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Biomedical subjects

J Kuhn

Publications and source records attributed to J Kuhn.

At least 73 records · Page 4Linked to original sources
PubMed1999

A phase I and pharmacological study of protracted infusions of crisnatol mesylate in patients with solid malignancies.

This Phase I and pharmacological study was performed to assess the feasibility of administering the polycyclic aromatic hydrocarbon crisnatol in increasingly prolonged continuous i.v. infusions to patients with advanced solid malignancies. The study also sought to characterize the-principal toxicities of crisnatol on this schedule, to recommend doses for subsequent disease-directed studies, and to characterize possible associations between pharmacological parameters and toxicity. Sixteen patients were treated with 40 courses of crisnatol administered as a continuous i.v. infusion. The initial dose-schedule was 750 mg/m2/day for 6 days, and the duration of the infusion was to be progressively increased by 3-day increments to 9, 12, 15, 18, and 21. Courses were to be repeated every 4 weeks. Moderate to severe central nervous system (CNS) toxicity precluded the administration of crisnatol 750 mg/m2/day for longer than 6 days, and, therefore, the dose of crisnatol was reduced to 600 mg/m2/day. At this dose, three of five patients receiving a 12-day infusion experienced dose-limiting toxicity, which consisted of pulmonary thromboembolism (two patients) and grade 4 thrombocytopenia (one patient). None of the six patients completing a 9-day infusion at 600 mg/m2/day developed dose-limiting toxicity during the first or second course of crisnatol. At this dose level, the plasma concentrations at steady state (Css) averaged 1607.8+/-261.1 ng/ml, which exceeds minimal inhibitory concentrations for most tumors in vitro (1000 ng/ml). In fact, the administration of crisnatol at a dose of 600 mg/m2/day for 9 days resulted in the longest duration that biologically relevant plasma crisnatol concentrations have been sustained. Plasma Css values were significantly higher in patients who experienced severe CNS toxicity compared with those who did not (2465.3+/-1213.5 versus 1342+/-447.3 ng/ml; P = 0.04). There were no relationships evident between the clearance of crisnatol and indices reflecting renal and hepatic functions. One patient with a glioblastoma multiforme experienced a partial response lasting 14 months. The relative lack of intolerable CNS toxicity at the recommended dose for Phase II studies of crisnatol, 600 mg/m2/day for 9 days, as well as the magnitude of the Css values achieved and the antitumor activity observed at this dose, are encouraging. However, the mechanisms for the apparently increased thrombogenicity observed in this trial are unclear and require further elucidation.

Adult↗
PubMed1998

The sentinel node in breast cancer--a multicenter validation study.

BACKGROUND: Pilot studies indicate that probe-guided resection of radioactive sentinel nodes (the first nodes that receive drainage from tumors) can identify regional metastases in patients with breast cancer. To confirm this finding, we conducted a multicenter study of the method as used by 11 surgeons in a variety of practice settings. METHODS: We enrolled 443 patients with breast cancer. The technique involved the injection of 4 ml of technetium-99m sulfur colloid (1 mCi [37 MBq]) into the breast around the tumor or biopsy cavity. "Hot spots" representing underlying sentinel nodes were identified with a gamma probe. Sentinel nodes subjacent to hot spots were removed. All patients underwent a complete axillary lymphadenectomy. RESULTS: The overall rate of identification of hot spots was 93 percent (in 413 of 443 patients). The pathological status of the sentinel nodes was compared with that of the remaining axillary nodes. The accuracy of the sentinel nodes with respect to the positive or negative status of the axillary nodes was 97 percent (392 of 405); the specificity of the method was 100 percent, the positive predictive value was 100 percent, the negative predictive value was 96 percent (291 of 304), and the sensitivity was 89 percent (101 of 114). The sentinel nodes were outside the axilla in 8 percent of cases and outside of level 1 nodes in 11 percent of cases. Three percent of positive sentinel nodes were in nonaxillary locations. CONCLUSIONS: Biopsy of sentinel nodes can predict the presence or absence of axillary-node metastases in patients with breast cancer. However, the procedure can be technically challenging, and the success rate varies according to the surgeon and the characteristics of the patient.

Axilla↗
PubMed1998

Localization of regional lymph nodes in melanomas of the head and neck.

OBJECTIVES: To study the efficacy of gamma-probe radiolocalization of the first draining (sentinel) lymph node (SLN) in stage N0 melanoma of the head and neck and to evaluate its potential role in the staging and treatment of this disease. DESIGN: Gamma-probe radiolocalization, a new alternative to blue-dye lymphatic mapping, uses a scintillation (gamma) probe to identify radiolabeled SLNs. In a consecutive sample clinical trial, gamma-probe radiolocalization of the SLN is compared with lymphoscintigraphy and blue-dye lymphatic mapping. Follow-ups ranged from 1.7 years to 4 years, with a mean follow-up of 2.5 years. SETTING: Tertiary and private care teaching hospital. PATIENTS: Between June 1993 and November 1995, 23 patients with stage N0 intermediate-thickness melanoma of the head and neck were enrolled in this volunteer sample. INTERVENTIONS: Twenty-four hours prior to surgery, a radioactive tracer was intradermally injected around the circumference of a primary melanoma. Twelve patients also had blue dye injected just prior to surgical resection. Using a handheld gamma probe, radiolabeled lymph nodes were identified and selectively removed with minimal dissection. In patients with nodes with histologic evidence of metastases, a regional lymphadenectomy was performed. MAIN OUTCOME MEASURES: The successful identification of radiolabeled SLNs, the correlation of SLN radiolabeling to lymphoscintigraphy and blue-dye mapping, and the long-term development of regional metastases. RESULTS: Surgeons successfully resected the radiolabeled SLNs in 22 (96%) of 23 patients. The success rate of blue-dye lymphatic mapping was 8 (75%) of 12 patients and lymphoscintigraphy was 20 (91%) of 22 patients. One hundred percent of blue-stained lymph nodes were radiolabeled. The one patient in whom no SLN could be identified developed regional disease at 17 months. CONCLUSIONS: Gamma-probe radiolocalization and resection of the radiolabeled SLN is a simple and reliable method of staging regional lymph nodes and determining the need for elective lymphadenectomy.

Adult↗
PubMed1998

Xylosylation of alternatively spliced isoforms of Alzheimer APP by xylosyltransferase.

Acceptor affinities of UDP-D-xylose:proteoglycan core protein beta-D-xylosyltransferase (XT) recognition signals in synthetic L-APP and L-APLP2 homologous peptides were determined. The Michaelis-Menten constants (KM) of the L-APP peptide TENEGSGLTNIK and the L-APLP2 peptide SENEGSGMAEQK were 20.1 and 18.9 microM, respectively. Therefore, the peptides proved to be as good acceptors for XT as the bikunin aminoterminus homologous peptide (KM = 22 microM). Due to the occurrence of L-APP and L-APLP2 transcripts in human brain tissue, XT activity was measured in human liquor cerebrospinalis. Mean values were calculated as 0.22 mU/L in males and 0.47 mU/L in females without disturbance of blood brain barrier. In addition, in homogenized rat brain tissue a mean XT activity of 0.75 mU/L was determined. Furthermore, XT activity was investigated in 21 different human cell lines. In 7 cell lines an enzyme activity was not detected in either extracellular space or cytoplasma. Our findings indicate that XT is not ubiquitously expressed in human cell types.

Alternative Splicing↗
PubMed1998

Pharyngeal acid reflux events in patients with vocal cord nodules.

OBJECTIVE: Gastroesophageal reflux has been implicated in the pathogenesis of vocal cord nodules. However, a cause-and-effect relationship has not been established. Because documentation of pharyngeal acid reflux events makes this correlation more plausible, the aim of the present study was to determine the frequency of pharyngeal acid reflux events in patients with vocal cord nodules. METHODS: Eleven patients with vocal cord nodules (mean age, 42 +/- 6 years) and eleven healthy volunteers (mean age, 45 +/- 6 years) were studied. Patients underwent barium esophagram and ambulatory 24-hour simultaneous three-site pharyngoesophageal pH monitoring. Controls only had ambulatory 24-hour simultaneous three-site pH monitoring. In the ambulatory pH monitoring studies, pH was recorded from the manometrically determined sites of pharynx (2 cm above upper esophageal sphincter), proximal esophagus (10 cm distal to pharyngeal site), and distal esophagus (5 cm above the lower esophageal sphincter). Pharyngeal acid reflux event was deemed acceptable if all three sites recorded a decrease in pH below 4 which was not related to meal or drinking. RESULTS: Pharyngeal acid reflux events occurred in seven of 11 patients with vocal cord nodules (1-4 episodes) and two of 11 controls (1-2 episodes) (P < .05). In both groups all pharyngeal acid reflux events occurred in upright position and were not associated with belching or coughing. Barium studies documented hiatal hernia in two patients and gastroesophageal reflux in five of 11 patients. However, none of the esophageal reflux events reached the pharynx on barium esophagram. CONCLUSIONS: Prevalence of pharyngeal acid reflux events is significantly higher in patients with vocal cord nodules compared with normal controls and suggests a contributory role for gastroesophagopharyngeal acid reflux in the pathogenesis of some vocal cord nodules.

Adolescent↗
PubMed1998

Stabilization of human immunodeficiency virus type 1 envelope glycoprotein trimers by disulfide bonds introduced into the gp41 glycoprotein ectodomain.

Biochemical and structural studies of fragments of the ectodomain of the human immunodeficiency virus type 1 (HIV-1) gp41 transmembrane envelope glycoprotein have demonstrated that the molecular contacts between alpha helices allow the formation of a trimeric coiled coil. By introducing cysteine residues into specific locations along these alpha helices, the normally labile HIV-1 gp160 envelope glycoprotein was converted into a stable disulfide-linked oligomer. Although proteolytic cleavage into gp120 and gp41 glycoproteins was largely blocked, the disulfide-linked oligomer was efficiently transported to the cell surface and was recognized by a series of conformationally dependent antibodies. The pattern of hetero-oligomer formation between this construct and an analogous construct lacking portions of the gp120 variable loops and of the gp41 cytoplasmic tail demonstrates that these oligomers are trimers. These results support the relevance of the proposed gp41 structure and intersubunit contacts to the native, complete HIV-1 envelope glycoprotein. Disulfide-mediated stabilization of the labile HIV-1 envelope glycoprotein oligomer, which has been suggested to possess advantages as an immunogen, may assist attempts to develop vaccines.

Amino Acid Sequence↗
PubMed1997

Surgical morbidity, mortality, and long-term survival in patients with peripancreatic cancer following pancreaticoduodenectomy.

BACKGROUND: Surgical resection of the primary tumor in peripancreatic cancer has been associated with an improved survival and decreased morbidity in the recent literature. The purpose of this review was to analyze the results at a single institution. METHODS: Between 1985 and 1995, 88 patients underwent a pancreaticoduodenectomy for adenocarcinoma of the pancreatic head region and had complete long-term follow-up. Patient records were reviewed to determine morbidity, mortality, and survival. RESULTS: Tumor histology included pancreatic head adenocarcinoma (n = 46), ampullary adenocarcinoma (n = 28), duodenal adenocarcinoma (n = 8), and cholangiocarcinoma (n = 6). Morbidity occurred in 26 patients (29%). Perioperative mortality was seen in 6 patients (7%). No perioperative mortality was seen over the last 3 years, which included 33 patients. The mean follow-up was 29 months, with a median survival of 19 months. At last follow-up, 24 patients were alive without disease with an average survival of 43 months (1 to 141). There were 54 patients who died with cancer with an average survival of 21 months (1 to 117). Based on Kaplan and Meier statistical analysis the estimated survival was 47% at 2 years and 25% at 5 years. The location of the primary tumor (P = 0.0006) and the presence of positive lymph nodes (P = 0.05) was shown to have a negative impact on survival. CONCLUSION: Pancreaticoduodenectomy can be done with acceptable morbidity and mortality. The outlook with this disease remains poor, but long-term survival can be achieved in some patients.

Adenocarcinoma↗
PubMed1997

Evidence for heterogeneous TCR V beta repertoire expression in mercury-induced immune disorders in rats.

Administration of subtoxic doses of HgCl2 affects differentially the immune system depending on the strain of rats tested. Susceptible Brown-Norway (BN) rats exhibit a CD4+ T cell-dependent polyclonal activation of B cells; in contrast, Lewis (LEW) rats are resistant and develop an immunosuppression mediated by CD8+ T cells recruited by CD4+ T cells. The mechanisms by which mercury induces immune disorders are poorly understood. We were interested in analyzing the diversity and mercury-mediated changes of the TCR Vbeta repertoire in the BN and LEW strains of rats at different times of HgCl2 exposure. Our results obtained after analysis of lymph node T cells by RNase protection assay, flow cytometry or immunoscope assay (i) were not consistent with a superantigen-like stimulus since we observed neither a V beta-selective expansion nor deletion that would have been expected and (ii) showed that in BN rats, as well as in LEW rats, an increase in the number of T cells was associated with the heterogeneous TCR V beta repertoire, thus supporting a polyclonal T cell activation. However, in BN rats the total number of T cells increased very rapidly, whereas in LEW rats only CD8+ T cells accumulated.

Animals↗
PubMed1997

Children of human immunodeficiency virus-infected members of the Army Reserve components.

OBJECTIVES: Little is known about the numbers of children who will be left without one or both parents because of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. This report evaluates childbearing patterns among U.S. Army reserve component members, a group largely made up of men with limited contact with the military. METHODS: HIV status was determined from routinely collected data, with demographic information obtained from personnel records. Number of children was estimated from number of dependents reported. No information was available on the infection status of children or spouses of members. RESULTS: There were 1,884 HIV-positive members, with an estimated total of 843 children. Childbearing patterns varied across several demographic characteristics. Among 14 metropolitan statistical areas, the proportion reporting any children and the number of children of infected members per 100,000 varied substantially. CONCLUSIONS: This report documents the numbers of children of HIV-positive adults in this population and provides evidence that certain metropolitan areas will be disproportionately affected.

Adult↗
PubMed1996

Earth-Based Observations of the Galileo Probe Entry Site

Earth-based observations of Jupiter indicate that the Galileo probe probably entered Jupiter's atmosphere just inside a region that has less cloud cover and drier conditions than more than 99 percent of the rest of the planet. The visual appearance of the clouds at the site was generally dark at longer wavelengths. The tropospheric and stratospheric temperature fields have a strong longitudinal wave structure that is expected to manifest itself in the vertical temperature profile.

Journal Article↗
PubMed1996

Th1/Th2 cytokine gene expression after mercuric chloride in susceptible and resistant rat strains.

Mercuric chloride (HgCl2) has contrasting effects on different rat strains: susceptible strains, e.g. Brown Norway (BN) develop polyclonal B cell activation, multiple autoantibodies and widespread tissue injury. Lewis (LEW) rats are resistant: no autoimmune response occurs after HgCl2; instead, there is immunosuppression. We have previously shown, by fully quantitative polymerase chain reaction (PCR), up-regulation of interleukin-4 (IL-4) gene expression in HgCl2-treated BN rats, implicating Th2 cells in the autoimmune syndrome. Involvement of the reciprocal Th1 subset, producing interferon-gamma (IFN-gamma), in resistance of LEW rats to HgCl2 has been suggested. We now report extensive analysis of Th1 and Th2 cytokine gene expression in spleen and lymph nodes of susceptible (BN) and resistant (LEW) rats after HgCl2. IL-4 and IFN-gamma were analyzed by quantitative PCR, other cytokines were assessed using semiquantitative PCR: the relative merits of these two techniques are discussed. We show pronounced up-regulation of IL-4 and more modest up-regulation of IFN-gamma in BN rats, but no up-regulation of either in LEW rats. Baseline levels of IFN-gamma were higher in Lew rats. Semiquantitative PCR showed increased expression of IL-2, IL-6 and IL-10 in BN; in LEW rats only IL-10 was increased. There was no marked change in IL-5, IL-13 or transforming growth factor-beta (TGF-beta) in either strain. These data further support the key role of IL-4 in HgCl2-induced autoimmunity, and suggest that failure of up-regulation of IL-4, together with higher baseline IFN-gamma expression, accounts for resistance of LEW rats to HgCl2. However, neither IFN-gamma nor TGF-beta can be implicated in HgCl2-induced immunosuppression in the LEW rat in vivo: our data suggest a role for IL-10 in this phenomenon.

Animals↗
PubMed1996

Interspecific luciferase beta subunit hybrids between Vibrio harveyi, Vibrio fischeri and Photobacterium leiognathi.

Bacterial luciferase (EC 1.14.14.3) is a heterodimer composed of alpha- and beta-chains encoded by luxA and luxB, respectively. Although some interspecific combinations of these subunits lead to active enzyme, others do not. The beta subunits of Vibrio fischeri and Photobacterium leiognathi form active enzyme with the alpha subunits of V.fischeri, P.leiognathi and Vibrio harveyi, while the beta subunit from V.harveyi only complements the alpha subunit of V.harveyi. Inactivity is caused by a lack of dimerization of the beta subunit of V.harveyi with the alpha subunits of V.fischeri and P.leiognathi. These observations served as the basis for a search to discover which segment of the beta polypeptide confers the ability to dimerize with the alpha subunits of V.fischeri and P.leiognathi. Intragenic beta subunit hybrids were made between V.harveyi, V.fischeri and P.leiognathi. Unique restriction sites were introduced into the respective luxB genes to divide them into four roughly equal segments. In all, 78 hybrids were constructed by in vitro techniques. The N-terminal segment of the peptide contains the signals that differentiate between the beta subunits of V.fischeri and P. leiognathi and the beta subunit of V. harveyi, and allow the former to dimerize with their alpha subunits. The second segment has no major effect on enzyme activity but does exhibit some context effects. Important interactions were found between the third and fourth segments of the polypeptide with respect to enzymatic activity.

Amino Acid Sequence↗
PubMed1996

Laser-assisted tympanostomy.

Laser-assisted tympanostomy (LAT) was performed in 70 ears to ventilate the middle ear space without using a pressure-equalizing tube. Using a CO2 laser attached to an operating microscope with a Microslad (microscope laser adaptor device), tympanostomies of 1.0 to 3.0 mm (average, 1.6 mm) in diameter were created and remained patent for an average of 3.14 weeks. Patency time was directly related to the size of the opening. Nearly all (97.9%) of the tympanostomies healed with no noticeable scarring and no persistent perforations. Seventy-eight percent of patients at the Florida Ear & Sinus Center (FESC, Sarasota, Fla.) and 84% of patients at the Head & Neck Surgery Group (New York) showed no evidence of recurrent effusion after a minimum follow-up of 3 months. LAT appears to be a safe, cost-effective procedure which can easily be performed in an office setting when bloodless opening in the tympanic membrane is needed for either treatment or diagnosis using endoscopes.

Adolescent↗
PubMed1996

Phase II study of paclitaxel in patients with recurrent malignant glioma.

PURPOSE: To assess the efficacy and toxicity of paclitaxel administered as a 3-hour infusion to patients with recurrent malignant glioma. PATIENTS AND METHODS: Adult patients with recurrent malignant glioma following radiation therapy, who had received no more than one prior chemotherapy regimen and who had a Karnofsky performance status (KPS) > or = 60, were treated with a 3-hour infusion of paclitaxel every 3 weeks. The initial dose was 210 mg/m2; dose escalation to 240 mg/m2 was allowed. Tumor response was assessed at 6-week intervals using radiographic and clinical criteria. Treatment was continued until documented tumor progression or a total of 12 paclitaxel infusions. RESULTS: Of 41 eligible patients, all were assessable for treatment toxicity and 40 (98%) were assessable for response. The response rate (disease stabilization or better) was 35%. Twenty-nine patients (71%) underwent dose escalation to 240 mg/m2 without the use of growth factors. Toxicities included alopecia (98%), nausea (22%), arthralgias (32%), CNS toxicity (24%), peripheral neuropathy (15%), cardiac toxicity (7%), and myelosuppression (10% grade 3 or 4 hematologic toxicity). No patient developed febrile neutropenia. There was one allergic reaction (2%). CONCLUSION: Paclitaxel is well tolerated at this dose schedule in patients with recurrent malignant glioma, and affords a modest response rate. Because minimal myelotoxicity was encountered in our patients, a dose-escalating phase I/II study of paclitaxel is planned to determine the maximal-tolerated dose (MTD).

Adult↗
PubMed1996

Intratympanic steroid treatment of inner ear disease and tinnitus (preliminary report).

Intratympanic instillation of Depo-Medrol (80 mg/cc), dexamethasone ophthalmic solution (1 mg/cc), or dexamethasone intravenous (4 mg/cc) solution produces improvement of cochlear function in certain patients with Meniere's disease, autoimmune inner ear disease and sudden sensorineural deafness. Tinnitus improved in 47%, most often in patients with Meniere's disease (9 of 15; 60%). The SRT improvement of greater than 10 dB or SD greater than 15% was documented in 41% (average improvement in SRT: 15 dB; SD: 24%). Patients with tinnitus and bilateral sensorineural hearing loss (i.e., presbycusis) did not benefit from the treatment. Prior to treatment with intratympanic medication, laser assisted tympanostomy with middle ear exploration, using otoendoscopy to determine the status of the round window niche and remove mucosal folds, helps in making the round window membrane accessible to local application of drops. Placing Gelfoam into the round window niche under direct vision, and using a Venturi Bobbin tube in the tympanic membrane, appears to be a satisfactory method for delivering medication to the inner ear fluids. The medication can be injected by the physician through the tube into the middle ear, or the patient can perform self-treatment at home, placing medication in the external auditory canal. A double-blind, cross-over study in patients with Meniere's disease is now in progress with Institutional Review Board (IRB) approval, which will be reported at a later date. This preliminary study has shown that intratympanic steroids may affect the symptoms of hearing loss and tinnitus in patients with various inner ear problems. Patients with Meniere's disease appear to respond in the highest percentage of cases. Hopefully, additional research will suggest the appropriate drugs which can be used to treat inner ear disease. Direct application of the drug to the round window membrane may increase the concentration in the inner ear fluids, thus avoiding the systemic effects.

Aged↗
PubMed1995

Mechanism of allergic cross-reactions. V. High incidence of unanticipated cross-stimulation by natural allergens of rat basophilic leukemia cells sensitized with monoclonal IgE antibodies.

The incidence of cross-stimulations by natural allergens was investigated using RBL-2H3 cells sensitized with five different mouse monoclonal anti-DNP IgEs and four mercury-induced rat monoclonal IgEs. Cells sensitized with 3 of the 5 monoclonal anti-DNP IgEs (clones SPE-7, SRT-1, LB4) responded by serotonin release upon stimulation by natural allergens such as Dermatophagoides pteronyssinus, horse dander and mugwort extracts. Serotonin release could be inhibited by monovalent DNP-lysine, indicating the involvement of DNP-binding sites of IgEs. Two of the clones (LO-DNP-30 and LA2) were negative on all tests with allergens. All but one (Hg32) of the mercury-induced rat IgE monoclonal antibodies tested positive with DNP-BSA, and with at least one of the six allergen extracts. IgE clone Hg12 mediated serotonin release with 5 of the 6 allergens tested.

Allergens↗
PubMed1995

Acute cutaneous reactions to docetaxel, a new chemotherapeutic agent.

BACKGROUND: Docetaxel (RP 56976) is a new chemotherapeutic agent that has shown promise in a number of animal studies and is currently undergoing phase I and phase II trials. Early in the phase I trials, it was noted that a significant number of patients were experiencing a variety of cutaneous complaints, so we elected to prospectively evaluate the cutaneous reactions occurring during the first three courses of therapy in the first 12 patients enrolled for phase I chemotherapy at our institutions. OBSERVATIONS: All but one patient had some type of cutaneous eruption over the three courses of therapy. Of the 27 evaluable courses of docetaxel given, 19 (70%) resulted in a cutaneous eruption with four (21%) being asymptomatic and 15 (79%) being at least mildly symptomatic. The most common reaction seen was characterized by discrete erythematous to violaceous patches or edematous plaques similar to acral erythema. CONCLUSION: Although a majority of patients receiving docetaxel experience some degree of cutaneous reaction, the eruptions are usually mildly symptomatic and almost always self-limiting.

Acute Disease↗