Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation.

Inflammation is an essential part of immunity against pathogens and tumors but can promote disease if not tightly regulated. Self and non-self-nucleic acids can trigger inflammation, through recognition by the cyclic GMP-AMP (cGAMP) synthetase (cGAS) and subsequent activation of the stimulator of interferon genes (STING) protein. Here, we show that RNA:DNA hybrids can be detected by cGAS and that the Lysyl-tRNA synthetase (LysRS) inhibits STING activation through two complementary mechanisms. First, LysRS interacts with RNA:DNA hybrids, delaying recognition by cGAS and impeding cGAMP production. Second, RNA:DNA hybrids stimulate LysRS-dependent production of diadenosine tetraphosphate (Ap4A) that in turn attenuates STING-dependent signaling. We propose a model whereby these mechanisms cooperate to buffer STING activation. Consequently, modulation of the LysRS-Ap4A axis in vitro or in vivo interferes with inflammatory responses. Thus, altogether, we establish LysRS and Ap4A as pharmacological targets to control STING signaling and treat inflammatory diseases.

The patient's view on rare disease trial design - a qualitative study.

BACKGROUND: Clinical trials in rare diseases are more challenging than trials in frequent diseases. Small numbers of eligible trial participants, often complicated by heterogeneity among rare disease patients, hamper the design and conduct of a 'classical' Randomized Controlled Trial. Therefore, novel designs are developed by statisticians. However, it is important to be aware of possible design aspects that may jeopardize the feasibility of trial conduct. If the burden of participation is considered out of proportion by patients or parents, recruitment may fail or participants may drop out before trial completion. In order to maximize the chance of success of trials in small populations, it is important to know which aspects of trial design are considered important by patients. RESULTS: We have interviewed all ten members of the Patient Think Tank (PTT) of the ASTERIX project, a European research consortium on methodology for clinical trials in small populations. The PTT members are rare disease patient representatives who have completed extensive training in clinical trial methodology. We have analyzed the interviews qualitatively according to Grounded Theory using a thematic analysis, and we structured the topics in four chronologically ordered themes: 1. Involvement in trial design; 2. Opinions on trial design; 3. Trial participation; 4. Phase after the trial. Our main findings are that the PTT-members recommend that patients are involved in trial design from an early stage on, and have influence on the outcomes and measurement instruments that are chosen in the trial, the length of the study, the choice of participants, and the information that is sent to potential participants. Also, according to the PTT-members, patient groups should consider setting up disease registries, placebo groups should be minimized, and more education on clinical trials is advised. CONCLUSIONS: Rare disease patient representatives who have been educated about clinical trial methodology think it is important to involve patient representatives in research at an early stage. They can be of advice in trial design in such a way that the ratio of potential benefit and burden of trial participation as well as the chosen outcome measures and in- and exclusion criteria are optimized.

The POWER-tool: Recommendations for involving patient representatives in choosing relevant outcome measures during rare disease clinical trial design.

In clinical trials, it is relevant to ask patients and/or their caregivers which aspects concerning their disease they consider important to measure when a new intervention is being investigated. Those aspects, useful as outcome measures in a trial, are of pivotal importance for the result of the trial and the subsequent decision-making. In rare diseases the choice of outcome measures may be even more important, due to the small numbers and heterogeneity of the patients that are included. We have developed a tool to involve patients in the determination of outcome measures and the choice of measurement instruments. This tool was developed together with a patient think tank, consisting of a group of rare disease patient representatives, and by interviewing end users. We have road-tested our tool in an ongoing trial, and evaluated it during a focus group meeting. The tool consists of three steps: 1) Preparation, 2) Consultation of patients, 3) Follow-up during which the consultation results are implemented in the trial design. The tool provides guidelines for researchers to include the patient's opinion in the choice of outcome measures in the trial design stage. We describe the development of the POWER-tool (Patient participation in Outcome measure WEighing for Rare diseases), and first experiences of the tool in an ongoing trial.

[Vitreous substitutes as drug release systems]. / Glaskörperersatz als Möglichkeit zur protrahierten Freisetzung von Medikamenten im Glaskörper.

Despite major improvements of vitreo-retinal surgical techniques proliferative vitreoretinopathy (PVR) remains a major challenge. Surgical therapy alone may not be sufficient in complicated cases of PVR. A combination of standard techniques such as pars plana vitrectomy with a vitreous substitute and a simultaneous adjuvant pharmacological treatment for the suppression of undesired proliferation of retinal cells and retinal scarring may be a promising therapeutic approach. However, due to the narrow therapeutic range and the short biological half-life of most anti-proliferative or anti-inflammatory drugs in the vitreous cavity, intravitreal slow-release systems for extended drug delivery are desirable. Vitrectomy for PVR normally requires a vitreous substitute. Consequently, a vitreous substitute that could also serve as a slow-release system for anti-proliferative or anti-inflammatory drugs would provide several advantages. This review gives an overview of recent developments of slow-release systems that may also be suitable as vitreous substitutes. Even standard internal tamponades such as silicone oils or gases may serve as extended drug-release systems under certain conditions. In the mean time polymerised hydrogels have been developed, which apart from providing an adequate tamponade effect, may facilitate an extended intravitreal release of various anti-proliferative and anti-inflammatory drugs for several weeks.

Optimization of reading conditions for flat panel displays.

Task Group 18 (TG 18) of the American Association of Physicists in Medicine has developed guidelines for Assessment of Display Performance for Medical Imaging Systems. In this document, a method for determination of the maximum room lighting for displays is suggested. It is based on luminance measurements of a black target displayed on each display device at different room illuminance levels. Linear extrapolation of the above luminance measurements vs. room illuminance allows one to determine diffuse and specular reflection coefficients. TG 18 guidelines have established recommended maximum room lighting. It is based on the characterization of the display by its minimum and maximum luminance and the description of room by diffuse and specular coefficients. We carried out these luminance measurements for three selected displays to determine their optimum viewing conditions: one cathode ray tube and two flat panels. We found some problems with the application of the TG 18 guidelines to optimize viewing conditions for IBM T221 flat panels. Introduction of the requirement for minimum room illuminance allows a more accurate determination of the optimal viewing conditions (maximum and minimum room illuminance) for IBM flat panels. It also addresses the possible loss of contrast in medical images on flat panel displays because of the effect of nonlinearity in the dependence of luminance on room illuminance at low room lighting.

Histopathological analysis in experimental macular surgery with trypan blue.

AIM: To analyse the effect of trypan blue on the retina in an experimental setting of macular surgery. METHODS: Porcine eyes were used within 3 hours after death. The eyes were hemisected and the vitreous removed. Trypan blue (0.15%) was applied over the trephined posterior pole, whereas the rest of the eye cup was filled with a balanced salt solution (BSS). The dye and the BSS were removed after 1 minute and the complete eye cup irrigated and filled with fresh BSS. Both the treated and untreated retinas were illuminated with a standard surgical light pipe and source at maximum power for 10 minutes. Both the trypan blue exposed retina and the non-treated surrounding retina were processed for histology. RESULTS: Exposure of the retina to trypan blue for 1 minute, followed by illumination caused no histologically detectable damage compared to the controls. No microarchitectural disorganisation, cellular disruption, or affection of the vitreoretinal interface was detected. CONCLUSIONS: These findings indicate that a 1 minute exposure of trypan blue followed by illumination does not cause an acute morphologically detectable toxic effect on the porcine retina.

Effect of room illuminance on monitor black level luminance and monitor calibration.

In this article we demonstrate the effect of room illuminance and surrounding monitor black level luminance on image quality for soft copy interpretation. Luminance values of a 10% central target and image quality evaluations and observer performance using a contrast-detail mammography (CDMAM) phantom demonstrate these effects. Our results indicate that high room illuminance has a more damaging effect on image quality when the surrounding monitor luminance is 0% to 5% of the maximum monitor luminance. The effect of room illuminance is less obvious when the surrounding monitor luminance is 20% of the maximum.

Medical device tracking: results of a case study of the implantable cardioverter defibrillator.

Case reports were received of a fatal tachycardia caused by a malfunction of an implantable cardioverter defibrillator (ICD), a device that is subject to the tracking regulations of the Food and Drug Administration's Center for Devices and Radiological Health. The case reports led to a decision to notify 5,604 patients of the need for reprogramming of their ICDs to prevent the tachycordia. In the first 60 days, a total of 98.7% of the patients were successfully located and their devices reprogrammed. Multiple logistic regression analysis was conducted to examine an extensive array of factors that might have been related to the time to reprogramming. Patient-specific factors such as age, sex, and ejection fraction did not serve as a barrier to reprogramming in the first week (p = NS). Patients whose regular physician had >5 patients with the ICD subject to the recall were significantly more likely to have their ICDs reprogrammed in the first week (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.85 to 2.43, p<0.001). Patients who changed physicians were significantly less likely to undergo reprogramming in the first week (OR 0.73, 95% CI 0.63 to 0.86, p<0.001). The experience of the recall of this tracked device is highly encouraging because it demonstrates that most tracked device recipients can be successfully located and receive medical intervention. Although tracking devices is a manufacturer's responsibility, the clinical community plays a critical role in its success. This report highlights the importance of understanding that role among physicians.

[The role of electrooculographic examinations in the glaucoma diagnosis]. / Znaczenie badan elektrookulograficznych w diagnostyce jaskry.

PURPOSE: To evaluate the significance of the electrooculography in the diagnosis of glaucoma. MATERIAL AND METHODS: We studied 31 patients with primary open-angle glaucoma (aged 22-69 years), 29 patients with normal-tension glaucoma (aged 19-77 years) and 22 healthy controls (aged 38-65 years). We performed routine ophthalmological examinations and electrooculography in all patients. RESULTS: Arden's coefficient results concerning electrooculography were the highest in control group and the lowest in primary open-angle glaucoma group, but the differences were not statistically significant. CONCLUSION: Electrooculographic examinations do not seem to be effective for detecting glaucoma.

Results of a nationwide survey of chest radiography: comparison with results of a previous study.

PURPOSE: To provide public health information by means of measurement of the radiation exposures that patients undergoing chest radiography would receive and to compare the results with those of a similar previous survey. MATERIALS AND METHODS: Surveyed facilities were randomly selected from each state. Patient exposure was evaluated along with film processing, half-value layer, and image quality. Additional information obtained concerned type of equipment, facility work load, radiographic technique, screen-film system, and grid type. RESULTS: Mean entrance air kerma in all facilities was 141 microGy (16.1 mR). Mean kilovoltage in all facilities was 101 kV. In 1994, 140 (90%) of 156 hospitals (vs 71% in 1984) and 92 (58%; nearly double the percentage in 1984) of 159 nonhospital sites were using grids. Scoring with the imaging test tool resulted in a mean spatial resolution of 2.3 cycles per millimeter, and a mean low-contrast sensitivity of about 3%. Two hundred fifty-three (80%) of 315 facilities surveyed were processing film at minimum acceptable performance levels. CONCLUSION: Mean entrance air kerma for all facilities did not substantially change. Although increased grid usage would lead to the expectation of higher measured exposures, this was offset by an increase in the use of faster screen-film combinations.

Mortality after aortic valve replacement: results from a nationally representative database.

BACKGROUND: Nationally representative estimates of in-hospital mortality after aortic valve replacement are needed to evaluate whether results from The Society of Thoracic Surgeons National Cardiac Surgery Database are applicable to other institutions in the United States performing these procedures. METHODS: Data from the 1994 Nationwide Inpatient Sample were used to estimate the patient characteristics and in-hospital mortality rates associated with aortic valve replacements performed in nonfederal hospitals in the United States. Procedural and hospital characteristics were examined for possible associations with in-hospital mortality. RESULTS: An estimated 46,397 aortic valve replacements were performed. In-hospital mortality occurred in 4.3% of first-time isolated aortic valve replacements and 6.4% overall. The highest quartile of procedure-specific hospital volume, compared with the lowest quartile, was associated with lower in-hospital mortality (adjusted odds ratio, 0.58; 95% confidence interval, 0.42 to 0.81). CONCLUSIONS: The in-hospital mortality rates observed in this study are very similar to those reported from The Society of Thoracic Surgeons database. These data provide substantial evidence that results from The Society of Thoracic Surgeons database are representative of those achieved at other institutions. However, procedure-specific hospital volume must be considered in applying these results to individual institutions.

Testing optimum viewing conditions for mammographic image displays.

The viewbox luminance and viewing room light level are important parameters in a medical film display, but these parameters have not had much attention. Spatial variations and too much room illumination can mask real signal or create the false perception of a signal. This presentation looks at how scotopic light sources and dark-adapted radiologists may identify more real diseases.

The epidemiology of cardiac pacemakers in the older US population.

OBJECTIVES: This study estimates the age distribution of older patients (>64 years) receiving implantable cardiac pacemakers in non-federal US hospitals and determines major characteristics of this group using a massive, nationally representative sample of inpatient discharge records. DESIGN: Discharge records were obtained from the 1992 Nationwide Inpatient Sample. Correlation with census data from 1992 was used to determine age and gender specific rates. SETTING: The Nationwide Inpatient Sample is a 20% stratified probability sample of non-federal US hospitals. PATIENTS: Records of all recipients (26,425) of an initial or replacement pacemaker were selected. RESULTS: Individuals 65 years of age and older received an estimated 131,361 initial and replacement pacemaker pulse generators (87% of the total) in non-federal US hospitals in 1992. Pacemaker implantation was performed in urban teaching hospitals (28.9%), non-teaching urban hospitals (57.8%), and rural hospitals (13.3%). The age specific implantation rates per 100,000 population were 226.5 (age 65-74 years), 585.9 (age 75-84 years), 874.9 (age 85-94 years), and 540.4 (more than 94 years). The age-adjusted rate for men was 70% greater than the corresponding rate for women. Major diagnoses of implant recipients included atrioventricular block (37.8%) and atrial fibrillation (28.5%). Two percent of pacemaker recipients died before discharge. CONCLUSIONS: The rate of pacemaker implantation increases sharply up to age 95. As the number of older people in the US population grows, particularly those in the age ranges greater than 75 and 85 years, a sharply increased number of pacemakers will be implanted unless other factors decrease the need for these devices. The data also demonstrate diffusion of this technology from academic centers.

Reported complications of silicone gel breast implants: an epidemiologic review.

PURPOSE: To review the range of local and systemic complications attributed to silicone breast implants and to evaluate the epidemiologic literature on these complications. DATA SOURCES: Epidemiologic studies of the potential risks of silicone breast implants identified by MEDLINE search and literature review. STUDY SELECTION: Epidemiologic studies with cohort, case-control, and cross-sectional designs. When epidemiologic studies were unavailable (as for estimates of local complications), case series were reviewed. DATA EXTRACTION: Epidemiologic studies evaluated for methodologic quality, including such characteristics as study design, sample size and selection, determination of silicone exposure and outcome variables, and duration of follow-up. DATA SYNTHESIS: The epidemiologic literature on the potential complications of silicone breast implants has concentrated primarily on connective tissue disorders and cancer. Estimated of the true incidence of local complications, such as rupture, capsular contracture, and breast pain, are unavailable. Studies of scleroderma and other defined connective tissue diseases suggest that implant recipients have no substantially increased risk for these disorders; however, the epidemiologic literature is insufficient to rule out an association between breast implants and connective tissue disease-like syndromes. Overall, the rate of breast cancer does not seem to be increased in women with silicone breast implants. However, the risk to women as they reach the postmenopausal years in not yet known. CONCLUSIONS: Information is insufficient to adequately advise women who currently have or are seeking to obtain breast implants about the overall risk of these devices. No epidemiologic study has indicated that the rate of well-defined connective tissue disease or breast cancer has greatly increased in women with silicone breast implants, but no studies have ruled out a moderately increased risk for these diseases. No studies have adequately addressed the crucial issue of local complications such as rupture and capsular contracture, although evidence increasingly points to a higher risk for rupture as implants age.

Prevalence of latex-specific IgE antibodies in hospital personnel.

BACKGROUND: Rubber latex hypersensitivity is an important concern for health care workers. PURPOSE: The Center for Devices and Radiological Health, in collaboration with the Consumer Product Safety Commission, conducted a multicenter study of the prevalence of latex-specific IgE antibodies among United States hospital personnel. MATERIALS AND METHODS: Nine hospitals participated in the cross-sectional study. A total of 504 hospital personnel completed questionnaires that provided an array of demographic, occupational, and clinical information, including a history, if any, of allergies and the use of latex and nonlatex gloves. More than three-quarters (76.5%) of the participants were tested for total IgE and latex specific IgE. RESULTS: A total of 21 (5.5%, 95% CI = 3%-7%) of the tested participants were positive for the presence of latex specific IgE antibodies, defined as a latex IgE level of > or = 0.6 ng/mL. Latex specific IgE antibodies were more prevalent in participants who reported tachycardia, palpitations, flushing, or wheezing associated with latex gloves (Odds Ratio = 10.2, 95% CI = 3.7-28.6). CONCLUSION: The study's results suggest that the prevalence of latex-specific IgE antibodies among hospital personnel is appreciable and these personnel and their health care providers should be aware of this entity.

The epidemiology of pacemaker implantation in the United States.

Data on pacemaker implantation were obtained from the Medical Device Implant Supplement to the 1988 National Health Interview Survey, a nationally representative, population-based survey of 47,485 households (122,310 persons). The survey yielded an estimate of 456,482 noninstitutionalized adults with pacemakers (prevalence, 2.6 per 1,000). Prevalence rose significantly with age, from 0.4 per 1,000 among persons ages 18-64 to 26 per 1,000 among those ages 75 or older. Age-adjusted prevalence in males was 1.5 times that in females, and in whites 1.6 times that in nonwhites, although these differences were of borderline statistical significance. Prevalence did not vary significantly by region of residence, educational level, or income, but was significantly increased (more than threefold) in those reporting any activity limitation compared with those with no limitation. Fifteen percent of pacemakers in use were replacements; about one-fifth of these had been replaced more than twice. Sixty percent of previous pacemakers had been in place for at least 5 years. These data provide the first nationwide, population-based estimates of the epidemiology of pacemaker implantation, focusing particularly on the demographics of U.S. pacemaker recipients.

The epidemiology of prosthetic heart valves in the United States.

The Center for Devices and Radiological Health of the Food and Drug Administration, in collaboration with the National Center for Health Statistics, conducted the Medical Device Implant Supplement to the 1988 National Health Interview Survey, generating the 1st available population-based estimates of the use of prosthetic heart valves in the United States. The 1988 National Health Interview Survey was a massive, nationally representative cross-sectional survey that encompassed 47,485 households and 122,310 individuals. Data from the Medical Device Implant Supplement indicate that an estimated 253,283 persons with 279,175 heart valves were present in the civilian, non-institutionalized US population (population prevalence of 1.1/1,000, 95% CI 0.8-1.3). Prevalence of valve prostheses ranged from 0.2 per 1,000 in those age 44 and under to 5.3 per 1,000 in those 75 years of age and older. Age-adjusted prevalence of valve prostheses did not differ significantly according to sex, race, region of residence, education, or income of recipients. Two thirds of aortic valve recipients identified by the survey were male, compared with only one third of mitral valve recipients. Approximately two thirds of both aortic and mitral valve implants were reported as mechanical. Reported use of anticoagulative agents was significantly more common in recipients of mechanical than of bioprosthetic valves. The single most common reported reason for prosthetic valve implantation was rheumatic heart disease. These data provide useful epidemiologic and public health planning information on prosthetic heart valve use.

An overview of occupational hazards among veterinarians, with particular reference to pregnant women.

Veterinarians are challenged by an imposing group of occupational hazards, including exposure to ionizing radiation, injury, infectious agents, and chemicals. In this paper, the health hazards in the typical veterinary practice are inventoried, and the risks of each are assessed. During the past few decades, there has been a significant increase in women entering the veterinary profession. Information is presented concerning the impact of various occupational hazards on the health of female practitioners and paraprofessionals, particularly in regard to the reproductive system. Many of the occupational hazards are exclusively, or more significantly, detrimental to females (particularly when pregnant) and to their unborn. Women must be aware of and avoid these hazards in their clinical environment. The purpose of this review is to assist practitioners in identifying and assessing the hazards in their practice and determining what steps must be taken to eliminate or reduce them.