Nervous System-related Disorders Research Articles

Critical Review on Carbon Nanomaterial Based Electrochemical Sensing of Dopamine the Vital Neurotransmitter

The clinical diagnosis of dopamine biomarkers plays a crucial role in classifying nervous system-related disorders, which are increasingly prevalent across all age groups worldwide. Accurate and thorough diagnosis is essential for administering appropriate drug therapies. However, it has been observed that there is a scarcity of diagnostic methods available in the market, highlighting a significant demand for such tools, particularly as the healthcare system transitions towards personalized medicine. This growing demand has garnered significant attention from researchers working in diagnostics. It is of great therapeutic and pharmacological significance to design and develop diagnostic instruments for the monitoring of dopamine levels both in vivo and in vitro. Extensive research efforts have been dedicated to devising realistic diagnostic techniques for assessing dopamine levels in bodily fluids, with a particular focus on electrochemical sensing methodologies. While studies related to electrochemical sensing of dopamine have shown promising advancements in terms of simplicity, speed, and sensitivity, there remains a notable gap in their application for clinical studies. Thus, this review aims to provide an overview of the latest progress in non-enzymatic (enzyme-free or direct electrochemical) electrochemical sensing of dopamine, specifically focusing on its integration with carbonaceous nanomaterials in electrodes. Additionally, the review discusses the potential for the commercialization of these laboratory-proven techniques soon, emphasizing their feasibility and practicality in real-world applications.

The impact of hypertensive disorders during pregnancy on maternal and fetal outcomes: A retrospective study in South Asian region of Pakistan

The current study was conducted to check the effect of high blood pressure on the health of mother and child living in south Asian region of Pakistan during all trimesters of pregnancy. For this retrospective research, 720 females during their deliveries were analyzed at Swat Medical College and Women's Hospital Mardan between June 2022 and June 2023. This current study found almost one fourth of the population suffer hypertensive disorders during any stage of pregnancy which leads to mild to severe pre-eclampsia and ultimately premature births. The observations indicated statistically high significance between hypertensive disorders and associated adverse symptoms like fetus with preterm delivery, c-sections, low birth weight, acute to chronic but reversible renal disorders, neonatal intensive care admissions and sometime central nervous system related disorders. So, this study concludes that more comprehensive parenteral care at the time of pregnancy and especially at the last trimesters. Keen attention towards symptoms and early diagnosis can help to reduce the severity of disease. The maternal and fetal health initiative schemes are required for public awareness.

In-depth Mechanism, Challenges, and Opportunities of Delivering Therapeutics in Brain Using Intranasal Route.

Central nervous system-related disorders have become a continuing threat to human life and the current statistic indicates an increasing trend of such disorders worldwide. The primary therapeutic challenge, despite the availability of therapies for these disorders, is to sustain the drug's effective concentration in the brain while limiting its accumulation in non-targeted areas. This is attributed to the presence of the blood-brain barrier and first-pass metabolism which limits the transportation of drugs to the brain irrespective of popular and conventional routes of drug administration. Therefore, there is a demand to practice alternative routes for predictable drug delivery using advanced drug delivery carriers to overcome the said obstacles. Recent research attracted attention to intranasal-to-brain drug delivery for promising targeting therapeutics in the brain. This review emphasizes the mechanisms to deliver therapeutics via different pathways for nose-to-brain drug delivery with recent advancements in delivery and formulation aspects. Concurrently, for the benefit of future studies, the difficulties in administering medications by intranasal pathway have also been highlighted.

Creutzfeldt–Jakob Disease, a Diagnostic Challenge and Management in ICU: A Case Report

PPrion disease is a group of neurogenerative disorders caused by misfolding of prion proteins into abnormal proteins. It is presented with multiple central nervous system-related disorders such as decreased cognitive function, movement disorder, seizure, speech problems, dementia, visual blurring, and limb weakness. It is rapidly progressive and highly fatal with an annual incidence of about one per million all over the world. A 65-year-old lady presented in our hospital with all the above mix-up complaints in poor general condition. All workups relevant to the above scenario were done to find the diagnosis. All possible metabolic cause was ruled out; however, magnetic resonance imaging of the brain led to suspicion of Creutzfeldt–Jakob disease. Electroencephalogram was done further to make this diagnosis confirm. The patient responded to the general supportive treatment and discharge with stable and improved status. Key words: Creutzfeldt Jacob disease, Prion, Intensive care unit, Electroencephalogram, Dementia.

Advances in basic research on choline and central nervous system development and related disorders

Choline is an essential nutrient that plays an integral role in all stages of the life cycle, with increasing interest in the relationship between choline and neurodevelopment. Choline is a major component in the synthesis of phospholipids, phosphatidylcholine and sphingolipids, and is an essential nutrient for methyl metabolism, acetylcholine synthesis and cell signaling. Choline plays an important role in neurogenesis and neural migration during fetal development, potentially influencing the development and prognosis of neurological disorders, but its mechanism of action is not yet clear. This article reviews the source and metabolism of choline, the effects and mechanism of choline on neurodevelopment and central nervous system related disorders.

Potential of particle size less than 15 nm via olfactory region for direct brain delivery via intranasal route

Central nervous system-related disorders are very difficult to manage with conventional therapeutics because of the selective and herculean nature of the blood-brain barrier which does not allow easy penetration of drug molecules into the brain. As a result, the efficacy of administered molecule is reduced manifold times, and difficult to ascertain the condition of the patient. An alternative route like the nose to the brain is subjectively being explored to enhance the brain's delivery. Recently various published testimonies have proved the nose to the brain can be an alternative route of administration for effective delivery to the brain. This review majorly highlights the hurdles in the delivery of the nasal route and explores the new areas available for delivery via the concept of particle size below 15 nm, which might penetrate the olfactory bulb via the paracellular spaces present in the olfactory epithelium, which starts from the brain and terminates in the nose. The success of this review might reveal new insights into drug delivery for brain targeting and the necessary delivery mechanism.

Prolonging effects of Valeriana fauriei root extract on pentobarbital-induced sleep in caffeine-induced insomnia model mice and the pharmacokinetics of its active ingredients under conditions of glycerol fatty acid ester as emulsifiers

Ethnopharmacological relevanceValeriana plant roots have traditionally been used to treat central nervous system-related disorders in European countries. Among this genus, the Japanese Pharmacopoeia registers the dried roots of V. fauriei Briq. (VF). However, insufficient pharmacological data are available for this species. Aim of the studyWe investigated the sedative effects of VF extract in a murine caffeine-induced insomnia model as well as the active ingredients and their pharmacokinetics to determine its basic pharmacological action mechanisms under conditions glycerol fatty acid ester is used as emulsifiers. Materials and methodsA murine insomnia model was created by caffeine. Samples derived from the ethanol extract of VF were administered per oral (p.o.), and caffeine was injected intraperitoneally (i.p.). Pentobarbital was injected i.p. and the sleep latency and duration were measured. To confirm the mechanism of action of VF, flumazenil, a specific γ-aminobutyric acid receptor type A (GABAA receptor) antagonist, was administered (i.p.) immediately prior to the sample administration. We examined the pharmacokinetic profiles of the active ingredients in the plasma, brain, urine, and feces of mice after the administration (p.o and intravenous (i.v.)) of VF samples. ResultsVF extract (5 g as VF/kg, p.o.) significantly shorten sleep latency and prolonged pentobarbital-induced sleep in caffeine-induced insomnia mice, partially mediated via the GABAergic nervous system, although a higher dose (10 g as VF/kg, p.o.) was required to exhibit the significant effects in normal mice. Kessyl glycol diacetate (KGD), the main constitutive compound in VF, did not shorten sleep latency but exhibited the same sleep prolonged effect at a dose related to VF extract. The concentration of kessyl glycol 8-acetate (KG8) in the plasma was higher than that of KGD in mice treated (p.o.) with VF extract. The profiles of brain concentrations of KGD and KG8 were similar to those in the plasma, and approximately 20% of those in the plasma were distributed throughout the brain. The excretions of KGD and KG8 in urine and feces was slightly detected, and an unknown large peak related to KG8 was detected in the urine of mice administered with VF extract by HPLC-MS/MS analysis. ConclusionsVF exhibits more sedative effects under stressed conditions, such as insomnia, and the major active ingredients are KGD and its metabolite KG8, which are distributed from the blood circulation into the brain by simple diffusion. KG8 is further metabolized into other metabolites that are easily excreted in the urine.

Development of indole-2-carbonyl piperazine urea derivatives as selective FAAH inhibitors for efficient treatment of depression and pain

Fatty acid amide hydrolase (FAAH), aserinehydrolase with significant role in thehydrolysis of endocannabinoids, is a promising therapeutic target for peripheral and central nervous system related disorders, including pain, neuroinflammation and depression. Employing a structure-based approach, a novel series of indole-2-carbonyl piperazine urea derivatives were designed and synthesized as FAAH inhibitors for the treatment of pain-depression comorbidity. Among them, compound 4i emerged as the most potent inhibitor (IC50 = 0.12 μM) with fine selectivity versus CES2, ABHD6, MAGL and the cannabinoid receptor, which also displayed superior metabolic stability in human liver microsome and an adequate pharmacokinetic profile in rodents. Treatment of depressed rats with 4i demonstrated favorable antidepressant-like effects not only by increasing the level of BDNF in the hippocampus but also by restraining the apoptosis of hippocampal neurons. Also, 4i effectively suppressed the LPS-induced neuroinflammation in vitro. Moreover, 4i exhibited potent analgesic activity, which indicated its promising therapeutical application for pain and depression. These meaningful results shed light on FAAH inhibitors as promising pain-depression comorbidity therapeutics.

Pretreatment with Carpolobia lutea ethanol extract prevents schizophrenia-like behavior in mice models of psychosis

Ethnopharmacological relevanceCarpolobia lutea decoction is widely used as a phytotherapeutic against central nervous system-related disorders including insomnia, migraine headache, and mental illness in West and Central Tropical Africa. AimThis study was designed to investigate the antipsychotic activity of Carpolobia lutea (EECL) in mice models of psychosis. MethodsMale Swiss mice (n = 5/group) were given EECL (100, 200, 400, and 800 mg/kg), haloperidol (1 mg/kg), clozapine (5 mg/kg) and vehicle (10 mL/kg) orally before amphetamine (5 mg/kg)-induced hyperlocomotion and stereotypy, apomorphine (2 mg/kg)-induced stereotypy, or ketamine (10, 30, and 100 mg/kg)-induced hyperlocomotion, enhancement of immobility and cognitive impairment. ResultsEECL (200, 400, and 800 mg/kg) prevented amphetamine- and apomorphine-induced stereotypies, as well as reduced hyperlocomotion induced by amphetamine and ketamine, all of which are predictors of positive symptoms. Regardless of the dose administered, EECL prevented the index of negative symptoms induced by ketamine. Furthermore, higher doses of EECL (400 and 800 mg/kg) also prevented ketamine-induced cognitive impairment, a behavioral phenotype of cognitive symptoms. ConclusionPretreatment with EECL demonstrated antipsychotic activity in mice, preventing amphetamine-, apomorphine-, and ketamine-induced schizophrenia-like symptoms, with 800 mg/kg being the most effective dose.

DIAGNOSTIC ROLE OF EXOSOMES IN VARIOUS DISEASES

Exosomes are lipid bilayer- enclosed membrane bound extracellular vesicles (EVs) that secreted by cells under physiological conditions called extracellular vesicles (EV). EVs participate in are natural carrier which can transfer DNAs, RNAs, proteins, and lipids in autocrine, paracrine and endocrine manner. Exosome cargo having cell cycle related mRNA from cancer promotes proliferation of vascular endothelial cells and exosome play a significant role in angiogenesis by vascular endothelial cells. Exosome cargos showed significant role in pathogenesis of central nervous system related disease and exosomal content can act as biomarkers for specific central nervous system related disorders. It has been observed that viral infected cell release exosome more frequently as compared to non- infected cells; which might be act as indicator of viral infection. It was found that exosomes act as extracellular communicator in ischemic signaling and myocardial repair and several studies evidently prove that in adult heart, exosome secreted by myocardial tissue involved in hetero-cellular communication. It has been suggested that exosomes could play an important role in prognosis of various disease like cancer, disease related to nervous system, infections disease and cardiovascular disease. Exosomes secretion plays important role in disease pathogenesis and may be serve as an important biomedical tool as a biomarker in early detection of various disease.

Fecal Microbiota Transplantation: A Microbiome Modulation Technique for Alzheimer's Disease.

Alzheimer’s disease (AD) is the most common form of dementia and the fifth leading cause of death among the elderly. AD involves parts of the brain that can lead to progressive memory loss and impaired language skills and cognitive thinking, affecting one’s ability to carry out daily activities. Aging, bad dietary habits, family history, as well as altered gut microbiota composition may play a role in the pathogenesis of AD. Although the association between the imbalance of gut microbiota and AD is still difficult to determine, it has been suggested that dysbiosis can lead to the increased secretion of lipopolysaccharides and amyloid, which may impair the permeability of the intestine and the blood-brain barrier. Moreover, it can progress the process of neuroinflammation, amyloid-beta formation, and ultimately neuronal death. Microbiota-targeted interventions such as personalized diet, probiotics, or fecal microbiota transplantation (FMT) might represent a potential therapeutic option for AD. This review article discusses the procedure of FMT and its possible side effects on the recipient’s body. In addition, we review the role of FMT in the context of its application in various nervous system-related disorders (AD, Parkinson’s disease, multiple sclerosis).

A Mechanistic approach of Peroxisome Proliferator-Activated Receptors and its subtypes on Clinical and preclinical model of Neurodegenerative disorders

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, belonging to the nuclear receptor family, which has high expression of three structurally homologous PPARs isotypes (PPARα, PPARβ/δ, and PPARγ) in brain. Several studies have discovered role of PPARs in oxidative stress, mitochondrial dysfunction, neuroinflammation and production of the toxic proteins in various neurodegenerative disorders such as Parkinson disease, Alzheimer’s disease, Huntington disease, Amyotrophic Lateral Sclerosis, Multiple sclerosis etc. Currently available drugs provide symptomatic relief, but disease progression cannot be stopped, because of their unclear molecular approach. The ability of PPAR to modulate the pathways involved in these conditions paved a path for future studies. Due to increasing challenges to treat central nervous system related disorders, hence PPARs have attracted much attention nowadays. In this review, we discussed various mechanisms of PPARs subtypes in neurodegenerative disorders. We congregate the molecular evidences which support PPARs as a therapeutic target to treat neurodegenerative disorders from preclinical and clinical studies and provide a basis for the potential therapeutic use of PPAR ligands in human diseases.

Recent Advances in the Endogenous Brain Renin-Angiotensin System and Drugs Acting on It.

The RAS (renin-angiotensin system) is the part of the endocrine system that plays a prime role in the control of essential hypertension. Since the discovery of brain RAS in the seventies, continuous efforts have been put by the scientific committee to explore it more. The brain has shown the presence of various components of brain RAS such as angiotensinogen (AGT), converting enzymes, angiotensin (Ang), and specific receptors (ATR). AGT acts as the precursor molecule for Ang peptides—I, II, III, and IV—while the enzymes such as prorenin, ACE, and aminopeptidases A and N synthesize it. AT1, AT2, AT4, and mitochondrial assembly receptor (MasR) are found to be plentiful in the brain. The brain RAS system exhibits pleiotropic properties such as neuroprotection and cognition along with regulation of blood pressure, CVS homeostasis, thirst and salt appetite, stress, depression, alcohol addiction, and pain modulation. The molecules acting through RAS predominantly ARBs and ACEI are found to be effective in various ongoing and completed clinical trials related to cognition, memory, Alzheimer's disease (AD), and pain. The review summarizes the recent advances in the brain RAS system highlighting its significance in pathophysiology and treatment of the central nervous system-related disorders.

Neuro-AIDS: Current Status and Challenges to Antiretroviral Drug Therapy (ART) for Its Treatment

Introduction:The infiltration of HIV into the brain alters the functions of the nervous system known as Neuro-AIDS. It leads to neuronal defects clinically manifested by motor and cognitive dysfunctions.Materials and Methods:Current antiretroviral therapy can prevent viral replication but cannot cure the disease completely. HAART-Highly active antiretroviral therapy is used for the treatment of HIV infection. Challenges in neuro-AIDS therapy are as shown in the graphical abstract. One of the challenges is latent viral reservoirs like the brain; which act as a sanctuary site for viruses. Nearly ~50% of HIV patients show neuropathological signs. Nervous system related disorders, including AIDS dementia, sensory neuropathy, and myelopathy have a 25% of prevalence in patients having access to a highly active combination of antiretroviral therapy.Results and Conclusion:Brain is one of the viral sanctuary sites for HIV. The current need of neuro-AIDS therapy is to target the brain as a viral reservoir. Drugs should cross or bypass the blood-brain barrier to reach the brain with effective concentrations. Current research on novel drug delivery approaches may prove helpful in treating neuro-AIDS and related disorders effectively.

Ethnobotanical investigations on plants used in folk medicine by native people of Kumaun Himalayan Region of India

Background:A large population in the rural area of Uttarakhand is still dependent upon traditional plant-based knowledge to combat various disease conditions. This study aimed to explore the ethnopharmacological information and document traditional uses of plants in the Kumaun Himalayan region. Here we show the study of nine villages of three districts of the Uttarakhand state in India, located in the western Himalayan region.Methods:A total of 26 traditional healers and experienced inhabitants between 30-85 years of age were interviewed by a semi-structured questionnaire. The data obtained was quantitatively evaluated using use value (UV). Further, the informant consensus factor (ICF) and fidelity level (FL) were also calculated for species having UV higher than 0.15.Results:A total of 56 plant species were reported from 34 families. The highest number of plant species were collected from Asteraceae and Lamiaceae families followed by Rosaceae. Primary uses of plants were categorized into 29 disease categories. The highest number of species was reported to be used for gastrointestinal disorders (11.21%) followed by immuno-modulation, anti-stress, as adaptogens (10.2%), analgesics (7.47%), for nervous system related disorders (6.54%) and as antimicrobials (6.54%).Conclusions:Local traditional knowledge and practice of plant-based medicine is quite widespread in the rural areas of Uttarakhand and is an indispensable part of the healthcare system. It plays a vital role in the absence of basic medical facilities and tremendous paucity of trained medical personnels.Keywords:Ethnobotany, Himalaya, Cordyceps, Uttarakhand

English

Neuropathic pain is the consequence of abnormal processing in the peripheral or central nervous system (CNS) elicited by neuronal injury. Due to its heterogeneous nature and important unwanted adverse effects of the commonly prescribed psychoactive drugs like benzodiazepines (BDZ), the treatment of neuropathic pain has remained a challenge for the scientific community. Flavonoids initially isolated from plants and used as tranquilizers in Folkloric medicine, have been reported to possess selective affinity for BDZ binding site. These positive ionotropic modulators of γ-amino butyric acid-A (GABAA) receptors enhance the chloride ion flux and provide a strong inhibitory effect. Therefore, for the treatment of central nervous system-related disorders such as neuropathic pain, these selective GABAA receptor modulators stand amongst the strongest candidates. This review provides an update on research development that has confirmed the activity of different flavonoids on GABAA receptors. Key words: Neuropathic pain, flavonoid, γ-amino butyric acid-A (GABAA) receptors, animal models neuropathy.

A systematic review on the neuroprotective perspectives of beta‐caryophyllene

Beta (β)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (β)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease. Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.

Feasibility and Utility of Tele-Neurorehabilitation Service in India: Experience from a Quaternary Center.

Background:Neurological rehabilitation service in developing countries like India is a great challenge in view of limited resources and manpower. Currently, neurological rehabilitation with a multidisciplinary team is limited to a few major cities in the country. Tele-neurorehabilitation (TNR) is considered as an alternative and innovative approach in health care. It connects the needy patients with the health-care providers with minimum inconvenience and yields cost-effective health care.Aim:The aim of this study was to study the socioclinical parameters, feasibility, and utility of TNR services in India.Methodology:A retrospective file review of TNR consultations provided through Telemedicine Center at a quaternary hospital-based research center in south India between August 2012 and January 2016.Results:A total of 37 consultations were provided to the patients belonging to four districts of Karnataka. The mean age of the patients was 34.7 (±19.5) years, 23 (62.1%) were aged between 19 and 60 years, and 31 (83.8%) were male. Thirty-one patients (83.8%) had central nervous system-related disorders such as stroke, cerebral palsy, and tubercular meningitis with sequelae or neuromuscular disorders such as Guillain–Barre Syndrome and Duchenne muscular dystrophy. Twelve patients (32.4%) were advised to consult higher centers in the vicinity, and the rest was referred to the district hospital.Conclusion:The findings suggest that TNR services are feasible, effective, and less resource intensive in delivering quality telemedicine care in India. More clinical studies are required to elucidate its full utility at different levels and in different parts of the country.

Scaffold hopping-guided design of some isatin based rigid analogs as fatty acid amide hydrolase inhibitors: Synthesis and evaluation

Fatty acid amide hydrolase (FAAH) represents a potential therapeutic target for number of peripheral and nervous system related disorders including neuropathic pain and neuroinflammation. A library of N-(2,4-dichlorobenzoyl) isatin Schiff bases 7a–7l and 8a–8c were designed using the contemporary scaffold-hopping approach, synthesized and investigated for their ability to inhibit human FAAH enzyme using fluorescence based Cayman assay kit. The synthesized compounds inhibited FAAH with IC50 values in the range from 1.49 to 12,858 μM. Compound, 3-(1H-benzoimidazol-2-ylimino)-1-(2,4-dichlorobenzoyl)indolin-2-one (8c) showed strong inhibition against FAAH with IC50 of 1.49 ± 0.03 μM. SAR studies revealed various structural aspects important for the potency of these analogs. In particular, our findings suggested the requirement of hydrophobic aryl/heteroaryl moiety at C-3 position of isatin for optimum rigidity and steric hindrance to the scaffold. Additionally, molecular docking studies supported the experimental results revealing that compound 8c well-occupied the enzymatic cleft with optimal binding orientation and interactions within the active site of FAAH which resulted in reduced susceptibility of compound to nucleophilic attack and prevented it from leaving the active site, thereby increasing the inhibition. Also, compound 8c presented potent antidepressant and anxiolytic properties without any neurotoxicity. In silico molecular properties and ADMET descriptors calculations related the lead FAAH inhibitor 8c presented the satisfactory drug-like characteristics and ADMET properties and thus considered for further optimization. To the best of our knowledge this is the first report on the FAAH inhibitory properties of isatin-based analogs, revealing that both indoline skeleton and heteroaryl substitution at C-3 can modulate the activity of FAAH enzyme. In conclusion, the present study provided a better understanding of the molecular fragments requisite for maintaining and/or improving FAAH inhibition activity.

Symptoms of menopause - global prevalence, physiology and implications.

The symptoms of menopause can be distressing, particularly as they occur at a time when women have important roles in society, within the family and at the workplace. Hormonal changes that begin during the menopausal transition affect many biological systems. Accordingly, the signs and symptoms of menopause include central nervous system-related disorders; metabolic, weight, cardiovascular and musculoskeletal changes; urogenital and skin atrophy; and sexual dysfunction. The physiological basis of these manifestations is emerging as complex and related, but not limited to, oestrogen deprivation. Findings generated mainly from longitudinal population studies have shown that ethnic, geographical and individual factors affect symptom prevalence and severity. Moreover, and of great importance to clinical practice, the latest research has highlighted how certain menopausal symptoms can be associated with the onset of other disorders and might therefore serve as predictors of future health risks in postmenopausal women. The goal of this Review is to describe in a timely manner new research findings on the global prevalence and physiology of menopausal symptoms and their impact on future health.