Evaluation of a training programme for Pharmacist Independent Prescribers in a care home medicine management intervention.

BACKGROUND: The provision of independent prescribing rights for United Kingdom (UK) pharmacists has enabled them to prescribe within their area of competence. The aim of this study was to evaluate an evidence-based training programme designed to prepare Pharmacist Independent Prescribers (PIPs) to safely and effectively assume responsibility for pharmaceutical care of older people in care homes in the UK, within a randomised controlled trial. METHODS: The training and competency assessment process included two training days, professional development planning against a bespoke competency framework, mentor support, and a viva with an independent General Practitioner (GP). Data on the PIPs' perceptions of the training were collected through evaluation forms immediately after the training days and through online questionnaires and interviews after delivery of the 6-month intervention. Using a mixed method approach each data set was analysed separately then triangulated providing a detailed evaluation of the process. Kaufman's Model of Learning Evaluation guided interpretations. RESULTS: All 25 PIPs who received the training completed an evaluation form (N = 25). Post-intervention questionnaires were completed by 16 PIPs and 14 PIPs took part in interviews. PIPs reported the training days and mentorship enabled them to develop a personalised portfolio of competence in preparation for discussion during a viva with an independent GP. Contact with the mentor reduced as PIPs gained confidence in their role. PIPs applied their new learning throughout the delivery of the intervention leading to perceived improvements in residents' quality of life and medicines management. A few PIPs reported that developing a portfolio of competence was time intensive, and that further training on leadership skills would have been beneficial. CONCLUSIONS: The bespoke training programme was fit for purpose. Mentorship and competency assessment were resource intensive but appropriate. An additional benefit was that many PIPs reported professional growth beyond the requirement of the study. TRIAL REGISTRATION: The definitive RCT was registered with the ISRCTN registry (registration number ISRCTN 17,847,169 ).

Laboratory Modeling of SARS-CoV-2 Exposure Reduction Through Physically Distanced Seating in Aircraft Cabins Using Bacteriophage Aerosol - November 2020.

Aircraft can hold large numbers of persons in close proximity for long periods, which can increase the risk for transmission of infectious disease.* Current CDC guidelines recommend against travel for persons who have not been vaccinated against COVID-19, and a January 2021 CDC order requires masking for all persons while on airplanes.†,§ Research suggests that seating proximity on aircraft is associated with increased risk for infection with SARS-CoV-2, the virus that causes COVID-19 (1,2). However, studies quantifying the benefit of specific distancing strategies to prevent transmission, such as keeping aircraft cabin middle seats vacant, are limited. Using bacteriophage MS2 virus as a surrogate for airborne SARS-CoV-2, CDC and Kansas State University (KSU) modeled the relationship between SARS-CoV-2 exposure and aircraft seating proximity, including full occupancy and vacant middle seat occupancy scenarios. Compared with exposures in full occupancy scenarios, relative exposure in vacant middle seat scenarios was reduced by 23% to 57% depending upon the modeling approach. A 23% exposure reduction was observed for a single passenger who was in the same row and two seats away from the SARS-COV-2 source, rather than in an adjacent middle seat. When quantifying exposure reduction to a full 120-passenger cabin rather than to a single person, exposure reductions ranging from 35.0% to 39.4% were predicted. A 57% exposure reduction was observed under the vacant middle seat condition in a scenario involving a three-row section that contained a mix of SARS-CoV-2 sources and other passengers. Based on this laboratory model, a vacant middle seat reduces risk for exposure to SARS-CoV-2 from nearby passengers. These data suggest that increasing physical distance between passengers and lowering passenger density could help reduce potential COVID-19 exposures during air travel. Physical distancing of airplane passengers, including through policies such as middle seat vacancy, could provide additional reductions in SARS-CoV-2 exposure risk.

The Role of Sulfur Dioxide in Stratospheric Aerosol Formation Evaluated Using In-Situ Measurements in the Tropical Lower Stratosphere.

Stratospheric aerosols (SAs) are a variable component of the Earth's albedo that may be intentionally enhanced in the future to offset greenhouse gases (geoengineering). The role of tropospheric-sourced sulfur dioxide (SO2) in maintaining background SAs has been debated for decades without in-situ measurements of SO2 at the tropical tropopause to inform this issue. Here we clarify the role of SO2 in maintaining SAs by using new in-situ SO2 measurements to evaluate climate models and satellite retrievals. We then use the observed tropical tropopause SO2 mixing ratios to estimate the global flux of SO2 across the tropical tropopause. These analyses show that the tropopause background SO2 is about 5 times smaller than reported by the average satellite observations that have been used recently to test atmospheric models. This shifts the view of SO2 as a dominant source of SAs to a near-negligible one, possibly revealing a significant gap in the SA budget.

The recovery of semen from bathwater using the Evidence Recovery System (ERS).

Sexual offences are under-reported and ascertaining accurate offence numbers is difficult. Any methods which could increase the ability to obtain biological evidence or reduce the additional distress associated with reporting a sexual offence may result in an increase in reporting this crime type. The Evidence Recovery System (ERS) is designed to collect trace evidence, including hairs, fibres and biological evidence, from bath or shower water in a non-invasive manner. Initially, samples of semen were placed in baths filled with water, and washing was simulated using a range of body wash products. The water was then drained through the ERS before its filters were subjected to acid phosphatase testing and haematoxylin and eosin staining of spermatozoa. Recovered spermatozoa were then graded accordingly. Following this, the experiment was repeated with the addition of dirt/dust particulates during the washing stage, to simulate recovery of biological evidence in a more realistic environment. The results showed that spermatozoa considered 'easy to find' could regularly be obtained from bathwater using the ERS. It appeared that this recovery was not affected by the presence of different body wash products. When dust/dirt particles were added, the number of spermatozoa recovered increased at two of the evidence collection stages. The difference in recovery was considered to be statistically significant. This study provides evidence to suggest the feasibility of use of the ERS as a method to collect semen evidence from individuals subjected to sexual offences. The recovery of spermatozoa does not appear to be affected by the presence of a body wash, but does appear to be improved when skin cells, hair and other debris are transferred into the water, as would be likely during a bath/shower. Further to this, the possibility of obtaining spermatozoa from the home bath or shower of a victim following a post-offence bathing experience is implied.

Airborne exposure patterns from a passenger source in aircraft cabins.

Airflow is a critical factor that influences air quality, airborne contaminant distribution, and disease transmission in commercial airliner cabins. The general aircraft-cabin air-contaminant transport effect model seeks to build exposure-spatial relationships between contaminant sources and receptors, quantify the uncertainty, and provide a platform for incorporation of data from a variety of studies. Knowledge of infection risk to flight crews and passengers is needed to form a coherent response to an unfolding epidemic, and infection risk may have an airborne pathogen exposure component. The general aircraf-tcabin air-contaminant transport effect model was applied to datasets from the University of Illinois and Kansas State University and also to case study information from a flight with probable severe acute respiratory syndrome transmission. Data were fit to regression curves, where the dependent variable was contaminant concentration (normalized for source strength and ventilation rate), and the independent variable was distance between source and measurement locations. The data-driven model showed exposure to viable small droplets and post-evaporation nuclei at a source distance of several rows in a mock-up of a twin-aisle airliner with seven seats per row. Similar behavior was observed in tracer gas, particle experiments, and flight infection data for severe acute respiratory syndrome. The study supports the airborne pathway as part of the matrix of possible disease transmission modes in aircraft cabins.

Surgical correction of pectus excavatum. How did we get here? Where are we going?

The currently applied techniques recommended for the repair of pectus excavatum anomalies are discussed, set against a historical review of early clinical studies and surgical interventions. The issues of the future direction pectus excavatum surgery may take are analyzed in detail, with the reviewer expressing reservations in connection with the recent trend to closed repair and concern over the potential for serious complications associated with the application of this technique.

Improving patient outcomes in fibrous dysplasia/McCune-Albright syndrome: an international multidisciplinary workshop to inform an international partnership.

To develop consensus on improving the management of patients, we convened an international workshop involving patients, clinicians, and researchers. Key findings included the diagnostic delay and variability in subsequent management with agreement to develop an international natural history study. We now invite other stakeholders to join the partnership. PURPOSE: The aim of this study was develop a consensus on how to improve the management of patients with fibrous dysplasia and prioritize areas for research METHODS: An international workshop was held over 3 days involving patients, clinicians, and researchers. Each day had a combination of formal presentations and facilitated discussions that focused on clinical pathways and research. RESULTS: The patient workshop day highlighted the variability of patients' experience in getting a diagnosis, the knowledge of general clinical staff, and understanding long-term outcomes. The research workshop prioritized collaborations that improved understanding of the contemporary natural history of fibrous dysplasia/McCune-Albright syndrome (FD/MAS). The clinical workshop outlined the key issues around diagnostics, assessment of severity, treatment and monitoring of patients. CONCLUSIONS: In spite of advances in understanding the genetic and molecular underpinnings of fibrous dysplasia/McCune-Albright syndrome, clinical management remains a challenge. From the workshop, a consensus was reached to create an international, multi-stakeholder partnership to advance research and clinical care in FD/MAS. We invite other stakeholders to join the partnership.

Effects of chronic prenatal ethanol exposure on mitochondrial glutathione and 8-iso-prostaglandin F2alpha concentrations in the hippocampus of the perinatal guinea pig.

It is hypothesised that oxidative stress is a key mechanism of ethanol neurobehavioural teratogenicity, resulting in altered endogenous antioxidant status and increased membrane lipid peroxidation in the hippocampus of chronic prenatal ethanol exposure (CPEE) offspring. To test this hypothesis, timed pregnant guinea-pigs (term, approximately gestational day (GD) 68) received chronic daily oral administration of (i) 4 g ethanol kg(-1) maternal bodyweight, (ii) isocaloric sucrose with pair feeding, or (iii) water. At GD 65 (term fetus) and postnatal day (PD) 0 (neonate), individual offspring were killed, the brain was excised and the hippocampi were dissected. Glutathione (GSH) concentration was measured in the cytosolic and mitochondrial fractions of hippocampal homogenate. The occurrence of lipid peroxidation was determined by measuring the concentration of 8-iso-prostaglandin F2+/- (8-iso-PGF2+/-). There was CPEE-induced decreased brain weight and hippocampal weight at GD 65 and PD 0, decreased mitochondrial GSH concentration in the hippocampus at PD 0, with no change in mitochondrial GSH concentration at GD 65 or cytosolic GSH concentration at GD 65 or PD 0, and no change in mitochondrial or whole-homogenate 8-iso-PGF2+/- concentration in the hippocampus at GD 65 or PD 0. The data demonstrate that CPEE produces selective mitochondrial dysfunction in the hippocampus of the neonatal guinea-pig, involving GSH depletion.

Multimodal MRI characterization of experimental subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality. We implemented an in-scanner rat model of mild SAH in which blood or vehicle was injected into the cistern magna, and applied multimodal MRI to study the brain prior to, immediately after (5min to 4h), and upto 7days after SAH. Vehicle injection did not change arterial lumen diameter, apparent diffusion coefficient (ADC), T2, venous signal, vascular reactivity to hypercapnia, or foot-fault scores, but mildly reduce cerebral blood flow (CBF) up to 4h, and open-field activity up to 7days post injection. By contrast, blood injection caused: (i) vasospasm 30min after SAH but not thereafter, (ii) venous abnormalities at 3h and 2days, delayed relative to vasospasm, (iii) reduced basal CBF and to hypercapnia 1-4h but not thereafter, (iv) reduced ADC immediately after SAH but no ADC and T2 changes on days 2 and 7, and (v) reduced open-field activities in both SAH and vehicle animals, but no significant differences in open-field activities and foot-fault tests between groups. Mild SAH exhibited transient and mild hemodynamic disturbances and diffusion changes, but did not show apparent ischemic brain injury nor functional deficits.

The RUDY study platform - a novel approach to patient driven research in rare musculoskeletal diseases.

BACKGROUND: Research into rare diseases is becoming more common, with recognition of the significant diagnostic and therapeutic care gaps. Registries are considered a key research methodology to address rare diseases. This report describes the structure of the Rare UK Diseases Study (RUDY) platform that aims to improve research processes and address many of the challenges of carrying out rare musculoskeletal disease research. RUDY is an internet-based platform with online registration, initial verbal consent, online capture of patient reported outcome measures and events within a dynamic consent framework. The database structure, security and governance framework are described. RESULTS: There have been 380 participants recruited into RUDY with completed questionnaire rates in excess of 50 %. There has been one withdrawal and two participants have amended their consent options. CONCLUSIONS: The strengths of RUDY include low burden for the clinical team, low research administration costs with high participant recruitment and ease of data collection and access. This platform has the potential to be used as the model for other rare diseases globally.

Effect of the carbocyclic nucleoside analogue MDL 201,112 on inhibition of interferon-gamma-induced priming of Lewis (LEW/N) rat macrophages for enhanced respiratory burst and MHC class II Ia+ antigen expression.

The effects of the carbocyclic nucleoside MDL 201,112 and the purine nucleoside adenosine on the interferon-gamma (IFN-gamma)-induced priming of macrophages (m phi s) for the respiratory burst and major histocompatibility class II (MHC class II) Ia+ antigen expression were compared. Priming of purified, peritoneal m phi s from Lewis (LEW/N) rats for 18 h with recombinant rat IFN-gamma (rRaIFN-gamma) in the presence of either adenosine (100 microM) or MDL 201,112 (10 microM) resulted in a fourfold decrease in superoxide anion (O2-) production after stimulation with opsonized zymosan. Both agents were effective even when added 2 or 4 h after rRaIFN-gamma treatment. Peritoneal m phi s from LEW/N rats stimulated with LPS/rRaIFN-gamma were observed to secrete immunoreactive and bioactive TNF-alpha over 18 h in vitro and this cytokine could be dose-dependently inhibited by MDL 201,112. MDL 201,112 did not bind to classical A1 or A2 receptors on rat brain homogenates. Physiological levels of adenosine deaminase, or treatment with the nucleoside transport inhibitor dipyridamole, reversed the effects of adenosine; however, these agents at physiological concentrations had little or no effect on the inhibition of O2- release mediated by MDL 201,112. Furthermore, incubation of LEW/N m phi s for 18 h in vitro with rRaIFN-gamma resulted in significant enhancement of MHC class II Ia+ antigen expression, and these levels could be blocked by nearly 50% by either MDL 201,112 (10 microM) or adenosine (100 microM). MDL 201,112 and adenosine were also effective in decreasing m phi opsonized zymosan-stimulated O2- levels and MHC class II Ia+ antigen expression in vivo. The effects of MDL 201,112 on the down-regulation of heat-killed M. tuberculosis-activated LEW/N m phi MHC class II Ia+ antigen expression in vitro appear to be mediated by a novel pathway, because there was no rank order of potency of ADO A1 or A2 agonist/antagonists (CCPA, NECA, XAC, or CPT) in our in vitro system. In summary, our data provide compelling evidence that immunoregulatory carbocyclic nucleoside analogues such as MDL 201,112 or adenosine appear to regulate LEW/N rat m phi activation through novel molecular mechanisms and may have important therapeutic implications for acute and chronic inflammatory diseases.

The effect of mild traumatic brain injury on peripheral nervous system pathology in wild-type mice and the G93A mutant mouse model of motor neuron disease.

Traumatic brain injury (TBI) is associated with a risk of neurodegenerative disease. Some suggest a link between TBI and motor neuron disease (MND), including amyotrophic lateral sclerosis (ALS). To investigate the potential mechanisms linking TBI to MND, we measured motor function and neuropathology following mild-TBI in wild-type and a transgenic model of ALS, G93A mutant mice. Mild-TBI did not alter the lifespan of G93A mice or age of onset; however, rotarod performance was impaired in G93A verses wild-type mice. Grip strength was reduced only in G93A mice after mild-TBI. Increased electromyography (EMG) abnormalities and markers of denervation (AchR, Runx1) indicate that mild-TBI may result in peripheral effects that are exaggerated in G93A mice. Markers of inflammation (cell edema, astrogliosis and microgliosis) were detected at 24 and 72h in the brain and spinal cord in wild-type and G93A mice. Levels of F2-isoprostanes, a marker of oxidative stress, were increased in the spinal cord 24h post mild-TBI in wild-type mice but were not affected by TBI in G93A mice. In summary, our data demonstrate that mild-TBI induces inflammation and oxidative stress and negatively impacts muscle denervation and motor performance, suggesting mild-TBI can potentiate motor neuron pathology and influence the development of MND in mice.

The role of donor lymphoid cells in the transfer of allograft tolerance.

Tolerance to murine skin allografts across a MHC disparity was induced by conditioning primary hosts with sublethal fractionated total-body irradiation (FTBI) and transfusion of allogeneic bone marrow (BM). Tolerance could be adoptively transferred to secondary hosts conditioned by FTBI with infusion of spleen cells from hosts bearing intact skin allografts greater than 60 days. Tolerance could not be transferred by tolerant host spleen (THS) preparations from which cells of the donor genotype had been deleted by cytotoxic alloantisera. Deletion of host genotype cells, however, did not diminish the capability of THS to transfer tolerance. All of the tolerizing activity of THS appeared to reside within cells of the donor genotype. Small numbers of normal donor spleen cells could induce tolerance in FTBI hosts but only at the expense of very high mortality, in contrast to the low mortality observed with tolerizing injections of allogeneic donor cells from THS or injections of normal semiallogeneic F1 hybrid spleen cells. If an active immune response is responsible for tolerance induction/transfer in this model, allogeneic donor lymphoid cells derived from BM, in contrast to donor spleen cells, must be capable of mounting this response without concomitant severe GVHD. In future experiments, cells of donor genotype can be isolated from THS and purified in sufficient numbers to compare their tolerizing efficiency vs. that of normal donor cells, detect possible suppression of normal host cell alloreactivity in vitro and identify the donor cell phenotypes involved.

Effects of Thy-1+ cell depletion on the capacity of donor lymphoid cells to induce tolerance across an entire MHC disparity in sublethally irradiated adult hosts.

Thy-1+ cell depletion with anti-Thy-1.2 mAb and complement markedly reduced the capacity of C57BL/6J, H-2b bone marrow to establish mixed lymphoid chimerism and induce tolerance to C57BL/6J skin grafts across an entire MHC disparity in BALB/c, H-2d hosts conditioned with sublethal, fractionated 7.5 Gy total-body irradiation. In this model tolerance can be transferred to secondary irradiated BALB/c hosts only by cells of C57BL/6J donor, not host, genotype isolated from the spleens of tolerant hosts. Thy-1+ cell depletion abolished the capacity of C57BL/6J donor cells from tolerant BALB/c host spleens to transfer tolerance. The capacity of semiallogeneic BALB/c x C57BL/6J F1, H-2d/b donor BM and spleen cells to induce chimerism and tolerance to C57BL/6J skin grafts in BALB/c parental hosts was also reduced by Thy-1+ cell depletion. Thus the requirement for donor Thy-1+ cells cannot be explained simply on the basis of alloaggression. It is unlikely that the requisite Thy-1+ cells are nonspecific suppressor cells: Thy-1+ cell depletion had no effect on the slight but significant prolongation of third-party C3H/HeJ, H-2k skin grafts in irradiated BALB/c hosts injected with allogeneic C57BL/6J or semiallogeneic BALB/c x C57BL/6J F1 BM compared to irradiated controls injected with medium only. Furthermore, injections of semiallogeneic F1 spleen cells had no significant effect on the survival of the third-party grafts, although these cells were fully capable of inducing tolerance, and their capacity to induce tolerance was significantly reduced by Thy-1+ cell depletion. The requirement for a specific population of lymphoid cells, i.e. Thy-1+, remains unexplained but suggests that donor cells might play a role in the induction or maintenance of tolerance in this model other than merely providing a circulating source of donor antigens.

Do donor cells function as veto cells in the induction and maintenance of tolerance across an MHC disparity in mixed lymphoid radiation chimeras?

Mixed lymphoid chimeras can be established across H-2b-->H-2d by injection of C57BL/6J (B-6) donor bone marrow cells into BALB/c hosts conditioned by sublethal irradiation, 235 cGy x3. These chimeras are specifically tolerant to both donor and host alloantigens. Tolerance cannot be broken even by injection of 4 x 10(8) normal BALB/c spleen cells (SC), suggesting a suppressor mechanism. In contrast to conventional suppression, however, in which suppressors are syngeneic to the cells they suppress, tolerance can be transferred only by cells of the allogeneic donor allotype (1,2). Thy 1+ cell depletion eliminates the capacity of the donor population to transfer tolerance and markedly reduces the capacity of B-6 BMC to induce tolerance (3). In the present studies spleen cells from tolerant chimeras (CSC), when coinjected in a 1:1 ratio, reduced the high GVHD mortality induced in irradiated H-2d/b F1 hybrids by injection of 2 x 10(7) normal BALB/c SC alone (P < .01). When coinjected at a 5:1 ratio CSC eliminated the GVHD mortality and weight loss induced by 5 x 10(6) BALB/c SC (P < .01). Depletion of B-6 cells from CSC removed their capacity to inhibit the GVHD induced by normal BALB/c SC. In contrast to conventional suppression, which requires the continued presence of suppressor cells, the BALB/c cells isolated from CSC, although unable to inhibit the GVHD of normal BALB/c SC, remained nonreactive against the H-2b allotype for a prolonged period following depletion of the B-6 cells. This prolonged response reduction dependent upon some interaction with allogeneic donor cells--which, in turn, are specifically nonreactive to host antigens--is compatible with a veto mechanism.

Sublethal fractionated total-body irradiation and donor bone marrow infusion for induction of allograft tolerance.

Tolerance to skin allografts across the strong histocompatibility barrier H-2b to H-2d was achieved with sublethal fractionated total-body irradiation, FTBI, delivered to H-2d mice in 3 doses of 250 rads within 24 hr, followed by transfusion of 3 X 10(7) H-2b donor bone marrow (BM) cells. H-2b skin allografts were applied within 48 hr after the initial radiation. 70% of the mice became long-term (greater than 180-day) survivors with fur-bearing grafts. Marked interexperiment variability in survival rates suggested that infection was the major cause of death in this model and lower weight gain and survival rates for allogenic BM vs. media-treated controls suggested that graft-versus-host disease (GVHD) was also a factor. The observation, however, that long-term survivors (70% of all mice) gained weight and appeared healthy suggested that the GVHD might be self-limiting. Chimeric analysis revealed that approximately 25% of spleen cells were of donor origin, both at short-term (6 weeks) and long-term (greater than 1 year) intervals after tolerance induction. In spite of hematopoietic chimerism, a low incidence of spontaneous tumors, less than 1%, occurred in the long-term survivors.

Evaluation of aortocoronary bypass graft status by computed tomography.

The efficacy of contrast-enhanced computed tomography to define graft patency status was studied in 42 patients with 100 aortocoronary vein grafts. The status of each graft had been determined earlier by angiography. A rotary fan beam whole body scanner with a 2 second scan duration was used. Initial scans determined the optimal level for study of the graft; patency was assessed by computed tomographic enhancement of the graft after intravenous bolus injection of 30 ml meglumine and sodium diatriazoate. The computed tomographic studies were evaluated without knowledge of the angiographic findings; graft status by computed tomography was interpreted as patent, occluded or equivocal. Overall, computed tomography correctly defined graft patency status in 79 of the 100 grafts and incorrectly identified it in 9; in 12 grafts, the computed tomographic diagnosis was equivocal. Computed tomography correctly identified 61 of 74 patent grafts and 18 of 26 occluded grafts. Patency status was correctly defined by computed tomography in 35 of 37 grafts to the left anterior descending artery, 23 of 30 grafts to circumflex branches and 19 of 31 grafts to the right coronary artery. These data indicate that computed tomography is a promising noninvasive method of determining patency of aortocoronary bypass grafts, especially of grafts to the left anterior descending artery.

Efficacy and safety of extended-release isosorbide mononitrate for stable effort angina pectoris.

The efficacy and safety of extended-release isosorbide mononitrate tablets were evaluated in patients with stable effort angina. In a double-blind study, 313 patients with stable effort-induced angina were randomized to receive placebo or extended-release isosorbide mononitrate: 30, 60, 120 or 240 mg once daily in the morning. Serial exercise testing was performed using the standard Bruce treadmill protocol on days 1, 7, 14, 28 and 42 immediately before morning drug administration, and 4 and 12 hours after administration. After initial dosing, all groups that received extended-release isosorbide mononitrate had significant (p < 0.01) increases in mean total exercise time of approximately 30 to 50 seconds in relation to placebo 4 and 12 hours after administration. On day 42, mean changes from baseline in total exercise time of patients who received 120 or 240 mg of extended-release isosorbide mononitrate exceeded placebo by approximately 50 to 60 seconds 4 hours after dosing (p < 0.01), and by 30 to 35 seconds 12 hours after dosing (p < or = 0.05). No significant difference was detected between responses to extended-release isosorbide mononitrate and placebo 24 hours after administration (i.e., immediately before the next dose). Thus, there was neither significant activity nor demonstrable rebound of effort-induced angina (zero-hour effect) at the end of the dosing interval. Transient headache was the most prevalent adverse experience. Extended-release isosorbide mononitrate (120 and 240 mg administered orally once daily) significantly prolonged exercise time to development of moderate effort-induced angina 4 and 12 hours after dosing during long-term therapy, without development of nitrate tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Peptidyl fluoromethyl ketones as inhibitors of cathepsin B. Implication for treatment of rheumatoid arthritis.

Peptidyl fluoromethyl ketones (FMKs), with the amino acid sequence Phe-Ala held constant but with variable N-terminal groups, were synthesized and tested for inhibition of the cysteine proteinase cathepsin B. The FMKs were effective in inhibiting cathepsin B activity in vitro. The inhibition was time dependent and was not reversed by dialysis, suggesting covalent modification of the enzyme. Cathepsin B activity present in livers and kidneys of rats treated with FMKs was reduced by 22-91% 4 hr after a single oral dose of 25 mg/kg. The FMKs inhibited the severity of inflammation and the extent of cartilage and bone damage in adjuvant-induced arthritis. These effects were seen during the late-stage of the disease with no effect on onset or incidence of disease. This is consistent with inhibition of protease-mediated damage. These FMKs or derivatives may be of clinical value in the treatment of arthritis.

Echocardiographic assessment of mitral stenosis by the left atrial emptying index.

Echocardiograms were performed in 35 patients prospectively with mitral stenosis to determine the usefulness of the left atrial emptying index (AEI) in estimating mitral valve orifice area (MVOA). Twnety-five control patients without evidence of cardiac disease had an AEI of 0.91 +/- 0.01. In the mitral stenosis group, the mean AEI was 0.47 +/- 0.09, with Gorlin and Gorlin calculated MVOAs of 1.44 +/- 0.56. There was close correlation between the AEI and MVOA (r = 0.93). The AEI did not correlate well with the left atrial size (r = 0.10), or the EF slope of the mitral valve (r = 0.20). The AEI was useful in separating patients with mitral stenosis into mild, moderate, and severe groups. Twelve out of 12 patients with severe mitral stenosis (MVOA less than or equal to 1.0 sq cm) had an AEI of less than or equal to 0.42. Ten out of 13 patients with moderate mitral stenosis (MVOA of 1.1--1.5 sq cm) had an AEI of 0.43 to 0.51. Eight out of ten patients with mild mitral stenosis (MVOA greater than or equal to 1.6 sq cm) had an AEI of greater than or equal to 0.52. The overall predictive value of the AEI in subclassifying the severity of mitral stenosis was 86 percent. In conclusion, the AEI appears to be a sensitive index in estimating MVOA in mitral stenosis.