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Biomedical subjects

J Cook

Publications and source records attributed to J Cook.

At least 109 records · Page 6Linked to original sources

Economic winners and losers after introduction of an effective new therapy depend on the type of payment system.

An effective therapy for a costly illness has economic consequences. There may also be differences between provider costs and payer costs and initial versus long-term costs; costs may also vary with the reimbursement scheme. Consider the case of an effective therapy to prevent restenosis after coronary angioplasty. Assume that the initial provider cost of angioplasty is $12,000 and that restenosis within 6 months results in repeat angioplasty in 20% of cases, with a follow-up cost of $2,400, or $14,400 total. Assume that a therapy costs $1,000 per angioplasty and decreases restenosis by 50%, resulting in repeat angioplasty in 10% of cases. This will result in an initial cost of $13,000 and a follow-up cost of $1,300, or $14,300 total. The total societal costs will be -$100, a slight savings. Thus, the $1,100 cost of therapy is offset by reduced costs associated with restenosis, and the societal costs are almost neutral. Assume that under fee for service providers charge costs plus 10% and that without the new therapy either a package price or a capitated system is revenue neutral. Changes in costs resulting from therapy to prevent restenosis are as follows (plus sign indicates cost or loss; minus sign indicates savings or profit): [table: see text] Under fee for service, the payer takes the risks, and the economic consequences to providers are minimal. The situation is reversed under capitation. For whoever takes the risk, there is an initial loss to pay for the therapy, but a long-term gain due to less restenosis. Under package pricing, the providers lose because of the cost of therapy and fewer procedures, while the payers gain. A new therapy, even if it is revenue neutral to society overall, may have considerable economic consequences, which vary with time and with the different perspectives of providers and payers.

Angioplasty, Balloon, Coronary↗

IL-16 inhibition of CD3-dependent lymphocyte activation and proliferation.

We have recently described the cDNA and predicted protein structure of a natural soluble CD4 ligand, IL-16. IL-16 is chemotactic for CD4+ T cells and induces functional IL-2 receptors in CD4+ T cells. The binding of IL-16 to CD4 results in activation of p56(lck), whose adaptor function is essential for the chemotactic response. Subsequently, increases in intracellular Ca2+ and phosphatidylinositol 1,4,5-trisphosphate occur, as does translocation of protein kinase C from cytosol to membrane. Because of the similarities between these signals and functions and those noted for the CD4 ligand HIV-1 gp120, we investigated the potential regulatory effects of IL-16 on CD3/TCR-mediated lymphocyte activation. Preincubation of human T cells with IL-16 up to 24 h before activation with plate-bound anti-CD3 Abs reduced T cell activation by 80%, as monitored by IL-2R expression and [3H]thymidine uptake. If IL-16 was added following anti-CD3 activation, no suppression was noted. The suppressive effects of preincubation with IL-16 were not rescued by the addition of rIL-2 and were not the result of priming for anti-CD3-induced apoptosis. In addition, IL-16 had no effect on surface expression of CD3 or CD4. However, IL-16 did reduce the magnitude of the anti-CD3-induced intracellular Ca2+ increase. These studies indicate that while the interaction of CD4 with its natural ligand, IL-16, results in Ag-independent chemotaxis and IL-2R expression, this pro-inflammatory state is associated with subsequent transient inhibition of responsiveness via the CD3/TCR complex.

Apoptosis↗

Tumor growth and tumor radiosensitivity in mice given myeloprotective doses of fibroblast growth factors.

BACKGROUND: Radiation at doses high enough to cure cancer also frequently destroys normal tissue. Development of agents that protect normal tissue without also protecting diseased tissue has been difficult. In vivo radioprotection of bone marrow by acidic and basic fibroblast growth factors (FGF1 and FGF2, respectively) has recently been demonstrated after whole-body irradiation of C3H/HeN mice. PURPOSE: Our purpose was to determine whether myeloprotective doses of those growth factors also protect malignant tumors. METHODS: First, we investigated the effects of exogenous FGF1 or FGF2 (FGF1/2) administration (treatment group receiving two intravenous injections of 3 micrograms FGF1/2 per mouse 24 hours and 4 hours before local irradiation of right hind leg and control group receiving two intravenous injections of 0.1 mL of saline) on growth and radiosensitivity of three transplantable murine tumors (one squamous cell carcinoma [SCC-VII] and two sarcomas [KHT and Rif-1]), all of which were grown in C3H/HeN mice. We then evaluated the effect of FGF1/2 on tumor cell proliferation, cell cycle distribution, and pulmonary metastatic frequency in the mice. Specifically, survival studies were performed in mice treated with 0, 6, 6.5, 7.5, 8.5, 9, or 10 Gy whole-body irradiation with or without FGF2 (n = 250). Rif-1 (n = 40), KHT (n = 40), and SCC-VII (n = 40) tumors were implanted in the hind leg of mice, and mice were treated with FGF2 or saline when their tumor-bearing thighs were 9 mm in diameter. In separate experiments (treatment group receiving two injections of 3 micrograms each of FGF2 [6 micrograms total] either intravenously or intratumorally 24 hours and 4 hours before local tumor irradiation and control group receiving 0.1 mL saline), tumor growth was followed, and mice were killed to count lung metastases and measure tumor proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine labeling at various times thereafter (three to eight mice per group). Tumor growth curves of untreated and irradiated tumors were determined with and without intravenous or intratumoral FGF1/2 in SCC-VII tumors (n = 120). Radiation doses to the tumor-bearing leg were 15 and 30 Gy for SCC-VII, 30 Gy for Rif-1, and 15 Gy for KHT. From each experiment, the mean (+/- 1 standard error) was calculated from data obtained from three to 20 mice. Statistical tests used included two-tailed Student's t test, the chi-squared test, and Fisher's exact test. All P values represent two-tailed tests of statistical significance. RESULTS: There was no statistically significant difference in tumor growth rate between FGF2-treated and saline-treated mice when FGF2 was administered intravenously at doses and schedules found to be optimally myeloprotective in whole-body irradiation experiments. Intravenous administration of FGF2 did not induce lung metastases, and it did not augment the S-phase fraction of tumor cells. Likewise, there was no evidence of enhanced cell proliferation as measured by PCNA-labeling index. Intratumoral injection of FGF1/2 did increase the size of SCC-VII tumors (P < .05 [Student's t test] at 3 days after treatment); however, the radiation response after intratumoral injection of growth factor was not compromised. CONCLUSION: Low intravenous doses of FGF1 or FGF2 appear to protect bone marrow from the toxic effects of radiation without increasing the rates of tumor growth or metastases or decreasing the radiosensitivity of tumors.

Animals↗

Drug delivery to brain tumors.

We develop a macroscopic model for delivering drug to brain tumors. The model accounts for bulk convective and diffusive transport across the blood-brain barrier and through the interstitial space. Through mathematical analysis and simulations, we assess the effects of changing parameters (within physiological bounds) on drug delivery. We find that there is an optimal treatment for convective drug delivery to the center of the tumor. We interpret this phenomenon in terms of traffic flow. The implications of our analyses on existing chemotherapeutic protocols are discussed.

Antineoplastic Agents↗

Subtilisin-catalyzed religation of proteolyzed hen egg-white lysozyme: investigation of the role of disulfides.

BACKGROUND: The use of proteases to form, instead of break, peptide bonds has expanded the repertoire of techniques available for protein semisynthesis. Several groups have previously reported the use of proteases in aqueous-organic solvents to form single amide bonds within proteins, but low yields and lengthy reaction times make this an impractical approach to protein synthesis. We recently found that proteolyzed triose phosphate isomerase can be re-ligated rapidly and efficiently by subtilisin, in mixed aqueous-organic solvent systems. RESULTS: We now report the use of subtilisin to resynthesize hen egg-white lysozyme from a mixture of its proteolyzed fragments in high yield and with rapid reaction times. This enzymatic religation can also be achieved after reduction of the four disulfide bonds present in lysozyme, with the same efficiency as that observed for the disulfide-containing proteolysis mixture. CONCLUSIONS: For egg-white lysozyme, the subtilisin religation reaction can be used to re-synthesize a proteolyzed protein even after reduction of disulfide bonds. The utility of this reaction in more generalized protein semisynthesis reactions is currently being explored.

Animals↗

Management preferences in stage I non-seminomatous germ cell tumours of the testis: an investigation among patients, controls and oncologists.

Increasingly, treatment choices leading to the same survival outcome can be offered to cancer patients (e.g. mastectomy or conservative surgery in early breast cancer). Two approaches available for post-orchidectomy, stage I patients with non-seminomatous germ cell tumours of the testis (NSGCTT), particularly those at high risk of relapse, include immediate adjuvant chemotherapy (two courses) or surveillance, with chemotherapy (typically four courses) given only on relapse. The aim of this study was to investigate which approach patients prefer. Questionnaires were given to newly diagnosed NSGCTT patients, to patients with previous experience of the two options and to non-cancer controls, including specialist testicular tumour oncologists. Participants were asked to choose between immediate chemotherapy, surveillance or for the doctor to decide, at recurrence risk levels ranging from 10% to 90%. Questionnaires were returned by 207 subjects in nine different groups. The risk thresholds at which subjects' management preference changed, within apparently homogeneous groups, varied greatly, although at least one subject in each group selected adjuvant chemotherapy at the lowest (10%) level of risk. Subjects tended to favour options of which they had previous experience. Cancer patients wanted the doctor to decide more frequently than controls. The wide variability observed makes it difficult to predict which option an individual will select. Personality factors and personal circumstances, other than specific experience and knowledge, are obviously influential. Many patients would prefer their doctor to decide, but variability among oncologists is as great as that among their patients.

Chemotherapy, Adjuvant↗

Determinants of haemoglobin level in steady-state homozygous sickle cell disease.

High total haemoglobin levels in homozygous sickle cell (SS) disease are a risk factor for painful crises, avascular necrosis of the femoral head, proliferative sickle retinopathy, and the acute chest syndrome. Since lowering the haemoglobin level may ameliorate these features, understanding the determinants of total haemoglobin may be of practical importance. A range of possible determinants including red cell characteristics, reticulocytes, serum iron, transferrin saturation, serum ferritin, alpha thalassaemia status, red cell mass and plasma volume, oxygen affinity, red cell survival, transferrin receptor and erythropoietin levels have been measured in 62 patients selected to provide a range of total haemoglobin and fetal haemoglobin levels. There were weak negative associations of haemoglobin with mean cell volume and mean cell haemoglobin concentration, strong negative associations with proportional reticulocyte counts, oxygen affinity, plasma volume, serum transferrin receptors, and erythropoietin levels and strong positive associations with red cell mass. Weighted analysis suggested that the statistically independent determinants of haemoglobin level were alpha thalassaemia, sex, red cell mass/body weight, plasma volume/body weight, fetal haemoglobin, and red cell count. The apparent contributions of red cell survival, P50, reticulocyte count, serum transferrin receptor and erythropoietin levels were explained by the effects of these other variables. The independent determinants as a group explained 91% of the variation in haemoglobin level.

Adult↗

The prevalence of psychiatric disorders in elderly residents of public housing.

BACKGROUND: This study estimates lifetime and one-month prevalence of psychiatric disorders among elderly public housing residents. METHOD: Nine hundred forty-five residents of six public housing developments for the elderly were administered the General Health Questionnaire (GHQ), the Mini-Mental State Examination (MMSE), and the CAGE by lay interviewers. Residents screening positive and a 10% random sample of screen negatives were administered the Structured Clinical Interview for DSM-III-R (SCID) and a DSM-III-R derived algorithm for dementia and delirium. Prevalence rates were estimated based on weighted data from 298 subjects. RESULTS: Thirty-six percent of participants screened positive on at least one instrument. Based on the case identification interview, estimated lifetime prevalence of psychiatric disorders was 57.6%, and one-month prevalence was 27.9%. Cognitive disorder (10.5%), mood disorder (8.0%), psychotic disorder (4.6%), and substance abuse/dependence (4.4%) were the most common current disorders. Mood disorders (26.6%) and substance abuse/dependence (23.0%) were the most prevalent lifetime disorders. Compared to data from the Epidemiologic Catchment Area, public housing residents have higher current rates of mood disorder, schizophrenia, and substance use disorder. CONCLUSIONS: Elderly residents of public housing suffer higher rates of psychiatric morbidity than older people living independently in the community. The high prevalence of psychiatric disorders in this growing population of low-income elderly presents a challenge to the delivery of mental health service.

Aged↗

Agranulocytosis and near fatal sepsis due to 'Mexican aspirin' (dipyrone).

The use of "unconventional" or alternative medicine has been reported in up to one third of American households, yet only 28% report the use of such agents to their physician. We present here a case of near fatal sepsis and agranulocytosis. The agranulocytosis is attributed to the use of dipyrone (Dolo-Tiaminol), which the patient obtained in Mexico as a stronger form of generic "aspirin." The pyrazolone class of analgesics, of which dipyrone is a derivative, was introduced in the late 19th century and had a meteoric rise in use until an associated rise in fatal agranulocytosis was discovered. These agents were banned by the Food and Drug Administration (FDA) in 1977. Dipyrone is thought to induce agranulocytosis by inducing an antibody response. With the widespread use of alternative treatments, it is important for physicians to inquire as to the use of unprescribed drugs. Several resources are available to aid with the identification of foreign drugs.

Agranulocytosis↗

A mathematical model of glioma growth: the effect of extent of surgical resection.

We have developed a mathematical model based on proliferation and infiltration of neoplastic cells that allows predictions to be made concerning the life expectancies following various extents of surgical resection of gliomas of all grades of malignancy. The key model parameters are the growth rate and the diffusion rate. These rates were initially derived from analysis of a case of recurrent anaplastic astrocytoma treated by chemotherapies. Numerical simulations allow us to estimate what would have happened to that patient if various extents of surgical resection, rather than chemotherapies, had been used. In each case, the shell of the infiltrating tumour that remains after 'gross total removal' or even a maximal excision continues to grow and regenerates the tumour mass remarkably rapidly. By developing a model that allows the growth and diffusion rates to define the distribution of cells at the time of diagnosis, and then varying these rates by about 50%, we created a hypothetical tumour patient population whose survival times show good agreement with the results recently reported by Kreth for treatments of glioblastomas. Tenfold decreases in the rates of growth and diffusion mimic the results reported by many other investigators with more slowly growing gliomas. Thus, the model quantitatively supports the ideas that (i) gliomas infiltrate so diffusely that they cannot be cured by resection alone, surgical or radiological, no matter how extensive that may be; (ii) the more extensive the resection, regardless of the degree of malignancy of the glioma, the greater the life expectancy; and (iii) measurements of the two rates, growth and diffusion, may be able to predict survival rates better than the current histological estimates of the type and grade of gliomas.

Cell Division↗

Three retroviral sequences in amphibians are distinct from those in mammals and birds.

We isolated and characterized three endogenous retroviral fragments from the dart-poison frog Dendrobates ventrimaculatus. These are the first retroviral sequences to be identified in amphibians, and consequently retroviruses have now been found in each of the five major vertebrate classes. Comparison of the amphibian retroviral fragments, termed DevI, DevII, and DevIII, with mammalian and avian isolates revealed significant differences between their nucleotide sequences. This suggested that they were only distantly related to the seven currently recognized retroviral genera. Additional analysis by phylogeny reconstruction showed that the amphibian retroviral fragments were approximately equally related to the Moloney leukemia-related viruses, the spumaviruses, and walleye dermal sarcoma virus. Hybridization experiments revealed that viruses closely related to DevI, DevII, and DevIII do not appear to be widespread in other vertebrates and that DevI, DevII, and DevIII are all present at high copy numbers within their amphibian hosts, typically at over 250 copies per genome. The viruses described here, along with two others which have recently been found in a fish and a reptile, indicate that there may be some major differences in the retroviruses harbored by different vertebrate classes. This suggests that further characterization of retroviruses of fish, reptiles, and amphibians will help in understanding the evolution of the whole retroviral family and may well lead to the discovery of retroviruses with novel biological properties.

Amino Acid Sequence↗

An exercise program in the treatment of fibromyalgia.

OBJECTIVE: To assess the utility of an exercise program, which included aerobic, flexibility and strengthening elements, in the treatment of fibromyalgia (FM). FM is a chronic musculoskeletal condition characterized by diffuse musculoskeletal pain and aching. It has been suggested that aerobic exercise is helpful in its treatment. METHODS: We studied 60 patients who met American College of Rheumatology criteria for FM and had no significant comorbidities. Measurements performed on each patient at the pre and poststudy assessment included the number of tender points (TP), total myalgic scores (TM), aerobic fitness (AF), flexibility and isokinetic strength. After initial evaluation patients were randomly assigned to either an exercise or a relaxation group. Each group met 3 times per week for 6 weeks for 1 h of supervised exercise or relaxation. All patients data were stored in a computerized database and statistical analysis was performed on all pre and poststudy assessments. RESULTS: Thirty-eight patients (18 exercise and 20 relaxation) completed the study. Analysis of our data showed no significant difference between the groups in their prestudy assessment. Poststudy assessments, however, showed a significant improvement between the exercise and relaxation groups in TP (p < 0.05), TM (p < 0.05), and AF (p < 0.05). Similar improvements were also found when the pre and poststudy assessment of the exercise group were compared. CONCLUSION: Exercise is helpful in the management of FM in the short term. It also shows that FM patients can undertake an exercise program which includes aerobic, flexibility, and strength training exercises without adverse effects. The long term utility of this type of exercise requires further evaluation.

Adult↗