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Biomedical subjects

M Kahn

Publications and source records attributed to M Kahn.

At least 19 recordsLinked to original sources
PubMed1997

FBL blood test as a predictive marker of breast cancer in high risk women.

The potential use of the ferritin bearing lymphocytes (FBL) blood test which enumerates oncofetal FBL as a biomarker for early breast cancer was explored. Analysis of the FBL positive test results carried out on high risk women who underwent biopsy in 1983-84 was found to be a significant predictor for early breast cancer (relative risk (RR) = 2.9, 95% confidence interval (CI) 1.4-5.8). A group of 635 women from the above study diagnosed in 1983-84 as having no evidence of breast cancer was further traced 8 years later with the aid of the National Cancer Registry. We identified 35 malignancies, including 19 cases of breast cancer. The RR of breast cancer for the FBL positive group was 2.51; 95% CI = 1.04-6.07 while for the other malignancies it was 0.93, 95% CI = 0.30-2.84. All the breast cancer cases in the FBL positive group were of the infiltrative duct carcinoma category and 71% were in early stage. In contrast, in the FBL negative group, 60% of the cases were infiltrative ductal carcinoma and most of them were at stage III. Positive FBL is associated with early manifestation of breast cancer and may be considered as a tool for the screening of breast cancer in high risk women.

Adolescent↗
PubMed1997

Clinical experience with everted cervical vein as patch material after carotid endarterectomy.

PURPOSE: The aim of this study was to evaluate the clinical efficacy of everted cervical veins used as patches after carotid endarterectomy. METHODS: A prospective nonrandomized comparative analysis was performed on patients with either everted cervical veins or saphenous veins as patches after carotid endarterectomy. Two hundred ninety-six patients underwent 329 carotid endarterectomies during an 8 1/2-year period (1987 to 1995). Saphenous vein patches were used in 125 (38%) cases and everted cervical veins in 167 (51%). These two groups were compared clinically and by sonographic surveillance. The mean follow-up of patients in this study was 27 +/- 11 months. RESULTS: No significant differences were noted regarding postoperative morbid events between the everted cervical and saphenous vein patch groups. Even at 5 years the percentage of patients without stroke for both groups exceeded 95%. Duplex surveillance studies also showed comparable percentages of recurrent moderate (50% to 69%) and severe (70% to 99%) stenosis, 5.6% and 6.9%, respectively, for everted cervical vein and 5.4% and 6.5%, respectively, for saphenous vein. Cumulative recurrent stenosis-free rates at 5 and 6 years exceeded 82% for each of the patch study groups. CONCLUSIONS: Based on the results of this study everted cervical veins are useful adjuncts to carotid endarterectomy, when patch angioplasty is necessary or desirable. Their performance is comparable to that of saphenous veins. Cervical veins are usually available, even when the saphenous vein is absent or inadequate. In addition, good saphenous veins can be spared and lower extremity excisions avoided.

Aged↗
PubMed1996

Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2.

We used PCR to amplify proteinase activated receptor-2 (PAR-2) from human kidney cDNA. The open reading frame comprised 1191 bp and encoded a protein of 397 residues with 83% identity with mouse PAR-2. In KNRK cells (a line of kirsten murine sarcoma virus-transformed rat kidney epithelial cells) transfected with this cDNA, trypsin and activating peptide (AP) corresponding to the tethered ligand exposed by trypsin cleavage (SLIGKV-NH2) induced a prompt increase in cytosolic calcium ion concentration ([Ca2+]i). Human PAR-2 (hPAR-2) resided both on the plasma membrane and in the Golgi apparatus. hPAR-2 mRNA was highly expressed in human pancreas, kidney, colon, liver and small intestine, and by A549 lung and SW480 colon adenocarcinoma cells. Hybridization in situ revealed high expression in intestinal epithelial cells throughout the gut. Trypsin and AP stimulated an increase in [Ca2+]i in a rat intestinal epithelial cell line (hBRIE 380) and stimulated amylase secretion in isolated pancreatic acini. In A549 cells, which also responded to trypsin and AP with mobilization of cytosolic Ca2+, AP inhibited colony formation. Thus PAR-2 may serve as a trypsin sensor in the gut. Its expression by cells and tissues not normally exposed to pancreatic trypsin suggests that other proteases could serve as physiological activators.

Adenocarcinoma↗
PubMed1996

Laparoscopic management of acute small-bowel obstruction.

BACKGROUND: A retrospective review is given of the authors' experience with a consecutive series of acute small-bowel obstruction unresponsive to medical management. METHODS: There were 33 exploratory laparoscopies. The etiology was accurately diagnosed in 100% of the cases. Twenty-five (76%) were secondary to postoperative adhesions, of which 18 (72%) were successfully treated by laparoscopic lysis of adhesions. Minilaparotomy was needed to treat iatrogenic perforation (two), gangrenous bowel (one), and Meckel's diverticulectomy (one). Formal laparotomy was utilized for small-bowel resection (two), malignant adhesions (two), and intolerance of pneumoperitoneum (one). Four cases of incarcerated hernias were treated by conventional herniorrhaphy. RESULTS: Overall, 67% of our cases were spared formal laparotomy. CONCLUSION: We conclude that laparoscopy is an excellent diagnostic modality in acute small-bowel obstruction, the majority of which can be simultaneously managed laparoscopically. Laparotomy should be reserved for malignant adhesions, surgical misadventure, or when the pathology dictates.

Acute Disease↗
PubMed1996

Improved method to create the common ostium variant of the distal arteriovenous fistula for enhancing crural prosthetic graft patency.

PURPOSE: Successful use of the distal adjunctive arteriovenous fistula (dAVF) for the enhancement of prosthetic graft patency rates in the crural position is critically dependent on the qualitative and quantitative aspects of the arterial and venous runoff. Precise technical performance of the fistula is equally vital to secure optimal results. The purpose of this study was to determine current prosthetic graft patency and limb salvage rates using a modified version of the common ostium dAVF. METHODS: The standard method to create the common ostium variant of dAVF has been modified to improve apposition of the "otomy" sites of the artery and vein, avoid twisting and stenosis by terminating the fistula suture line at the artery-vein junctures, reshaping the ovoid ostium to a rectangular shape, and finally, use of multiple interrupted heel-toe sutures. RESULTS: Since 1979 we have created 290 fistulas in 281 patients who required leg revascularization procedures. In different time periods we have documented improving graft patency and limb salvage rates. Fistula patency, reflected by annual attrition rates of 13% to 26% per year, continues as a challenge for long-term results. Current 3-year secondary cumulative graft patency and limb salvage rates by life table analysis are 61% and 74%, respectively. The conduit material may play a role with regard to steal phenomena and the need for banding techniques. CONCLUSION: Configuration of the adjunctive dAVF may impact on prosthetic graft patency in the crural position. In addition, the type of graft material used for bypass may be instrumental in preventing or precipitating the steal phenomenon. These issues require further study to better understand flow dynamics, patterns of intimal hyperplasia, and blood distribution as a function of conduit material and impedance of the arterial and venous runoff.

Adult↗
PubMed1996

Effect of foot and ankle MR imaging on clinical decision making.

PURPOSE: To evaluate the effect of magnetic resonance (MR) imaging of the ankle and hindfoot on clinical decision making. MATERIALS AND METHODS: Eighty-one consecutive patients were prospectively examined with MR imaging of the foot and ankle. The referring clinician (one of two orthopedic surgeons or one of two podiatrists) assigned a clinical diagnosis (with a corresponding confidence score of 1-5) and a tentative treatment plan before and after the MR imaging examination and reading. A two-tailed, paired Student t test was used to determine the effects of MR imaging on the diagnosis and treatment. RESULTS: Of the 81 patients examined, 38 (47%) had a post-MR imaging diagnosis that differed from the pre-MR imaging diagnosis (P < .001). Treatment plans were subsequently changed in 28 patients (34%) (P < .001). MR imaging had a statistically significant effect regardless of the assigned, pre-MR imaging clinical confidence rating. MR imaging was also noted to play a key role in surgical planning regardless of the effect on diagnosis. CONCLUSION: MR imaging of the foot and ankle has an effect on clinical decision making. Regardless of the clinician's confidence in diagnosis, MR imaging consistently plays a central role in further defining the diagnosis and treatment.

Adolescent↗
PubMed1996

Conserved structure and adjacent location of the thrombin receptor and protease-activated receptor 2 genes define a protease-activated receptor gene cluster.

BACKGROUND: Thrombin is a serine protease that elicits a variety of cellular responses. Molecular cloning of a thrombin receptor revealed a G protein-coupled receptor that is activated by a novel proteolytic mechanism. Recently, a second protease-activated receptor was discovered and dubbed PAR2. PAR2 is highly related to the thrombin receptor by sequence and, like the thrombin receptor, is activated by cleavage of its amino terminal exodomain. Also like the thrombin receptor, PAR2 can be activated by the hexapeptide corresponding to its tethered ligand sequence independent of receptor cleavage. Thus, functionally, the thrombin receptor and PAR2 constitute a fledgling receptor family that shares a novel proteolytic activation mechanism. To further explore the relatedness of the two known protease-activated receptors and to examine the possibility that a protease-activated gene cluster might exist, we have compared the structure and chromosomal locations of the thrombin receptor and PAR2 genes. MATERIALS AND METHODS: The genomic structures of the two protease-activated receptor genes were determined by analysis of lambda phage, P1 bacteriophage, and bacterial artificial chromosome (BAC) genomic clones. Chromosomal location was determined with fluorescent in situ hybridization (FISH) on metaphase chromosomes, and the relative distance separating the two genes was evaluated both by means of two-color FISH and analysis of YACs and BACs containing both genes. RESULTS: Analysis of genomic clones revealed that the two protease-activated receptor genes share a two-exon genomic structure in which the first exon encodes 5'-untranslated sequence and signal peptide, and the second exon encodes the mature receptor protein and 3'-untranslated sequence. The two receptor genes also share a common locus with the two human genes located at 5q13 and the two mouse genes at 13D2, a syntenic region of the mouse genome. These techniques also suggest that the physical distance separating these two genes is less than 100 kb. CONCLUSIONS: The fact that the thrombin receptor and PAR2 genes share an identical structure and are located within approximately 100 kb of each other in the genome demonstrates that these genes arose from a gene duplication event. These results define a new protease-activated receptor gene cluster in which new family members may be found.

Amino Acid Sequence↗
PubMed1996

Peptide secondary structure mimetics: applications to vaccines and pharmaceuticals.

An important goal of structural biochemistry is the reduction of complex molecules to small functional units that are amenable to high-resolution structural analysis and rapid modification. The dissection of multidomain proteins into small synthetic conformationally restricted components is an important step in the design of low molecular weight nonpeptides that mimic the activity of the native protein. Mimetics of critical functional domains might possess beneficial properties in comparison to the intact proteinaceous species with regard to specificity and therapeutic potential, and are valuable probes for the study of molecular recognition events, and the development of novel vaccines and pharmaceuticals.

Amino Acid Sequence↗
PubMed1996

Effects of long-term retinoic acid treatment on epidermal differentiation in vivo: specific modifications in the programme of terminal differentiation.

To investigate the effects of long-term all-trans-retinoic acid (RA) treatment on epidermal differentiation in vivo, rhino mice were treated topically with 0.005% RA, and their epidermis was analysed histologically and biochemically after 5, 13 and 26 weeks of treatment. Effects of RA were observed first in the living layers of the epidermis, and then in the non-viable stratum corneum. Five weeks of topical RA led to thickening of the spinous and granular compartments, induction of keratins K6, K16 and K17, and suppression of filaggrin expression. After 13 and 26 weeks of RA treatment, the number of anucleate cornified cell layers remained similar to controls, but additional changes in histology and protein expression were observed. The results showed that prolonged administration of topical RA induced epidermal hyperproliferation, but did not suppress differentiation, in contrast to results observed in keratinocyte cultures. However, the distinct histological and biochemical changes observed in the spinous, granular and cornified layers of RA-treated skin after 26 weeks of treatment, suggested that the progeny of RA-treated basal cells undergo a modified programme of terminal differentiation. Considering the present data together with results of previous in vivo studies, we propose that long-term topical RA treatment retards, or specifically modulates, the later stages in epidermal differentiation, or programmed cell death.

Animals↗
PubMed1995

Trypanosoma cruzi amastigote adhesion to macrophages is facilitated by the mannose receptor.

Trypanosoma cruzi is an obligate intracellular protozoan parasite. The mammalian stage of the parasite life cycle describes amastigotes as an intracellular form that replicates, and trypomastigotes as an extracellular form that disseminates and invades cells. Recent studies, however, have demonstrated that amastigotes circulate in the blood of infected mammals and can invade mammalian cells. In this report, a T. cruzi surface glycoprotein gene, SA85-1.1, was expressed as an immunoglobulin chimera, and this recombinant globulin was used to screen normal mouse tissues for adhesive interactions. This approach identified a subset of macrophages in the skin and peripheral lymph node that bind the T. cruzi surface glycoproteins through the mannose receptor. To further examine the T. cruzi mannose receptor carbohydrate ligands, the interaction between T. cruzi and the mannose-binding protein, a mammalian lectin with similar carbohydrate binding specificities as the mannose receptor, was examined. These studies demonstrated that the mannose-binding protein recognized amastigotes, but not trypomastigotes or epimastigotes, and suggested that amastigotes would also be recognized by the mannose receptor. Therefore, amastigote adhesion to macrophages was investigated, and these experiments demonstrated that the mannose receptor contributes to amastigote adhesion. The data identify the first mammalian lectins that bind to T. cruzi, and are involved in T. cruzi invasion of mammalian cells. The data suggest that amastigotes and trypomastigotes may have developed different mechanisms to adhere to and invade host cells. In addition, it has been established that IFN-gamma-activated macrophages express low levels of the mannose receptor and are trypanocidal; this suggests that the interaction between amastigotes and the mannose receptor enables amastigotes to increase their adherence with a population of macrophages that are nontrypanocidal and permissive for their intracellular replication.

Animals↗
PubMed1995

The three-dimensional solution structure of a constrained peptidomimetic in water and in chloroform. Observation of solvent induced hydrophobic cluster.

A large number of protein-protein interactions involved turn or loop regions. The excised linear peptides from these regions reveal complex conformational averaging. To circumvent this motional averaging and to stabilize the beta-turn conformation, extensive effort has been devoted to the design of constrained peptidomimetics. Here, we report the three-dimensional solution structure of a 12-membered cyclic peptidomimetic. The structures were calculated from NMR studies performed in chloroform and in water at 263 and 278K, respectively. This 12-membered cyclic scaffolding is part of a program to design and to construct conformationally stable beta-turn peptidomimetics. The impact of the surrounding environment on the conformation of this constrained peptidomimetic is discussed. The general structural features of the cyclic mimetic are retained in both environments; however, the formation of a hydrophobic patch in the aqueous solvent is evident.

Amino Acid Sequence↗
PubMed1995

Characterization of two proteinase inhibitor (ATI) cDNAs from alfalfa leaves (Medicago sativa var. Vernema): the expression of ATI genes in response to wounding and soil microorganisms.

cDNAs encoding two Bowman-Birk proteinase inhibitors were isolated from the leaves of alfalfa (Medicago sativa). The cDNAs are derived from a small gene family (3 to 10 genes) encoding alfalfa trypsin inhibitors (ATIs). Each cDNA clone encoded a mature ATI that was part of a larger, putative preprotein. ATI mRNAs are continuously expressed in flower parts, but are mechanically wound-inducible in the stems and leaves. ATI mRNA is shown to be continuously present in roots of soil-grown plants, but its presence is primarily in response to microorganisms present in the soil. Additionally, while mechanical wounding of the alfalfa roots induced ATI mRNA synthesis both in the roots and in the leaves, microbial infection of the roots triggered ATI mRNA synthesis in the roots but not in the leaves. These results suggest that both local and systemic signalling pathways for proteinase inhibitor synthesis are present in alfalfa plants.

Amino Acid Sequence↗
PubMed1995

Experience with a new valvulotome for lower-extremity revascularization procedures by the in situ method.

Between November 1990 and November 1992, 50 consecutive cases requiring lower-extremity revascularization by the in situ method were compared with regard to use of two different valve cutters, the Hall valvulotome and the Insitucat. There were no amputations in patients with patent grafts, nor were any infections or false aneurysms noted during the course of this study. In the Insitucat group (n = 25), primary patency was achieved in 19 cases. Five of the six graft failures underwent additional procedures of which three remained patent, adding to the secondary patency rate (22 of 25). The greatest problem with regard to maintaining primary graft patency was that of missed or retained valves, but the incidence of this problem decreased during the course of this study as experience was gained with the catheter in conjunction with angioscopy. Experience with the Insitucat valvulotome has demonstrated its efficacy, though enhanced by monitoring the results with angioscopy. The development and discovery of focal stenotic areas and retained valves by surveillance sonography have resulted in enhanced (assisted) primary graft patency rates. The incidence of these problems appears to be comparable with that occurring with other means of producing valvular incompetence for an in situ reconstruction where valvulotomes of similar design are employed. This was confirmed by comparative analysis with another group of 25 in situ vein bypasses performed during the same time period but during the Hall valvulotome.

Aged↗
PubMed1995

The immune response and the eye. TCR alpha-chain related molecules regulate the systemic immunity to antigen presented in the eye.

Injection of antigen into the anterior chamber (AC) of the eye results in the induction of immune deviation in which antibody production is activated and delayed-type hypersensitivity (DTH) is inhibited. This system is termed anterior chamber associated immune deviation (ACAID) and the model is used to examine certain aspects of the immunologic privilege of the eye. Recent studies have established that following antigen presentation in the eye, an 'ACAID-inducing' signal is produced that directly enters the blood. This signal then homes to the spleen where T cells that down-regulate DTH are activated. For many antigens this 'ACAID signal' is a soluble protein released within 2 days of AC injection. Although the presence of this molecule (or molecules) has been described using several antigens, the exact nature of the soluble mediator has escaped characterization. We have further explored the nature of this signal using HSV-1-induced immune deviation. Our results show the soluble 'signal' was released by T cells that encounter antigen in the ocular microenvironment. This mediator was antigen specific, contained TCR alpha-chain (but not the TCR beta-chain) determinants and had an apparent molecular weight of 46 kDa. These results show that the release of soluble TCR alpha-chain from sites of T cell interaction within the microenvironment of the eye can regulate systemic immune responses. These results have implications for the control of immune response that might be damaging to organs such as the eye.

Animals↗
PubMed1995

Identification of the neurotrophic factor sequence of prosaposin.

Prosaposin, recently identified as a neurotrophic factor (1), is the precursor of saposins A, B, C, and D. The neurotrophic activity of prosaposin resides in the saposin C domain. We have pinpointed the active sequence to a linear 12-mer located in the NH2-terminal sequence of saposin C (LIDNNKTEKEIL). Nanomolar concentrations of a 22-mer peptide encompassing this region stimulated neurite outgrowth and choline acetyltransferase activity, and prevented cell death in neuroblastoma cells. In primary cerebellar granule cells, the 22-mer also stimulated neurite outgroth. Studies of the neuroblastoma line NS20Y using a radiolabeled 18-mer from the neurotrophic region identified a high-affinity (Kd = 70 pM) binding site indicative of receptor-ligand interaction. The 22-mer stimulated protein phosphorylation of several proteins, some of which were tyrosine-phosphorylated after brief exposure similar to saposin C. Circular dichroism studies demonstrated that the 22-mer was converted from a random to a helical structure by addition of ganglioside GM1. The results are consistent with receptor-ligand binding by the peptide initiating a signal transduction cascade and resulting in neuronal differentiation.

Amino Acid Sequence↗
PubMed1994

Portable software tools for 3D radiation therapy planning.

PURPOSE: Produce a collection of software tools (computer programs) that support three-dimensional (3D) radiation therapy planning. The tools are not a complete 3D planning system. Instead, they work with any 3D planning system that meets certain minimal specifications. The tools assist in deriving anatomic data from images, generating target volume contours, evaluating treatment plans, and verifying accurate treatment delivery. The tools are portable: they can run without source code changes in any computing environment that provides a library of functions and data definitions called the Foundation. The Foundation couples the portable tools to the (usually nonportable) file system and dose calculation associated with a particular 3D planning system. METHODS AND MATERIALS: Tools were written at three different (geographically separated) institutions. Software developers from all three sites specified the Foundation. The programmers' interface to the Foundation is portable, but a Foundation implementation need not be portable. Each group implemented a Foundation adapted to the (different) 3D planning system used at their site. RESULTS: All tools run at all three sites without source code changes. Each Foundation was implemented in a few person-months of programming effort. The program text and documentation for the tools have been placed in the public domain. CONCLUSIONS: It is practical and economical to produce portable radiotherapy treatment planning tools. Providers of 3D planning programs should offer Foundations for their systems, so they can be used with tools. Researchers considering new computer programs should write them as tools, so they can work with any 3D planning system.

Costs and Cost Analysis↗
PubMed1994

Conformational rearrangements required of the V3 loop of HIV-1 gp120 for proteolytic cleavage and infection.

HIV gp120 is specifically cleaved at a single site in the V3 loop between Arg315 and Ala316 by thrombin. Previous observations by others have indicated that binding to CD4 enhances the rate of V3 loop cleavage, and that this cleavage is a prerequisite for HIV infection. Other observations also suggest that the cleavage site is in a type II beta-turn centered at Pro313-Gly314. However, our docking experiments indicate that this conformation cannot dock to thrombin and other trypsin-like serine proteases. Thus, based on the thrombin-bound conformation of peptide substrates, we propose that CD4 binding, at a site remote from the V3 loop, induces and stabilizes a trans to cis isomerization of the highly conserved residue Pro313, and that this conformational shift is a prerequisite for cleavage by a 'thrombin-like' cellular protease and subsequent infection.

Binding Sites↗