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Biomedical subjects

M Freund

Publications and source records attributed to M Freund.

At least 271 records · Page 15Linked to original sources
PubMed1988

Interaction of human immunodeficiency virus with human sperm in vitro.

Transmission of human immunodeficiency virus (HIV) in semen by sexual intercourse is believed to be a major etiological factor in the spread of the disease. In order to explore the role of sperm in this transmission, cell-free HIV-1(IIIB) was coincubated with human sperm for 5 h. After incubation, unattached HIV-1 was extensively washed off the cells and the presence and location of HIV-1 in or on the sperm was determined by electron microscopic (EM) and immunofluorescence methods. Examination of sperm at the EM level showed that HIV-1 attaches to the sperm surface and enters the sperm through the intact cell membrane. Immunofluorescence studies, using polyvalent anti-HIV antibodies, demonstrated the presence of small round fluorescent particles in 5-10% of sperm heads after 5 h of incubation. A search for HIV-1 receptors (CD4 epitopes) revealed the presence of OKT4 epitopes, including OKT4A, B, D, and F on 5-10% of sperm by epifluorescence microscopy and on 10-20% of sperm by flow-cytometric analysis. These in vitro data suggest that human sperm may be the primary cellular element in the transmission of HIV by semen.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Recombinant human granulocyte-macrophage colony stimulating factor (rh GM-CSF) after bone marrow transplantation.

Bone marrow transplantation improves the chances of survival in a variety of hematological malignancies. However, infectious complications during the post-transplant phase contribute significantly to morbidity and mortality. To reduce the duration of granulocytopenia, which is approximately 20 days after BMT, in this study patients with ALL, relapsed or high-grade NHL, relapsed or refractory HD, or Neuroblastoma stage III/IV, were given rh GM-CSF to assess the effects on hematological and immunological reconstitution after conditioning therapy and BMT. The results of 9 patients are presented. After autologous BMT and subsequent rh GM-CSF therapy, a peripheral blood neutrophil count of 500/microliters was reached within 8-12 days, i.e., between 7 and 10 days earlier than would have been expected without rh GM-CSF. Furthermore, it appeared that rh GM-CSF was useful in case of insufficient bone marrow regeneration post autologous transplant. The influence of rh GM-CSF after allogeneic BMT is not yet clear. Further studies will be necessary to evaluate the potential of this promising new drug after BMT.

Adult↗
PubMed1988

High-dose methotrexate: pharmacokinetics in children and young adults.

Pharmacokinetics of methotrexate (MTX) was studied in 34 patients (age 1-25 years, median 12 years) predominantly with primary brain tumors and osteosarcoma, who received a total of 64 high-dose infusions (12 g/m2/4 h, maximum dose 20 g), followed by leucovorin rescue (COSS 82). Serum samples were collected over a period of at least 72 h after the end of infusion and MTX was measured by enzyme immunoassay (EMIT). The data were fitted to a biexponential equation using a nonlinear regression analysis. The concentration-time decay of MTX in serum observed in 29/34 patients receiving 4 x 15 mg/m2/d p.o. leucovorin up to 5 days was biphasic with mean half-lives (+/- SD) of 2.42 +/- 0.45 h for t1/2 alpha and 19.9 +/- 7.6 h for t1/2 beta. The steady-state volume of distribution (Vss) was 0.56 +/- 0.18 l/kg and the total body clearance (CL) 71 +/- 20 ml/min/m2 (mean +/- SD). Peak serum concentrations ranged from 674-1778 mumol/l (mean +/- SD, 1201 +/- 293 mumol/l). In 5/34 patients who received a prolonged leucovorin rescue due to a delayed MTX elimination t1/2 alpha was greater than 3.1 h. The data of this study suggest that patients with MTX serum concentrations of less than or equal to 6.3 mumol/l at 24 h, less than or equal to 0.77 mumol/l at 48 h, and less than or equal to 0.33 mumol/l at 72 h after the end of infusion, and a t1/2 alpha of less than or equal to 3.1 h (97.5th percentiles) are at low risk of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults.

In a prospective multicenter study, 368 acute lymphoblastic leukemia (ALL) patients aged 15 to 65 years were treated with an intensified induction and reinduction regimen; 272 (73.9%) achieved complete remission (CR). The median remission duration (MRD) is 24.3 months, and the probability of being in continuous CR (CCR) at greater than 5 years is .37. The median survival for all 368 patients is 27.5 months, and the probability of being alive at 5 years is .39. For the 272 patients in remission the median survival is 58.4 months, and the probability of being alive at 5 years is .49. A lower CR rate was seen for patients with bleeding at diagnosis or with splenomegaly/hepatosplenomegaly. The prognostic factors unfavorable for remission duration were time to CR greater than 4 weeks v less than 4 weeks (P = .0002), age greater than 35 years v less than 35 years (P = .0008), leukocyte count greater than 30,000/microL v less than 30,000/microL (P = .0112), and null ALL v common ALL (c-ALL)/T cell ALL (T-ALL) (P = .05). The remission duration correlated strongly (P = .0001) with the number of these independent prognostic factors. In patients with none of these adverse factors the MRD has not yet been reached, with one adverse factor the MRD is 21.9 months, and with two or three adverse factors the MRD is only 9.6 months. For the immunologic subtype T-ALL, the probability of being in CCR at greater than 5 years is .55; for c-ALL, .34; and for null ALL, .24. According to these results, patients were stratified into a low-risk group with a CCR rate of .62 and a high-risk group with a CCR rate of .28, with the latter now allocated to either further chemotherapy or bone marrow transplantation in first remission.

Adolescent↗
PubMed1987

A point mutation in a type I procollagen gene converts glycine 748 of the alpha 1 chain to cysteine and destabilizes the triple helix in a lethal variant of osteogenesis imperfecta.

Synthesis of type I procollagen was examined in fibroblasts from a proband with a lethal perinatal variant of osteogenesis imperfecta. After trypsin digestion of the type I procollagen, a portion of the alpha 1 (I) chains was recovered as disulfide-linked dimers. Digestion of the protein with vertebrate collagenase and mapping of cyanogen bromide peptides suggested that a new cysteine residue was present between residues 551 and 775 of the alpha 1 (I) chain. Sequencing of cloned cDNAs prepared using mRNA from the proband's fibroblasts demonstrated that some of the clones contained a single base mutation that converted the glycine codon in amino acid position 748 of the alpha 1 (I) chain to a cysteine codon. About 80% of the type I procollagen synthesized by the proband's fibroblasts had a decreased thermal stability. The results, therefore, were consistent with the conclusion that normal pro-alpha 1 (I) chains and pro-alpha 1 (I) chains containing a cysteine residue in the alpha chain domain were synthesized in about equal amounts and incorporated randomly into type I procollagen. However, only about 10% of the alpha 1 (I) chains generated by trypsin digestion were disulfide-linked. Further studies demonstrated a decreased rate of secretion of type I procollagen containing the new cysteine residue and decreased processing of the protein by procollagen N-proteinase in cultures of postconfluent fibroblasts. Both parents were phenotypically normal and their fibroblasts synthesized only normal type I procollagen. Therefore, the mutation in the proband was a sporadic one and is very likely to have caused the connective tissue fragility that produced the lethal phenotype.

Amino Acid Sequence↗
PubMed1987

[Low-dose alpha-interferon treatment of hairy cell leukemia].

Fifteen patients (36-71 years old) with histologically proven hairy-cell leukemia were treated with a low dose of IFN-alpha. The treatment consisted of 1 million I.U. given daily subcutaneously. After 1 month the dose was reduced in all patients 1 million I.U. thrice weekly. Four of the 15 patients have been splenectomized, with two patients receiving chemotherapy prior to the IFN treatment. All patients exhibited at least one cytopenia. The IFN treatment was well tolerated. Only two of the 15 patients experienced mild fever after the first injection, one patient had apathia and mild somnolence after 2 months of therapy. At present 15 patients can be evaluated: 6-18 months after start of therapy two patients showed a complete response with normalization of both peripheral blood and bone marrow, 10 patients experienced a partial response, while one patient showed a slight response with improvement of the thrombocyte count only. Two patients showed no improvement after 3 months of therapy; these patients are presently being treated with 5 million I.U. IFN-alpha thrice weekly. In spite of the low number of patients these data strongly indicate that IFN-alpha-2 is effective in hairy-cell leukemia at this low dose.

Adult↗
PubMed1987

[Beta interferon therapy in hairy cell leukemia].

Eleven patients with histologically proven hairy-cell leukemia were treated for 2 to 6 months with a natural beta-interferon (beta-IFN) preparation (3 X 4 million units week i.v.). Three of the eight evaluable patients experienced a partial response, two a minor response, and three no improvement. A reduction of the hairy-cell infiltration of the bone marrow was observed in one patient. Typical IFN side-effects with flu-like symptoms were noted. These results demonstrate that IFN-beta has some clinical efficacy in hairy-cell leukemia.

Adult↗
PubMed1987

Visual versus cinemicrographic evaluation of human sperm motility and morphology.

Ratings of human sperm motility by visual estimation through the microscope remain important measures of semen quality and of male fertility. More objective methods, including cinemicrography, time lapse photography, and videomicrography, are advocated. Subjective (visual) and objective (cinemicrographic) ratings of motility were compared. Sixty workers in 30 laboratories rated motilities of 40 specimens on motion picture film, and motilities were also measured by cinephotomicrographic methods. The morphology of each of the motile and immotile sperm was rated. In 34 of 40 specimens visual ratings were higher (range = +2 to +31%) than actual percentage motility. Specimens with both high sperm concentration and forward progression received the highest overestimations by visual rating. This was especially apparent in specimens with the highest motility. There was a statistically significant positive relationship between sperm motility and morphology rated on a one-by-one basis, but the relationship was too small to influence the visual rating of human sperm motility.

Humans↗
PubMed1987

Considerations about the cloverleaf skull.

The study of four cloverleaf skulls (two fetuses, one infant, and a young adult) concerns two Pfeiffer syndromes, a thanatophoric dysplasia and an isolated case. Clinical and radiologic examinations showed malformations at the level of the calvarium, the base, orbital cavities, and, sometimes, limb abnormalities. Correlations between these findings and the microradiographic analysis of nondemineralized sections elucidate this trilobular appearance of the skull. Premature temporoparietal suture closure terminates at a constricted surface of the lateral sides of the skull during the fetal life. Extension of the synostosis to coronal and frontal sutures and thickening of the occipital bone squama block lengthening of the skull. The consecutive reduction in skull volume is compensated by the maintenance of the permeability during the neonatal period of the sagittal and lambdoid sutures. Microradiographic examination shows that this anomaly may be of vascular origin and associated with abnormal osteoclastic resorption.

Adult↗
PubMed1986

The mechanism of action of lymphokines. IX. The enzymatic basis of hydrogen peroxide production by lymphokine-activated macrophages.

The purpose of this study was to elucidate the biochemical basis of the enhanced hydrogen peroxide (H2O2) production by guinea pig peritoneal macrophages (MP) cultured in lymphokine (LK)-containing medium. The markedly augmented H2O2 generation by these cells, demonstrable by the horseradish peroxidase (HRP)-catalyzed oxidation of phenol red, is distinguished by its lack of dependence on a second stimulus. We demonstrate that H2O2 production is truly spontaneous and is not caused by a stimulant present among the H2O2 assay reagents. The principal candidate for such a role was HRP type II (a mixture of five isoenzymes) that was reported to be capable of eliciting an oxidative burst in MP. Four distinct HRP isoenzymes that were found incapable of provoking an oxidative response were nevertheless adequate for demonstrating H2O2 production by LK-activated MP. Blocking the MP receptor for mannose by the addition of mannan to the assay system resulted in enhanced detection of H2O2 by low concentrations of HRP type II and by three out of four HRP isoenzymes. Treatment of MP with LK-containing medium for 72 hr did not result in a significant change in the activity of cellular superoxide dismutase (SOD) compared with MP cultured for the same length of time in control medium. By using the specific inhibitor of copper, zinc-containing SOD, sodium diethyldithiocarbamate (DDC), and the universal SOD inhibitor, sodium nitroprusside, we found that the predominant enzyme in guinea pig peritoneal MP is probably manganese-containing SOD. Incubation of LK-activated MP with nitroprusside resulted in almost total inhibition of H2O2 production and a simultaneous switch to superoxide (O2-) liberation. Similar exposure to DDC had no effect. These data indicate that H2O2 produced by LK-activated MP is derived exclusively by enzymatic dismutation of O2- mediated by a manganese-containing SOD. The increase in spontaneous H2O2 production induced by LK is therefore secondary to augmented O2- production that occurs at a cellular location where O2- is accessible to SOD. The enzymatic basis of the enhanced oxygen radical production was investigated by determining the kinetic parameters of the O2- -forming NADPH oxidase of resting LK-treated MP in a cellfree system in which O-2 production was induced by sodium dodecyl sulfate. The Km for NADPH and the Vmax of the enzyme of LK-treated MP were not different from those of the enzyme of MP incubated in control medium. We conclude that LK treatment of MP does not modulate the NADPH oxidase itself but, most likely, a process related to activation of the enzyme.

Animals↗