Impact of the recommendations for the redefinition of myocardial infarction on diagnosis and prognosis in an unselected United Kingdom cohort with suspected cardiac chest pain

We prospectively and blindly assessed the diagnostic and prognostic impact of implementation of the European Society of Cardiology/American College of Cardiology recommendations for redefinition of myocardial infarction (MI) in an unselected cohort of patients with suspected cardiac chest pain, with particular attention to prespecified clinical groups. All patients admitted to our institute with suspected cardiac chest pain were enrolled. Physicians provided usual care using serial electrocardiograms/creatine kinase (CK)/aspartate transaminase according to World Health Organization (WHO) criteria for MI, while blinded to additional measurements of cardiac troponin T (cTnT) and CK-MB mass. After discharge, diagnoses based on WHO and new criteria were compared, and major adverse cardiac events monitored for 6 months. Implementation of the new recommendations classified an additional 26.1% of patients as having MI compared with WHO criteria, and produced an overall diagnostic alteration in 11.5%. Two thirds of the additional patients with MI were previously diagnosed with unstable angina, whereas one third had "other cardiac" or "noncardiac" diagnoses. A similar MI cohort to the cTnT diagnosis was identified using a CK-MB mass discriminator value of 5 microg/L, but not 10 microg/L. The 6-month prognosis was similar in patients diagnosed with MI by new (cTnT) and WHO criteria, with the new criteria thus identifying a further high-risk cohort in the WHO negative group. In our cohort, the new Joint European Society of Cardiology/American College of Cardiology recommendations identify one fourth more patients as having MI. The 6-month prognosis of those patients reclassified as having MI was similar to those diagnosed with MI by both criteria.     

The effect of changing practice on fall prevention in a rehabilitative hospital: the Hospital Injury Prevention Study

OBJECTIVES: To determine whether a change in practice to introduce a multidisciplinary fall-prevention program can reduce falls and injury in nonacute patients in a rehabilitation hospital. DESIGN: A quasi-experimental study. SETTING: Three geriatric wards with a similar design, equipment, staffing levels, and skill mix. PARTICIPANTS: Eight hundred twenty-five consecutive patients. INTERVENTION: The patients' fall-risk status was assessed using the Downton Score. Current practice was maintained on the two control wards (n=550). On the experimental ward (n=275), a fall-prevention program was introduced. A multidisciplinary team met weekly specifically to discuss patients' fall risk and formulate a targeted plan. Patients at risk were identified using wristbands; risk factors were corrected or environmental changes made to enhance safety. MEASUREMENTS: Primary outcomes were number of fallers, recurrent fallers, total falls, patients sustaining injury, and falls per occupied bed days. Secondary outcomes were place of discharge and mortality. RESULTS: Patients were matched for age and risk status. Control wards had proportionally more fallers (20.2% vs 14.2%: P=.033), patients sustaining injury (8.2% vs 4%: P=.025), and total number of falls (170 vs 72: P=.045). These results did not remain significant after controlling for differing length of stay. There was no reduction in recurrent fallers (6.4% vs 4.7%: P=.43) and no effect on place of discharge (home discharges; 57.5% vs 60.7%: P=.41) or mortality (15.3% vs 13.8%: P=.60). CONCLUSION: This study shows that falls might be reduced in a multidisciplinary fall-prevention program, but the results are not definitive because of the borderline significance achieved and the variable length of stay. More research on fall prevention in hospital is required, particularly as to what interventions, if any, are effective at reducing falls in this group of patients.     

Vasoconstrictor response to prostacyclin in rabbit pulmonary circulation

We have determined the effect of prostacyclin (PGI2) on segmental vascular resistance in rabbit lungs. Lungs of 26 rabbits were isolated and perfused with blood; 16 adult, greater than 6 months old, five juvenile, 6-8 week old and five neonatal, 2-3-week old. Six of the adult lungs were pretreated with indomethacin to block cyclooxygenase, prior to infusion of PGI2. In all lungs, flow was adjusted initially to keep pulmonary artery pressure approximately 20 cmH2O, left atrial and airway pressures being 8 and 6 cmH2O, respectively (zone 3), and then kept constant. We measured pulmonary artery pressure continuously and in the 10 untreated adult lungs, in which a vasoconstrictor response to PGI2 was obtained, we also measured pressures in 20-50 microns diameter subpleural arterioles and venules by the micropipette-servonulling method. We found that in juvenile and neonatal rabbit lungs, PGI2 did not change total vascular resistance significantly but in untreated adult lungs, it caused a significant increase in total vascular resistance only after a dose of 10 micrograms/kg. This age-related difference in vasoconstrictor response to PGI2 was not related to baseline total vascular resistance in the three groups of lungs. In adult lungs, vasoconstriction occurred mainly in arteries with a small effect in veins. Circulating levels of thromboxane B2, leukotriene C4, and 6-keto-PGF1 alpha increased following PGI2 infusion in adult lungs, whereas in neonatal lungs, only 6-keto-PGF1 alpha increased significantly. Indomethacin pretreatment completely abolished the vasoconstrictor response to PGI2. We conclude that PGI2-induced vasoconstriction is age and dose dependent in isolated rabbit lungs and that a cyclooxygenase product, such as thromboxane A2, may play a role in mediating the vasoconstriction.     

Dose–Effect Relationship of BB-10010/MIP-1 Alpha on Proliferation in Murine Small Intestinal Epithelium:

BB10010/MIP-1 alpha reduces the number of proliferating cells in the small intestine, strongly suggesting a radioprotective potential in this organ. This study was designed to optimize BB10010 administration for maximal radioprotection. In single administration protocols 1 or 4 mg/kg of BB10010 was injected into mice 2, 4 or 10 hr before death. In double administration protocols an initial dose of either 0.4 or 200 g/kg, and a second dose (2.5 hr apart) of 200 g/kg 4 hr before death were administered. The number of vincristine-arrested metaphases were counted on individually microdissected crypts from the midpoint of the small intestine. When compared to the smaller doses of BB 10010 used in our previous studies, the higher doses used in these experiments did not result in any further reduction in the number of proliferating cells under any of the protocols assessed. Furthermore, some values were found to be above not only those observed with the smaller doses, but also above untreated controls. It is concluded that a single dose of 200 g/kg of BB10010 offers the most consistent reduction of mitotic cells, and is, therefore, considered optimal for assessment of radioprotection.     

A review on pharmacophoric designs of antiproliferative agents

Past few decades have witnessed the dawn of new diseases in which cancer is a major problem and the race ensued to eradicate cancer by charting out various effective therapeutic regimens. Circumventing resistance issues and combating the toxicity and selectivity problems are matter-of-concern in cancer treatment. Persistent failure to ensure complete remission and eradication of cancer instigated the researchers to exploit the strategies of combining pharmacophores as targeted therapeutic agents. Momentous improvement in the pharmacokinetic as well as pharmacodynamic profile resulting in the enhancement of bioavailability was seen with the introduction of these pharmacophores. The scope of molecular hybridization can be clearly exemplified through the US-FDA approved estramustine and others such as CUDC-101, CBLC-137, PLX3397, E-3810, and CUDC-907 that are currently in different phases of clinical trials. This review seeks to highlight and discuss anti-proliferative activity of some important hybrid, dual, and multi-targeted pharmacophores reported to date along with their designs, structure activity relationships, scope, and limitations. Further, an emphasis has been made to summarize US-FDA approved as well as drugs currently undergoing clinical trials of anticancer drug development.     

Lymphocytic myocarditis in an overlap syndrome of systemic sclerosis and polymyositis

Clinical Rheumatology -     

White Matter Changes in Dementia: Role of Impaired Drainage of Interstitial Fluid

White matter abnormalities on magnetic resonance imaging (MRI) are associated with dementia and include white matter hyperintensities (WMH; also termed leukoaraiosis) and visible perivascular spaces (PVS). We review the potential role of impaired drainage of interstitial fluid in the pathogenesis of WMH and PVS. Whereas the volume of extracellular space in the grey matter is tightly controlled, fluid accumulates and expands the extracellular spaces of the white matter in acute hydrocephalus, vasogenic edema and WMH. Although there are no conventional lymphatic vessels in the brain, there is very effective lymphatic drainage for fluid and solutes along restricted pathways in the basement membranes of cerebral capillaries and arteries in young individuals. Lymphatic drainage of the brain is impaired with age and in association with apolipoprotein E ε4, risk factors for Alzheimer's disease and cerebral amyloid angiopathy (CAA). Deposition of proteins in the lymphatic drainage pathways in the walls of cerebral arteries with age is recognized as protein elimination failure angiopathy (PEFA), as in CAA and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL). Facilitating perivascular lymphatic drainage from the aging brain may play a significant role in the prevention of CAA, WMH and Alzheimer's disease and may enhance the efficacy of immunotherapy for Alzheimer's disease.     

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults

BackgroundAnticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking.ObjectiveCompare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people.DesignProspective cohort study.SettingPrimary care (Australia and USA).Participants19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100.MeasurementsBaseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition.ResultsAt baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1–2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications.LimitationsResidual confounding and reverse causality are possible. Assessment of dose or duration was not possible.ConclusionsHigh anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-020-06550-2.KEY WORDS: anticholinergic burden, dementia, stroke, potentially inappropriate medication