Biomedical subjects

F Forouhar

Publications and source records attributed to F Forouhar.

At least 19 recordsLinked to original sources

PubMed2001

The crystal structure of the influenza matrix protein M1 at neutral pH: M1-M1 protein interfaces can rotate in the oligomeric structures of M1.

The influenza matrix protein (M1) forms a protein layer under the viral membrane and is essential for viral stability and integrity. M1 mediates the encapsidation of the viral RNPs into the viral membrane by its membrane and RNP-binding activities. In order to understand the roles of M1-M1 protein interactions in forming the M1 layer, X-ray crystallographic studies of a M1 fragment (1-162) were carried out at neutral pH and compared with an acidic pH structure. At neutral pH the asymmetric unit was a stacked dimer of M1. A long molecular ribbon of neutral stacked dimers was formed by translation as dictated by the P1 space group. The elongated ribbon had a positively charged stripe on one side of the ribbon. A similar M1-M1 stacking interface was also found in the acidic asymmetric unit. However, within the acidic stacked dimer the molecules were not straight, but rotated in relation to each other by slightly changing the M1-M1 stacking interface. The acidic structure possessed an additional M1-M1 twofold interface. Protein docking confirmed that the M1-M1 stacking and M1-M1 twofold interfaces could be used to form a double ribbon of M1 molecules. By iterative repetition of the rotated relationship among the M1 molecules, a helix of M1 was generated. These studies suggest that M1 has the ability to form straight or bent elongated ribbons and helices. These oligomers are consistent with previous electron microscopic studies of M1, which demonstrated that isolated M1 formed elongated and flexible ribbons when isolated from what appeared to be a helical shell of M1 in the influenza virus.

Crystallography, X-Ray↗

PubMed2000

Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome.

Papillary thyroid carcinoma usually is sporadic, but may occur in a familial form. The complete clinical and pathological phenotype of familial papillary thyroid carcinoma (fPTC) has not been determined, and the susceptibility gene(s) is unknown. We investigated the clinical and pathological characteristics of an unusually large three-generation fPTC kindred to characterize more fully the clinical phenotype. We performed linkage analysis to determine the chromosomal location of a fPTC susceptibility gene. In addition to the known association of fPTC with nodular thyroid disease, we observed the otherwise rare entity of papillary renal neoplasia (PRN) in two kindred members, one affected with PTC and the other an obligate carrier. The multifocality of PRN in one subject adds weight to the likelihood of a true genetic predisposition to PRN. Both genetic linkage and sequence analysis excluded MET, the protooncogene of isolated familial PRN, as the cause of the fPTC/PRN phenotype. A genome-wide screening and an investigation of specific candidate genes demonstrated that the fPTC/PRN phenotype was linked to 1q21. A maximum three-point log of likelihood ratio score of 3.58 was observed for markers D1S2343 and D1S2345 and for markers D1S2343 and D1S305. Critical recombination events limited the region of linkage to approximately 20 cM. A distinct inherited tumor syndrome has been characterized as the familial association of papillary thyroid cancer, nodular thyroid disease, and papillary renal neoplasia. The predisposing gene in a large kindred with this syndrome has been mapped to 1q21.

Adult↗

PubMed1999

Familial papillary thyroid carcinoma is genetically distinct from familial adenomatous polyposis coli.

Familial papillary thyroid carcinoma (fPTC) is an inherited tumor syndrome characterized by isolated papillary thyroid carcinoma (PTC) in affected subjects. Its etiology is unknown. Large multigeneration families with PTC are very rare, and therefore, modern genetic linkage studies have not been applied extensively to this disorder. Familial adenomatous polyposis coli (FAP) is an inherited tumor syndrome enriched in PTC. FAP is caused by germline mutations of the adenomatous polyposis coli (APC) gene that is located in the 5q21 region. It is not known if fPTC is a phenotypic variant of FAP, or if it is a genetically distinct disorder. We report a large 3-generation fPTC kindred and use linkage analysis to test the hypothesis that fPTC and FAP are genetically distinct. In this kindred there are 25 living informative subjects; 5 have PTC, and 1 is an obligate carrier. Inheritance is autosomal dominant with incomplete penetrance. There is vertical transmission, multifocal disease, an average age of onset of 36 years, and 1 subject has colon cancer. The probability is approximately 1 in 2 billion against the clustering of 5 sporadic PTC cases in this kindred. To test for linkage to the APC gene we used 2 highly polymorphic markers, D5S656 and D5S421, which are located within a maximum distance of 1.7 megabase (Mb) of the APC gene and within an estimated genetic region of less than 1 centimorgan (cM) from each other. After polymerase chain reaction (PCR) amplification 18 family members were genotyped. Construction and inspection of haplotypes showed that the affected subjects do not share the same allelic composition. Using a penetrance ratio of 75%, linkage was excluded at 2 cM and 3 cM on both sides of D5S656 and D5S421, respectively. The combined haplotype of these 2 markers provided an exclusion region of 4 cM. We conclude that fPTC is genetically distinct from FAP.

Adenomatous Polyposis Coli↗

PubMed1995

Bronchogenic carcinoma presenting as a pseudopregnancy.

A young woman with an occult bronchogenic carcinoma presented with secondary amenorrhea and an elevated beta subunit of human chorionic gonadotropin that was mistakenly attributed to pregnancy. Physicians should be aware that this carcinoma may present solely with an elevated beta human chorionic gonadotropin value, and the potential exists for confusion with a pregnancy state in women of childbearing age.

Adult↗

PubMed1993

Cyclocreatine inhibits neutrophil accumulation in the myocardium of a canine model of coronary artery occlusion and reperfusion.

This study tests the hypothesis that the administration of cyclocreatine before ischemia inhibits the release of neutrophil chemotactic factors from myocardial tissues and subsequently reduces neutrophil accumulation into ischemic areas. Adult mongrel dogs underwent left anterior descending coronary artery occlusion for 1 h, followed by a 2-h reperfusion. Cyclocreatine-treated dogs (n = 6) were injected intravenously with cyclocreatine solution (600 mg/kg) 1 h before the experiment and during ligation of the coronary artery. Control dogs (n = 6) were injected with saline. Neutrophil chemotactic activity was measured in plasma samples using standard modified Boyden chambers. In controls dogs, significantly elevated levels of chemotactic activity were recovered in blood samples taken during reperfusion (i.e., 2.8-3.5-fold; P < .0001) as compared to base-line activity recovered before occlusion. Preliminary biochemical characterizations revealed that the recovered chemotactic factors (via checkerboard analysis) are proteins of high molecular weight (greater than 100 kDa). Biopsy samples of control hearts showed an accumulation of a large number of neutrophils in the ischemic portions. Cyclocreatine-treated dogs, on the contrary, showed low levels of chemotactic activity during reperfusion, which correlated with the absence of neutrophils in ischemic areas. These results indicate the capability of cyclocreatine to inhibit the release of neutrophil chemotactic factors from ischemic myocardium, which subsequently prevented neutrophil accumulation.

Amino Acid Sequence↗

PubMed1990

Identification of human immunodeficiency virus in the heart of a patient with acquired immunodeficiency syndrome.

A 35-year-old homosexual white male diagnosed as having human immunodeficiency virus (HIV) infection presented with recurrent pericardial effusion, and HIV was isolated from the pericardial fluid. Autopsy revealed an extensive gross infiltrative lesion in the left ventricle of the heart. Microscopic examination of the myocardium demonstrated multifocal atypical lymphoid cell infiltrations associated with scattered foci of myocardial necrosis. The atypical lymphoid cells were immunoreactive to UCHL-1, a T cell antigen antibody. HIV was immunocytochemically identified in the cardiac lymphocytic infiltrate with anti-p24 monoclonal antibodies. This finding was supported by ultrastructural examination and in situ hybridization study.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Cyclocreatine inhibits the production of neutrophil chemotactic factors from isolated hearts.

This study was designed to determine the effect of cyclocreatine on the release of neutrophil chemotactic factors (NCF) from isolated rabbit hearts. We tested the hypothesis that if ischemia is important for the formation of NCF from the myocardium, then blocking (or delaying) ischemic changes with cyclocreatine should inhibit the release of NCF. Two models were used, including (1) perfusion of rabbit hearts (Langendorff apparatus) with oxygenated (95% oxygen) Krebs-Henseleit buffer (K-H buffer) containing 5% cyclocreatine for 120 minutes, and (2) incubating hearts with phosphate-buffered saline (PBS) containing 5% cyclocreatine for 120 minutes. For both models, rabbits were injected intravenously with 10 ml of 5% cyclocreatine solution 30 minutes before the animals were killed and the hearts removed. Control rabbits were injected with 5% creatine solution or saline for 30 minutes before perfusing hearts with K-H buffer or incubating with PBS. Chemotactic activity was assayed in the perfusates and supernatants using modified Boyden chambers and rabbit peritoneal neutrophils as indicator cells. The chemoattractant f-Met-Leu-Phe (f-MLP) was the positive control for a 100% response rate. Isolated hearts perfused with cyclocreatine showed significantly lower chemotactic activity (ie, 1.24 +/- 1% f-MLP; P less than 0.0001) compared to hearts perfused with K-H buffer (129 +/- 18%) or creatine (227 +/- 42%) (mean +/- standard error). Similar results were obtained using incubated hearts. Next the effect of cyclocreatine on neutrophils in the Boyden chamber was determined and it was found that it did not alter neutrophil migration, which excludes a direct inhibitory effect on the cells. Furthermore supernatant from cyclocreatine-treated hearts did not inhibit neutrophil chemotaxis to C5a, indicating absence of a chemotaxis inhibitor in this preparation. Results of these studies suggest that the observed low activity recovered in perfusate and supernatant of cyclocreatine-treated hearts is a result of reduction in the synthesis and/or release of the factors from myocardial tissues. Similar to previously established data, cyclocreatine treatment significantly preserved myocardial nucleotide levels (ie, adenosine triphosphate and creatine phosphate), which supports our hypothesis that the formation of NCF is ischemia dependent and that maintaining elevated levels of myocardial energy nucleotides reduced chemotactic factor release.

Adenosine Triphosphate↗

PubMed1989

Cardiac derived neutrophil chemotactic factors; preliminary biochemical characterization.

The purpose of this study is to investigate whether isolated hearts perfused with cardioplegic solution release inflammatory mediators such as neutrophil chemotactic factors (NCF). Three conditions were tested, including: (1) perfusion of rabbit hearts with crystalloid cardioplegic solution (4 degree C) saturated with air (95% oxygen) and containing dextrose (i.e. complete system), (2) perfusion of rabbit hearts with non-oxygenated cardioplegic solution, containing dextrose (i.e. minus oxygen system), and (3) perfusion of hearts with cold cardioplegic solution saturated with air in the absence of dextrose (i.e. minus dextrose system). At various time intervals (5 min, 1, 2, 3 and 4 h) samples of circulated perfusate were removed and assayed for the presence of NCF using modified Boyden chambers. Rabbit peritoneal neutrophils were the indicator cells. The standard chemoattractant, f-Met-Leu-Phe (f-MLP) was the positive control. High levels of neutrophil chemotactic activity were detected in perfusate of all above described hearts perfused for 4 h (i.e. 194 +/- 22% of f-MLP control--complete system, 126 +/- 13%--minus oxygen and 136 +/- 10%-minus dextrose). Histological evaluation of these hearts showed evidence of global ischemia. We also detected significant levels of NCF in effluent of hearts perfused for 5 min, 1, 2 and 3 h. Similar to perfused hearts, isolated rabbit hearts incubated for 4 h with non-oxygenated cardioplegic solution (in presence and absence of dextrose) released high levels of NCF (132 +/- 18%-intact heart; and 100 +/- 6% myocardial segments). Standard checkerboard analysis revealed that the observed activity released from these hearts is chemotactic.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Tc-99m diphosphonate uptake in malignant fibrous histiocytoma: a possible iron-related effect.

A man with malignant fibrous histiocytoma of the thigh had avid uptake of Tc-99m MDP in the lesion. Review of tissue sections showed considerable accumulation of iron in the tumor. Iron is known to be a potential nidus for deposition of the Tc-99m diphosphonates. A review was made of tissue sections from two other reported cases of malignant fibrous histiocytoma which also had significant accumulation of Tc-99m diphosphonates. Both revealed iron within the tumor. The origin of the iron is unknown (perhaps from necrosis and hemorrhage, from trauma, or from innate phagocytic activity of the histiocytes). However, this observation may serve as a stimulus to studies attempting to discern the underlying mechanisms of extraosseous deposition of the Tc-99m diphosphonates.

Adult↗

PubMed1987

Congenital melanoma with multiple prenatal metastases.

A 1.95-kg fetus delivered at 33 weeks' gestational age survived less than 1 hour. Physical examination and autopsy disclosed an enormous, protuberant primary malignant melanoma of the skin, enveloping most of the back. A rim of surrounding hyperpigmented skin proved to be a giant congenital melanocytic nevus (GCMN), from which the cutaneous melanoma had arisen. Autopsy demonstrated metastatic melanoma in the lungs, liver, spinal cord, leptomeninges, and placenta. Radiography and dissection confirmed that the melanoma had minimal connection to spinal or neural structures. The mother was clinically free of tumor 8 months after she was delivered of the infant. Pathologic, radiographic, histologic, immunohistochemical, and ultrastructural investigations of this unique case are presented.

Female↗

PubMed1987

Management of endoscopically removed malignant colon polyps.

The medical records of 87 patients with 89 malignant colorectal polyps removed endoscopically between 1971 and 1983 were reviewed retrospectively. Fifty-five polyps contained carcinoma-in-situ. Four polyps had "pseudo-invasion" by displaced mucosal glands. Thirty polyps contained invasive carcinoma. No patients with carcinoma-in-situ or "pseudo-invasion" had either local residual disease or metastatic disease at the time of colectomy or which was detected during subsequent follow-up. Four patients (14%) with invasive cancer would have been inadequately treated by polypectomy alone, since one had residual disease at the polypectomy site, one had nodal metastases, one had liver metastases at the time of colectomy, and one subsequently developed liver metastases. Three histologic criteria correctly predicted all four cases where residual or recurrent disease was present: involvement of the polypectomy resection margin, lymphatic invasion within the polyp, and poorly differentiated histology. Polyp size, histology (villous adenoma, adenomatous polyp, or villo-adenomatous polyp), or anatomic location did not identify those patients who warranted further therapy. We conclude that polypectomy alone is adequate treatment for polyps containing carcinoma-in-situ. Polypectomy alone is also adequate treatment for most polyps containing invasive carcinoma. However, patients with lymphatic involvement within the polyp, poorly differentiated cancer, or resection margin involvement should probably undergo colectomy.

Adult↗

PubMed1987

Inflammatory mediators in alkali-burned corneas: preliminary characterization.

Leukocyte chemotactic factors (LCF) are important inflammatory mediators which activate and recruit leukocytes from the circulation into sites of tissue damage. These factors were recently detected in the tear fluid of inflamed eyes induced by alkali burn. It remains unclear, however, whether the detected LCF are released from injured corneal tissues or leaked from the circulation. Using a corneal cup model developed in our laboratory, we began examining the capability of corneal tissues to produce LCF in response to alkali injury. We also evaluated the influence of citric acid on the production of LCF from corneas preinjured by the alkali sodium hydroxide (NaOH). For these studies, the epithelial surfaces of corneas isolated from bovine and human eyes were exposed to 1N NaOH for 35 seconds at room temperature. The NaOH was then removed and the epithelial surfaces washed once with buffer and incubated with culture medium for 1, 2, 4, and 6 hours at 37 degrees C/5% CO2 atmosphere. Our results showed that (1) NaOH2 induced corneal epithelial cell injury ranging from cell discoloration and moderate damage of the upper half of the epithelium (1-4 hrs) to total destruction of the epithelium (6 hrs); (2) NaOH-injured corneas (2 hr incubation post injury) produced significant levels of chemotactic activity (via checkerboard analysis) specific for neutrophils (115% maximum chemotactic response [MCR]) and mononuclear cells (94% MCR); (3) preliminary characterization of these factors revealed that they are protease and heat sensitive, extractable by organic solvents, and possess molecular weight values greater than 100,000 daltons; and (4) incubation of NaOH-pretreated corneas with 0.01% citric acid for 2 hours markedly inhibited the production of LCF for both neutrophils (98% inhibition) and mononuclear cells (91% inhibition). Results of these studies indicate that alkali-burned bovine and human corneas generate leukocyte chemoattractants which differ in their biochemical characteristics from previously known low molecular weight chemotactic factors such as C5a, interleukin-1, or leukotriene B4.

Animals↗

PubMed1985

Monoclonal antibody DF3 correlates with tumor differentiation and hormone receptor status in breast cancer patients.

The murine monoclonal antibody (MAb) designated DF3, reacts with a 300-kd human mammary epithelial antigen which is expressed on apical borders of secretory mammary epithelial cells and in the cytosol of less differentiated malignant cells. Human mammary tumors have been evaluated for the level of DF3 antigen as a correlate to clinicopathologic parameters related to degree of tumor differentiation: nuclear grade (NG), histologic grade (HG), and estrogen receptor status (ER). More DF3 antigen was present in breast carcinomas with NG 1 and 2 as compared to tumors with NG 3 (p = .002). Similarly DF3 antigen presence was greater in HG 1 and 2 tumors than in HG 3 (p less than .001). The results also demonstrate that quantitative differences in the presence of the DF3 differentiation antigen correlate with estrogen receptor status. Twenty-two of 23 ER positive tumors were also DF3 positive. Only 6 of 23 ER negative tumors were reactive to MAb DF3 (p less than .001). There was, however, no correlation between DF3 reactivity and absolute levels of estrogen or progesterone receptor. These findings confirm our hypothesis that MAb DF3 reacts to a differentiation antigen present in some human breast carcinomas. The DF3 antigen phenotype can serve as an independent phenotypic marker with correlations to standard indicators of degree of differentiation and estrogen receptor status of infiltrating ductal carcinomas of the breast, and should thus be evaluated as a prognostic indicator in breast cancer patients. The data also suggests that DF3 histochemistry may be a useful alternative in assessing estrogen receptor status of small breast cancers where there is an insufficient amount of tumor present for biochemical assay of hormone receptor levels.

Antibodies, Monoclonal↗

PubMed1985

In vitro migration of tumor cells from human neoplasms: inhibition by lymphokines.

We have previously described a noncytotoxic lymphokine, TMIF, with the capacity of inhibiting the in vitro migration of a variety of serially passaged experimental animal tumors, but not non-neoplastic cells. In the present study, we describe conditions for the assay of human tumor cell movement utilizing agarose microdroplets. Using this procedure, we were able to demonstrate that TMIF is as effective in inhibiting the in vitro migration of suspensions of tumor cells obtained from spontaneous human neoplasms, as it is in inhibiting model tumor systems. This finding demonstrates that responsiveness to TMIF is not merely a property conferred on tumor cells by prior serial passage. Also, by demonstrating that tumors of human origin are responsive, the present study raises the possibility that studies of TMIF in neoplastic disease may provide information of prognostic value. Also, they provide the hope that if TMIF proves therapeutically effective in animal models, those results may be translated to human disease.

Cell Migration Inhibition↗

PubMed1985

Congenital, spontaneously regressing histiocytosis: case report and review of the literature.

A patient had numerous skin lesions at birth and they regressed over the next few weeks. Results of the peripheral blood smear and bone marrow examinations were normal. The diagnosis of self-healing histiocytosis was substantiated by the clinical course and characteristic histology. This was subsequently confirmed by the electron microscopic finding of Langerhans' granules within the histiocytic cells, which were positive for S100 by immunoperoxidase.

Female↗

PubMed1985

An in vitro model of leukocyte mediated injury to the corneal epithelium.

To enhance efforts directed at unraveling the role and mechanisms of leukocytes in mediating injury to corneal epithelium, an isolated bovine corneal cup was developed and evaluated. Bovine peripheral leukocytes and lysates were added to the corneal epithelial surface of isolated cornea for various periods after which the degree of morphologic changes and cell damage were assessed using light and electron microscopy. Results of these studies indicate that leukocyte/epithelial cell interactions are characterized by five successive stages: (1) leukocyte adhesion to superficial layer of the epithelium, (2) leukocyte penetration beneath the superficial epithelium, (3) epithelial cell injury, (4) leukocyte phagocytosis of killed epithelial cells and (5) ulceration and total destruction of the full thickness of the epithelial layer. The above sequence appears to be both time and dose dependent; that is epithelial cells exposed to leukocytes for short periods (5-60 minutes) or to low dose levels (10(5) - 10(7) cells/ml) shows leukocyte adhesion and penetration beneath the superficial layer of the epithelium, (stage 1 and 2), while longer exposures (2-3 hours) or higher numbers of leukocytes (10(7) - 10(8) cells/ml), leads to deeper penetration of epithelium by leukocytes and epithelial injury (Stages 3,4,and 5). We also observed that direct contact of intact leukocytes with epithelial cells is apparently necessary to induce this type of injury. These findings demonstrate the ability of leukocytes to destroy corneal epithelial cells and the value of this new ocular model for studies of the basic immunology of ocular inflammation.

Animals↗

PubMed1985

Reversal of gamma-radiation-induced leukemogenesis in mice by immunomodulation with thiabendazole and dinitrofluorobenzene.

The effect of thiabendazole (TBZ) and dinitrofluorobenzene (DNFB) on radiation-induced leukemogenesis was investigated in the C57BL/6 mouse model. Administration of TBZ-DNFB during, post, or during and post irradiation successfully blocked leukemogenesis, as indicated by the absence of leukemia blast cells in thymus and peripheral blood, as well as prevented thymic lymphoma. TBZ-DNFB treatment prevented the development of leukemia when studies were terminated both after 7 months of last irradiation (disease fully developed) and after 5 months of last irradiation (disease in the process of development). This TBZ-DNFB treatment also resulted in a significant increase in survival.

Animals↗

PubMed1985

Short term survival following perfusion with fluosol-DA for cardiopulmonary bypass.

Seven dogs were perfused on cardiopulmonary bypass for one hour using a perfusate which included one liter of Fluosol in order to investigate tissue oxygenation during perfusion as well as possible biochemical and histopathologic effects of Fluosol on various organs. Tissue oxygenation during cardiopulmonary bypass was evaluated by measuring arterial and venous oxygen tensions as well as oxygen content and arterial pH. Biochemical studies were measured pre and post bypass and were followed up to 48 hours following discontinuation of cardiopulmonary bypass. The animals were observed clinically for evidence of abnormal behavior during 30 days of follow-up and were then sacrificed. Biopsies from the heart, lung, liver, spleen, kidney and brain were examined by light and electron microscopy. Excellent tissue oxygenation and normal acid base status was seen uniformly during cardiopulmonary bypass. Clinical status and biochemical parameters remained normal during followup. Histopathologic examination revealed only a marked increase in phagocytic histiocytes in the reticuloendothelial system of liver and spleen with sinusoidal compression but no functional impairment.

Animals↗