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Biomedical subjects

J S Cohen

Publications and source records attributed to J S Cohen.

At least 19 recordsLinked to original sources
PubMed1996

The Physicians' Desk Reference. Problems and possible improvements.

The Physicians' Desk Reference (PDR) is a widely used source of drug information by American physicians and patients, but as we shall discuss, it suffers from numerous shortcomings. The PDR is a collection of written and pictorial information that is provided and paid for by pharmaceutical manufacturers. The written material for a given drug is a compilation of data and recommendations that are identical to those in the drug's package insert. The wording and directives that are included in these package inserts (and thus in the PDR) represent information that the pharmaceutical companies are permitted to present following discussion and approval by the Food and Drug Administration (FDA), Rockville, Md. The PDR is thus a negotiated effort of commercial enterprises and governmental regulators.

Aged↗
PubMed1996

NMR investigations of duplex stability of phosphorothioate and phosphorodithioate DNA analogues modified in both strands.

Duplex formation from the self-complementary 12mer d(CGCGAATTCGCG) (Dickerson dodecamer) in which all phosphodiester linkages were replaced by phosphorothioate or phosphorodithioate linkages was studied using variable-temperature 1H and 31P NMR spectroscopy. Melting temperatures of the dodecamer, measured spectrophotometrically, showed significant decrease upon sulfur substitution (Tm 49 degrees C for the phosphorothioate and 21 degrees C for the phosphorodithioate, compared with 68 degrees C for the unmodified oligomer, in 1 M salt). Hyperchromicity observed upon melting of the dithioate was surprisingly low. NOESY spectra of the monothioate showed a cross-peak pattern characteristic for a right-handed duplex. Imino proton resonances of the duplex, shown by the mono- and the dithioate, were similar to those of the parent compound. In spite of monophasic melting curves, temperature dependence of the imino proton resonances and phosphorus resonances of the phosphorodithioate indicated heterogeneity with respect to base-pairing, compatible with the presence of a hairpin loop. Relaxation times (T1) of the imino protons in the phosphorothioate, determined by the saturation recovery method, were considerably shorter than in the unmodified oligomer. Base-pair lifetimes in the unmodified Dickerson dodecamer, determined by catalyst-dependent changes in relaxation rates of imino protons, were in the range of 2-30 ms at 20 degrees C. Strongly reduced base-pair lifetimes were found in the phosphorothioate analogue.

DNA↗
PubMed1996

Treatment of perianal infection following bone marrow transplantation.

PURPOSE: Bone marrow transplantation (BMT) is often associated with profound neutropenia. Allogeneic transplant recipients also have defects in both humoral and cellular immunity and thus are subject to increased risk of serious, often life-threatening, infection even beyond the period of granulocyte recovery. The current study was undertaken to evaluate patients who required operative intervention for perianal sepsis following BMT. METHODS: The bone marrow transplant database at a single institution was used to identify all patients diagnosed with perianal infections after autologous or allogeneic BMT. Charts were reviewed in a retrospective manner. RESULTS: Over a ten-year period ending in November 1993, 963 BMT were performed at the City of Hope National Medical Center. Twenty-four patients were diagnosed with perianal infections following their transplants. Fifteen patients did not have purulent collections requiring drainage and were treated with antibiotics and supportive measures alone. Nine patients (37.5 percent) required surgical intervention between 10 and 380 days following transplantation. At the time of surgical intervention, seven patients had purulent collections and two patients had acute and chronic inflammation, tissue necrosis, and fibrosis. Of the two patients with an absolute neutrophil count less than 1,000, a purulent collection was found in one of the patients. Cultures taken from perianal abscesses were almost all polymicrobial, and the most common organisms were Escherichia coli, Bacteroides, Enterococcus, and Klebsiella. For those patients undergoing surgical intervention, mean time to complete wound closure by secondary intention was 37.6 days; five patients healed in less than 15 days, two patients healed at 93 and 114 days, and two patients had persistent, open wounds at time of death, which was unrelated to their perianal disease. Five patients were receiving systemic steroids at time of surgical intervention; this did not appear to affect time to wound healing. CONCLUSIONS: Perianal infections are a rare complication of BMT. Majority of these infections are polymicrobial, and organisms isolated are similar to those seen in the perianal infections of nonimmunosuppressed patients. Despite steroid use, granulocytopenia does not exclude the possible presence of purulent collections, and clinical examination should guide the decision for surgical drainage. In general, perianal wound healing is not prolonged in BMT patients.

Abscess↗
PubMed1996

Re-forming the flat anterior chamber with Healon.

A shallow or flat anterior chamber may occur after complicated cataract surgery, a filtering procedure for glaucoma, or combined surgery. We describe a technique for injecting sodium hyaluronate (Healon) into the anterior chamber through the previous paracentesis tract in the operating room or at the slitlamp microscope. Re-forming the anterior chamber with Healon may pre-empt the anatomical sequelae of prolonged anterior chamber shallowing and prevent the need for more invasive surgery.

Aged↗
PubMed1996

A second locus for Rieger syndrome maps to chromosome 13q14.

Rieger syndrome is a genetically and phenotypically heterogeneous disorder typically characterized by malformations of the eyes, teeth, and umbilicus. The syndrome is inherited as an autosomal dominant trait and exhibits significant variable expressivity. One locus associated with this disorder has been mapped to 4q25. Using a large four-generation pedigree, we have identified a second locus for Rieger syndrome located on chromosome 13q14.

Abnormalities, Multiple↗
PubMed1995

Hormone dependence of breast cancer cells and the effects of tamoxifen and estrogen: 31P NMR studies.

Many breast tumors appear to progress from estrogen-dependent growth to a more malignant phenotype characterized by estrogen-independent growth, antiestrogen resistance, and a high metastatic potential. Utilizing 31P NMR spectroscopy on human breast cancer cells growing in vitro, we have investigated the effects of 17 beta-estradiol and tamoxifen on the metabolic/bioenergetic spectra of a series of human breast cancer cells that vary in their estrogen and antiestrogen responsiveness. A comparison of baseline spectra associates higher levels of phosphodiesters and UDP-glucosides (e.g. UDP-glucose, UDP-N-acetylglucosamine), and lower phosphocholine/glycerylphosphocholine and phosphocholine/phosphoethanolamine ratios, with the acquisition of estrogen-independent growth in estrogen receptor expressing cells. No metabolic changes are clearly associated with the metastatic phenotype. Whilst estrogen treatment produces no consistently significant spectral changes in any of the cell lines, the estrogen-independent and estrogen-responsive MCF7/MIII cell line responds to tamoxifen treatment by significantly increasing all spectral resonances 30%-40% above baseline values. This may reflect a tamoxifen-induced change to a more differentiated or apoptotic phenotype, or an attempt by the cells to reverse the inhibitory effects of the drug. The ability to detect metabolic changes in response to tamoxifen by NMR spectroscopy may provide a novel means to identify those tumors that are responsive to antiestrogen therapy.

Adenocarcinoma↗
PubMed1995

Antisense approaches to cancer gene therapy.

Recent advances in the use of oligodeoxynucleotide and plasmid-derived RNA as antisense agents of special relevance to cancer gene therapy are summarized with emphasis on agents and systems which have lead to clinical trials and/or regression of established tumors in animal model systems. Transformed cell lines bearing plasmids and viruses designed for the transcription of antisense RNA have the advantage that they can be characterized thoroughly and the effects of antisense RNA on target gene expression and phenotype can be studied easily in vivo. Promising results make the considerable efforts of applying oligodeoxynucleotides in whole animals and in clinical trials more plausible. Conversely, oligodeoxynucleotide experiments which yield promising results in tissue culture can be generalized to the in vivo setting by development of clones of cells bearing plasmid-derived antisense RNA against the same target. Several examples of the concordant results for oligodeoxynucleotide and plasmid-derived antisense RNA against the same target are considered. The importance of examination of antisense effects in syngeneic and immunocompetent hosts is illustrated by studies of insulin-like growth factor and insulin-like growth factor receptor where tumor regression and protection against tumor formation have been observed for particular cell types in defined settings.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Antisense pro-drugs: 5'-ester oligodeoxynucleotides.

Oligonucleotides bearing a terminal lipophilic group attached through a biodegradable ester bond should be useful as antisense pro-drugs with improved cellular uptake. The synthesis of 5'-ester oligonucleotides is, however, problematic due to lability of the ester bond during aqueous ammonia treatment that is commonly used for the deprotection of synthetic oligonucleotides. The synthesis of 5'-palmitoyl oligodeoxynucleotides was accomplished in good yield by the use of a combination of base-labile tert-butylphenoxyacetyl amino protecting groups (t-BPA), the oxalyl-CPG anchor group, and ethanolamine (EA) as a deprotecting reagent.

Acylation↗
PubMed1994

Attitudes toward assisted suicide and euthanasia among physicians in Washington State.

BACKGROUND: Despite considerable public interest in legalizing physician-assisted suicide and euthanasia, little is known about physicians' attitudes toward these practices. METHODS: We sent questionnaires to 1355 randomly selected physicians in the state of Washington, including all hematologists and oncologists and a disproportionately high number of internists, family practitioners, psychiatrists, and general surgeons. To avoid ambiguity in our survey, instead of "physician-assisted suicide," we used the phrase "prescription of medication [e.g., narcotics or barbiturates] or the counseling of an ill patient so he or she may use an overdose to end his or her own life." Instead of "euthanasia," we used the phrase "deliberate administration of an overdose of medication to an ill patient at his or her request with the primary intent to end his or her life." RESULTS: Of the 1355 eligible physicians who received our questionnaire, 938 (69 percent) responded. Forty-eight percent of the respondents agreed with the statement that euthanasia is never ethically justified, and 42 percent disagreed. Fifty-four percent thought euthanasia should be legal in some situations, but only 33 percent stated that they would be willing to perform euthanasia. Thirty-nine percent of respondents agreed with the statement that physician-assisted suicide is never ethically justified, and 50 percent disagreed. Fifty-three percent thought assisted suicide should be legal in some situations, but only 40 percent stated that they would be willing to assist a patient in committing suicide. Of the groups surveyed, hematologists and oncologists were most likely to oppose euthanasia and assisted suicide, and psychiatrists were most likely to support these practices. CONCLUSIONS: The attitudes toward physician-assisted suicide and euthanasia of physicians in Washington State are polarized. A slight majority favors legalizing physician-assisted suicide and euthanasia in at least some situations, but most would be unwilling to participate in these practices themselves.

Attitude of Health Personnel↗
PubMed1994

On the rapid deprotection of synthetic oligonucleotides and analogs.

The efficiency of oligodeoxynucleotide deprotection is greatly enhanced using a combination of: (a) ethanolamine, and especially a mixture of hydrazine, ethanolamine and methanol, in place of the usual aqueous ammonia; (b) tert-butylphenoxyacetyl amino protecting groups, and (c) oxalyl link between the first nucleotide and the polymeric support. The extent of base modification, particularly of C, is shown to be extremely low, and the quality of deprotected oligonucleotides is as high as in the case of ammonia deprotection. This method is also shown to be applicable to the preparation of phosphorothioate and methylphosphonate oligodeoxynucleotides and oligoribonucleotides.

Base Sequence↗
PubMed1994

Measurement of pharmacodynamic effects of dexamethasone on epidermis by phosphorus nuclear magnetic resonance spectroscopy in vitro.

An intact, viable epidermal preparation was perfused and phosphoenergetic and phospholipid metabolite levels were measured by 31P NMR. The preparation was stable in the NMR perfusion apparatus for 24 h. The effects of inclusion of ethanolamine and dexamethasone-21-acetate in the perfusion media on phosphorus-containing metabolites was assessed by examination of serial 31P NMR spectra. Phosphomonoesters increased significantly during the fourth hour of perfusion with ethanolamine (3 mM) and remained elevated. A corresponding decrease in nucleotide triphosphates was noted, but phosphocreatine (PCr) remained unchanged. Dexamethasone perfusion resulted in a biphasic effect on phosphomonoester metabolism and a dose-dependent decrease in PCr and nucleotide triphosphate levels. A log-linear relationship was observed between dexamethasone dose in the 1-100-nM range and a decrease in PCr. These techniques with an isolated intact epidermal preparation are useful for elucidating mechanisms of corticosteroid action on the skin and serve as a basis for developing a mechanistically relevant topical corticosteroid bioequivalence technique.

Animals↗
PubMed1994

Lymphocyte activation-31P magnetic resonance studies of energy metabolism and phospholipid pathways.

31P NMR spectra of perfused lymphocytes embedded in alginate capsules and activated by interleukin-2 (IL-2) are remarkably different from those of control lymphocytes. The main differences are the appearance and gradual increase of phosphodiester signals, glycerophosphocholine and glycerophosphoethanolamine. These metabolic changes also occur following perfusion with phorbol ester and after incubation with phytohemagglutinin (PHA) and are not dependent on a special growth medium. Nifedipine, a calcium channel blocking drug, inhibits the effects of PHA, but not of IL-2. There are no NMR spectral differences between peripheral lymphocytes, stimulated for 3 weeks, and tumor-infiltrating lymphocytes. Thus, sustained accelerated turnover of phosphatidylcholine (PC) and phosphatidylethanolamine is an inherent feature of the activation process. 31P NMR spectra of lymphocytes are characterized by a low phosphocholine signal. Perfusion studies with high concentrations of choline and the use of dapsone, an inhibitor of phosphocholine cytidyltransferase, indicate that choline kinase plays a key role in regulating PC synthesis in human lymphocytes.

Choline Kinase↗
PubMed1994

Metabolism of breast cancer cells as revealed by non-invasive magnetic resonance spectroscopy studies.

The basis for the use of nuclear magnetic resonance (NMR) spectroscopy as a tool to study the metabolism of breast cancer cells is described. The differences between proton (1H), carbon (13C), and phosphorus (31P) NMR methods is explained, and the techniques of cell extracts, cell suspensions and perfusion methods for cells are detailed. In order to perfuse cells they are preferably trapped in a gel matrix, either in the form of a thread or a bead. The gel must have appropriate properties that enables efficient oxygenation and availability of nutrients and drugs. The metabolic effects of perfusion of breast cancer cells with nutrients, drugs, and hormones are reported, and the clinical relevance of these results and methods are outlined.

Adenocarcinoma↗
PubMed1994

Phosphorothioate oligonucleotides inhibit the replication of lentiviruses and type D retroviruses, but not that of type C retroviruses.

Phosphorothioate analogs of oligodeoxynucleotides at a concentration of 2 microM protected Himalayan tahr cells from infection by caprine arthritis encephalitis virus (CAEV) and equine dermis cells from infection by equine infectious anemia virus (EIAV). The characteristics of this inhibition against these lentiviruses are similar to those previously described for the inhibition of HIV-1 in ATH8 cells [17]. Thus, the 28-mer homo-oligomer of cytidine [S-(dC)28] was at least as effective as three anti-sense sequences targeted to the LTR, gag, and env regions of CAEV. The effectiveness of homo-oligomers of equal length was in the order C >> A > T, and a random 28-copolymer with a composition of 2C:1G was as effective as S-(dC)28. Shorter oligonucleotides were less effective (28 > 14 > 5 mers) for all base compositions tested. While replication of a simian type D retrovirus was inhibited by S-(dC)28, this compound did not inhibit the cytopathogenicity of two type C retroviruses, amphotropic murine leukemia virus (MuLV), and baboon endogenous virus, when they were tested in the same cell lines used to support the replication of lentiviruses. Southern blot analysis of the high molecular weight DNA of drug-treated CAEV-infected cells showed that S-(dC)28 was acting at or before the reverse transcription step. Our present data and the earlier finding that S-(dC)28 is a potent in vitro inhibitor of the MuLV reverse transcriptase [15] suggest that S-(dC)28 is acting very early in the replication cycle of these lentiviruses. Since MuLV reverse transcriptase is inhibited in vitro, but its replication is not blocked in permissive cells, our data suggest that the phosphorothioate oligonucleotides are preventing virus attachment.

Animals↗