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Biomedical subjects

H Kaufman

Publications and source records attributed to H Kaufman.

At least 19 recordsLinked to original sources
PubMed1992

Immunogenicity and safety of a recombinant vaccinia virus vaccine expressing the carcinoembryonic antigen gene in a nonhuman primate.

We have previously reported the development of a recombinant vaccinia virus vaccine expressing the human carcinoembryonic antigen (CEA) gene, designated rV(NYC)-CEA. This construct has been shown to elicit specific anti-CEA immune responses and an antitumor effect in a murine tumor model. In the studies reported here, the safety and immunogenicity of this recombinant vaccinia virus were evaluated in a rhesus monkey model. Human CEA is a M(r) 180,000 glycoprotein expressed in approximately 90% of gastrointestinal carcinomas and in some breast and non-small cell lung carcinomas. This family also includes normal cross-reacting antigen (NCA). Rhesus monkeys, like humans, have some NCA on the surface of their granulocytes. Eight monkeys were immunized 3 or 4 times by skin scarification with the recombinant CEA vaccine and four monkeys received wild-type vaccinia virus as control. After three vaccinations, all rV(NYC)-CEA-vaccinated animals exhibited a strong anti-CEA antibody response as measured by enzyme-linked immunosorbent assay. The functional ability of these antibodies to mediate lysis of a CEA-bearing tumor cell was demonstrated using human effector cells. This response could be enhanced by interleukin 2. Cellular immunity to CEA was measured by delayed-type hypersensitivity upon intradermal challenge with purified CEA. Only those animals receiving the recombinant vaccine displayed significant anti-CEA responses. Furthermore, peripheral blood mononuclear cells from immunized monkeys were found to proliferate in response to CEA stimulation. All vaccinated monkeys developed local skin irritation at the site of the vaccination, regional lymphadenopathy, and low-grade fevers after immunization. Following immunization with rV(NYC)-CEA, the response was consistent with the usual constitutional symptoms seen with human smallpox virus immunization. Blood counts, differentials, and hepatic and renal chemistries remained normal in all animals throughout the study and for up to 1 year following the primary vaccination. No evidence of immunological cross-reactivity to NCA was found by either a fall in the granulocyte count or analyses for anti-NCA antibodies. Thus, the rV(NYC)-CEA vaccine appears to be safe in rhesus monkeys. The administration of a CEA recombinant vaccine to rhesus monkeys induces both a humoral and a cell-mediated immune response directed against human CEA.

Animals↗
PubMed1992

Antitumor activity and immune responses induced by a recombinant carcinoembryonic antigen-vaccinia virus vaccine.

BACKGROUND: Human carcinoembryonic antigen (CEA) is a 180-kd glycoprotein expressed in human colorectal, gastric, pancreatic, breast, and non-small-cell lung carcinomas. Previous studies have demonstrated enhanced immune responses to other antigens presented with vaccinia virus proteins via a recombinant vaccinia virus construct. In addition, we have developed a recombinant CEA-vaccinia virus construct, designated rV(WR)-CEA, and have demonstrated humoral anti-CEA responses in mice after immunization with that virus. PURPOSE: The goals of this study were (a) to construct a recombinant CEA-vaccinia vaccine in a less virulent vaccinia strain that is potentially safe and effective for treatment of patients whose tumors express CEA and (b) to evaluate the ability of the recombinant CEA-vaccinia vaccine to prevent and reverse tumor growth in mice and to elicit cell-mediated and humoral anti-CEA immune responses. METHODS: Using the New York City strain of vaccinia virus, which is used in smallpox vaccination and is more attenuated for humans than rV(WR), we derived a recombinant CEA-vaccinia construct, designated rV(NYC)-CEA. The ability of this construct to induce antitumor immunity was evaluated in mice receiving subcutaneous injections of murine colon adenocarcinoma cells expressing the human CEA gene. RESULTS: Administration of rV(NYC)-CEA in mice induced strong anti-CEA antibody responses, as well as CEA-specific cell-mediated responses, including delayed-type hypersensitivity, lymphoproliferative, and cytotoxic responses. Vaccination of mice with the rV(NYC)-CEA rendered them resistant to the growth of subsequently transplanted CEA-expressing tumors. Moreover, when mice were vaccinated 7 days after tumor cell injection, tumor growth was either greatly reduced or eliminated. No toxic effects were observed in any of the mice. CONCLUSION: These studies demonstrate that antitumor activity can be induced with the use of a recombinant CEA-vaccinia virus construct derived from an attenuated vaccinia strain, and they reveal the range of cell-mediated and humoral responses induced by this recombinant vaccine.

Adenocarcinoma↗
PubMed1992

Multiple-model adaptive predictive control of mean arterial pressure and cardiac output.

A multiple-model adaptive predictive controller has been designed to simultaneously regulate mean arterial pressure and cardiac output in congestive heart failure subjects by adjusting the infusion rates of nitroprusside and dopamine. The algorithm is based on the multiple-model adaptive controller and utilizes model predictive controllers to provide reliable control in each model subspace. A total of 36 linear small-signal models were needed to span the entire space of anticipated responses. To reduce computation time, only the six models with the highest probabilities were used in the control calculations. The controller was evaluated on laboratory animals that were either surgically or pharmacologically altered to exhibit symptoms of congestive heart failure. During trials, the controller performance was robust with respect to excessive switching between models and nonconvergence to a single dominant model. A comparison is also made with a previous multiple-drug controller design.

Animals↗
PubMed1991

A recombinant vaccinia virus expressing human carcinoembryonic antigen (CEA).

Carcinoembryonic antigen (CEA) is a 180-kDa glycoprotein expressed on most gastrointestinal carcinomas. A 2.4-kb cDNA clone, containing the complete coding sequence, was isolated from a human colon tumor cell library and inserted into a vaccinia virus genome. This newly developed construct was characterized by Southern blotting, DNA hybridization studies, and polymerase chain reaction analysis. The CEA gene was stably integrated into the vaccinia virus thymidine kinase gene. The recombinant was efficiently replicated upon serial passages in cell cultures and in animals. The recombinant virus expresses on the surface of infected cells a protein product recognized by a monoclonal antibody (COL-I) directed against CEA. Immunization of mice with the vaccinia construct elicited a humoral immune response against CEA. Pilot studies also showed that administration of the recombinant CEA vaccinia construct was able to greatly reduce the growth in mice of a syngeneic murine colon adenocarcinoma which had been transduced with the human CEA gene. The use of this new recombinant CEA vaccinia construct may thus provide an approach in the specific active immunotherapy of human GI cancer and other CEA expressing carcinoma types.

Adenocarcinoma↗
PubMed1990

A circulatory model for combined nitroprusside-dopamine therapy in acute heart failure.

A computer model was developed to approximate the hemodynamic responses of dopamine and nitroprusside in acute left ventricular pump failure. The model is intended to aid the design of a multiple drug infusion system. A non-linear electrical analog model with baroreflex feedback was used to simulate the circulatory system. Heart failure was represented by a reduction in left ventricular inotropy. Pharmacodynamic relationships between the drugs studied and several elements of the system were incorporated into the model to simulate the overall drug responses which include secondary interactions between vascular components. Despite several shortcomings, the model showed good agreement with experimental and clinical data.

Acute Disease↗
PubMed1979

Transitory hypoadrenalism due to long-term treatment with antiovulatory compounds.

A considerable number of women receiving antiovulatory compounds or estrogens complain of weakness and fatigability, suggesting a state of clinical hypoadrenalism. For this reason, levels of plasma ACTH and plasma cortisol were determined in 25 women with such complaints both during treatment and at various intervals after cessation of this treatment. The results obtained showed that there was a significant inhibition of ACTH secretion during long-term treatment with antiovulatory compounds or estrogens, and in half of the cases, there was a delay in normalization of the pituitary-adrenal axis following interruption of the drug, supporting a state of transitory hypoadrenalism.

Adrenal Insufficiency↗
PubMed1979

Successful treatment of Cushing's disease with o,p'-DDD followed by pituitary irradiation in a 19-year-old male patient.

A 19-year-old male patient with Cushing's disease was treated for 15 months with a gastric-insoluble preparation of o,p'-DDD. The daily o,p'-DDD dose (range, 2 to 12 g) was adjusted periodically according to the urinary excretion of 11-hydroxycorticosteroids. Because of a rise in the plasma ACTH level from 135 to 300 pg/ml 12 months after the start of the o,p'-DDD therapy, the dose was reduced from 6 to 2 g/day and external pituitary irradiation (4,480 rads) was initiated. Insulin-induced hypoglycemia and stimulation tests with luteinizing-hormone-releasing factor and thyrotropin-releasing hormone, performed before initiation of o,p'-DDD and six months after pituitary irradiation, did not reveal any disturbance in the secretion of human growth hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone or prolactin. The clinical and laboratory signs of Cushing's disease disappeared gradually, and the patient tolerated the drug well, even at a dose of 12 g/day. The only abnormalities found during o,p'-DDD treatment were low serum thyroxine levels, which returned to normal after discontinuation of the drug, and a transient drop in thrombocyte count. At present, two years after the discontinuation of o,p'-DDD therapy and pituitary irradiation, the patient is symptom free and receives no medication.

Adult↗
PubMed1978

Transplant size and elevated intraocular pressure. Postkeratoplasty.

Elevated intraocular pressure after keratoplasty is a well-recognized phenomenon both in aphakia and in combined lens extraction and penetrating keratoplasty. Ninety-two consecutive cases of penetrating keratoplasty procedures were studied. These were randomly assigned to group A or B. Group A received a donor transplant 0.5 mm larger than the recipient bed. Group B received donor buttons equal in size to the recipient bed. Intraocular pressure was measured preoperatively and daily until the patients were discharged. Group A, which had aphakic penetrating keratoplasty or the combined procedure (0.5-mm larger button), also had significantly lower intraocular pressures (P less than .001) than group B (same size button). There was no difference in postoperative intraocular pressure between groups A and B for those who had phakic penetrating keratoplasties. A larger donor size can alleviate induced "aphakic keratoplasty glaucoma."

Aged↗
PubMed1978

Unilateral adrenalectomy and pituitary irradiation in the treatment of ACTH-dependent Cushing's disease in children and adolescents.

In four juvenile patients with Cushing's disease, the therapeutic approach used was unilateral adrenalectomy followed by irradiation of the pituitary. The follow-up time of these patients has ranged from 1.5 to 10 years. All four are clinically well. Concentrations of adrenal steroids are within normal limits and they require no additional medication. It is felt that this method gives young patients the chance for normal growth and pubertal development as well as a normal social life, so important in the stressful adolescent years, thus avoiding the handicap incurred by bilateral adrenalectomy and the consequent requirement for continuous substitution therapy.

Adolescent↗
PubMed1978

Gonadotrophin release in untreated congenital virilising adrenal hyperplasia.

A 9.9-year-old boy and a 9.8-year-old girl with virilising congenital adrenal hyperplasia were subjected to an IV LH-RH (luteinising hormone-releasing hormone) test (so microgram/m2 before initition of therapy with corticosteroids. The pattern of response of LH and follicle-stimulating hormone to LH-RH was found to correspond to the stage of their precocious sexual development and advanced bone age, but not to their chronological age. This finding has implications with regard to the mechanism controlling gonadotrophin secretion at puberty.

Adrenocortical Hyperfunction↗
PubMed1978

Pregnancy in a case of Nelson's syndrome.

A woman suffering from Cushing's disease from the age of 17 who had been treated consecutively with pituitary irradiation, bilateral partial adrenalectomy and o,p'-DDD (Mitotane, USP) presented the clinical picture of Nelson's syndrome (hypoadrenalism with secondary hypersecretion of ACTH and MSH) at the age of 32. Under substitution therapy with corticoids she became pregnant for the first time at the age of 38. The course of the pregnancy was normal and at term she was delivered of a normal child by Cesarean section. The materno-fetal relationship, the increased risk of pituitary infarction during pregnancy and the possible teratogenic effect of chemotherapy in such cases are discussed.

Adrenal Cortex Hormones↗
PubMed1977

Gonadal function in Bloom's syndrome.

Five patients with Bloom's syndrome aged from 2 8/12 to 27 years, all of whom had hypogonadism, were subjected to an i.v. LHRH test and two of them to an i.m. HCG test. There was increased responsiveness of plasma LH and FSH, indicating that the hypogonadism is primary in nature and of early development. The tubular element of the testis seems to be mainly affected, as indicated by the particularly high FSH response to LHRH stimulation, a history of sterility in the two adult patients and documented azoospermia in one of them. The Leydig cells seem to be less affected and secrete sufficient androgens to enable puberty within acceptable normal limits. Hypogonadism seems to be a major characteristic of Bloom's syndrome.

Abnormalities, Multiple↗
PubMed1977

Plasma LH and FSH response to LRH and plasma testosterone levels in boys with irregular puberty.

Nineteen boys with irregular puberty (IP), defined as a discrepancy of two or more pubertal stages between the criteria for genitalia and that for pubic hair, were subjected to a standard LRH test (50 microng/m2, iv) and the response of gonadotrophins as well as the basal levels of plasma testosterone, LH and FSH were compared to those of boys with normal, regular puberty. When the results were plotted against the pubertal stage for genitalia (Pg), it was found that in the boys with IP the basal plasma testosterone levels were lower and the response of plasma LH to LRH stimulation lesser than in the controls. However, when these parameters were plotted against the pubertal stage for pubic hair (Ph) it was found, that in the boys with IP the plasma testosterone levels were significantly higher and the response of both LH and FSH stimulation greater than in the control group. It was concluded that irregular puberty in boys may be regarded as a normal variation. The delayed development of sexual hair and penile length, and retarded pubertal growth spurt and bone age maturation seen in these boys, with normal testicular development, may be explained by a temporary reduced peripheral sensitivity to androgens and a compensatory effort by the pituitary, manifested in increased secretion of LH and testosterone, relatively to their pubertal stage for pubic hair.

Adolescent↗
PubMed1976

Evaluation of pituitary-adrenal function in patients with chronic bronchial asthma following substitution of steroid treatment with disodium cromoglycate (Lomudal).

In a group of 32 steroid-dependent asthmatic patients an attempt was made to replace steroid treatment with disodium cromoglycate (Lomudal). Withdrawal of steroids was accompanied by a transitory stage of combined corticotropin-Lomudal treatment for 6 to 8 mo. Pituitary-adrenal function was assessed by ACTH and Metopirone test. Before treatment an impairment of pituitary-adrenal function was found in most of our patients, although in 26 patients a normal increment of plasma cortisol was found after ACTH stimulation. At the end of the combined treatment, 17 patients are now on Lomudal with normal pituitary-adrenal function, 9 patients need small quantities of steroids occasionally, and 6 patients are steroid-dependent.

17-Hydroxycorticosteroids↗