Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation.

Protamine sulfate is a positively charged polypeptide widely used to reverse heparin-induced anticoagulation. Paradoxically, prospective randomized trials have shown that protamine administration for heparin neutralization is associated with increased bleeding, particularly after cardiothoracic surgery with cardiopulmonary bypass. The molecular mechanism(s) through which protamine mediates this anticoagulant effect has not been defined. In vivo administration of pharmacologic doses of protamine to BALB/c mice significantly reduced plasma thrombin generation and prolonged tail-bleeding time (from 120 to 199 seconds). Similarly, in pooled normal human plasma, protamine caused significant dose-dependent prolongations of both prothrombin time and activated partial thromboplastin time. Protamine also markedly attenuated tissue factor-initiated thrombin generation in human plasma, causing a significant decrease in endogenous thrombin potential (41% +/- 7%). As expected, low-dose protamine effectively reversed the anticoagulant activity of unfractionated heparin in plasma. However, elevated protamine concentrations were associated with progressive dose-dependent reduction in thrombin generation. To assess the mechanism by which protamine mediates down-regulation of thrombin generation, the effect of protamine on factor V activation was assessed. Protamine was found to significantly reduce the rate of factor V activation by both thrombin and factor Xa. Protamine mediates its anticoagulant activity in plasma by down-regulation of thrombin generation via a novel mechanism, specifically inhibition of factor V activation.

Pretreatment haematological laboratory values predict for excessive myelosuppression in patients receiving adjuvant FEC chemotherapy for breast cancer.

BACKGROUND: A predictive model that identifies patients at risk of excessive neutropenia following chemotherapy would be valuable in guiding the use of supportive therapies. PATIENTS AND METHODS: We conducted a retrospective analysis of 741 patients who had received adjuvant 5-fluorouracil, epirubicin, cyclophosphamide (FEC) chemotherapy for breast cancer. The cause of every schedule alteration was identified. The ability of pretreatment haematological indices to predict for excessive myelosuppression was assessed. RESULTS: Pretreatment absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) were strongly associated with the risk of neutropenic events (NEs), febrile neutropenia (FN) or receiving suboptimal chemotherapy dose intensity (DI<85%). The timing and pattern of NEs suggest that they reflect intrinsic chemosensitivity rather than cumulative toxicity and that FN results from chance infection rather than protracted myelosuppression. By combining quintiles on the basis of the rank order of ANC and ALC, we defined five groups of patients with variable risks of NE (18%-52%), DI<85% (9%-36%) and FN (4%-21%). CONCLUSIONS: Pretreatment differential white blood cell count can be used to identify patients at increased risk of significant myelosuppression with FEC chemotherapy. Patients in the highest risk group have a risk of FN>20% and would qualify for primary prophylaxis with granulocyte colony-stimulating factor support under current guidelines.

Clarithromycin vs ciprofloxacin as adjuncts to rifampicin and ethambutol in treating opportunist mycobacterial lung diseases and an assessment of Mycobacterium vaccae immunotherapy.

BACKGROUND: The mainstays of treatment for pulmonary disease caused by opportunist mycobacteria are rifampicin (R) and ethambutol (E). The role of macrolides, quinolones and immunotherapy with Mycobacterium vaccae is not clear. A trial was undertaken to compare clarithromycin (Clari) and ciprofloxacin (Cipro) as third drugs added to [corrected] 2 years of treatment with R and E for pulmonary disease caused by M avium-intracellulare (MAC), M malmoense and M xenopi (REClari and RECipro). An optional comparison of immunotherapy with M vaccae vs no immunotherapy was also performed. METHODS: Progress was monitored annually during the 2 years of treatment and for 3 years thereafter. If the patient was not improving at 1 year the regimen was supplemented by the addition of the drug not received in the original allocation of treatment. RESULTS: 371 patients (186 REClari, 185 RECipro) entered the study (170 MAC, 167 M malmoense, 34 M xenopi). All-cause mortality was high for both groups (44% REClari, 43% RECipro); for MAC it was higher with REClari than with RECipro (48% vs 29%) but for M malmoense (42% vs 56%) and M xenopi (29% vs 47%) it was higher with RECipro (p = 0.006). 3% died from their mycobacterial disease (REClari = RECipro). At the end of treatment, 4% of REClari and 10% of RECipro patients still had positive cultures. Among those with negative cultures at the end of treatment, 6% of the REClari group and 4% of the RECipro group had relapsed. At 5 years 30% of the REClari group were known to have completed treatment as allocated and to be alive and cured compared with 21% of the RECipro group (p = 0.04), but this difference was principally due to those with M malmoense (REClari 38%, RECipro 20%). Patients with MAC or M xenopi were more likely to have a poor outcome than those with M malmoense (p = 0.004), with no difference between REClari and RECipro. Overall, 20% in each group were unable to tolerate the regimen allocated, Cipro being associated with more unwanted effects than Clari (16% vs 9%, p = 0.05). No significant differences in outcomes were found between M vaccae-treated patients and those not treated with M vaccae immunotherapy. CONCLUSION: Considering all three species together, there were no differences in outcome between the REClari and RECipro groups. Immunotherapy did not improve outcome. New therapies, optimised management of co-morbid conditions and a more holistic approach must be explored in the hope of improving outcome.

Comparison of somatostatin analog and meta-iodobenzylguanidine radionuclides in the diagnosis and localization of advanced neuroendocrine tumors.

A comparison has been made of [(123)I]meta-iodobenzylguanidine ([(123)I]MIBG) and [(111)In]pentetreotide scintigraphy in 54 patients with a variety of neuroendocrine tumors of whom 46 patients had metastatic disease. [(111)In]Pentetreotide scintigraphy was more sensitive in detecting metastatic lesions, as demonstrated on computed tomography and/or magnetic resonance scanning, than [(123)I]MIBG: 67% vs. 50% for carcinoid tumors (n = 24), 91% vs. 9% for pancreatic islet cell tumors (n = 12), 100% vs. 60% for medullary thyroid carcinomas (n = 5), and 75% vs. 100% for pheochromocytomas/paragangliomas (n = 4). In only 2 patients were lesions seen with [(123)I]MIBG scanning that were not apparent with [(111)In]pentetreotide. With the exception of pancreatic islet cell tumors, both radionuclides exhibited a similar sensitivity in detecting hepatic metastases, whereas in three patients the two radionuclides exerted a complementary role as different deposits exhibited uptake to only 1 or the other radionuclide. Hepatic metastases were the most important clinical predictor of a positive scan for both radionuclides. Neither elevated 5-hydroxyindoleacetic acid levels nor any other hormonal marker was predictive of a positive scan. In 8 patients with clinical and/or hormonal evidence of a neuroendocrine tumor but negative conventional radiology, [(111)In]pentetreotide scintigraphy was more sensitive than [(123)I]MIBG (37.5% vs. 12.5%) in detecting lesions. In conclusion, scintigraphy with [(111)In]pentetreotide detects more metastatic lesions than [(123)I]MIBG in patients with carcinoid and pancreatic islet cell tumors and medullary thyroid carcinomas; [(123)I]MIBG scintigraphy may be more sensitive for sympathoadrenomedullary tumors. The radionuclides may exert a complementary role in the detection and treatment of neuroendocrine tumors in occasional patients, as areas of different pattern of uptake were identified within the same patient. These data have implications not only for staging such tumors, but also for identifying patients who might benefit from treatment using either [(131)I]MIBG or radioactive somatostatin analogs.

Biomarkers of human colonic cell growth are influenced differently by a history of colonic neoplasia and the consumption of acarbose.

The nutritional effects of butyrate on the colonic mucosa and studies of transformed cells suggest that butyrate has anti-colon cancer effects. If butyrate has antineoplastic effects, mucosal growth contrasts between normal subjects and those with a history of colonic neoplasia would parallel changes in growth characteristics caused by butyrate in a colon neoplasia population. To test this hypothesis, rectal biopsies from a survey of colonoscopy patients (n = 50) with and without a history of colonic neoplasia (controls) were compared. Similarly, rectal biopsies were compared from subjects (n = 44) with a colon neoplasia history in an acarbose-placebo crossover trial. Control subjects in the colonoscopy survey had higher bromodeoxyuridine (BrdU) uptake than subjects with a history of neoplasia (P = 0.05). The control subjects also had a higher correlation of BrdU and Ki-67 labeling (P = 0.003). Both findings were paralleled by acarbose use. Acarbose augmented BrdU uptake (P = 0.0001) and improved the correlation of BrdU and Ki-67 labeling (P = 0.013). Acarbose also augmented fecal butyrate (P = 0.0001), which was positively correlated with Ki-67 labeling (P = 0.003). p52 antigen had an earlier pattern of crypt distribution in subjects with a history of colon neoplasia but was not affected by acarbose use. Lewis-Y antigen was expressed earlier in the crypt with acarbose but had similar expression in the colonoscopy survey groups. The use of acarbose to enhance fecal butyrate concentration produced mucosal changes paralleling the findings in control subjects as opposed to those with neoplasia, supporting the concept of an antineoplastic role for butyrate.

Trends in antituberculosis drug resistance in Karonga District, Malawi, 1986-1998.

SETTING: Karonga District, Malawi. OBJECTIVES: To examine long term trends in initial and acquired resistance to antituberculosis drugs in a rural area of Africa. DESIGN: Monitoring of all patients with culture-confirmed tuberculosis 1986-1998. RESULTS: Initial drug resistance results were available for 1121 patients. The proportion resistant to any of the first line drugs (streptomycin, isoniazid, rifampicin or ethambutol) was 9.6%, and to isoniazid 7.2%. Initial resistance to at least isoniazid and rifampicin (multidrug resistance) was seen in only six patients. No initial resistance to ethambutol was found. There was no significant change in initial drug resistance over time. Overall, 22/120 (18%) patients with previous treatment were resistant to at least one drug; only one had multidrug resistance. Acquired resistance decreased over the period of the study. There were no associations between age, sex or human immunodeficiency virus (HIV) status and initial or acquired drug resistance. CONCLUSIONS: Changes in acquired resistance may reflect the recent performance of a control programme more quickly than those in initial resistance. It is encouraging that acquired resistance decreased and levels of multidrug resistance were low despite more than a decade of use of rifampicin. The lack of association between HIV and drug resistance confirms findings elsewhere in Africa.

Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment.

Langerhans cell histiocytosis (LCH) is a rare disorder in which granulomatous deposits occur at multiple sites within the body, but which often involves the hypothalamo-pituitary axis (HPA). Although diabetes insipidus (DI) is a well recognized complication, the frequency of anterior pituitary and other nonendocrine hypothalamic (NEH) involvement has not been well defined, particularly in adult patients with the disease. We have evaluated the frequency and progression of LCH-related anterior pituitary and other NEH dysfunction and their responses to treatment in 12 adult patients with histologically proven LCH and DI. They were followed up for a median of 11.5 yr (range, 3-28 yr) after the diagnosis of DI was made. Study evaluations comprised clinical (including formal psychometric assessment where appropriate), basal and dynamic pituitary function tests, and radiology with computed tomography and/or magnetic resonance imaging scanning. Eleven patients received systemic treatment, and 5 patients received external beam radiotherapy confined to the HPA. The median age at diagnosis of DI was 34 yr (range, 2-47 yr); DI was the presenting symptom in four patients, whereas the remaining eight each developed DI 1-20 yr (median, 2 yr) after the diagnosis of LCH. Eight patients developed one or more anterior pituitary hormonal deficiencies at a median of 4.5 yr (range, 2-22 yr) after the diagnosis of DI: GH deficiency developed in eight patients (median, 2 yr; range, 2-22 yr), FSH-LH deficiency in 7 patients (median, 7 yr; range, 2-22 yr), and TSH and ACTH deficiency in five patients (median, 10 yr; range, 3-16 and 3-19 yr), respectively; five patients developed panhypopituitarism. In addition, seven patients with anterior pituitary dysfunction also developed symptoms of other NEH dysfunctions at a median of 10 yr (range, 1-23 yr): five morbid obesity (body mass index, >35), five short term memory deficits, four sleeping disorders, two disorders of thermoregulation, and one adipsia. All patients developed disease outside of the hypothalamus during the course of the study, and no fluctuation of disease activity in the HPA region was noted. Radiological examination of the HPA was abnormal in each of the eight patients with anterior pituitary involvement and in the seven patients with NEH dysfunction (one or more abnormalities): seven had thickening of the infundibulum, and one had hypothalamic and thalamic signal changes. All patients who had a magnetic resonance imaging scan had absence of the bright spot of the posterior pituitary on the T1-weighted sequences, and in four patients with DI and normal anterior pituitary function this was the only abnormality. The five patients who received radiotherapy to the HPA achieved a partial or complete radiological response, and there was no evidence of tumor progression in this region. No form of therapy, including chemotherapy, improved any established hormonal deficiencies or symptoms of NEH. In summary, in our adult patients with hypothalamic LCH and DI, anterior pituitary hormonal deficiencies developed in 8 of 12 patients; these occurred over the course of 20 yr. They were frequently accompanied by structural changes of the HPA, although these were often subtle in nature. In addition, symptoms of NEH dysfunction developed in up to 90% of such patients and complicated management. Radiotherapy may be useful in achieving local control of tumor, but established anterior, posterior pituitary, and other NEH dysfunctions do not improve in response to current treatment protocols. Patients with LCH and DI, particularly those with multisystem disease and a structural lesion on radiology, should undergo regular and prolonged endocrine assessment to establish anterior pituitary deficiency and provide appropriate hormonal replacement.

An exercise in critical thinking using role playing.

Attitudes, knowledge, and skills of critical thinking are developed in a role-playing simulation. Using diabetes mellitus, students solve lifelike problems within the role-playing experience, develop sensitivity and awareness of another's life experience with illness, and generate empathy toward persons with diabetes. Critical thinking is demonstrated in student's double-entry journals.

DNA binding alkaloids from Prosopis alba.

The known beta-phenethylamine ( 1) and the new alkaloid 2-beta-methyl-3-beta-hydroxy-6-beta-piperidinedodecanol ( 2) were isolated from the aerial parts of PROSOPIS ALBA. Both compounds showed DNA binding effects of 27 and 50%, respectively, at 0.50 mg/ml.

Longitudinal changes in dehydroepiandrosterone concentrations in men and women.

Dehydroepiandrosterone, an adrenal steroid, has many purported roles in the body and has been used as an oral supplement in the treatment of various illnesses. Because little is known about normal changes over time in dehydroepiandrosterone concentrations, we studied the 5-year change in plasma dehydroepiandrosterone concentrations in 614 free-living adults. Two hundred seventy-three males and 341 females had dehydroepiandrosterone and dehydroepiandrosterone sulfate concentrations measured in 1989 and 1994. Demographic data were also obtained. Dehydroepiandrosterone concentrations differed significantly by sex and 5-year age group. The average decline in dehydroepiandrosterone was 5.6%/year, and the rate of decline was directly related to age but not to sex, measures of adiposity, or serum glucose. Dehydroepiandrosterone sulfate concentrations differed significantly by sex and age group. The average decline in the sulfated hormone was 2.0%/year and was not related to age, sex, measures of adiposity, or serum glucose. Knowledge of the natural course of age-related changes in dehydroepiandrosterone and dehydroepiandrosterone sulfate concentrations is essential to our understanding of the relationship of dehydroepiandrosterone to chronic diseases.

Does QI work? The Management to Improve Survival in Congestive Heart Failure (MISCHF) study.

BACKGROUND: In an ongoing study, a randomized, controlled trial is being conducted on the effects of a collaborative quality improvement program on practice patterns and patient outcomes regarding congestive heart failure (CHF) in community hospitals in upstate New York. CHF is associated with severe morbidity and mortality, with annual rates of death exceeding 50% among patients with the most severe disease. PHASE I: Phase I of the study was designed to model the processes of care and outcomes, develop valid disease-specific risk adjustment techniques, and target areas for quality improvement (QI) intervention. Beginning April 1, 1995, and ending December 31, 1995, baseline data were collected during hospitalization and for six months postdischarge for all 1,402 consecutive patients assigned diagnosis-related groups (DRGs) 127 and 124. Preliminary analyses revealed high rates of hospital readmission (46%) and postdischarge death (18%), with significant interhospital variation. QI INITIATIVES: Initiatives include educational programs on CHF, feedback of Phase I data to clinicians and administrators, design and implementation of a clinical care pathway, improvement of the emergency department (prehospital) phase of CHF management, and improvement in patient education and discharge planning. SUMMARY AND CONCLUSIONS: The study suggests that community hospitals, many without extensive experience in clinical investigation, can voluntarily collaborate to design and implement a timely QI initiative that is evidence based, clinically relevant, and scientifically sound. Preliminary results have led to better understanding of the processes of care and determinants of outcome for patients with heart failure. Phase II of the study should yield insights into the providers' response to a locally derived intervention and the effects of such a program on patient outcomes.

The control of the gonadotrophin releasing hormone pulse generator in relation to opioid and nutritional cues.

Human fertility is ultimately dependent upon the regular pulsatile release of gonadotrophin releasing hormone (GnRH) from hypothalamic neurons. The GnRH pulse generator is subject to modulation by a variety of substances, some of which reflect the individual's metabolic status. Endogenous opioids exert a tonic inhibitory effect on GnRH release; this opioid inhibition is dependent upon the gonadal steroid milieu, and may play a role in the initiation of the mid-cycle luteinizing hormone surge. Putative metabolic signals also influence the GnRH pulse generator, and after performing a cross-sectional hormonal and metabolic analysis of amenorrhoeic athletes, we propose that insulin-like growth factor binding protein 1 (IGFBP-1) is such a signal and may play a role in the initiation of puberty.

Potassium restoration in hypertensive patients made hypokalemic by hydrochlorothiazide.

Among 447 hypertensive patients, most with a history of diuretic-induced hypokalemia, 252 developed diuretic-induced hypokalemia while receiving hydrochlorothiazide, 50 mg/d. In a randomized study we evaluated the efficacy of three drug regimens in restoring potassium levels while maintaining blood pressure control: hydrochlorothiazide (50 mg/d) plus potassium supplement (20 mmol/d); hydrochlorothiazide (50 mg/d) plus potassium supplement (40 mmol/d); or hydrochlorothiazide (50 mg/d) with triamterene (75 mg/d) in one combination tablet. In all groups, mean serum levels of potassium rose within 1 week and showed no further change thereafter. However, the hydrochlorothiazide/triamterene and hydrochlorothiazide plus 40 mmol of potassium regimens were significantly more effective in restoring serum potassium levels than was the hydrochlorothiazide plus 20 mmol of potassium regimen. A significant increase in magnesium levels was observed only in the group treated with the hydrochlorothiazide/triamterene combination. Each regimen provided continued control of mild to moderate hypertension.

The effects of visual feedback on hemispheric alpha asymmetries and reported processing strategies: a single-subject experimental design.

A double reversal single-subject experimental design was used to study the effects of visual feedback on the hemispheric alpha asymmetries of a male subject during a linguistic task. Results indicated that the subject demonstrated flexibility in hemispheric alpha and corresponding processing strategies employed when an alpha biofeedback procedure was used. These results provide further support for the notion that right and left hemispheric activation is associated with different, yet compatible, cognitive strategies and that both can be manipulated under conditions of feedback.

The possible role of aero-allergens in the epidemic of asthma deaths.

The 'epidemic' of asthma deaths observed in the mid 1960s remains unexplained; various aetiological factors having been suggested. We suggest that aero-allergenic factors may have been important based on an analysis of aero-allergens in Cardiff over a 17-year period: a striking temporal association exists between the concentration of hyaline ascospores and increased asthma deaths. These spores, which are particularly prevalent in the summer months, have been inadequately studied as a cause of severe asthma.

Locus of control and degree of compliance in hemodialysis patients.

An experiment was conducted to test the hypothesis that dialysis patients with an internal locus of control orientation will show a higher rate of compliance to medication and dietary restrictions than those patients with an external locus of control. The results strongly supported the hypothesis. The possibility of interventions to modify patient locus of control is discussed, as is the use of this widely studied personality variable in predicting patient compliance.

Chemical modification of crude timothy grass pollen extract. II. Class and specificity of antibodies induced by chemically modified timothy grass pollen extract.

The effects have been studied of three different chemical modifications of timothy grass pollen extract on various immunological properties. The ability to induce IgG antibody with specificity for native antigen was least affected by glutaraldehyde treatment; IgE antibody production was reduced to a similar extent by all three modifications; there was no increase in IgM production; delayed reactions were reduced. New antigenic determinants were introduced by all the modifications, but the effect was minimal following glutaraldehyde treatment. The significance of these results and the potential application of modified allergen in hyposensitisation therapy are discussed.