Focused VHEE (very high energy electron) beams and dose delivery for radiotherapy applications.

This paper presents the first demonstration of deeply penetrating dose delivery using focused very high energy electron (VHEE) beams using quadrupole magnets in Monte Carlo simulations. We show that the focal point is readily modified by linearly changing the quadrupole magnet strength only. We also present a weighted sum of focused electron beams to form a spread-out electron peak (SOEP) over a target region. This has a significantly reduced entrance dose compared to a proton-based spread-out Bragg peak (SOBP). Very high energy electron (VHEE) beams are an exciting prospect in external beam radiotherapy. VHEEs are less sensitive to inhomogeneities than proton and photon beams, have a deep dose reach and could potentially be used to deliver FLASH radiotherapy. The dose distributions of unfocused VHEE produce high entrance and exit doses compared to other radiotherapy modalities unless focusing is employed, and in this case the entrance dose is considerably improved over existing radiations. We have investigated both symmetric and asymmetric focusing as well as focusing with a range of beam energies.

Macronyssid mites in oral mucosa of long-nosed bats: occurrence and associated pathology.

Macronyssid mites (Radfordiella) have been found in the oral mucosa of the long-nosed bat (Leptonycteris nivalis), which occurs from Texas southward throughout much of Mexico. This is the first report of mites of the suborder Mesostigmata attached in the oral cavity of a mammal. Osteolysis of hard palate and odontolysis of teeth result from infestations of mites adjacent to the upper premolars and molars; destruction of bone, teeth, and Connective tissue often leads to exfoliation of teeth in life. Oral mites have not been found in Leptonycteris sanborni, a species in part sympatric with Leptonycteris nivalis.

Measuring angles on digitalized radiographic images using Microsoft PowerPoint.

OBJECTIVE: To introduce the "virtual goniometer", a method of measuring angles on digital images using Microsoft PowerPoint, a readily available and inexpensive software programme. METHODS: Twenty-six X-rays of scoliosis curves were photographed with a digital camera. Six examiners measured the angles of curvature on their computers using the goniometer (Set 1). Under a blinded protocol, repeated measurements on these digitalized X-rays were done three weeks later (Set 2). Intra-observer differences were analyzed. To assess validity, four examiners also measured the angles using the Cobb method. Measurements achieved by both methods were analyzed by the paired samples t-test. To assess inter-observer differences, the Pearson correlation coefficient was calculated. RESULTS: Pearson correlation coefficients were significant, r (24) > or = 0.975, p < 0.001. For intraobserver variability, the average 95% CI range was 2.23 degrees between Set 1 and Set 2. The average 95% CI range was 2.38 degrees for the difference between the digital and Cobb methods. CONCLUSIONS: Clinicians using this technique can reliably assume that repeated measurements of scoliosis curvatures will vary in the range of less than 3 degrees. The 95% CI range for intra-observer variability, an index of the technique's repeatability, was > or = 2.4 degrees. A high correlation of measurements can also be expected between different observers with the goniometer. This new technique allows practitioners to utilize an easily accessible computer programme to evaluate angular deformities on digitalized radiographic images accurately and hence reliably make clinical decisions based on these measurements.

The Institute of Medicine's report on drug safety: constructive and ambitious, but does it go far enough?

In September 2004, controversy surrounded the Food and Drug Administration (FDA). It climaxed more than a decade of safety concerns involving legitimate and perceived problems with FDA-approved drugs. In response, the FDA's Center for Drug Evaluation and Research (CDER) asked the Institute of Medicine (IOM) to examine the current systems for ensuring drug safety and recommend specific actions and improvements.

Rat liver adenyl cyclase activity in various thyroid states.

Thyroidectomized and euthyroid rats were injected with three doses of triiodothyronine (T(3)) or of the diluent over a 6 day period, and liver homogenates were assayed for basal, epinephrine-stimulated, and NaF-stimulated adenyl cyclase activity. Based on NaF-stimulated levels, total adenyl cyclase activity, expressed per milligram of liver protein, was increased after thyroidectomy. Administration of T(3) to either hypothyroid or euthyroid rats, however, had no effect on the NaF-stimulated levels. Basal and epinephrine-stimulated enzyme activities were the same in hypothyroid, euthyroid, and hyperthyroid (euthyroid + T(3)) liver homogenates. In contrast, injections of T(3) in hypothyroid rats increased the activities of basal and epinephrine-stimulated adenyl cyclase. In view of the findings in euthyroid and hyperthyroid liver, it is possible that this effect is transient. In general, no correlation was found between the effects of thyroid hormone on respiration and on adenyl cyclase activity of the rat liver. These results imply that the hepatic thermogenic response to thyroid hormone is not mediated by stimulation of adenyl cyclase activity with the possible exception of the early effects of T(3) in the athyroid rat.

A new colon carcinoma cell line (LIM1863) that grows as organoids with spontaneous differentiation into crypt-like structures in vitro.

A new colon carcinoma cell line (LIM1863) has been characterized. This cell line is unique in that the culture consists of organoids which are morphologically and functionally organized. Histological studies of the organoids show that the cells are arranged around a central lumen and the nuclei are polarized to the periphery. Two major morphological types are present: a columnar cell with a polarized, structurally normal brush border and goblet cells. The cells are also functionally mature and express the brush border enzymes aminopeptidase N, dipeptidyl peptidase IV, alkaline phosphatase, and sucrase-isomaltase. These enzymes are localized to the luminal membrane and the apical cytoplasm (of some cells). The goblet cells contain mucus and this mucus is secreted into the lumen. This functional differentiation suggests that the organoids contain precursor cells capable of differentiating along both the columnar and goblet cell pathways. At present no endocrine cells have been detected by morphological or histochemical analysis. The organoids have been in continuous culture with regular passaging for 21 months and also grow and differentiate normally in serum-free medium.

Presence of laminin fragments in cyst fluid from patients with autosomal dominant polycystic kidney disease (ADPKD): role in proliferation of tubular epithelial cells.

Cyst fluid samples obtained from eight patients with autosomal dominant polycystic kidney disease (ADPKD) were analysed for the presence of the basement membrane component laminin and its breakdown products, using ELISA and immunoblotting techniques. Whole laminin was not detected, whereas laminin fragments of 270, 155, 87, 56, and 14 kDa were detected at a mean total value of approximately 0.5 microgram/ml. The laminin fragments were assessed for their effect on cultured normal and ADPKD epithelial cells. Both cell types showed accelerated growth under these conditions. These findings suggest that basement membrane degradative fragments present in cyst fluid may contribute to cystic epithelial cell proliferation and may therefore be important in the pathogenesis of ADPKD.

Isolation of pepsin-resistant laminin fragments from human placenta: effect on epithelial cells cultured from the kidneys of patients with autosomal dominant polycystic kidney disease (ADPKD).

Laminin isolated from human placenta was subjected to prolonged pepsin digestion. Seven peptide fragments (designated N1 to N7) were separated by ion-exchange chromatography and gel filtration and characterised by SDS-polyacrylamide gel electrophoresis and immunoblotting. The molecular size of the laminin fragments varied from approx. 900,000 (N1) to 28,000 (N7). Epithelial cells obtained from normal kidneys and patients with autosomal dominant polycystic kidney disease (ADPKD) were cultured. The incorporation of [3H]thymidine was measured over 96 h to determine the effect of the addition of the different fragments and whole laminin from EHS tumour to the cells. The rate of growth of both normal and polycystic cells was increased in the presence of the laminin fragments but this effect was more pronounced in the ADPKD cells.

High resolution proton magnetic resonance spectroscopy of cyst fluids from patients with polycystic kidney disease.

High field 1H-NMR spectra of fluid collected from the cysts of six renal transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) have been measured and the major metabolite signals assigned. Quantitative NMR measurements have revealed a combination of unusual biochemical features of the cystic fluids that shows them to be distinct from both blood plasma and urine. Isoleucine, lysine, threonine and valine were present at mM concentrations, in cyst fluid and in some cases levels up to 2 orders of magnitude higher than normal plasma or urine were recorded. Mean glucose concentrations in the cyst fluids ranged from 3.4-9.6 mM and a number of organic acids and bases, including acetate, lactate, succinate, creatinine and dimethylamine were also present at high concentration and in different ratios to those found in either plasma or urine. The majority of cyst fluids examined also contained significant quantities of glycoproteins with characteristic 1H-NMR signals from N-acetyl groups of amino-sugar and sialic acid side chains which had a high degree of molecular mobility (as indicated by their relatively long T2 relaxation times, greater than 120 ms). High levels of ethanol (0.5-12.6 mM/l) were found in all fluid samples from the six transplanted patients (confirmed by conventional analysis). In general there was little variation in the 1H-NMR spectral patterns of either the intra- or interpatient cyst fluids, although the contribution of the protein macromolecules to individual spectra was lower in a few cysts. This constancy of biochemical composition probably reflects the chronic nature of the accumulation of cyst fluid and a long turnover of the cystic fluid components which has the effect of averaging composition. These findings suggest that the dynamic composition of cyst fluid from ADPKD patients is unique among the other body fluids and that the unusual composition may be related to epithelial polarity reversal of the cystic epithelium which could also contribute to the growth of the cysts.

Value of epidemiologic studies in determining the true incidence of adverse events. The nonsteroidal anti-inflammatory drug story.

BACKGROUND: Evidence supporting differential toxic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) often is derived from spontaneous reports of adverse events to the US Food and Drug Administration (FDA). These reports represent observations from an undefined, exposed population that are not collected in a standardized manner and therefore are subject to reporting biases. Epidemiologic studies, in which the numbers of patients experiencing an adverse event and exposed to the drug are known, provide more reliable measures of risk and can place spontaneous reports in perspective. OBJECTIVE: To compare both data sources with regard to NSAID-associated gastrointestinal, liver, and skin events. METHODS: We obtained spontaneous reports of these adverse events for diclofenac, nabumetone, naproxen, and piroxicam. Published epidemiologic studies of these events were reviewed. RESULTS: Spontaneous reports did not mirror reliably the results of epidemiologic studies. Spontaneous reports showed higher associations of gastrointestinal and skin events with nabumetone and piroxicam and hepatic events with diclofenac. Epidemiologic studies generally did not show differential risk among these NSAIDs. CONCLUSIONS: When the 4 NSAIDs are compared in epidemiologic studies, there is no quantitative basis for identifying 1 as more or less toxic than the others, underlining the hazard of deriving quantitative conclusions from spontaneous reports. Spontaneous reports are an unreliable measure of risk; rather, they may provide evidence of the relative awareness of specific toxic effects among physicians.

The relative gastrointestinal toxicity of the nonsteroidal anti-inflammatory drugs.

To assess the relative rate or upper gastrointestinal (UGI) tract bleeding associated with nonsteroidal anti-inflammatory drugs (NSAIDs), we performed a retrospective cohort study using 1980 billing data from all Medicaid patients in the states of Michigan and Minnesota. The rate of UGI tract bleeding in the 30 days following each drug exposure was examined in the 88,044 patients dispensed only one of seven NSAIDs. The rate of UGI tract bleeding differed significantly among users of these drugs. Stratification and logistic regression were used to adjust for multiple potential confounding factors, without substantive changes in the results. An alcohol-drug interaction was found. Sulindac users had the highest rate of UGI tract bleeding, and it was the only drug statistically different from ibuprofen. When the average daily dose of sulindac received was divided by the maximum recommended daily dose, it was notably higher than those for other drugs. Repeated analyses using data from 1982 confirmed these results. We conclude that there are significant and consistent differences in the incidence of UGI tract bleeding associated with the use of NSAIDs in this population.

Oral contraceptives and other risk factors for gallbladder disease.

Prior studies of the association between oral contraceptives (OCs) and gallbladder disease (GBD) have yielded conflicting results. To clarify this association, a retrospective (historical) cohort study was performed on a very large data base including 1980 and 1981 Medicaid billing data from the states of Michigan and Minnesota in which 138,943 users of OCs were compared with 341,478 nonusers. The crude relative risk (RR) and 95% confidence interval (CI) for symptomatic GBD resulting in medical care was 1.14 (CI 1.09 to 1.20), with a clear dose-response (P less than 0.001). Age markedly modified the effect of OCs on GBD. The RR (CI) decreased from 3.1 (2.7 to 3.6) in women 15 to 19 years old to 1.2 (0.9 to 1.5) in women 40 to 44 years old, providing an explanation for previously conflicting reports. The effects of a number of other risk factors on GBD, some which have been controversial, were also confirmed. Adjustment for these did not change the results. In conclusion, OCs are risk factors for GBD, although the risk is of sufficient magnitude to be of potential clinical importance only in young women.

PIP: To clarify the association between oral contraceptives (OCs) and gallbladder disease (GBD), a retrospective (historical) cohort study was performed with 1980 and 1981 Medicaid billing data from the states of Michigan and Minnesota in which 138,943 users of OCs were compared to 341,478 nonusers. There were 12,292 cases of GBD that required medical attention during the 2-year study, giving an overall prevalence rate of 25.6/1000 persons over the 2 years. Of the 138,943 OC users in this study, 3889 had GBD, giving a prevalence of 28.0/1000 persons in the 2-year study. Of the 341,478 nonusers, 8403 had GBD, resulting in a prevalence rate of 24.6/1000 persons in these 2 years. The overall prevalence rate in the unexposed subjects in Michigan was higher than that in Minnesota (28.5 vs. 12.3/1000 persons in the 2 year, respectively). This difference in prevalence by state may rest in part from differences in urbanization or to the known differences in racial distribution. Comparing Minnesota with Michigan, blacks are markedly underrepresented (5.9% versus 35.6%), Indians are overrepresented (3.9% versus 0.37%), and Orientals are overrepresented (5.7% versus 0.48%). Alternatively, this difference in prevalence by state may result from administrative dissimilarities between the 2 Medicaid programs, such as in differences in the number of diagnoses that can be provided per visit and the number of visits that can be included on each claim form. The results indicate that subsequent analyses need to be state specific or state adjusted. The crude relative risks confidence intervals for the effect of OCs on GBD were 1.14 overall, 1.08 for Michigan, and 1.39 for Minnesota. While the proportion of subjects using OCs decreased with advancing age, the prevalence of GBD increased steadily with age in both users and nonusers. Stratification by 5-year age intervals revealed age to be a strong modifier of the effect of OCs on GBD, with younger women at a higher risk of GBD from OCs than middle-aged women. The effects of a number of other risk factors on GBD also were confirmed. Adjustment for these failed to change the results. The relationship between OCs and GBD remained statistically significant even after age, state, and each confounding variable was controlled for logistic regression. In sum, OCs are risk factors for GBD, although the risk is of sufficient magnitude to be of potential clinical importance only in young women.

Intracortical osteosarcoma.

A case of osteosarcoma arising in the tibia of a 15-year-old boy is reported. Of particular interest was the benign roentgenographic appearance and the confinement of the tumor within the cortex of the bone, an extremely rare phenomenon consistent with origin within the primitive mesenchyme of the Haversian canals.

Radiocontrast media. Regulatory aspects.

The FDA regulates the development, manufacturing, marketing, and postmarketing surveillance of radiocontrast and medical imaging agents, which it defines as drugs. In the current environment, the trend by many institutions toward cost consciousness and quantitative evaluation of all aspects of health care indicates that FDA regulations will represent only one of several regulatory forces that will affect the development and use of all drugs.

Risk of selected serious cardiac events among new users of antihistamines.

This retrospective cohort study examined the risk of selected serious cardiac events in new users of either astemizole or sedating antihistamines identified from the COMPASS Ohio Medicaid population of approximately 1 million active lives per year (1986-1992). (COMPASS is an automated claims database.) There were 15,585 patients in the astemizole group and 30,105 in the sedating antihistamines group. Reports of ventricular arrhythmia or sudden death occurring within 30 days of the first antihistamine claim were identified from Medicaid claims. Medical records were obtained and reviewed by a clinician for validity of diagnoses. Records for patients without a full 30 days of follow-up were sought in the National Death Index. Death certificates were obtained for all patients who died within 30 days of the first antihistamine claim. Of 53 cases identified, 6 were in the astemizole group and 47 in the sedating antihistamines group. The relative risk for all selected cardiac events among astemizole users compared with sedating antihistamine users was 0.25 (95% confidence interval: 0.11 to 0.58), and this estimate did not change substantially when adjusted for age; sex; race; recent history of cardiovascular disease, arrhythmias, asthma/pulmonary disease, or malignant neoplasms; or concomitant prescription of other drugs. This study provided no evidence that astemizole users are at increased risk for cardiac events in the first month of use when compared with users of sedating antihistamines.

Prescribing of selective serotonin reuptake inhibitors, anxiolytics, and sedative-hypnotics by general practitioners in The Netherlands: a multivariate analysis.

A study of the prescribing of anxiolytics and sedative-hypnotics and the occurrence of anxiety or sleep disorders before and after the initiation of selective serotonin reuptake inhibitor (SSRI) therapy may provide insight into differences in individual SSRIs. The purpose of our study was to evaluate whether and in what way the likelihood of being prescribed an anxiolytic or sedative-hypnotic or receiving a diagnosis of an anxiety or sleep disorder differed in patients prescribed either fluoxetine or paroxetine by a general practitioner (GP) in the Netherlands, where these two agents are the most commonly prescribed SSRIs. Episodes of SSRI treatment were constructed from a recently available GP database in the Netherlands. Logistic regression analysis was used to determine whether, after controlling for other observable factors, the receipt of paroxetine or fluoxetine was a statistically significant determinant for receipt of an anxiolytic or sedative-hypnotic or a diagnosis of an anxiety or sleep disorder. We found that patients who were prescribed fluoxetine as their index drug were less likely to receive a concomitant sedative-hypnotic on their index date compared with patients receiving paroxetine. After controlling for other observable factors, such as use of anxiolytics and sedative-hypnotics before SSRI therapy or on the index date or the existence of comorbid anxiety or sleep disorders, patients starting fluoxetine therapy were no more likely than patients starting paroxetine therapy to receive an anxiolytic or sedative-hypnotic or a diagnosis of an anxiety or sleep disorder during the 60-day post period. The likelihood of a patient's being diagnosed with or receiving a prescription for an anxiety or sleep disorder does not appear to be a differentiating factor between the prescribing of fluoxetine or paroxetine by GPs in the Netherlands.

Progestins and breast cancer: an epidemiologic review.

OBJECTIVE: To provide a worldwide review of all studies that have examined the relationship between progestins, as contained in both contraceptive and postmenopausal replacement therapies, and breast cancer risk. An overview of utilization patterns for progestins, as well as a review of possible biological mechanisms for progestins' action on breast tissue, are also presented. DATA IDENTIFICATION: All major epidemiologic studies conducted since 1980 have been identified through MEDLINE searches through the published literature and personal communications with prominent researchers in the area. STUDY SELECTION: Only studies that specifically examined the effects of progestin use are discussed here; these include investigations of progestins, in combination or singularly, as the main hypothesis or a subgroup analysis. RESULTS: The majority of studies have examined combination estrogen and progestin products (oral contraceptives), and subgroup analyses of progestins have been impeded by low statistical power and the fact that each progestin possesses different types of pharmacological activity. Only a few studies of long-acting injectable progestins exist, confirming a general lack of specific information on the progesterone-breast cancer relationship. Investigations of the effect on breast cancer of the addition of progestins to postmenopausal replacement therapy have also produced inconsistent results. CONCLUSIONS: To date, there is no consistent evidence of an association between progestins and breast cancer. There is need for further study, particularly of patients in potentially high-risk groups, including those with (1) extended hormone exposure before age 25 and/or first full term pregnancy and (2) exposure in the postmenopausal period.

PIP: Major epidemiologic studies since 1980 which looked at the relationship between progestins in contraceptive and postmenopausal replacement therapies and breast cancer risk were reviewed and analyzed to determine to what extent progestin use may influence breast cancer risk. Most of these studies centered on combination oral contraceptives that contain estrogen and progestin. Low statistical power restricted any subgroup analyses of progestins. Another obstacle was that the pharmacological activity of each progestin is different. Further, scientists cannot agree on the biological mechanism of progestin action on breast tissue. In addition, the link between progestins and breast cancer may actually change during and after the reproductive cycle. Just a limited number of studies on long-acting injectables had taken place which did not provide specific information on the progesterone and breast cancer association. Also, the results of studies examining the effect of adding progestins to postmenopausal replacement therapy on breast cancer were contradictory. Since no clear evidence of a relationship between progestins and breast cancer exists, scientists need to conduct further studies. These studies should concentrate on women in potentially high risk groups which include those who have been exposed extensively to hormones before 25 years of age and/or 1st full-term pregnancy, those who have been exposed postmenopausally, and nulliparous women who began menstruating when younger than 13 years old.

Selective serotonin reuptake inhibitors have broadened the utilisation of antidepressant treatment in accordance with recommendations. Findings from a Swedish prescription database.

BACKGROUND: With the advent of the selective serotonin reuptake inhibitors (SSRIs), the use of antidepressants has increased drastically in Sweden. The use of tricyclic antidepressants (TCAs) has, however, decreased. METHODS: We surveyed a prescription database in the Swedish county of Jämtland and compared prescription patterns for patients prescribed SSRIs with those prescribed TCAs. RESULTS: The incidence of treatments of antidepressants increased from 0.76% to 1.33% during the period 1991-1996. There were no significant differences between SSRIs and TCAs with regard to patients having only one prescription dispensed within three months from the index prescription, or patients who switched class of antidepressant. Only a minority of the treatments were continued for at least six months, but significantly more SSRI than TCA treatments (42% and 27%). A second treatment period suggesting recurrence was three-times more common in the TCA group than in the SSRI group. CONCLUSION: Provided that the increased use of SSRIs is mainly for depression, these drugs appear, despite a lower efficacy in severe depression, to have enabled a broader utilisation of antidepressants with regard to incidence, dosage and duration, in accordance with recommendations. Further analyses of this phenomenon relative to diagnostic criteria and outcome measures are required.

Reason for discontinuation of newly prescribed antihypertensive medications: methods of a pilot study using computerized patient records.

Objective-The purpose of this pilot study was to examine the feasibility of using computerized medical records retrospectively to identify patients and their physicians for subsequent survey to examine discontinuation of a newly prescribed antihypertensive medication in primary care, while maintaining patient confidentiality.Design-A case - control study utilizing UKPCD (formerly MediPlus(R)), a large automated database of computerized medical records, and direct collection of information from patients and their physicians.Setting-Eight selected general practices in the United Kingdom.Participants-Thirty-two patients, identified with a newly prescribed antihypertensive (index) medication and classified by their treatment status (discontinuer vs continuer) and five physicians were surveyed.Results-The participation rate was low among physicians (19%), likely to be due to recruitment during the holiday season, but higher among eligible patients (70%). A higher proportion of discontinuers (37%) refused or failed to respond to the invitation to participate compared with continuers (27%). For most patients, self-reported treatment status matched the UKPCD-based classification of discontinuer or continuer (kappa = 0.67); agreement of UKPCD data with physicians was moderate (kappa = 0.53). The extent and accuracy of the information collected from patients demonstrated that they were able and willing to report detailed knowledge of their medications and recent symptoms. Discontinuers, however, had difficulty recalling the discontinued medication on their own, possibly due to the amount of time elapsed between the event and the questionnaire administration.Conclusion-This pilot study demonstrates the feasibility of examining medication discontinuation in an ambulatory setting by utilizing a large automated database of computerized records to identify and recruit eligible physicians and their hypertensive patients for study, while maintaining patient and physician privacy. Modifications to the methodology to increase physician and patient participation and recall, and to decrease the time between the index event and patient query would increase its utility in larger studies. Copyright (c) 2000 John Wiley & Sons, Ltd.

Multiple granular cell tumor.

Eleven cases of granular cell tumor were reviewed. In two of the cases multiple sites of involvement were seen. The tumor occurred in the oral cavity in both of these cases and each was initially wrongly diagnosed as squamous cell carcinoma. The most common site was the subcutaneous tissue (nine patients) and the tongue was involved in three cases. In one patient the parotid gland was involved. Eight of the patients were females and three were males; seven were black and four were white. The importance of differentiating between squamous cell carcinoma and granular cell tumor is stressed, as is the need for a simple wide surgical excision.