides. The innervation of the intestinal and respiratory mucosa of CF patients has been investigated in order to determine if there is any derangement of the peptide-containing nerve fibres that supply these tissues. The present work demonstrates that, in CF, there is a deficiency of vasoactive intestinal peptide immunoreactivity (VIP-IR) in nerve fibres in the nasal and intestinal mucosa. There is not a generalized loss of fibres that are immunoreactive for this peptide, however, since VIP-IR fibres innervating the intestinal muscle are largely unaffected. Moreover, other types of nerve fibres innervating the nasal mucosa and the mucosa of the intestinal villi appear to be unaffected in CF patients. Physiological evidence indicates that vasoactive intestinal peptide is contained in secretomotor neurons and is a powerful stimulant of secretion; loss of function restricted to these neurons is consistent with the clinical manifestations of CF.     

Immunohistochemical evidence of insulin-like growth factor II in human small hepatocellular carcinoma with hepatitis C virus infection: Relationship to fatty change in carcinoma cells

It has recently been reported that insulin-like growth factor II (IGF-II) may play a role in the pathogenesis of hepatocellular carcinoma (HCC). We studied the relationship between the expression of IGF-II and fatty change in human small HCC using immunohistochemical staining techniques. Liver biopsy specimens were obtained from 35 patients with HCC (consisting of 15 patients with fatty change and 20 patients without fatty change). All patients had serum markers for the hepatitis C virus (HCV) and histological findings obtained from non-tumourous lesions showed liver cirrhosis or chronic active hepatitis. Immunohistochemical staining was performed using a monoclonal antibody against rat IGF-II. A positive immunoreaction was found in 69% (24/35) of HCC. Insulin-like growth factor II was immunodetected in 80% (12/15) of HCC with fatty change but only in 60% (12/20) of those without fatty change. In most cases, IGF-II was not found in hepatocytes from non-tumourous lesions. We believe this to be the first time that IGF-II has been detected immunohistochemically in small HCC derived from HCV infection. This growth factor was more frequently immunodetected in HCC with fatty change than without. As insulin is an essential factor for the metabolism of fatty acids, IGF-II may play an important role in both fatty degeneration and in the proliferation of HCC cells. Furthermore, immunohistochemical IGF-II staining may contribute to the diagnosis of HCC, particularly in early stages accompanied by fatty change.