A clinical study of artery of Percheron infarction.

Artery of Percheron (AOP) infarction, a rare cause of acute altered mental status (AMS), is characterized by bilateral paramedian thalamic infarction. The aim of this study was to review the clinical manifestation, radiological patterns, treatment, and prognosis of patients with AOP infarction. This retrospective case series included patients with AOP infarction from 2009 to 2020 from a medical center in Taiwan. We defined AOP infarction as acute bilateral paramedian thalamic infarction from magnetic resonance imaging, and patients were further categorized by their additional AOP territorial involvements. We determined outcomes with the modified Rankin Scale at discharge. Among the 10 included patients, AMS was the most common presentation (90%). We identified two patients with bilateral vertebral artery (VA), five with unilateral posterior cerebral artery (PCA), and one with bilateral PCA occlusion. Atherosclerosis was the most common presumed etiology (60%). Two and eight patients had favorable and unfavorable prognoses, respectively. PCA occlusion, rather than VA and BA occlusion, was common in angiography. Residual symptoms often resulted in significant disability at discharge. Basilar tip syndrome may share indistinguishable thalamic infarct patterns with AOP infarction but could be differentiated by angiography and other infarcted territories.

The radiological prognostic factors of transcatheter arterial chemoembolization to hepatocellular carcinoma.

Transcatheter arterial chemoembolization (TACE) is the recommended treatment modality for intermediate stage hepatocellular carcinoma (HCC). The aim of this study was to determine the HCC radiological characteristics associated with prognosis of patients with intermediate stage HCC receiving TACE. Patients with HCC BCLC stage B from January 2005 to December 2009 were collected. According to mRECIST criteria, patients with complete response and partial response were assigned to the objective response (OR) group, while those with stable disease and progressive disease were assigned to the nonobjective response (non-OR) group. Among a total of 128 enrolled patients, there were 66 (51.6%) and 62 (48.4%) patients in the OR group and non-OR group, respectively. The clinical parameters in the two groups were similar, although HCC size was smaller in the OR group. Logistic analysis found combined radiological characteristics including complete lipiodol retention, tumor feeding artery blockage, and no residual tumor blush were significant correlated with achievement of OR (odds ratio 2.46, 95% CI 1.08-5.61, P = .032). However, no radiological characteristics had significant strength to predict overall survival. Patients with OR after TACE had significantly longer survival time than those with non-OR. Combined characteristics of complete lipiodol retention, tumor feeding artery blockage, and no residual tumor blush had a positive impact on OR in TACE. In patients receiving TACE, those who achieved OR had a better overall survival.

Artery of Percheron Occlusion in China: A Case Report and Chinese Literature Review.

INTRODUCTION: The artery of Percheron (AOP) is a rare anatomical variant in which bilateral paramedian thalami are supplied by a single vascular branch arising from the P1 segment of the posterior cerebral artery. We present a case of AOP occlusion presenting as loss of consciousness and summarize the literature in Chinese to find the clinical characteristics. CASE REPORT: An 83-year-old woman was found unconscious for 1 day at home and was sent to the hospital the next day. Cerebral magnetic resonance imaging on day 1 of the patient showed a recent bilateral paramedian thalamic infarction. Simultaneously, magnetic resonance angiography found evident artery stenosis of the right P1 segment of the posterior cerebral artery, suggesting that the patient was diagnosed with AOP occlusion. Since the patient has missed the best time for thrombolytic therapy, anticoagulant therapy was given immediately; as the patient was then found to have pulmonary infections, antibiotic therapy was also initiated. The neurological status of this patient improved very slow. In about 2 weeks, the patient becomes more conscious but still could not speak or move. CONCLUSION: Our report suggests that unusual mood disorder and language disorder of aged patients might indicate the AOP occlusion, and cerebral imaging of magnetic resonance imaging (better with magnetic resonance angiography) should be performed to establish the diagnosis of AOP occlusion. The fast and accurate diagnosis of stroke because of AOP occlusion could best benefit the patients.

Association with clinic risk factors of Percheron artery infarction and magnetic resonance imaging involvement patterns.

Radiological imaging is important in the diagnosis of the artery of Percheron (AOP) infarction. This study aimed to discuss the magnetic resonance imaging (MRI) findings of this abnormal variant of arterial supply. Patients who presented to our hospital with stroke symptoms between 2010 and 2019 and underwent brain MRI were evaluated retrospectively. Eleven patients with AOP infarction were included in the study. The mean age of the patients was 67.4 ± 9.6 years. Seven (63.6%) of the patients were male and four (36.4%) were female. Accompanying diseases were hypertension in eight patients (72.7%) and coronary artery disease in five (45.4%). In eight patients (72.3%), the infarction of AOP extended under the third ventricle wall, and 90.9% of the patients had an asymmetrical radiographic pattern of ischemic damage. With the widespread use of endovascular stroke treatment, it has become critical to establish a rapid and accurate diagnosis of stroke to achieve recovery without sequela. Therefore, although the infarction of AOP is rare, a rapid and accurate diagnosis is important due to possible morbidity and mortality and can be undertaken using MRI.

Isolated acute pseudobulbar palsy with infarction of artery of percheron: case report and literature review.

INTRODUCTION: Pseudobulbar palsy (PBP) is characterized by supranuclear lesions in the corticobulbar pathway. Neoplasia, inflammatory, demyelinating, and stroke are possible etiologies of this disorder. CASE REPORT: We report an elderly female who presented with dysarthria. She was dysarthric with a hypernasal voice, no apraxia or aphasia was observed. Tongue movements were slow with limited amplitude. Her soft palate dropped bilaterally; gag reflex was present. Also, she reported swallowing difficulty and choking with her saliva. Bilateral vertical and horizontal gaze were intact to either voluntary or oculocephalic movements. A cranial CT scan was suggestive of artery of Percheron (AOP) infarction. Brain magnetic resonance imaging showed hypersignal on diffusion-weighted and T2-weighted images and hyposignal on apparent diffusion coefficient in both thalami. CT angiography scan revealed an AOP originating from the left posterior cerebral artery. The swallowing study with a videofluoroscopic demonstrated oral and pharyngeal phases with severe dysfunction. CONCLUSION: To the authors' knowledge, there are two cases of individuals with artery of Percheron infarction who developed PBP associated with other clinical syndromes. Still, isolated PBP following infarction of Percheron's artery was not reported. We hypothesized that the PBP may have occurred because of the existence of vascular territory variations in the perforating arteries that arise from the AOP.

[Bilateral paramedian thalamic infraction due artery of Percheron occlusion]. / Infarto talámico paramedial bilateral por oclusión de la arteria de Percherón.

INTRODUCTION: Artery of Percheron (AOP) is an anatomical variant responsible for the bilateral irrigation of both the medial thalami and rostral sector of the brainstem. Its obstruction causes infarcts in these areas. OBJECTIVE: To describe a clinical case of AOP infarction, highlighting the clinical and imaging fin dings to consider this pathology in the pediatric population with acute altered state of consciousness. CLINICAL CASE: A healthy 17-year-old adolescent presented with altered state of consciousness and diplopia, which was resolved in a few hours. Brain MRI showed a bilateral medial thalamic infarction, diagnosing an occlusion of the AOP. The only presumed etiological element was the presence of a patent foramen ovale. Surgical correction of the cardiac defect and anticoagulation were performed, with complete recovery. CONCLUSION: It is essential to know the clinical-radiological pattern of this condition, which is very characteristic, but infrequent in the pediatric age.

Inhibition of interleukin-6 signaling attenuates aortitis, left ventricular hypertrophy and arthritis in interleukin-1 receptor antagonist deficient mice.

The aim of the present study was to examine whether inhibition of Interleukin (IL)-6 signaling by MR16-1, an IL-6 receptor antibody, attenuates aortitis, cardiac hypertrophy, and arthritis in IL-1 receptor antagonist deficient (IL-1RA KO) mice. Four weeks old mice were intraperitoneally administered with either MR16-1 or non-immune IgG at dosages that were adjusted over time for 5 weeks. These mice were stratified into four groups: MR16-1 treatment groups, KO/MR low group (first 2.0 mg, following 0.5 mg/week, n=14) and KO/MR high group (first 4.0 mg, following 2.0 mg/week, n=19) in IL-1RA KO mice, and IgG treatment groups, KO/IgG group (first 2.0 mg, following 1.0 mg/week, n=22) in IL-1RA KO mice, and wild/IgG group (first 2.0 mg, following 1.0 mg/week, n=17) in wild mice. Aortitis, cardiac hypertrophy and arthropathy were histologically analyzed. Sixty-eight percent of the KO/IgG group developed aortitis (53% developed severe aortitis). In contrast, only 21% of the KO/MR high group developed mild aortitis, without severe aortitis (P<0.01, vs KO/IgG group). Infiltration of inflammatory cells, such as neutrophils, T cells, and macrophages, was frequently observed around aortic sinus of the KO/IgG group. Left ventricle and cardiomyocyte hypertrophy were observed in IL-1RA KO mice. Administration of high dosage of MR16-1 significantly suppressed cardiomyocyte hypertrophy. MR16-1 attenuated the incidence and severity of arthritis in IL-1RA KO mice in a dose-dependent manner. In conclusion, blockade of IL-6 signaling may exert a beneficial effect to attenuate severe aortitis, left ventricle hypertrophy, and arthritis.

Artery of Percheron infarction presenting as nuclear third nerve palsy and transient loss of consciousness: a case report.

BACKGROUND: Thalamic blood supply consists of four major vascular territories. Out of them paramedian arteries supply ipsilateral paramedian thalami and occasionally rostral mid brain. Rarely both paramedian arteries arise from a common trunk that arise from P1 segment of one sided posterior cerebral artery (PCA). This is usually due to hypoplastic or absent other P1 and this common trunk is termed Artery of Percheron (AOP). Its prevalence is in the range of 7-11% among the general population and AOP infarcts account in an average of 0.4-0.5% of ischemic strokes. Clinical presentation of AOP infarction is characterized by impaired arousal and memory, language impairment and vertical gaze palsy. It also can present with cerebellar signs, hemi paresis and hemi sensory loss. We herein present a case of AOP infarction presenting as transient loss of consciousness and nuclear third nerve palsy. CASE PRESENTATION: A 51 year old previously healthy male, was brought to us, with a Glasgow coma scale (GCS) of 7/15. GCS improved to 11/15 by the next day, however he had a persisting expressive aphasia. Right sided nuclear third nerve palsy was apparent with the improvement of GCS. He did not have pyramidal or cerebellar signs. Thrombolysis was not offered as the therapeutic window was exceeded by the time of diagnosis. Diagnosis was made using magnetic resonance imaging (MRI) that was done after the initial normal non-contrast computer tomography (NCCT) brain. He was enrolled in stroke rehabilitation. Aspirin and atorvastatin was started for the secondary prevention of stroke. He achieved independency of advanced daily living by 1 month, however could not achieve full recovery to be employed as a taxi driver. CONCLUSIONS: Because of the rarity and varied clinical presentation with altered levels of consciousness, AOP infarcts are easily overlooked as a stroke leading to delayed diagnosis. Timely diagnosis can prevent unnecessary investigations and the patient will be benefitted by early revascularization. As it is seldom reported, case reports remain a valuable source of improving awareness among physicians about this clinical entity.

Polydatin for treating atherosclerotic diseases: A functional and mechanistic overview.

With the advancement of science and technology, the living standards of human beings have continuously improved, but the incidence and mortality from atherosclerosis worldwide have also increased by year. Although interventional surgery and the continuous development of new drugs have significant therapeutic effects, their side effects cannot be ignored. Polydatin, an active ingredient isolated from the natural medicine Polygonum cuspidatum, has been shown to have a prominent role in the treatment of cardiovascular diseases. Polydatin treats atherosclerosis mainly from three aspects: anti-inflammatory, regulating lipid metabolism and anti-oxidative stress. This article will review the pharmacological mechanism of polydatin in anti-atherosclerosis, the biological characteristics of Polygonum cuspidatum, the toxicology and pharmacokinetics of polydatin and will provide ideas for further research.

New Insight into the Mechanisms of Ginkgo Biloba Extract in Vascular Aging Prevention.

BACKGROUND: Aging-associated vascular dysfunction promotes cardiovascular diseases. Recently, Ginkgo biloba extract (GBE) has attracted considerable attention in the prevention of aged vasculature. METHODS: This review discusses the pathophysiological alterations in aged vasculature and the underlying mechanisms of GBE in vascular aging suppression. RESULTS: Both arterial stiffening and endothelial dysfunction are critical aging-related vascular phenotypes that result in the progression of cardiovascular diseases in the general population. Consistent oxidative stress and inflammatory reaction lead to vascular dysfunction. GBE ameliorates aging-related vascular dysfunction, due to its antioxidant and anti-inflammatory properties. The main effects of GBE in aged vasculature might be associated with the longevity signaling pathways. GBE also attenuates the progression of vascular aging in diabetes mellitus via regulation of glucose and lipid metabolism. CONCLUSION: GBE plays an important role in the prevention of vascular aging process. It is a promising therapeutic approach to ameliorate aging-related vascular dysfunction and cardiovascular diseases.

B Vitamins and Fatty Acids: What Do They Share with Small Vessel Disease-Related Dementia?

Many studies have been written on vitamin supplementation, fatty acid, and dementia, but results are still under debate, and no definite conclusion has yet been drawn. Nevertheless, a significant amount of lab evidence confirms that vitamins of the B group are tightly related to gene control for endothelium protection, act as antioxidants, play a co-enzymatic role in the most critical biochemical reactions inside the brain, and cooperate with many other elements, such as choline, for the synthesis of polyunsaturated phosphatidylcholine, through S-adenosyl-methionine (SAM) methyl donation. B-vitamins have anti-inflammatory properties and act in protective roles against neurodegenerative mechanisms, for example, through modulation of the glutamate currents and a reduction of the calcium currents. In addition, they also have extraordinary antioxidant properties. However, laboratory data are far from clinical practice. Many studies have tried to apply these results in everyday clinical activity, but results have been discouraging and far from a possible resolution of the associated mysteries, like those represented by Alzheimer's disease (AD) or small vessel disease dementia. Above all, two significant problems emerge from the research: No consensus exists on general diagnostic criteria-MCI or AD? Which diagnostic criteria should be applied for small vessel disease-related dementia? In addition, no general schema exists for determining a possible correct time of implementation to have effective results. Here we present an up-to-date review of the literature on such topics, shedding some light on the possible interaction of vitamins and phosphatidylcholine, and their role in brain metabolism and catabolism. Further studies should take into account all of these questions, with well-designed and world-homogeneous trials.

Regulation of calcific vascular and valvular disease by nuclear receptors.

PURPOSE OF REVIEW: This review addresses recent developments in studies of lipid regulation of calcific disease of arteries and cardiac valves, including the role of nuclear receptors. The role of lipid-soluble signals and their receptors is timely given the recent evidence and concerns that lipid-lowering treatment may increase the rate of progression of coronary artery calcification, which has been long associated with increased cardiovascular risk. Understanding the mechanisms will be important for interpreting such clinical information. RECENT FINDINGS: New findings support regulation of calcific vascular and valvular disease by nuclear receptors, including the vitamin D receptor, glucocorticoid receptor, nutrient-sensing nuclear receptors (liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors), and sex hormone (estrogen and androgen) receptors. There were two major unexpected findings: first, vitamin D supplementation, which was previously believed to prevent or reduce vascular calcification, showed no cardiovascular benefit in large randomized, controlled trials. Second, both epidemiological studies and coronary intravascular ultrasound studies suggest that treatment with HMG-CoA reductase inhibitors increases progression of coronary artery calcification, raising a question of whether there are mechanically stable and unstable forms of coronary calcification. SUMMARY: For clinical practice and research, these new findings offer new fundamental mechanisms for vascular calcification and provide new cautionary insights for therapeutic avenues.

The gut microbiome and cardiovascular disease: current knowledge and clinical potential.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The human body is populated by a diverse community of microbes, dominated by bacteria, but also including viruses and fungi. The largest and most complex of these communities is located in the gastrointestinal system and, with its associated genome, is known as the gut microbiome. Gut microbiome perturbations and related dysbiosis have been implicated in the progression and pathogenesis of CVD, including atherosclerosis, hypertension, and heart failure. Although there have been advances in the characterization and analysis of the gut microbiota and associated bacterial metabolites, the exact mechanisms through which they exert their action are not well understood. This review will focus on the role of the gut microbiome and associated functional components in the development and progression of atherosclerosis. Potential treatments to alter the gut microbiome to prevent or treat atherosclerosis and CVD are also discussed.

Btk Inhibitors as First Oral Atherothrombosis-Selective Antiplatelet Drugs?

Bruton's tyrosine kinase (Btk) is essential for B cell differentiation and proliferation, but also platelets express Btk. Patients with X-linked agammaglobulinemia due to hereditary Btk deficiency do not show bleeding, but a mild bleeding tendency is observed in high dose therapy of B-cell malignancies with ibrutinib and novel second-generation irreversible Btk inhibitors (acalabrutinib and ONO/GS-4059). This review discusses recent studies that may explain this apparent paradox and gives mechanistic insights that suggest a unique potential of low dose irreversible Btk inhibitors as atherothrombosis-focused antiplatelet drugs.

Site-specific chelation therapy with EDTA-loaded albumin nanoparticles reverses arterial calcification in a rat model of chronic kidney disease.

Medial arterial calcification (MAC) is a common outcome in diabetes and chronic kidney disease (CKD). It occurs as linear mineral deposits along the degraded elastin lamellae and is responsible for increased aortic stiffness and subsequent cardiovascular events. Current treatments for calcification, particularly in CKD, are predominantly focused on regulating the mineral disturbance and other risk factors. Ethylene diamine tetraacetic acid (EDTA), a chelating agent, can resorb mineral deposits, but the systemic delivery of EDTA may cause side effects such as hypocalcemia and bone resorption. We have developed elastin antibody conjugated albumin nanoparticles that target only degraded elastin in vasculature while sparing healthy tissues. In this study, we tested a targeted nanoparticle-based EDTA chelation therapy to reverse CKD-associated MAC. Renal failure was induced in Sprague-Dawley rats by a high adenine diet supplemented by high P and Ca for 28 days that led to MAC. Intravenous delivery of DiR dye-loaded nanoparticles confirmed targeting to vascular degraded elastin and calcification sites within 24 hours. Next, EDTA-loaded albumin nanoparticles conjugated with an anti-elastin antibody were intravenously injected twice a week for two weeks. The targeted nanoparticles delivered EDTA at the site of vascular calcification and reversed mineral deposits without any untoward effects. Systemic EDTA injections or blank nanoparticles were ineffective in reversing MAC. Reversal of calcification seems to be stable as it did not return after the treatment was stopped for an additional four weeks. Targeted EDTA chelation therapy successfully reversed calcification in this adenine rat model of CKD. We consider that targeted NP therapy will provide an attractive option to reverse calcification and has a high potential for clinical translation.

Mineral bone disorders in chronic kidney disease.

As the GFR loss aggravates, the disturbed mineral metabolism worsens the bone microstructure and remodelling - scenario, which is known as CKD-mineral bone disease (MBD). CKD-MBD is characterized by : (i) abnormal metabolism of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D; (ii) abnormalities in bone turnover, mineralization, volume linear growth or strength; (iii) soft-tissue calcifications, either vascular or extra-osseous. Uremic vascular calcification and osteoporosis are the most common complications related to CKD-MBD. Disregulated bone turnover by uremic toxin or secondary hyperparathyroidism disturbed bone mineralization and makes it difficult for calcium and inorganic phosphate to enter into bone, resulting in increased serum calcium and inorganic phosphate. Vascular calcification worsens by hyperphosphatemia and systemic inflammation. Since vitamin D deficiency plays an important role in renal osteodystrophy, supplement of nutritional vitamin D is important in treating uremic osteoporosis and vascular calcification at the same time. Its pleotropic effect improves the bone remodeling initiated by osteoblast and alleviates the risk factors for vascular calcification with less hypercalcemia than vitamin D receptor analogs. Therefore, nutritional vitamin D should be considered in managing CKDMBD.

Missense mutation of VKORC1 leads to medial arterial calcification in rats.

Vitamin K plays a crucial role in the regulation of vascular calcifications by allowing activation of matrix Gla protein. The dietary requirement for vitamin K is low because of an efficient recycling of vitamin K by vitamin K epoxide reductase (VKORC1). However, decreased VKORC1 activity may result in vascular calcification. More than 30 coding mutations of VKORC1 have been described. While these mutations have been suspected of causing anticoagulant resistance, their association with an increase in the risk of vascular calcification has never been considered. We thus investigated functional cardiovascular characteristics in a rat model mutated in VKORC1. This study revealed that limited intake in vitamin K in mutated rat induced massive calcified areas in the media of arteries of lung, aortic arch, kidneys and testis. Development of calcifications could be inhibited by vitamin K supplementation. In calcified areas, inactive Matrix Gla protein expression increased, while corresponding mRNA expression was not modified. Mutation in VKORC1 associated with a limited vitamin K intake is thus a major risk for cardiovascular disease. Our model is the first non-invasive rat model that shows spontaneous medial calcifications and would be useful for studying physiological function of vitamin K.

Treatment of atherosclerosis by traditional Chinese medicine: Questions and quandaries.

Atherosclerosis and its complications, such as myocardial infarction and stroke, are the major causes of morbidity and mortality, and development of effective therapies for both prevention and treatment of this disease is critically important. Currently, there are many drugs available for atherosclerotic disease, but the lipid-lowering drugs statins are still the first-choice for treatment of hypercholesterolemia, a major risk factor for atherosclerosis. On the other hand, traditional Chinese medicines, mainly Chinese herbal medicines (CHM), have been widely used in China and in other Asian countries for the treatment of atherosclerotic diseases. Although many CHMs have been reported to be effective for treating atherosclerotic diseases for more than two thousand years, there are still many difficulties for their use, such as lack of scientific evidence assessed by rigorous clinical trials, complicated components and unclear pharmacological mechanisms, which often hamper the widespread use of CHMs in Western countries. Due to these concerns, CHMs are usually considered as complimentary or alternative treatment for atherosclerotic diseases. In this review, we provide an overview of the pathophysiology of atherosclerosis viewed by Western and traditional Chinese medicine, summarize pros and cons on the efficacy of CHMs for atherosclerosis and discuss what is necessary for CHM use to spread to Western societies.

Acupuncture Combined with Hydrotherapy in Diabetes Patients with Mild Lower-Extremity Arterial Disease: A Prospective, Randomized, Nonblinded Clinical Study.

BACKGROUND The aim of this pragmatic study was to explore the intervention of acupuncture combined with hydrotherapy and perceived effects in type 2 diabetic patients with recently diagnosed, mild, lower-extremity arterial disease (LEAD) in comparison with a control group. MATERIAL AND METHODS One hundred twenty-six diabetes patients who were diagnosed mild LEAD according to ankle-brachial blood pressure index (ABPI) and peripheral neuropathy symptom were randomly assigned to either an experimental (n=64) or control group (n=62). The experimental group attended and completed (1) a 30-min session of acupuncture in certain selected points, and (2) a 30-min hydrotherapy exercise every 2 days for 15 weeks. The outcome parameters were assessed at baseline, after intervention, and at 6-week follow-up. RESULTS The intervention was associated with an improvement in leg flow conductance and partial physical capacities, including chair-sit-and-reach, the walking impairment questionnaire (WIQ), and physical component summary score (PCS), compared to the control group. The treatment benefits were sustained throughout the 6-week follow-up endpoint. There was no difference in fasting glucose levels, Hb1Ac, blood pressure, or BMI after the intervention. At the endpoint of 6-week follow-up, acupuncture plus hydrotherapy appeared to reduce inflammatory response by decreasing IL-6, TNF-α, malondialdehyde, and SOD, and increasing glutathione. CONCLUSIONS Acupuncture plus hydrotherapy, without significant glycemic-controlling effects in the type 2 diabetic patients with mild LEAD, exerts a measurable benefit in disease-specific physical functions and health-related quality of life. Our results suggest that the combined therapy regulates the inflammatory process and oxidative stress and contributes to immune protection.

Persistent anterograde amnesia due to the artery of Percheron occlusion: a case report.

Bilateral thalamic infarction involving the artery of Percheron (AOP) can cause diagnostic difficulties due to the varying clinical presentations. AOP infarcts presented with isolated memory impairment are not common and the factors affecting the persistence of memory disorders are still unknown. A 41-year-old male patient was hospitalized with acute unconsciousness. MRI disclosed bilateral paramedian thalamic infarction The patient had isolated memory deficit and his anterograde amnesia continued without any change in the past decade. More cases might answer the questions concerning the intra- and extra-thalamic structures responsible for the amnesic syndrome and the factors affecting the persistence of the symptoms.