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Biomedical subjects

J Lynch

Publications and source records attributed to J Lynch.

At least 199 records · Page 11Linked to original sources
PubMed1991

Polyamine involvement in the secretion and action of TGF-alpha in hormone sensitive human breast cancer cells in culture.

These experiments were designed to test polyamine (PA) involvement in the secretion and action of transforming growth factor alpha (TGF-alpha) in hormone responsive MCF-7 breast cancer cells in liquid culture. At the same time, we evaluated the influence of culture conditions (with serum vs. serum depleted) and subclonality of MCF-7 cells on PA involvement in estrogen (E2) and TGF-alpha stimulated cell proliferation. Despite inducing a profound suppression of cellular PA levels and inhibiting basal and E2-stimulated growth, administration of the PA synthesis inhibitor alpha-difluoromethylornithine (DFMO) did not influence either basal or E2-induced TGF-alpha secretion. In the same experiments, on the other hand, addition of DFMO completely blocked the growth stimulatory effect of exogenous TGF-alpha. However, when the culture conditions were changed to serum-free medium, TGF-alpha and E2-induced cell proliferation was affected modestly or not at all by DFMO administration, despite similar suppression of cellular ornithine decarboxylase (ODC) activity and PA levels. In addition, different clones of MCF-7 cells differed in their sensitivity to the antiproliferative effect of DFMO as well as in basal levels of ODC activity and PA. We conclude that PAs are not involved in basal or E2-stimulated TGF-alpha secretion in MCF-7 breast cancer cells. On the other hand, PAs do seem to be important mediators of TGF-alpha and E2-induced breast cancer cell proliferation, though the degree of such involvement appears to be influenced by serum factors and clonal variability of MCF-7 cells.

Breast Neoplasms↗
PubMed1991

Failure to detect homocysteine in the acid-hydrolysed plasmas of recent myocardial infarct patients.

We have sought the very high levels of homocysteine-containing compounds in the plasma hydrolysates of myocardial infarct patients reported by Olszewski and Szostak (Atherosclerosis, 69 (1988) 109-113). We studied 6 adult males with recent myocardial infarcts and 6 healthy adult males. We found that after hydrolysis of their plasmas for 5 h in 4 mol/l HCl at 110 degrees C, the amino acid chromatographs contained several small peaks in addition to the expected substantial peaks of the protein-constituent amino acids. However, the small peaks which eluted at the same times as homocysteine, homocystine and the mixed disulphide of homocysteine and cysteine, were in each case shown not to represent these compounds. Furthermore no homocysteine thiolactone was found in the chromatographs. We found no significant differences in the size of the small peaks between the patients and the controls. Prolonged hydrolysis resulted in decreased size of all but one of the small peaks suggesting that they were hydrolytic intermediates in the breakdown of plasma proteins. Electrophoresis at pH 10.39 of the unhydrolysed plasmas showed that the proteins were not significantly more homocysteinylated in patients than in controls. Thus we have been unable to substantiate some key observations made by Olszewski and Szostak.

Amino Acids↗
PubMed1991

Hereditary nonpolyposis colorectal cancer (Lynch syndromes I & II). Genetics, pathology, natural history, and cancer control, Part I.

Hereditary nonpolyposis colorectal cancer (HNPCC) is common, accounting for about 4-6% of the total colorectal cancer burden. It is heterogeneous and appears to be delineated into two clinical subsets, Lynch syndromes I and II. Lynch syndrome I is characterized by an autosomal dominantly inherited proclivity to early onset colonic cancer with proximal predominance and an excess of multiple primary colonic cancer. Lynch syndrome II has all of these features plus extracolonic cancer sites, the most common of which is endometrial carcinoma. The lack of premonitory physical signs or biomarkers of HNPCC makes diagnosis difficult. A careful family history, tempered by an understanding of the clinical and pathologic features of HNPCC, is the key to its assessment. This paper reviews HNPCC's natural history, its integral extracolonic cancer associations, its differential diagnosis, surveillance, and management strategies. Attention is focused upon the need for biomarker research in the interest of improving control of HNPCC.

Adenomatous Polyposis Coli↗
PubMed1991

Hereditary ovarian cancer. Pedigree studies, Part II.

Hereditary ovarian carcinoma is heterogenous. There are at least three genetic variants, namely, hereditary site-specific ovarian carcinoma, hereditary breast/ovarian carcinoma syndrome, and Lynch syndrome II. Early age of onset characterizes these disorders. A crucial hallmark of these disorders is the integral association of extraovarian cancers, such as carcinoma of the endometrium and colon in Lynch syndrome II. We have described 24 pedigrees of ovarian cancer-prone families in order to depict the several differing heterogenous variants. Interest in hereditary ovarian cancer has increased remarkably, due in part to the fact that its surveillance has been wholly unsatisfactory, as have therapeutic measures. Prevention through prophylactic oophorectomy offers hope. However, there is a risk for extraovarian peritoneal serous papillary carcinoma, consonant with primary cancer of the ovary. This must be discussed with these at-risk patients. Until a biomarker of acceptable sensitivity and specificity is identified, the family history must remain the key to hereditary ovarian cancer diagnosis.

Adult↗
PubMed1991

Identification and regulation of insulin-like growth factor binding proteins produced by hormone-dependent and -independent human breast cancer cell lines.

Using molecular hybridization, ligand blotting and immunoprecipitation, our studies were designed to identify the insulin-like growth factor binding proteins (IGFBPs) produced by human breast cancer cells in culture and evaluate their regulation by estradiol (E2) and polyamines (PA). We demonstrate that the hormone-dependent MCF-7 and -independent BT-20 cell lines express the mRNA for IGFBP-2 (1.7 kb) and secrete this BP (31 kDa) in the conditioned medium. In contrast, the hormone-independent MDA-MB-231 cell line does not express the IGFBP-2 gene, while synthesizing and secreting IGFBP-1. E2 administration (10(-9) M) did not significantly influence IGFBPs secretion in MCF-7 cells. Addition of alpha-difluoromethylornithine (DFMO, 4 mM), an inhibitor of PA biosynthesis, consistently lowered IGFBP-2 mRNA in the MCF-7 and BT-20 cell lines and IGFBP-1 mRNA in MDA-MB-231 cells. Surprisingly, however, this compound either did not influence IGFBPs secretion in MCF-7 cells or actually increased their secretion in the BT-20 and MDA-MB-231 cell lines. PA involvement in IGFBPs production by breast cancer cells is complex and may involve differential regulation of transcriptional and post-translational events.

Breast Neoplasms↗
PubMed1991

Validation of World Health Organization guidelines for cancer pain relief during the last days and hours of life.

The efficacy of the World Health Organization's guidelines for cancer pain relief was examined in 401 dying patients. At the time of death, only 3% of the patients experienced severe or very severe pain; whereas 52% had no pain at all, 24% experienced only mild or moderate pain, and 20% were unable to rate their pain intensity. Analgesic drugs were the mainstay of therapy during the last 24 hr of life, being administered by mouth in 47% and parenterally in 44% of the patients. Only 9% of the patients required no systemic analgesics. Nonopioid analgesics alone were effective in 5% and a combination of nonopioids and "weak" opioids were effective in 16% of the patients. In the remaining 70% of the patients "strong" opioids alone or in combination with nonopioid analgesics were necessary to achieve adequate pain reduction. Additional adjuvant drugs to treat special types of pain or other symptoms were prescribed in 90% of the patients. Nonpharmacological measures, such as radiotherapy, nerve blocks or neurosurgery played only a very minor role at this stage of the disease. This study shows that cancer pain can be treated satisfactorily until death.

Adolescent↗
PubMed1991

Use of a 25-gauge Whitacre needle to reduce the incidence of postdural puncture headache.

We studied 200 orthopaedic inpatients (111 males) aged 15-84 yr who received spinal anaesthesia with one of two types of Whitacre spinal needle: 22-gauge or 25-gauge. The incidence of headache, backache, failure of spinal anaesthesia and patient acceptability was investigated using a questionnaire. The incidence of postdural puncture headache (PDPH) was 4% in the 22-gauge group and 2% in the 25-gauge group. The incidence of backache and headache of other origin was similar in both groups. Spinal anaesthesia was carried out successfully in all patients in both groups. Patient acceptance was high (98%) and there were no serious complications observed. We conclude that spinal anaesthesia is easy to perform with a 25-gauge pencil-point needle and is associated with a low incidence of PDPH.

Adolescent↗
PubMed1991

The effect of E. coli STa enterotoxin on the absorption of weakly dissociable anti-malarial drugs from rat intestine in vivo.

1. The effect of E. coli heat stable (STa) enterotoxin on the absorption of radiolabelled anti-malarial weak bases and their appearance in peripheral blood was assessed in vivo by a recirculation procedure in rat intestinal loops. 2. Enterotoxin increased the jejunal disappearance of quinine (P less than 0.05), trimethoprim (P less than 0.05), proguanil (P less than 0.05) and chloroquine (P less than 0.001) and left pyrimethamine disappearance unaltered. Peripheral blood levels of trimethoprim (P less than 0.02) and proguanil (P less than 0.05) were higher after STa exposure. 3. In the ileum, enterotoxin increased the luminal disappearance (P less than 0.05) and peripheral blood appearance (P less than 0.001) of chloroquine. The luminal disappearance rate of trimethoprim was reduced (P less than 0.05) and that of pyrimethamine unchanged. 4. The increased jejunal absorption of the anti-malarial drugs occurred despite STa causing a reduction in the amount of net fluid absorption. It seems likely that the enhanced absorption with STa exposure is related to the effect of STa on the microclimate pH. An elevation in the microclimate pH would increase the amount of undissociated weak base available for non-ionic diffusion. 5. The favourable elevation of microclimate pH by STa seemed to be outweighted by the reduced fluid absorption in the ileum. Only chloroquine still showed enhanced absorption in the ileum and this may have been because unlike the other antimalarial drugs, chloroquine has two dissociable groups likely to be affected by the mucosal surface pH changes.

Acid-Base Equilibrium↗
PubMed1991

Comparison of clinical, radionuclide, and radiographic features of osteoarthritis of the hands.

Simultaneous clinical, scintigraphic, and macroradiographic assessments were carried out on 32 patients with hand osteoarthritis and the results at entry and one year reported. The presence and growth of osteophyte correlated with symptoms and a positive scan. The scan did not detect the radiographic features of juxta-articular radiolucencies, subchondral sclerosis, or cartilage thinning. Osteophytes, particularly when fast growing, produce pain, a 'hot' scan, and may predict disintegration of joint architecture.

Arthrography↗
PubMed1991

Follicle-stimulating hormone and insulin regulation of 17 beta-estradiol secretion and granulosa cell proliferation within immature rat ovaries maintained in perifusion culture.

The present study examined the effects of FSH and insulin (IN) on 17 beta-estradiol (E2) secretion and granulosa cell proliferation. For these studies, immature rat ovaries were maintained in perifusion culture and continuously exposed to FSH (0-800 ng RP-1 eq/ml) and /or IN (0.2 U/ml). At specific times, the ovaries were removed from perifusion, and the perifusate was assayed for E2 by RIA. The ovaries were then incubated with [3H]thymidine ([3H]T) in order to estimate granulosa cel mitotic activity. FSH increased E2 secretion in a dose-dependent manner (P less than 0.05), but did not enhance [3H]T incorporation (P greater than 0.05) after 48 h of perifusion. Conversely, IN increased [3H]T incorporation (P less than 0.05) without stimulating E2 secretion (P greater than 0.05) after 48 h of perifusion. FSH alone or in combination with IN stimulated [3H]T incorporation at 24 h of perifusion compared to both zero hour control (P less than 0.05) and IN treatments (P less than 0.05). The inability of FSH to stimulate [3H]T incorporation after 48 h did not appear to be due to increased E2, since IN stimulated [3H]T incorporation in the presence of 100 ng E2/ml. Further, continuous exposure to FSH was required to maintain E2 secretion, demonstrating that after 24 h, FSH loses its capacity to stimulate granulosa cell [3H]T incorporation, but not E2 secretion. Finally, when ovaries are pretreated with FSH for 48 h and then exposed to FSH and/or IN, [3H]T incorporation was stimulated, and E2 secretion inhibited. These data suggest that 1) initially, FSH acts to stimulate mitosis then promotes granulosa cell E2 secretion; and 2) once granulosa cells begin to secrete E2 they are still capable of mitosis, but their mitotic activity is no longer directed by FSH.

Animals↗
PubMed1991

Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor.

CGS 16949A (fadrozole hydrochloride), a potent cytochrome P450-mediated steroidogenesis inhibitor, blocks aromatase at low doses, but other biosynthetic steps at higher concentrations. Recent studies demonstrated inhibition of C11-hydroxylase, corticosterone methyloxidase-II, and deoxycorticosterone to corticosterone conversion with this agent at some-what higher concentrations than those required for blockade of aromatase. Based upon phase I studies, we postulated that relatively selective inhibition of aromatase might be possible if sufficiently low doses of CGS 16949A were used. A phase II study in 54 postmenopausal women with metastatic breast cancer examined the effects of low dose CGS 16949A on estrogen, mineralocorticoid, and glucocorticoid secretion. Two dose schedules and two dose levels were chosen based upon our prior dose escalation protocol study. Plasma estrone, estradiol, and estrone sulfate as well as urinary estrone and estradiol fell equally with 1.8-4 mg CGS 16949A given either on a twice daily or three times daily dose schedule. Isotopic kinetic studies demonstrated an 84% decrease in the rate of conversion of androstenedione to estrone to 0.40 +/- 0.07% (patients receiving 1.8-4 mg CGS 16949A daily). With these three regimens, basal levels of aldosterone and cortisol did not change significantly over a 12-week period of observation. Clinical examination, plasma electrolytes, and urinary sodium/potassium ratios suggested no biological evidence of mineralo-corticoid deficiency. ACTH-stimulated cortisol concentrations, however, were blunted at each dose level compared to pretreatment values. Nonetheless, peak responses exceeded 550 nmol/L, or a basal to peak difference of 190 nmol/L or greater, in 97% of instances. This probably reflected inhibition of C11-hydroxylase, since basal and ACTH-stimulated levels of 11-deoxycortisol were increased in response to CGS 16949A. Androstenedione and 17 alpha-hydroxyprogesterone also exhibited an upward trend in response to drug treatment. ACTH-stimulated aldosterone levels were blunted to a greater extent than those of cortisol, probably as a reflection of corticosterone methyloxidase type II blockade. Overall, the results suggest that CGS 16949A, at doses of 1.8-2 mg daily, blocks aromatase effectively and does not produce clinically important inhibition of cortisol or aldosterone biosynthesis. Thus, this agent can probably be used safely without glucocorticoid or mineralocorticoid supplementation.

17-alpha-Hydroxyprogesterone↗
PubMed1991

Developing a program to assist Turner's syndrome patients and families.

Turner's Syndrome [TS] is a chromosomal disorder that affects one in 2500 women. It results in an array of physical difficulties, including short stature, lack of secondary sexual development and cognitive problems. Little research exists to document the psychosocial problems and needs of individuals with TS and their families. The current literature and the results of a regionally based needs assessment are reviewed to guide program development, with emphasis on the emotional and informational needs of these families. Suggestions are provided for strategic early communication and information sharing, development of skill-specific support groups, family networks and family therapy.

Aftercare↗
PubMed1991

Free-standing surgery centers; the wave of the future.

To summarize, it should be realized that acceptance of surgicenters has happened. Surgery centers expect heightened awareness of their services as patients, in conjunction with their own physicians, make decisions based on cost, service, and convenience of the care provided. As copayments and deductibles increase, consumers have become better educated, taking a more active role in selecting their health care providers. This activity has given rise to joint ventures between physicians and hospitals offering new ambulatory care packages previously based in hospitals alone. The net effect will divide the health care industry into two markets, one that will manage high-intensity surgical procedures and one that will promote outpatient surgical procedures.

Hospitals↗
PubMed1991

Intermittent femoral nerve blockade for anterior cruciate ligament repair. Use of a catheter technique in 208 patients.

The duration of postoperative analgesia following femoral nerve block with a catheter technique was studied. Intermittent doses of bupivacaine were given to 208 consecutive patients presenting for open repair of the anterior cruciate ligament, initially 0.5% and thereafter 0.25% 0.4 ml/kg 2-4 times daily. Supplementary analgesia with piritramide 0.15 mg/kg I.M. was provided 4-6 hourly as required and the number of analgesic demands recorded. Based on the duration of analgesia and on the number of analgesic demands required, good or satisfactory analgesia was obtained in 88% of the patients. The catheter remained an average of 2.8 days in position and no infectious or irreversible neurological complications were seen. It is concluded that femoral nerve block using a catheter technique, provides safe and reliable analgesia, improves patient mobility, has a high patient acceptance and is capable of reducing systemic analgesic demand following anterior cruciate ligament repair.

Adult↗
PubMed1991

The importance of non-opioid analgesics for cancer pain relief according to the guidelines of the World Health Organization.

In a retrospective study of 1070 cancer patients being treated according to guidelines of the World Health Organization during a period of 55,285 days, the importance, efficacy and side-effects of non-opioid analgesics were evaluated. The non-opioids were given alone on 6917 days and in combination with weak opioids on 15,253 days, with strong opioids on 24,246 days and with spinal opioids on 1008 days. In evaluating efficacy and safety, it was not possible to differentiate adequately between the effects of non-opioids, opioids and adjuvant drugs, but it was demonstrated that an adequate combination of these drugs was effective and safe in the treatment of cancer pain.

Aged↗
PubMed1991

Quantitative microfocal radiographic assessment of disease and progression in osteoarthritis of the hand.

Macroradiographic examination of the wrists and hands of 32 patients with osteoarthritis (OA) over an 18 month period showed that, compared with healthy control subjects, 44% of the patients had significant joint space narrowing at entry, which increased to 65%. Subchondral cortical thickness was greater in all patients at entry and increased with time. Osteophytes and juxtaarticular radiolucencies were present in all patients at study entry; by the end, osteophytes had increased in number and area, and juxtaarticular radiolucencies in area only. We conclude that in OA of the hand, bony changes have progressed significantly before joint space narrowing.

Aged↗