Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral transcriptional response that provides an initial barrier to replication and impacts both innate and adaptive immune responses. Retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) proteins mediate intracellular virus recognition and are activated by viral RNA ligands to induce antiviral signal transduction. While the mechanisms of RIG-I regulation are already well understood, less is known about the more enigmatic melanoma differentiation-associated 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2). Emerging evidence suggests that these two RLRs are intimately associated as both accomplices and antagonists of antiviral signal transduction.
The interferon antiviral system is a primary barrier to virus replication triggered upon recognition of nonself RNAs by the cytoplasmic sensors encoded by retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology gene 2 (LGP2). Paramyxovirus V proteins are interferon antagonists that can selectively interact with MDA5 and LGP2 through contact with a discrete helicase domain region. Interaction with MDA5, an activator of antiviral signaling, disrupts interferon gene expression and antiviral responses. LGP2 has more diverse reported roles as both a coactivator of MDA5 and a negative regulator of both RIG-I and MDA5. This functional dichotomy, along with the concurrent interference with both cellular targets, has made it difficult to assess the unique consequences of V protein interaction with LGP2. To directly evaluate the impact of LGP2 interference, MDA5 and LGP2 variants unable to be recognized by measles virus and parainfluenza virus 5 (PIV5) V proteins were tested in signaling assays. Results indicate that interaction with LGP2 specifically prevents coactivation of MDA5 signaling and that LGP2's negative regulatory capacity was not affected. V proteins only partially antagonize RIG-I at high concentrations, and their expression had no additive effects on LGP2-mediated negative regulation. However, conversion of RIG-I to a direct V protein target was accomplished by only two amino acid substitutions that allowed both V protein interaction and efficient interference. These results clarify the unique consequences of MDA5 and LGP2 interference by paramyxovirus V proteins and help resolve the distinct roles of LGP2 in both activation and inhibition of antiviral signal transduction.
IMPORTANCE Paramyxovirus V proteins interact with two innate immune receptors, MDA5 and LGP2, but not RIG-I. V proteins prevent MDA5 from signaling to the beta interferon promoter, but the consequences of LGP2 targeting are poorly understood. As the V protein targets MDA5 and LGP2 simultaneously, and LGP2 is both a positive and negative regulator of both MDA5 and RIG-I, it has been difficult to evaluate the specific advantages conferred by LGP2 targeting. Experiments with V-insensitive proteins revealed that the primary outcome of LGP2 interference is suppression of its ability to synergize with MDA5. LGP2's negative regulation of MDA5 and RIG-I remains intact irrespective of V protein interaction. Complementary experiments demonstrate that RIG-I can be converted to V protein sensitivity by two amino acid substitutions. These findings clarify the functions of LGP2 as a positive regulator of MDA5 signaling, demonstrate the basis for V-mediated LGP2 targeting, and broaden our understanding of paramyxovirus-host interactions.
Paramyxovirus V proteins bind to MDA5 (melanoma differentiation-associated gene 5) and LGP2 (laboratory of genetics and physiology gene 2) but not RIG-I (retinoic acid-inducible gene I). The results demonstrate MDA5 R806 is essential for inhibition by diverse V proteins. Complementary substitution for the analogous RIG-I L714 confers V protein recognition. The analogous LGP2 R455 is required for recognition by measles V protein, but not other V proteins. These findings indicate that paramyxoviruses use a single amino acid to distinguish MDA5 from RIG-I and have evolved distinct contact sites for LGP2 interference.
Ramelteon is the first member of a novel class of hypnotics and acts as a selective melatonin receptor agonist. In 2005, ramelteon was approved by the US Food and Drug Administration for the treatment of insomnia characterized by sleep onset problems. Its unique mechanism of action made it a promising candidate compared with the widely used hypnotics that act on the benzodiazepine receptor complex. Several studies have examined its efficacy and safety as a hypnotic agent. The primary efficacy of ramelteon was found to lie in a decrease in latency to persistent sleep, as measured by polysomnographic tests. Other sleep-related measures, such as total sleep time and number of nightly awakenings, show less pronounced improvement when treated with ramelteon. In addition, no rebound insomnia or abuse potential was observed in clinical studies. Although additional studies are necessary, current data on the acute and next-morning effects of ramelteon did not indicate cognitive or psychomotor impairment. Overall, ramelteon is safe and well tolerated, although some questions remain regarding its long-term efficacy and safety. These issues and possibilities for use in other patient groups should be addressed in future research.
ramelteon; melatonin; insomnia; hypnotics
There are no studies of autonomic function comparing Alzheimer's disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).
To assess cardiovascular autonomic function in 39 patients with AD, 30 with VAD, 30 with DLB, 40 with PDD and 38 elderly controls by Ewing's battery of autonomic function tests and power spectral analysis of heart rate variability. To determine the prevalence of orthostatic hypotension and autonomic neuropathies by Ewing's classification.
There were significant differences in severity of cardiovascular autonomic dysfunction between the four types of dementia. PDD and DLB had considerable dysfunction. VAD showed limited evidence of autonomic dysfunction and in AD, apart from orthostatic hypotension, autonomic functions were relatively unimpaired. PDD showed consistent impairment of both parasympathetic and sympathetic function tests in comparison with controls (all p<0.001) and AD (all p<0.03). DLB showed impairment of parasympathetic function (all p<0.05) and one of the sympathetic tests in comparison with controls (orthostasis; p = 0.02). PDD had significantly more impairment than DLB in some autonomic parameters (Valsalva ratio: p = 0.024; response to isometric exercise: p = 0.002). Patients with VAD showed impairment in two parasympathetic tests (orthostasis: p = 0.02; Valsalva ratio: p = 0.08) and one sympathetic test (orthostasis: p = 0.04). These results were in contrast with AD patients who only showed impairment in one sympathetic response (orthostasis: p = 0.004). The prevalence of orthostatic hypotension and autonomic neuropathies was higher in all dementias than in controls (all p<0.05).
Autonomic dysfunction occurs in all common dementias but is especially prominent in PDD with important treatment implications.
A case of an 82‐year‐old woman who experienced repeated falls is described. She exhibited a cardioinhibitory carotid sinus hypersensitivity after right carotid sinus massage (CSM), but without evidence of orthostatic hypotension. After a pacemaker was implanted, she did not experience any falls, dizziness or syncope. Her balance eventually deteriorated, but she remained cognitively intact and died from lung cancer at the age of 89 years. Neuropathological examination showed only age‐related Alzheimer's disease pathology and a few α‐synuclein‐positive granular deposits and neurites in the dorsal nucleus of the vagus and solitary tract nucleus in the medulla, but a marked α‐synuclein pathology in the stellate ganglia. The cardioinhibitory element of her CSM was possibly because of the α‐synuclein pathology in the ganglion, which impaired sympathetic transmission. This case shows another phenotype among patients with α‐synucleinopathy.
To compare changes in cerebral autoregulation in response to controlled, lower body negative pressure‐induced hypotension in patients with carotid sinus syndrome (CSS) and case controls.
Prospective case controlled study.
Secondary and tertiary referral falls and syncope service.
17 consecutive patients with CSS and 11 asymptomatic controls.
Hypotension insufficient to cause syncope induced by lower body negative pressure (minimum 30 mm Hg fall in systolic blood pressure (SBP)) during concomitant transcranial Doppler ultrasonography.
Main outcome measures
Cerebral autoregulation (systolic, diastolic and mean middle cerebral arterial blood flow velocities and cerebrovascular resistance) with continuous end‐tidal carbon dioxide and haemodynamic monitoring.
Cerebral autoregulatory indices differed significantly between patients with CSS and controls. Systolic, diastolic and middle cerebral arterial blood flow velocities were, respectively, 9.2 m/s (95% confidence interval (CI) 2.9 to 15.4 m/s), 4.7 m/s (95% CI 1.5 to 7.9 m/s) and 6.9 m/s (95% CI 2.5 to 11.4 m/s) slower in patients with CSS. Cerebrovascular resistance was significantly greater in patients with CSS than in controls at SBP nadir and suction release; differences were 0.9 mm Hg/m/s (95% CI 0.0 to 1.7 mm Hg/m/s) and 0.8 mm Hg/m/s (95% CI 0.0 to 1.7 mm Hg/m/s), respectively. End‐tidal carbon dioxide and systemic haemodynamic variables were similar for patients and controls at baseline and during lower body negative pressure.
Cerebral autoregulation is altered in patients with CSS. This difference may have aetiological implications in the differential presentation with falls and drop attacks rather than syncope.
ageing; carotid arteries; cerebral autoregulation; cerebrovascular circulation; syncope
CAMCOG; CANTAB; pacemaker; cognitive function; pacing mode
Forty two (47%) of patients met the criteria for OH. Subjects with OH were older than those without OH, but there was no difference in PD disease duration or severity, MMSE or depression rating between the groups.
Background: Carotid sinus syndrome (CSS) is a common cause of syncope in older persons. There appears to be a high prevalence of carotid sinus hypersensitivity (CSH) in patients with dementia with Lewy bodies (DLB) but not in Alzheimer's disease.
Objective: To compare the prevalence of CSH in DLB and Alzheimer's disease, and to determine whether there is an association between CSH induced hypotension and brain white matter hyperintensities on magnetic resonance imaging (MRI).
Methods: Prevalence of CSH was compared in 38 patients with DLB (mean (SD) age, 76 (7) years), 52 with Alzheimer's disease (80 (6) years), and 31 case controls (73 (5) years) during right sided supine carotid sinus massage (CSM). CSH was defined as cardioinhibitory (CICSH; >3 s asystole) or vasodepressor (VDCSH; >30 mm Hg fall in systolic blood pressure (SBP)). T2 weighted brain MRI was done in 45 patients (23 DLB, 22 Alzheimer). Hyperintensities were rated by the Scheltens scale.
Results: Overall heart rate response to CSM was slower (RR interval = 3370 ms (640 to 9400)) and the proportion of patients with CICSH greater (32%) in DLB than in Alzheimer's disease (1570 (720 to 7800); 11.1%) or controls (1600 (720 to 3300); 3.2%) (p<0.01)). The strongest predictor of heart rate slowing and CSH was a diagnosis of DLB (Wald 8.0, p<0.005). The fall in SBP during carotid sinus massage was greater with DLB (40 (22) mm Hg) than with Alzheimer's disease (30 (19) mm Hg) or controls (24 (19) mm Hg) (both p<0.02). Deep white matter hyperintensities were present in 29 patients (64%). In DLB, there was a correlation between magnitude of fall in SBP during CSM and severity of deep white matter changes (R = 0.58, p = 0.005).
Conclusions: Heart rate responses to CSM are prolonged in patients with DLB, causing hypotension. Deep white matter changes from microvascular disease correlated with the fall in SBP. Microvascular pathology is a key substrate of cognitive impairment and could be reversible in DLB where there are exaggerated heart rate responses to carotid sinus stimulation.
urinary sodium concentrations; vasovagal syncope
Falls are common in older subjects and result in loss of confidence and independence. The Falls Efficacy Scale (FES) and the Activities-specific Balance Confidence scale (ABC) were developed in North America to quantify these entities, but contain idiom unfamiliar to an older British population. Neither has been validated in the UK. The FES and the ABC were modified for use within British culture and the internal consistency and test-retest reliability of the modified scales (FES-UK and ABC-UK) assessed. A total of 193 consecutive, ambulant, new, and return patients (n=119; 62%) and their friends and relatives ("visitors", n=74; 38%) were tested on both scales, while the last 60 subjects were retested within one week. Internal reliability was excellent for both scales (Cronbach's alpha 0.97 (FES-UK), and 0.98 (ABC-UK)). Test-retest reliability was good for both scales, though superior for the ABC-UK (intraclass correlation coefficient 0.58 (FES-UK), 0.89 (ABC-UK)). There was evidence to suggest that the ABC-UK was better than the FES-UK at distinguishing between older patients and younger patients (|tABC| = 4.4; |tFES| = 2.3); and between fallers and non-fallers (|tABC| = 8.7; |tFES| = 5.0) where the t statistics are based on the comparison of two independent samples. The ABC-UK and FES-UK are both reliable and valid measures for the assessment of falls and balance related confidence in older adults. However, better test-retest reliability and more robust differentiation of subgroups in whom falls related quality of life would be expected to be different make the ABC-UK the current instrument of choice in assessing this entity in older British subjects.
Keywords: quality of life; falls; elderly; health status measurement
A 65 year old woman had a 12 year history of frequent, recurrent seizure-like episodes labelled as treatment resistant epilepsy after neurological evaluation and follow up and treatment with multiple antiepileptic medications. Carotid sinus massage provoked 5.6 seconds asystole with symptom reproduction, and she has remained symptom-free after permanent pacemaker implantation for her carotid sinus syndrome and withdrawal of antiepileptic medications.
Keywords: syncope; carotid sinus; pacing; artificial; epilepsy
OBJECTIVE—To assess the diagnostic value of supine and upright carotid sinus massage in elderly patients.
DESIGN—Prospective controlled cohort study.
SETTING—Three inner city accident and emergency departments and a dedicated syncope facility.
PATIENTS—1375 consecutive patients aged > 55 years presenting with unexplained syncope and drop attacks; 25 healthy controls.
INTERVENTIONS—Bilateral supine carotid sinus massage, repeated in the 70° head up tilt position if the initial supine test was not diagnostic of cardioinhibitory and mixed carotid sinus hypersensitivity.
MAIN OUTCOME MEASURES—Diagnosis of cardioinhibitory or mixed carotid sinus hypersensitivity; clinical characteristics of supine v upright positive groups.
RESULTS—226 patients were excluded for contraindications to carotid sinus massage. Of 1149 patients undergoing massage, 223 (19%) had cardioinhibitory or mixed carotid sinus hypersensitivity; 70 (31%) of these had a positive response to massage with head up tilt following negative supine massage (95% confidence interval, 25.3% to 37.5%). None of the healthy controls showed carotid sinus hypersensitivity on erect or supine massage. The initially positive supine test had 74% specificity and 100% sensitivity; these were both 100% for the upright positive test. The clinical characteristics of the supine v upright positive subgroups were similar.
CONCLUSIONS—The diagnosis of carotid sinus hypersensitivity amenable to treatment by pacing may be missed in one third of cases if only supine massage is performed. Massage should be done routinely in the head up tilt position if the initial supine test is negative.
Keywords: carotid sinus; tilt table testing; syncope; elderly patients
Objective—To determine the benefit of midodrine, an α agonist, on symptom frequency and haemodynamic responses during head up tilt in patients with neurocardiogenic syncope.
Setting—Cardiovascular investigation unit (a secondary and tertiary referral centre for the investigation and management of syncope).
Patients—16 outpatients (mean (SD) age 56 (18) years; five men) with frequent hypotensive symptoms (more than two syncopal episodes and fewer than 20 symptom free days per month), and reproducible syncope with glyceryl trinitrate (GTN) during head up tilt.
Design and intervention—Randomised double blind placebo controlled study. Patients were randomised to receive either placebo or midodrine for one month. Symptom events were recorded during each study month. At the end of each study month patients completed a quality of life scoring scale (Short Form 36) and a global assessment of therapeutic response. They received GTN with head up tilt for measurement of heart rate (electrocardiography), phasic blood pressure (digital photoplethysmography), and thoracic fluid index (transthoracic impedance plethysmography) during symptom provocation.
Results—Patients administered midodrine had an average of 7.3 more symptom free days than those who received placebo (95% confidence interval (CI) 4.6 to 9; p < 0.0001). Eleven patients reported a positive therapeutic response with midodrine (p = 0.002). All domains of quality of life showed improvement with midodrine, in particular physical function (8.1; 95% CI 3.7 to 12.2), energy and vitality (14.6; 95% CI 7.3 to 22.1), and change in health status (22.2; 95% CI 11 to 33.4 ). Fourteen patients who were given placebo had tilt induced syncope compared with six given midodrine (p = 0.01). Baseline supine systolic blood pressure was higher and heart rate lower in patients who received midodrine than in those who were given placebo ( p < 0.05). A lower thoracic fluid index in patients administered midodrine indicates increased venous return when supine and during head up tilt. There were no serious adverse effects.
Conclusions—Midodrine had a conspicuous beneficial effect on symptom frequency, symptoms during head up tilt, and quality of life. Midodrine is recommended for the treatment of neurocardiogenic syncope in patients with frequent symptoms.
Keywords: midodrine; neurocardiogenic syncope; head up tilt test
Syncope and falls are often considered to be two separate diagnoses with two separate sets of aetiologies. However, although it remains controversial, the existence of an overlap between syncope and falls is becoming increasingly acknowledged. In the elderly, determining the cause of a fall can be difficult. Approximately 30% of cognitively normal elderly people are unable to recall documented falls three months later and a witness account for syncopal events is unavailable in about 50% of patients. We have found that in almost 40% of patients in whom an attributable diagnosis of carotid sinus syndrome was made, the only presenting symptoms were falls alone or falls with dizziness; syncope was denied. Amnesia for loss of consciousness can be demonstrated in over 20% of all patients with a diagnosis of carotid sinus syndrome and in 50% of those patients who present only with falls or falls and dizziness. There is a suggestion from studies in postprandial hypotension and orthostatic hypotension, where similar haemodynamic changes are found in patients complaining of either syncope or falls, that this phenomenon may be generalisable. The importance of the presence of an overlap between syndrome and falls in the elderly lies in the healthcare implications of missed diagnoses of cardiovascular syncope for which there are established effective treatments. Consideration of syncope in the differential diagnosis of unexplained falls should reduce the numbers of falls for which no attributable diagnosis is found and result in an improved standard of health care for elderly patients who fall.
OBJECTIVE: To determine whether single chamber ventricular demand (VVI) pacing is adequate for elderly patients with carotid sinus syndrome. DESIGN: Prospective double blind randomised cross over study. SETTING: Tertiary referral centre. PATIENTS: 30 consecutive patients aged over 60 years with carotid sinus syndrome referred for cardiac pacing. INTERVENTION: Patients underwent dual chamber pacemaker implantation and were then randomised to two three-month periods of VVI and DDI pacing. MAIN OUTCOME MEASURES: Responses to cardiovascular tests (vasodepression during carotid sinus massage, pacemaker effect, postural blood pressure measurements, and response to head up tilt), and symptoms. RESULTS: 11 patients developed profound hypotension during upright carotid sinus massage while pacing VVI compared with only two while pacing DDI. The upright pacemaker effect was greater in VVI (VVI, -31 (SD 19) mm Hg v DDI, -4 (12) mm Hg; P < 0.001). Postural blood pressure measurements and responses to head up tilt did not vary. Eleven patients were unable to tolerate VVI pacing and had to be withdrawn early from this limb of the study (group A). Fourteen of the remainder completed diary cards and did not express a preference (group B). No patient preferred VVI. Group A patients were older (group A, 78 (6) years v group B, 70 (9) years; P < 0.05), were more likely to be female (group A, 73% v group B, 14%; P < 0.01), and were more likely to have orthostatic hypotension while pacing DDI (group A, 46% v group B, 0%; P < 0.01). Group A and B patients could not be differentiated by other prepacing clinical or haemodynamic variables. CONCLUSIONS: Elderly patients with carotid sinus syndrome are likely to develop symptomatic hypotension following VVI pacing. The optimum pacing mode for individual patients cannot be predicted by simple cardiovascular tests before pacing.
OBJECTIVE: To evaluate tolerance of fludrocortisone in older patients with hypotensive disorders. DESIGN: Prospective case series. SETTING: Syncope clinic. PATIENTS: 64 Consecutive patients over 65 years (mean age 80 years) with one or more hypotensive disorders (orthostatic hypotension, vasodepressor carotid sinus syncope, and/or vasodepressor neurocardiogenic syncope. INTERVENTIONS: Fludrocortisone in daily doses of 100 micrograms [corrected] (72%), 50 micrograms [corrected] (27%), and 200 micrograms [corrected] (one patient). MAIN OUTCOME MEASURES: Adverse events, treatment withdrawal. RESULTS: During follow up 13 patients died of unrelated causes. Of the remainder 33% discontinued fludrocortisone at a mean of five months. Reasons for discontinuing treatment were hypertension, five; cardiac failure, four; depression, three; oedema, three; and unspecified, two. In those who continued treatment supine systolic and diastolic blood pressure did not differ significantly from baseline (follow up two to 21 months). Hypokalaemia developed in 24% at a mean of eight months; in no case was treatment withdrawn because of hypokalaemia. CONCLUSION: Fludrocortisone, even in low doses, is poorly tolerated in the long term in older patients with hypotensive disorders.
BACKGROUND: Anticoagulants are effective in preventing stroke in those with atrial fibrillation, but most patients remain untreated. AIM: To investigate the prevalence of disability, cognitive impairment, and problems with compliance in a representative sample of the elderly with atrial fibrillation, and to determine whether they would want treatment and how they would like services to be arranged. METHOD: In a survey of a random sample of 4843 elderly subjects, those with atrial fibrillation were identified using electrocardiograms. Views on treatment were obtained using a structured interview. Disability was assessed using the Office of Population Censuses and Surveys Disability Scale and cognitive status using the Mini Mental State Examination. General practitioners were asked, via questionnaire, for their views on each subject's compliance. RESULTS: Two hundred and seven elderly people with atrial fibrillation were identified. Almost all subjects expressed a willingness to undertake treatment to prevent stroke and preferred blood testing performed outside of hospital. Disability (82.7%), cognitive impairment (25.7%), and problems with compliance (25.0%) were common, but the prevalence of these difficulties was not substantially different from the general elderly population, and in many cases they could be overcome (e.g. only 10% of subjects had problems with compliance and no-one who could help them to comply). CONCLUSIONS: Most elderly people with atrial fibrillation would accept treatment to prevent stroke. Disability, cognitive impairment, and problems with compliance may make it difficult to treat this patient group. An increase in the use of anticoagulants should be accompanied by the development of services appropriate to this frail population.
Consecutive referrals to a syncope clinic were asked about the frequency of enquiries about driving status by referring general practitioners and/or hospital specialists. Although 40% were drivers, only 13% of patients had been previously asked about driving, and 12% of drivers had experienced symptoms whilst driving. This represents an important oversight on the part of referring doctors.
The demand for anticoagulation services is rising. Warfarin anticoagulation has been shown to reduce the risk of stroke in patients with non-valvular atrial fibrillation by 68%. This raises issues about how services are best organized to initiate and monitor anticoagulation in this potentially large group of patients. We report the results of a regional postal survey undertaken to describe the views of general practitioners and consultants regarding warfarin anticoagulation in light of this potentially high increase in demand.