High-intensity Doses Research Articles

Prevalence of medication-related problems in complex chronic patients and opportunities for improvement

ObjectiveTo estimate the prevalence of medication-related problems in patients treated in continuous care units and to identify the therapeutic areas in which these problems were more concentrated. MethodObservational descriptive prospective study. Review of clinical histories and outpatient treatment by a hospital pharmacist. Communicating medication-related problems detected to the responsible doctor. Analysis of the therapeutic areas in which the problems were most concentrated. Results85 patients were reviewed, and 368 potential medication-related problems were identified. The areas with the most prevalent medication-related problems were the long-term use of hypnotics, sub-optimal analgesia, optimizable antidepressant treatment, statins in patients older than 75 years in primary prevention and in those with high-intensity doses in secondary prevention, patients with heart failure without angiotensin-converting enzyme inhibitors, and proton-pump inhibitors without indication. ConclusionsTraining interventions should be implemented and computer assistance should be developed to help avoid the most prevalent medication-related problems.

Effectiveness of different percutaneous electrolysis protocols in the endogenous modulation of pain: A Double-Blinded Randomized Clinical Trial

ObjectiveThis randomized clinical trial investigated if the application of percutaneous electrolysis (PE) enhances endogenous pain mechanisms (EPM) when compared with a simple needle application (acting as sham). MethodsForty-six asymptomatic subjects, aged 18–40 years, were randomized into three groups receiving a single ultrasound-guided PE intervention consisting of a needle insertion on the lateral epicondyle: sham (without electrical current), low-intensity (0.3 mA, 90s), or high-intensity (three pulses of 3 mA, 3s) PE. Widespread pressure pain thresholds (PPT), conditioned pain modulation (CPM), and temporal summation (TS) were bilaterally assessed in the lateral epicondyle, bicipital groove, transverse process of C5 and tibialis anterior muscle. Outcomes were obtained by an assessor blinded to the treatment allocation of the subjects. ResultsNo significant changes in CPM were observed in either group (omnibus ANOVA all, P > .05). A significant bilateral increase in PPT in the lateral epicondyle in the high intensity group as compared with the sham group was observed (P < .01). A significant decrease of TS in both low (P = .002) and high (P = .049) intensity groups on the right, but not on the left, tibialis anterior was also observed when compared with the sham group. ConclusionsOne session of PE is able to slightly stimulate modulatory pathways related to nociceptive gain, particularly pressure pain sensitivity and temporal summation but not conditioning pain modulation, when compared with a sham needle intervention, with changes even contralaterally. No significant differences were found between low- and high-intensity doses of percutaneous electrolysis.

Comparative effectiveness of statins on non-high density lipoprotein cholesterol in people with diabetes and at risk of cardiovascular disease: systematic review and network meta-analysis

ObjectiveTo compare the efficacy of different statin treatments by intensity on levels of non-high density lipoprotein cholesterol (non-HDL-C) for the prevention of cardiovascular disease in people with diabetes.DesignSystematic review and...

MANAGEMENT OF PATIENTS WITH DYSLIPIDEMIA IN THE PRACTICE OF FAMILY MEDICINE

Dyslipidemia is an important problem for family doctors, as it is a risk factor for the development of atherosclerotic cardiovascular diseases (ACVD). ACVD is the cause of more than 4 million deaths in Europe today. Women in this sad statistic are 2.2 million, and men - 1.8 million. It is expected, that mortality due to cardiovascular diseases in men aged up to 65 years is significantly higher than in women (430 thousand and 193 thousand, respectively).&#x0D; The ESC/EAS-2019 (European Society of Cardiology / European Society of Atherosclerosis) updated guidelines on the management of people with dyslipidemia (DLP) provide specific recommendations that can be used by family doctors in Ukraine in their daily preventive and curative work. The ESC/EAS-2019 (European Society of Cardiology / European Society of Atherosclerosis) and the Ukrainian Society of Atherosclerosis (USA) guidelines emphasize that the cornerstone of the prevention and treatment of ACVD is primarily the detection and correction of DLP. The prevalence of DLP in Ukraine is about 20%.&#x0D; At the same time, for effective correction of DLP it is important to verify the type of dyslipidemia, isolate genetically determined forms of dyslipidemia (familial hypercholesterolemia), establish cardiovascular risk, select the most effective measures of lifestyle modification and formulate therapeutic goals of prevention / treatment.&#x0D; In the treatment of DLP apart from lifestyle modification, the drugs of choice are statins in high-intensity doses. Ezetimibe and PCSK-9 inhibitors can be used in addition to statin therapy in case of its ineffectiveness or side effects. It was found, that resistance to statins and their intolerance is the basis for the use of non-statin hypolipidemic drugs (nutraceuticals), among which the most studied are ω-3 PUFA and phytosterols.&#x0D; The ESC / EAS (2019) guidelines state that consumption of ω-3 PUFAs is associated with a lower risk of death from CVD and stroke. It was noted, that the mechanism of reducing TG levels under the influence of ω-3 PUFA may be related to their ability to interact with PPAR (receptors that activate the proliferation of peroxisomes) and reduce the secretion of apoprotein B. Recent clinical studies confirm the need for high doses of highly purified form of ω-3 PUFA for patients with elevated TG levels, despite treatment with statins.&#x0D; Another non-statin drug that reduces LDL levels is bempedoic acid. Studies have shown a significant reduction in LDL levels in patients receiving additional bempedoic acid. The effectiveness of bempedoic acid as a monotherapy of DLP is now being studied.&#x0D; This review presents new data on the effectiveness of the combination of sugar cane extract policosanol with ω-3 PUFA (docosahexaenoic acid 10%). The drug of this composition "Cardioneurin" is present on the pharmaceutical market of Ukraine. Clinical studies have shown, that in case of resistance or intolerance to statins, especially in high doses, a hybrid strategy of lipid-lowering therapy can be used - a combination of low-intensity doses of statins with a combined nutraceutic "Cardioneurin". This treatment reduces the level of atherogenicity by 22%, which gives grounds for its use in the practice of family doctors.&#x0D; Other forms of policosanol (other than sugar cane), such as those derived from beeswax or wheat germ, do not have an adequate evidence base.&#x0D; Thus, dyslipidemia is the primary and main factor in the development of ACS, it in most cases occurs long before the emergence of other important risk factors and may even be a prerequisite for their occurrence. Epidemiological evidence suggests, for example, that DLP may in itself be a risk factor for STEMI / NSTEMI and unstable angina.

Commentary on "Intensive Bimanual Intervention for Children Who Have Undergone Hemispherectomy: A Pilot Study".

“How should I apply this information?” Sensorimotor deficits that result from hemispherectomy are more severe and debilitating than other forms of hemiplegia. For families with a child who requires this surgical approach and the clinicians who support them during their postoperative rehabilitation, little information is available regarding motor changes in response to specific interventions. This preliminary work offers hope. Regardless of the subject's interhemispheric lateralization, type of hemiplegia, or length of time from surgery, clinically meaningful changes in bimanual function were reported with Hand-Arm Bimanual Intensive Training (HABIT). Given this approach received a “green-light” rating by Novak et al1 in a 2019 systematic review and it is grounded in key principles associated with experience-dependent neuroplasticity, this finding is not surprising. These key principles are focused on: task-specific practice, goal-directed tasks and activities, high-intensity doses of meaningful practice, and self-generated, active movement. From a family's perspective, HABIT represents an escape from “appointment fatigue” and an opportunity to intensively practice real-life activities. “Our daughter became more aware and intentional about using her affected side, and ... activities carried over to home!” “What should I be mindful of when applying this information?” Ninety hours of intervention within a 2-week period requires a high level of commitment from families, children, clinicians, health care organizations that employ clinicians, and third-party payers. Cost-effectiveness analysis is not considered nor are sustainable funding mechanisms discussed. For therapists providing intervention in school-based settings, this intensity of service and the one-on-one support it requires is not feasible; for those in outpatient settings, the time required for organizing and implementing HABIT, the materials needed to engage children across a broad range of ages for 6 hours of daily therapy, and the limited reimbursement options for therapists' one-on-one involvement require a high level of creativity and pose unique challenges. Future research should explore family perspectives, cost-effectiveness, and dose-response parameters that might further individualize the length of necessary intervention. Sandra L. Willett, PT, PhD, PCS Emily Drew, PT, PCS Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska Jennifer Dibbern Parent, Omaha, Nebraska

Statin (mis)use in older people: A cross-sectional study using French health insurance databases.

To describe the occurrence of potential statin misuse, its characteristics and associated factors in older people. A retrospective cross-sectional study was conducted in Alsace and Lorraine (France) using French health insurance databases. Study population comprised community-dwelling patients and nursing homes residents aged 80 and over, who received at least one statin prescription between January 1, 2017 to April 30, 2017 (N= 38 268). Potential statin misuse was identified considering off-label uses, high-intensity doses, drug contraindications and statin-drug interactions. At least one potential statin misuse was detected for 19 468 patients (50.9%). Off-label prescription was the most frequent misuse observed (53.6%), followed by high-intensity statin dose (30.5%). Polypharmacy (five to nine drugs) and excessive polypharmacy (10 or more drugs) were the main risk factors associated with potential statin misuse (adjusted OR=2.6 and 4.7 respectively). Nursing home, multi-morbidity and the presence of multiple prescriptions from different doctors for the same patient were other risk factors significantly associated. Two sensitivity analyzes (reconsiderations of off-label and high statin dose definitions) revealed the same statistical trend. Potential statin misuse is frequent in people aged 80 and over. These findings should serve as a warning to health care professionals and hopefully will contribute to ensure an appropriate and safe use of statin in aged population.

The Risk of Muscular Events Among New Users of Hydrophilic and Lipophilic Statins: an Observational Cohort Study

BackgroundStatins are effective lipid-lowering drugs for the prevention of cardiovascular disease, but muscular adverse events can limit their use. Hydrophilic statins (pravastatin, rosuvastatin) may cause less muscular events than lipophilic statins (e.g. simvastatin, atorvastatin) due to lower passive diffusion into muscle cells.ObjectiveTo compare the risk of muscular events between statins at comparable lipid-lowering doses and to evaluate if hydrophilic statins are associated with a lower muscular risk than lipophilic statins.Design/SettingPropensity score-matched cohort study using data from the United Kingdom-based Clinical Practice Research Datalink (CPRD) GOLD.PatientsNew statin users. Cohort 1: pravastatin 20-40 mg (hydrophilic) vs simvastatin 10-20 mg (lipophilic), cohort 2: rosuvastatin 5-40 mg (hydrophilic) vs atorvastatin 10-80 mg (lipophilic), and cohort 3: simvastatin 40-80 mg vs atorvastatin 10-20 mg.Main MeasuresThe outcome was a first record of a muscular event (myopathy, myalgia, myositis, rhabdomyolysis) during a maximum follow-up of 1 year.Key ResultsThe propensity score-matched cohorts consisted of 1) 9,703, 2) 7,032, and 3) 37,743 pairs of statin users. Comparing the risk of muscular events between low-intensity pravastatin vs low-intensity simvastatin yielded a HR of 0.86 (95% CI 0.64-1.16). In the comparison of moderate- to high-intensity rosuvastatin vs equivalent doses of atorvastatin, we observed a HR of 1.17 (95% CI 0.88-1.56). Moderate- to high-intensity simvastatin was associated with a HR of 1.33 (95% CI 1.16-1.53), when compared with atorvastatin at equivalent doses.LimitationsWe could not conduct other pairwise comparisons of statins due to small sample size. In the absence of a uniform definition on the comparability of statin doses, the applied dose ratios may not fully match with all literature sources.ConclusionsOur results do not suggest a systematically lower risk of muscular events for hydrophilic statins when compared to lipophilic statins at comparable lipid-lowering doses.

An expanded repertoire of intensity-dependent exercise-responsive plasma proteins tied to loci of human disease risk

Routine endurance exercise confers numerous health benefits, and high intensity exercise may accelerate and magnify many of these benefits. To date, explanatory molecular mechanisms and the influence of exercise intensity remain poorly understood. Circulating factors are hypothesized to transduce some of the systemic effects of exercise. We sought to examine the role of exercise and exercise intensity on the human plasma proteome. We employed an aptamer-based method to examine 1,305 plasma proteins in 12 participants before and after exercise at two physiologically defined intensities (moderate and high) to determine the proteomic response. We demonstrate that the human plasma proteome is responsive to acute exercise in an intensity-dependent manner with enrichment analysis suggesting functional biological differences between the moderate and high intensity doses. Through integration of available genetic data, we estimate the effects of acute exercise on exercise-associated traits and find proteomic responses that may contribute to observed clinical effects on coronary artery disease and blood pressure regulation. In sum, we provide supportive evidence that moderate and high intensity exercise elicit different signaling responses, that exercise may act in part non-cell autonomously through circulating plasma proteins, and that plasma protein dynamics can simulate some the beneficial and adverse effects of acute exercise.

Lipid-lowering drug prescriptions in a group of Colombian patients.

Introduction. Lipid-lowering drugs, especially statins, have shown great relevance in preventing and treating cardiovascular diseases.Objective. To determine the prescription patterns of lipid-lowering drugs and the variables associated with their use in a Colombian population.Materials and methods. This is a cross-sectional descriptive study. From a drugdispensing database of approximately 4.5 million Colombian health system affiliates, patients of all ages and both sexes treated with lipid-lowering agents (statins, fibrates, ezetimibe) were identified between January and March, 2017. Demographic, pharmacological and co-medication variables were included.Results. In total, 103,624 patients were identified as being treated with lipid-lowering agents. The average age was 67.5 years, and 49.8% were 65 years or older. Women comprised 58.0% of the patients. Statins were the most used (n=96,910; 93.5%), and atorvastatin (n=80,812; 78.0%) and lovastatin (n=12,621; 12.2%) were the most frequent. The mean atorvastatin dose was 30.3 mg/day, and 49.9% of its users received presentations of 40 mg or more. A total of 9,258 (8.9%) patients received fibrates, and only 780 (0.8%) were taking ezetimibe. Of this population, 94.9% were treated with lipid-lowering monotherapy, and 97.3% (n=100,813) had co-medication for their comorbidities, with the most frequent being antihypertensive (89.1%), antiplatelet (57.8%), antidiabetic (31.5%) and antiulcerative agents (34.2%).Conclusions. Atorvastatin is currently the most frequently used lipid-lowering drug in this group of Colombian patients, especially in monotherapy and at doses close to the defined daily dose. Only half received high-intensity doses. New studies are required to verify the efficacy of these therapies.

Clinical Controversy in Transplantation: Tacrolimus Versus Cyclosporine in Statin Drug Interactions.

Objective: To review the available literature that provides evidence for the absence of statin interactions with tacrolimus compared with cyclosporine. Data Sources: A literature search of PubMed was performed (1990 to June 2019) using the following search terms: calcineurin inhibitors, tacrolimus, cyclosporine, statins, atorvastatin, simvastatin, and drug interactions. Clinical practice guidelines, article bibliographies, drug interaction database references, and product monographs were also reviewed. Study Selection and Data Extraction: Relevant English-language studies describing the mechanism of interaction, the magnitude of pharmacokinetic alterations, and safety were evaluated. In vitro data and studies conducted in adult humans were considered. Data Synthesis: Studies demonstrate pharmacokinetic differences between cyclosporine and tacrolimus, particularly with regard to inhibition of 2 hepatic transporters: P-glycoprotein and organic anion transporting polypeptide (OATP). Compared with cyclosporine, tacrolimus does not affect these transporters, does not enhance statin exposure, and does not increase statin-associated safety events. Relevance to Patient Care and Clinical Practice: Clinical practice guidelines allude to the need to reduce statin doses in the setting of tacrolimus. Some providers have adopted this practice, and doing so may prevent transplant recipients from attaining cardiovascular benefit, especially when increased or high-intensity doses are required. The pharmacokinetic differences between tacrolimus and cyclosporine highlight different interaction potential with statins. Conclusions: Clinicians need to be aware that tacrolimus and cyclosporine are not the same with regard to causing drug interactions with statins. Tacrolimus can be used with statins without the need for dose adjustments because of lack of an interaction.

Abstract 16990: Impact of 2013 ACC/AHA Cholesterol Management Guidelines on Statins Use Among Nationally Representative Adult Populations in United States: Medical Expenditure Panel Survey (2010-2015)

Background: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Cholesterol Management Guidelines recommended statin as the first-line lipid-lowering therapy (LLT) for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). We aim to examine the impact of the guidelineson statin use in the US. Methods: Using the2010-2015 Medical Expenditure Panel Survey (MEPS) data, we estimated trends in statin utilization in adults age 40-75 years in 4 defined groups: (1) All adults, adults with: (2) established ASCVD, (3) diabetes mellitus [DM] and no ASCVD and, (4) estimated 10-year risk &gt;=7.5% in absence of ASCVD and DM. Joint-point regression (JPR) analysis was used to examine changes in statin use trend around the period of the guideline’s publication. Results: We found no statistically significant change in statin use. (Figure) The use of any statin therapy in 2010-2012 ranged from 24.6 to 25.1%, and 24.6 to 25.1% in 2014-2015 among all adults. Statin use among those with ASCVD ranged from 58.8 to 56.6% (2010-2012) and 56.7-57.8% (2014-2015). Similar trends were noted in our two other study groups. However, a significantly higher proportion of statin users among established ASCVD patients reported use of high intensity doses: 34.3 to 38.1% post- versus 29.6 to 31.6% pre-guideline publication with an average annual percentage change (AAPC) of 4.9 (95% CI: 2.9-6.9). (Figure) Joint point regression showed no statistically significant inflection in the trend line of all and high-intensity statin use in any of the study groups after guideline publication. Conclusion: There was a mild increase in high-intensity statin use after the 2013 ACC/AHA guidelines release, but no impact on overall statin use in US two years after publication. Barriers to guideline adoption and opportunities to increase the impact of guidelines on clinical practice need to be investigated.

PCV22 - LIPID-LOWERING DRUG PRESCRIPTIONS IN A GROUP OF COLOMBIAN PATIENTS.

Lipid-lowering drugs, especially statins, have shown great relevance in preventing and treating cardiovascular diseases. Their usage profiles can vary considerably over time with changes in approved molecules, in the health system or clinical guidelines. The objective was to determine the prescription patterns of lipid-lowering drugs and the variables associated with their use in a Colombian population. Cross-sectional descriptive study. From a drug-dispensing database of approximately 4.5 million Colombian health system affiliates, patients of all ages and both sexes treated with lipid-lowering agents (statins, fibrates, ezetimibe) were identified during January-March 2017. Demographic, pharmacological and co-medication variables were included. In total, 103,624 patients were identified as being treated with lipid-lowering agents. The average age was 67.5 years, and 49.8% were 65 years or older. Women comprised 58.0% of the patients. Statins were the most used (n = 96.910; 93.5%), and atorvastatin (n = 80.812; 78.0%) and lovastatin (n = 12.621; 12.2%) were the most frequent. The average atorvastatin dose was 30.3 mg/day, and 49.9% of its users received presentations of 40 mg or more. A total of 9,258 (8.9%) patients received fibrates, and only 780 (0.8%) were taking ezetimibe. Of this population, 94.9% were treated with lipid-lowering monotherapy, and 97.3% (n = 100,813) had co-medication for their comorbidities, with the most frequent being antihypertensive (89.1%), antiplatelet (57.8%), antidiabetic (31.5%) and antiulcerative agents (34.2%). Atorvastatin is currently the most frequently used lipid-lowering drug in this group of Colombian patients, especially in monotherapy and at doses close to the defined daily dose. Only half received high-intensity doses. New studies are required to verify the efficacy of these therapies.

Trends in Use of High-Intensity Statin Therapy After Myocardial Infarction, 2011 to 2014

BackgroundData prior to 2011 suggest that a low percentage of patients hospitalized for acute coronary syndromes filled high-intensity statin prescriptions upon discharge. Black-box warnings, generic availability of atorvastatin, and updated guidelines may have resulted in a change in high-intensity statin use. ObjectivesThe aim of this study was to examine trends and predictors of high-intensity statin use following hospital discharge for myocardial infarction (MI) between 2011 and 2014. MethodsSecular trends in high-intensity statin use following hospital discharge for MI were analyzed among patients 19 to 64 years of age with commercial health insurance in the MarketScan database (n = 42,893) and 66 to 75 years of age with U.S. government health insurance through Medicare (n = 75,096). Patients filling statin prescriptions within 30 days of discharge were included. High-intensity statins included atorvastatin 40 or 80 mg and rosuvastatin 20 or 40 mg. ResultsThe percentage of beneficiaries whose first statin prescriptions filled following hospital discharge for MI were for high-intensity doses increased from 33.5% in January through March 2011 to 71.7% in October through November 2014 in MarketScan and from 24.8% to 57.5% in Medicare. Increases in high-intensity statin use following hospital discharge occurred over this period among patients initiating treatment (30.6% to 72.0% in MarketScan and 21.1% to 58.8% in Medicare) and those taking low- or moderate-intensity statins prior to hospitalization (from 27.8% to 62.3% in MarketScan and from 12.6% to 45.1% in Medicare). In 2014, factors associated with filling high-intensity statin prescriptions included male sex, filling beta-blocker and antiplatelet agent prescriptions, and attending cardiac rehabilitation within 30 days following discharge. ConclusionsThe use of high-intensity statins following hospitalization for MI increased progressively from 2011 through 2014.

Statin use, intensity, and 3-year clinical outcomes among older patients with coronary artery disease

Clinical trial evidence suggests that statin therapy reduces adverse clinical events and provides even greater benefit at high-intensity doses in coronary artery disease (CAD) patients, yet few studies have examined this in clinical practice. We linked detailed in-hospital data (2005-2009) on 15,729 Get With The Guidelines-CAD patients ≥65 years prescribed statins to Centers for Medicare and Medicaid Services claims. High-intensity statin therapy was defined as discharge prescription of atorvastatin ≥40 mg, rosuvastatin ≥20 mg, or simvastatin 80 mg. We used Kaplan-Meier curves to calculate all-cause mortality, major adverse cardiovascular events (MACEs), and all-cause readmission at 3 years postdischarge; log-rank tests to compare survival via overall statin use and intensity; and Cox proportional hazards regression with inverse propensity weighting to evaluate adjusted rates of adverse events over 3 years postdischarge. Of 35,903 patients meeting inclusion criteria, 24,367 (67.9%) were discharged on statin. Of 15,729 patients with statin intensity information, 4488 (28.5%) received high-intensity therapy; these recipients were more often younger, male, and had acute myocardial infarction. After inverse propensity weighting adjustment, statin use was associated with significantly lower hazards of mortality (hazard ratio 0.89, 95% CI 0.84-0.93) and MACE (0.92, 0.88-0.96), but not readmission (1.01, 0.97-1.04). High-intensity (vs low/moderate) use was not associated with lower risk of all-cause mortality (1.07, 1.00-1.14), MACE (1.05, 0.99-1.11), or readmission (1.05, 1.00-1.10). Clinically relevant subgroups had similar results. In older hospitalized CAD patients, use of statin therapy at discharge was associated with improved long-term outcomes. Consistent with current American College of Cardiology/American Heart Association cholesterol guideline recommendations supporting moderate- rather than high-intensity statin therapy in CAD patients >75 years, high-intensity statin therapy was not associated with incremental benefit in this older population.

Management of the neurological manifestations of APS—what do the trials tell us?

Purpose: To systematically review evidence from clinical trials about the management of neurological manifestations of Antiphospholipid Syndrome (APS). Methods: Articles reporting case-control, cohort and prospective studies and treatment trials of primary or secondary stroke prevention in patients with aPL were identified in an OVID literature search from 1966 to 2004, using the keywords: APS, aPL and cerebrovascular disease. Articles were evaluated according to the standard system for assessing medical evidence to answer the following questions: (1) What is the role of aPL and recurrent stroke risk in both primary and secondary APS populations? (2) What is the evidence to support specific treatment strategies for secondary prevention of aPL-associated stroke? (3) What is the evidence to support specific treatment strategies for primary prevention of aPL-associated stroke? Conclusions: (1) aPL are a risk factor for incident stroke (Grade A, established as useful for the given condition in the specified population). (2) The evidence to support the role of aPL in recurrent stroke is conflicting and, therefore, inconclusive. (3) Warfarin at moderate-intensity doses is equally effective in preventing a recurrent thrombotic event as warfarin at high-intensity doses in patients with APS (Grade A evidence, established as useful for the given condition in the specified population). (4) Warfarin, at moderate-intensity doses is as effective as aspirin (at a dose of 325 mg/day) in preventing recurrent thrombotic events in patients who are aPL-positive at the time of an initial stroke (Grade B evidence, probably useful for the given condition in the given population). (5) Currently there are no data to support the use of any prophylactic therapy in patients with aPL and no clinical manifestations for the purposes of preventing an incident stroke.

The Reaction of Kidney Tubules in Tissue Culture to Roentgen Rays

The present report deals with experiments to ascertain whether cells, when in states of physiological activity, are more susceptible to irradiation than when they are not. The tissue used was from the mesonephros of nine- or ten-day chick embryos grown in tissue culture. The amount of irradiation necessary to produce an effect was found to be extraordinarily high. There is a latent period and the intensity of the reaction depends upon the dosage and the condition and type of the cells. Investigations of the past few years in this laboratory (1) have shown that fragments of kidney tubules of the chick mesonephros continue to function in tissue culture. The secretory activity of the proximal tubules is strikingly shown by their ability to accumulate phenol red from the medium This suggested a means of testing the effect of x-rayon the secretory mechanism. The cultures were prepared by placing teased fragments of the mesonephros in hanging drops of a mixture of fowl plasma and Tyrode solution on coverslips and incubating at 37.5° C. After a few hours the cut ends of the tubules heal over, converting the tubules into closed segments which, when secretion occurs, become progressively distended. In some cases the epithelial cells at the cut ends grow out to form sheets extending beyond the explant. In cultures of twenty-four to forty-eight hours the closed segments of proximal tubules within the explanted fragment become distended with secreted fluid. With plasma alone the distention is distinctly less than when phenol red or magnesium sulphate is added to the medium. In the latter case the distention is taken to indicate an enhancement of the secretory process. The outgrowth from the explant consists of wandering cells, fibroblasts, and sheets of proliferating epithelium. The cultures thus provide for a study of epithelial tissue as organized tissue in the form of secreting tubules and as unorganized tissue in the form of outgrowing sheets. The exposure of the cultures to x-ray treatment necessitated subjecting them to room temperature for about one to two hours. This causes a temporary cessation of secretory activity (1), which is speedily resumed on returning the cultures to body temperature. The controls and experimental cultures were always submitted to the same change of temperature. The x-ray equipment was a dual tube, self-rectifying machine. This provides two cross-firing beams of x-rays of high intensity and large doses can be administered in a few minutes’ exposure. The secondary voltage was kept at 200 kv. and the current passing through each tube was 30 rna. The output intensity, measured in air at the point of treatment (T. S. D. 14.8 cm.) after filtration by the heavy glass tube wall, was approximately 2,700 r/min. In general, these tissue culture studies deal with the effect of irradiation on secreting and non-secreting renal epithelium, and on other activities of cells, including motility and regenerative processes.