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Biomedical subjects

M Lawson

Publications and source records attributed to M Lawson.

At least 19 recordsLinked to original sources

Autonomic dysfunction in systemic sclerosis: sympathetic overactivity and instability.

PURPOSE: This study was designed to assess the prevalence and nature of autonomic dysfunction (AD) in 34 patients with systemic sclerosis (SSc). PATIENTS AND METHODS: Patients were questioned for current symptoms possibly related to AD. Five noninvasive cardiovascular autonomic function tests and sequential plasma catecholamine estimations at rest, during standing, and during sustained handgrip were performed. Seven patients with manometrically documented esophageal involvement and high resting plasma adrenaline levels were treated with clonidine (75 to 375 micrograms/d). One month later, resting plasma catecholamine estimations and esophageal motility studies were repeated. RESULTS: Autonomic testing revealed AD in each patient, while symptoms were experienced by 33 of them. Findings on two of the three heart rate tests and both blood pressure tests were significantly impaired as compared with those in 25 matched control subjects. Mean resting plasma adrenaline levels were 18 times higher than in 10 matched controls (p less than 0.001). Plasma catecholamine (adrenaline, noradrenaline, and dopamine) concentrations and mean arterial blood pressures fluctuated inappropriately during standing and sustained handgrip in 28 (82%) of the patients. The presence of headaches correlated significantly with sympathetic overactivity and instability (p less than 0.05). Resting plasma adrenaline concentrations correlated inversely with disease duration (p less than 0.05). Significant suppression of sympathetic overactivity and increases in resting lower esophageal sphincter pressures were observed in the seven patients treated with clonidine. CONCLUSION: AD is extremely common in SSc. It is characterized by parasympathetic impairment and marked sympathetic overactivity, particularly in early disease. The potential role of AD in the pathogenesis of SSc deserves further study.

Adult

Indomethacin and protein binding of methotrexate.

Indomethacin, a non-steroidal anti-inflammatory drug is known to increase the efficacy and toxicity of methotrexate, the widely used anti-cancer drug in man. The mechanism for this interaction has not been clearly established. However, since these drugs bind with albumin, a possible displacement of methotrexate by indomethacin from albumin might explain this interaction. To investigate the possible interaction an in-vitro protein-binding displacement study was carried out in 17 normal volunteers and in two groups of eight cancer patients. One group of patients had active disease and the other was in complete clinical remission. Serum samples were obtained and protein levels estimated. The protein binding of methotrexate was measured alone and with indomethacin using equilibrium dialysis. Statistical analysis of results suggested that the binding of methotrexate is not influenced by indomethacin, confirming that methotrexate is not displaced by indomethacin.

Adult

Aberrant expression of intestinal mucin antigens associated with colorectal carcinoma defined by a panel of monoclonal antibodies.

Small intestine mucin antigen (SIMA) is an oncofoetal antigen for the colon and is distinct from the normal large intestinal mucin antigen (LIMA). In the present study, a panel of anti-SIMA and anti-LIMA monoclonal antibodies (MAb) was used to charaterise altered mucin expression in colorectal adenocarcinomas, by immunohistochemistry and quantitative immunoassays of tissue extracts. These results are compared with CEA expression and correlated with various clinicopathological indices. All mucin MAb reacted with a high proportion of the 100 colon cancers of every stage, histological type (including non-mucinous cancers), differentiation, site, or size. Inappropriate SIMA production was detected by either anti-SIMA MAb 4D3 or 4A1, even in 85% of early stage cancers. MAb 4D3 reacted with a higher proportion of cancers of smaller size and better differentiation. At the subcellular level, both anti-SIMA MAb showed reactivity typical of normal mucin, i.e., goblet cell and extracellular mucin. The normal colonic antigen, LIMA, was also detectable in the majority of cases, but quantitatively overproduced in some cases and reduced in others. However, in contrast to SIMA, LIMA was detected in predominantly undifferentiated cancer cells but not in goblet cells. Heterogeneity of MAb reactivity between cases and complementarity within each cancer was frequently observed. Mucin reactive with at least one of the MAb was detected in all of the CEA-negative cancers. A high rate of inappropriate SIMA expression was also detected in the perineoplastic transitional mucosa (88%, c.f. CEA, 35%) and adjacent, morphologically normal mucosa (80% c.f. CEA, 24%), indicating biochemical changes similar to the cancer. This panel of anti-mucin MAb demonstrated altered mucin glycoprotein metabolism associated with the development and progression of most colorectal cancers, which emphasises their utility as indicators of neoplastic change in the colon, and their superiority to CEA.

Aged

Plasma metronidazole concentrations after single and repeated vaginal pessary administration.

Metronidazole concentrations in plasma were measured by h.p.l.c. in 12 healthy female volunteers after single and repeated vaginal administration of 500 mg metronidazole pessaries. The area under the plasma concentration-time curve (AUC(0,12 h) was 8.4 +/- 3.9 micrograms ml-1 h (mean +/- s.d.) on day 1 and 20.6 +/- 7.1 micrograms ml-1 h (mean +/- s.d.) on day 5. The peak plasma drug concentration on day 1 was 1.2 +/- 0.6 micrograms ml-1 (mean +/- s.d.) and on day 5 it was 2.0 +/- 0.7 micrograms ml-1 (mean +/- s.d.). The plasma concentration of metronidazole at steady state was above the minimum inhibitory concentration (MIC) for anaerobic Streptococci and Clostridium tetani. These results demonstrate much lower systemic exposure than after oral administration.

Adult

Interaction of ketoprofen and frusemide in man.

The effects of ketoprofen on frusemide-induced diuresis, natriuresis and renin release were studied in 12 healthy male volunteers. Each received frusemide 40 mg once daily with either ketoprofen 100 mg twice daily or placebo for two periods of 5 days separated by a treatment-free period according to a randomized, double-blind, cross-over study design. Ketoprofen significantly reduced frusemide-induced diuresis on Day 1 but not on Day 5 of treatment. The natriuresis induced by frusemide on Day 1 or Day 5 of treatment did not differ significantly whether ketoprofen or placebo was administered, although the mean urinary sodium excretion values were consistently lower following ketoprofen. Ketoprofen did not affect the kaliuretic response to frusemide on Day 1 or Day 5 of treatment. The increase in plasma renin activity after frusemide was inhibited by ketoprofen on both Day 1 and Day 5. These results suggest that ketoprofen reduces the diuresis and renin release induced by frusemide, but that the reduction in diuretic response may become less important after their repeated coadministration.

Adult

Follow-on milks.

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Animals

Identification of a domain in cytochrome C that displaces [3H]TCP binding from rat brain membrane receptors: synthesis of beta-neuroprotectin.

1. A stereospecific radioreceptor binding assay for the phencyclidine analogue, [3H]TCP, was utilized to screen for inhibition of binding in extracts of rat brain. 2. Extracts were prepared from rat cerebral cortex and hippocampus by methods employing aqueous acid. The extracts were fractionated by reversed phase-HPLC (RP-HPLC) and tested for activity in the radioreceptor assay. Three zones of activity were detected. The middle zone was further purified by high performance-size exclusion chromatography (HP-SEC). 3. Size exclusion chromatography revealed a single zone of activity corresponding to mol. wts of ca 12,000-31,000 daltons. A fraction from this zone was digested with trypsin, and the resulting enzyme fragments, isolated by a combination of HP-SEC and RR-HPLC, were identified as fragments of rat cytochrome C. 4. Horse cytochrome C was digested with trypsin and the fragments were similarly purified on the basis of the [3H]TCP binding displacement assay. The fragments were sequenced and found to be trypsin cleavage products of a single largely invariant domain of the cytochrome C molecule: Lys-Lys-Lys-Asp-Glu-Arg-Ala-Asp-Leu-Ile-Ala-Tyr-Leu-Lys-Lys. 5. beta-neuroprotectin (D)-Ala-Asp-Leu-Ile-Ala-Tyr-Leu-NH2, inhibits [3H]TCP binding and provides protection against NMDA mediated neuronal cell death at low concentrations.

Amino Acid Sequence

Isolation and identification of a peptide from rat brain which inhibits [3H]TCP binding.

1. A stereospecific radioreceptor binding assay for the phencyclidine analogue [3H]TCP was utilized to screen for inhibitors of binding in extracts of rat brain. 2. Extracts were prepared from rat cortex and hippocampus by methods employing aqueous acid or acidified methanol. Samples were fractionated by reversed phase-HPLC (RP-HPLC) and tested for activity in the radioreceptor assay. Three zones of activity were detected. The most active fraction was further purified by high performance-size exclusion chromatography. 3. Size exclusion chromatography revealed two zones of activity, corresponding to mol. wts of 4000-8000 Da and 1000-2000 Da. Final purification of the lower molecular weight material was achieved by RP-HPLC. 4. Two well-separated peaks were shown to be homogeneous. Their amino acid sequences were determined by automated Edman degradation and data base searching identified these two peaks as the undecapeptide Substance P and its oxidized counterpart (Substance P sulfoxide). 5. Comparative HPLC of synthetic Substance P, or its sulfoxide, as well as spectral analysis confirmed the identity of the isolated peptides. 6. Synthetic Substance P inhibits specific [3H]TCP binding in the radioreceptor assay.

Amino Acid Sequence

Outpatient percutaneous central venous access in cancer patients.

A 1-year experience of percutaneous subclavian catheterization in outpatients with cancer was reviewed to document reliability, safety, and cost. There were 763 catheter insertions attempted with prospective documentation of complications in 664 consecutive patients. Catheter insertion was successful in 722 attempts (95%). There were only 13 pneumothoraces (2%). Thirty catheters required repositioning (4%). The average catheter duration was 191 days (range: 0 to 892 days). Fifty-six catheters (8%) were removed because of suspected infection. Documented catheter sepsis occurred in 21 patients (3%); catheter site infection occurred in 8 patients (1%). Thus, only 0.22 infections per catheter year occurred during this 382 catheter-year experience. The estimated cost of catheter insertion was $562, which is one-third the estimated cost for tunneled catheters ($1,403) and for reservoir devices ($1,738). In our experience, percutaneous subclavian catheterization is a reliable, cost-effective method compared with tunneled or reservoir devices, with an equivalent incidence of catheter-related infections. The cornerstone of our success with this program is a staff dedicated to catheter care and intensive patient education. In centers where a large number of patients require central venous access, percutaneous catheterization should be the technique of choice.

Ambulatory Care

Comparison of chlortenoxicam and indomethacin on frusemide-induced diuresis.

A single oral dose of chlortenoxicam 4 mg, a new non-steroidal anti-inflammatory drug, significantly antagonized the diuretic and natriuretic actions of frusemide when compared with placebo in normal human volunteers. Indomethacin 50 mg significantly reduced the natriuretic, but not diuretic action of frusemide.

Adult

How many electrocardiographic leads are required for exercise treadmill tests?

Forty-four consecutive patients who had perfusion defects on thallium-201 scanning and positive exercise treadmill tests were prospectively studied. Thirty-eight (86%) subjects had diagnostic ST segment changes in lead V5, 37 (84%) in lead V4, and 44 (100%) in either lead V4, V5 or both. Thirty patients had ST segment changes in the inferior leads, 20 in lead aVR, and only four in lead I and/or aVL. All of these latter subjects had diagnostic ST segments in lead V4 and/or V5. It is concluded that: combined electrocardiographic leads V4 and V5 detect the vast majority of ischemic changes during exercise treadmill testing, regardless of the site of perfusion defects detected by thallium-201 scanning; and monitoring the inferior and lateral leads rarely provides more diagnostic information.

Coronary Disease

Local infusion of urokinase for the lysis of thrombosis associated with permanent central venous catheters in cancer patients.

We assessed the efficacy of local fibrinolytic therapy in 35 axillary-subclavian vein thromboses (SVT) that occurred in cancer patients with percutaneous central venous catheters (CVC). These catheters were indwelling for a median of 1 month (range, one day to 10 months) before thrombosis developed. Urokinase was administered at a dose of 500 to 2,000 U/kg/h. Complete lysis occurred in 25 of 30 thrombi that were directly infused, after a median of four days. Complete lysis occurred in one of 12 thrombi that could not be directly infused with urokinase and in two of six with associated phlebitis. Eighty-one percent of the thrombi that were symptomatic for less than 1 week before treatment resolved, compared with 56% present for longer than 1 week. Sixteen patients who had complete (12) or partial (four) thrombolysis did not have their CVCs removed. All four patients with partial thrombolysis had recurrent thrombosis at a median of eight days (range, one to 90). Only two patients who had complete thrombolysis had recurrent thrombosis, at 8 and 16 months. Only minor hemorrhagic toxicity was seen.

Adult

Effect of 5-aminosalicylic acid (5-ASA) and other salicylates on short-chain fat metabolism in the colonic mucosa. Pharmacological implications for ulcerative colitis.

5-Aminosalicylic acid (5-ASA) suppressed nitrite-stimulated oxidation of the fatty acid n-butyrate in a dose-dependent manner in isolated human and rat colonic epithelial cells. 4-ASA had one-sixth of the capacity of 5-ASA and sulphapyridine (SP) little of the capacity of 5-ASA to suppress fatty acid oxidation in human colonic epithelial cells. Sulphasalazine (SASP), azodisalicylic acid (ADS), acetyl-5-ASA and acetyl salicylic acid (ASA) did not suppress fatty acid oxidation in rat colonocytes. The suppression index of fatty acid oxidation (SIFO) of respective salicylic acids correlated with the reported clinical effectiveness of each drug against ulcerative colitis (UC). The capacity of 5-ASA to affect nitrite-stimulated oxidation of fat in the colonic mucosa suggests that nitrite ions and control of fatty acid oxidation play a central role in the development and therapy of active UC.

Aminosalicylic Acids

Student situation.

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Education, Nursing