Rivka Gal

Anti-IL-10 Therapeutic Strategy Using the Immunomodulator AS101 in Protecting Mice from Sepsis-Induced Death: Dependence on Timing of Immunomodulating Intervention

The role of IL-10 in experimental sepsis is controversial. The nontoxic immunomodulator, ammonium trichloro(dioxoethylene-o,o′)tellurate (AS101) has been previously shown to inhibit IL-10 expression at the transcriptional level. In this study, we show that in mice subjected to cecal ligation and puncture (CLP), treatment with AS101 12 h after, but not before, CLP significantly increased survival of septic mice. This was associated with a significant decrease in serum IL-10 and in IL-10 secretion by peritoneal macrophages 24–48 h after CLP. At that time, the ability of these cells to secrete TNF-α and IL-1β was restored in AS101-treated mice. The increased survival of AS101-treated mice was due to the inhibition of IL-10, since cotreatment with murine rIL-10 abolished the protective activity of AS101. AS101 increased class II Ag expression on peritoneal macrophages, severely depressed in control mice, while it did not affect the expression of class I Ags. This was accompanied by a significant elevation in the level of IFN-γ secreted by splenocytes. Moreover, AS101 ameliorated bacterial clearance in the peritoneum and blood and decreased severe multiple organ damage, as indicated by clinical chemistry. Furthermore, myeloperoxidase levels in the liver and lung of AS101-treated mice, an indirect means of determining the recruitment of neutrophils, were significantly decreased. We suggest that nontoxic agents such as AS101, with the capacity to inhibit IL-10 and stimulate macrophage functions, may have clinical potential in the treatment of sepsis, provided they are administered during the phase of sepsis characterized by immune suppression.

The protective role of the immunomodulator AS101 against chemotherapy‐induced alopecia studies on human and animal models

The immunomodulator AS101 has been demonstrated to exhibit radioprotective and chemoprotective effects in mice. Following phase‐I studies, preliminary results from phase‐II clinical trials on non‐small‐cell‐lung‐cancer patients showed a reduction in the severity of alopecia in patients treated with AS101 in combination with chemotherapy. To further substantiate these findings, the present study was extended to include 58 patients treated either with the optimal dose of 3 mg/m2 AS101 combined with carboplatin and VP‐16, or with chemotherapy alone. As compared with patients treated with chemotherapy alone, there was a significant decrease in the level of alopecia in patients receiving the combined therapy. The newly developed rat model was used to elucidate the protective mechanism involved in this effect. We show that significant prevention of chemotherapy‐induced alopecia is obtained in rats treated with Ara‐C combined with AS101, administered i.p. or s.c. or applied topically to the dorsal skin. We show that this protection by AS101 is mediated by macrophage‐derived factors induced by AS101. Protection by AS101 can be ascribed, at least in part, to IL‐1, since treatment of rats with IL‐1RA largely abrogated the protective effect of AS101. Moreover, we demonstrate that in humans there is an inverse correlation between the grade of alopecia and the increase in IL‐1α. In addition, protection by AS101 could be related to PGE2 secretion, since injection of indomethacin before treatment with AS101 and Ara‐C partly abrogated the protective effect of AS101. To assess the ability of AS101 to protect against chemotherapy‐induced alopecia, phase‐II clinical trials have been initiated with cancer patients suffering from various malignancies.

Abdominal and digestive system associations of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a hereditary epidosic febrile syndrome that is expressed by acute spells of fever, painful manifestations in the abdomen, chest and joints, and slow development of nephropathic amyloidosis. Despite the recent cloning of the FMF gene (MEFV) and the identification of about 40 disease-related mutations, the diagnosis is still clinically dependent, and the pathogenesis and most of the clinical heterogeneity remain to be explained.Because episodic abdominal pain affects 95% of FMF patients, most of them are seen by gastroenterologists and undergo complete or partial abdominal imaging before the diagnosis is made. Focusing on recent advances in FMF, this article reviews both common and infrequent manifestations that a gastroenterologist may encounter during workups of FMF patients. These include episodic abdominal pain, paralytic or mechanical ileus, constipation, diarrhea, ascites, malabsorption, bowel infarction, and bleeding, arising directly from FMF or secondary to FMF common associations such as amyloidosis, vasculitides, inflammatory bowel disease, irritable bowel syndrome, or colchicine side effects. This article will help the gastroenterologist to cope with most clinical situations related to the abdominal and alimentary tract in patients with FMF.

Patterns of Protein Kinase C Isoenzyme Expression in Transitional Cell Carcinoma of Bladder Relation to Degree of Malignancy

We determined the pattern of protein kinase C (PKC) isoform expression in human cell lines by Western blotting and immunofluorescent staining techniques. In addition, we examined PKC isoform expression in tissue samples of transitional cell carcinoma (TCC) of the bladder. PKC delta, PKC beta II, and PKC eta were found primarily in the RT4 cell line (low-grade tumor), and PKC zeta was expressed most strongly in the SUP cell line (invasive tumor). In tissue samples of urinary bladder cancer, PKC isoenzymes were expressed differentially as a function of tumor stage and grade; expression of PKC beta II and PKC delta was high in normal tissue and in low-grade tumors and decreased with increasing stage and grade of TCC. The opposite pattern was seen with PKC zeta. The differences in expression of specific isoenzymes as related to levels of malignancy of the cell lines and tissue samples suggest that the PKC family has an important role in normal and neoplastic urothelium.

99mTc-MIBI scintigraphy of parathyroid adenomas and its relation to tumour size and oxyphil cell abundance

The aim of this study was to assess the correlation between technetium-99m methoxyisobutylisonitrile (MIBI) uptake by parathyroid adenomas, oxyphil cell content and volume of the lesions. Thirty-one patients with parathyroid adenomas were evaluated prospectively. Preoperative double-phase 99mTc-MIBI scintigraphy was performed in all patients and tracer uptake by parathyroid lesions was assessed semi-quantitatively employing region of interest ratios to normal adjacent neck areas. Surgical specimens underwent histological evaluation and oxyphil cell content was determined. The intensity of tracer uptake was compared with oxyphil cell content, volume of the lesions and serum levels of calcium and parathormone. 99mTc-MIBI tracer uptake was correlated with oxyphil cell content, volume of parathyroid lesions and the functional status of the parathyroid adenomas. Tracer accumulation in oxyphil cells might partially explain the preferential 99mTc-MIBI retention in parathyroid lesions.

Salivary duct carcinoma in major and minor salivary glands. A clinicopathological analysis of four cases.

Salivary duct carcinomas are an uncommon but distinct group of highly malignant salivary gland tumours. We report the clinical course, pathological findings and surgical treatment of this tumour in 4 patients. In one patient an intraductal tumour developed in a minor salivary gland, while in the other three patients, a major salivary gland was involved by an infiltrating salivary duct carcinoma. We point out the highly aggressive biological behaviour of the tumour when occurring in the major salivary glands, in contrast to the benign course of the intraductal carcinoma in the minor salivary gland.

Lymph node-revealing solution

PURPOSE: Detection of metastatic lymph nodes in colon cancer is essential for determining stage and, thus, therapeutic modalities. However, very small lymph nodes can easily be missed during routine examination. The aim of this study is to describe a new and easy technique for detecting tiny nodes in colonic specimens. METHODS: Thirty problematic cases, in which an unsatisfactory number of lymph nodes was found by the traditional method, were investigated. The entire mesocolonic fat was immersed for six hours in a lymph node-revealing solution (LNRS) composed of various traditional fixatives and fatty solvents. After six hours, the lymph nodes stood out as white, chalky nodules on the background of yellow fat. They were then excised, processed, and stained. RESULTS: Total number of lymph nodes found by the traditional method in the 30 cases was 88. After LNRS, 258 additional lymph nodes, measuring from 0.5 to 7 mm in largest diameter, were found. Of the 12 cases in which no lymph nodes were found by the traditional method, 8 became No and 4 became N1. Of the 14 cases first classified as No, 4 became N1; of the 4 classified at first as N1, 2 became N2 after LNRS. Upstaging from Dukes B to C occurred in eight cases. Quality of the sections and histochemical and immunohistochemical stains after LNRS was similar to that of formalin-fixed tissues. CONCLUSIONS: LNRS is an easy, rapid, and inexpensive technique for detecting very small lymph nodes. These may contain metastases, a fact that changes the stage of disease and influences the mode of therapy.

The residual ovary syndrome: a 20-year experience

OBJECTIVE To address the controversy of ovarian preservation during a hysterectomy for benign indications by using our experience with residual ovary syndrome (ROS). STUDY DESIGN Over a period of 20 years, 2561 hysterectomies (during which one or both ovaries were preserved) were performed at the Golda Medical Center, Israel. A retrospective, quasi, case-control analysis was undertaken. RESULTS The incidence of ROS was 2.85%. While chronic pelvic pain was the principle indication for subsequent reexploration in 52 patients (71.3%), an asymptomatic pelvic mass noted during routine follow-up examination accounted for 24.6% of operations for ROS. The majority (75.4%) of patients underwent surgery during the first 10 years, while the highest incidence occurred within the first 5 years (46.6%). Furthermore, histological examination revealed functional cysts, benign neoplasm and ovarian carcinoma in 50.7%, 42.6% and 12.3% of the cases, respectively (in nine patients more than one pathology was observed). CONCLUSIONS Since ROS was found to occur in 1/35 women who had undergone previous hysterectomies mainly due to physiologic ovarian function and benign cyst formation, but not malignancy, we believe that routine oophorectomy is justified in premenopausal women over 45 years of age. However, the final decision to perform elective oophorectomy at the time of hysterectomy for benign disease should be established on an individual basis, taking into consideration age, individual and family risk factors, the patients preference and ability to ensure long-term compliance to exogenous hormone replacement therapy.

Significance of angiogenesis and microvascular invasion in renal cell carcinoma

The aim of this study is to evaluate the relationship between tumor angiogenesis and microvascular invasion, and the subsequent development of metastatic disease in patients undergoing surgery for renal cell carcinoma (RCC). The study group consisted of 102 patients who underwent surgery for RCC between the years 1990 and 1997 in our institute with a mean follow up period of 81.3 months. Paraffin blocks were stained for Factor VIII-related antigen and CD34 which decorate endothelial cells in order to assess angiogenesis and microvascular invasion and their relevance for developing metastatic disease. When Factor VIII-related antigen staining was used we found that the microvessel count correlated with the development of metastatic disease with a mean count of 49.7 for patients with no evidence of disease and a mean count of 95.5 for patients who developed metastatic disease (p<0.05). We also found that microvascular invasion correlated with the development of metastatic disease. It was demonstrated in 55.5% of patients who developed metastatic disease versus 23.8% of patients with no evidence of disease with Factor VIII staining (p<0.05), and in 33.3% and 7.1%, respectively (p<0.05) with CD34 staining. This study suggest that demonstration of intense angiogenesis and microvascular invasion may be a predictor of a more aggressive tumor mandating closer follow up and consideration of adjuvant therapy.

Oropharyngeal Fatty Infiltration in Obstructive Sleep Apnea Patients: A Histologic Study

It has been suggested that due to fatty infiltration, obstructive sleep apnea (OSA) patients have a narrower pharyngeal airway than normal persons. To identify potential fatty infiltration of pharyngeal tissues that may contribute to OSA, a histologic study of the distal soft palate was performed. Histologic sections of 46 oropharyngeal specimens were evaluated. This included 25 overweight OSA patients (25/31), 6 normal-weight OSA patients (6/31), and a control group of 15 healthy (non-OSA) individuals. A semiquantitative analysis of the fatty tissue was performed. In all 31 OSA patients an excess of fatty infiltration was found in the histologic oropharyngeal specimens in comparison to the control group. No correlation was found between the pharyngeal fatty infiltration degree, the body mass index, and the apnea index. Irrespective of their body weight, in none of the patients without OSA was excessive fatty infiltration seen. It is suggested that excessive pharyngeal fatty infiltration plays a role in upper airway obstruction in OSA and that it can be associated with the development of apnea.