Improved arterial inflammation with high dose omega-3 fatty acids in patients with elevated lipoprotein(a): Selective effect of eicosapentaenoic acid?

Elevated lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease. However, there are no approved and effective treatments for lowering Lp(a) and the associated cardiovascular risks. Omega-3 fatty acids (ω-3FAs), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have both triglyceride-lowering and anti-inflammatory properties. This pilot study investigated the effect of high dose ω-3FAs (3.6 g/day) on arterial inflammation in 12 patients with elevated Lp(a) (> 0.5 g/L) and stable coronary artery disease (CAD) receiving cholesterol-lowering treatment. Arterial inflammation was determined using 18F-fluorodexoyglucose positron emission tomography/computed tomography before and after 12-weeks intervention. ω-3FAs significantly lowered plasma concentrations of triglycerides (-17%, p < 0.01), Lp(a) (-5%, p < 0.01) as well as aortic maximum standardized uptake value (SUVmax) (-4%, p < 0.05). The reduction in SUVmax was significantly inversely associated with average on-treatment EPA (r = -0.750, p < 0.01), but not DHA and triglyceride, concentrations. In conclusion, high dose ω-3FAs decrease arterial inflammation in patients with elevated Lp(a) and stable CAD, which may involve a direct arterial effect of EPA.

Self-Assembled CuCo2S4 Nanoparticles for Efficient Chemo-Photothermal Therapy of Arterial Inflammation.

Cardiovascular disease caused by atherosclerosis (AS) seriously affects human health. Photothermal therapy (PTT) brings hope to the diagnosis and treatment of AS, with the development of nanotechnology. To improve treatment efficiency, self-assembled CuCo2S4 nanocrystals (NCs) were developed as a drug-delivery nanocarrier, triggered by near-infrared (NIR) light for efficient chemophotothermal therapy of arterial inflammation. The as-prepared self-assembled CuCo2S4 NCs exhibited excellent biocompatibility and a very high chloroquine (CL)-loading content. In addition, the self-assembled CuCo2S4 NCs/CL nanocomposites showed good photothermal performance, due to strong absorption in the NIR region, and the release of CL from the NCs/CL nanocomposites was driven by NIR light. When illuminated by NIR light, both PTT from the NCs and chemotherapy from the CL were simultaneously triggered, resulting in killing macrophages with a synergistic effect. Moreover, chemo-photothermal therapy with CuCo2S4 NCs/CL nanocomposites showed an effective therapeutic effect for arterial inflammation, in vivo. Our work demonstrated that chemo-photothermal therapy could be a promising strategy for the treatment of arterial inflammation against atherosclerosis.

Curcumin and Curcuma longa Extract in the Treatment of 10 Types of Autoimmune Diseases: A Systematic Review and Meta-Analysis of 31 Randomized Controlled Trials.

Objective: To evaluate the randomized controlled trials (RCTs) of Curcumin and Curcuma longa Extract in the treatment of autoimmune diseases. Methods: Databases such as Embase, Web of Science, PubMed and The Cochrane Library were searched from the database establishment to February 2022 to collect RCTs of Curcumin and Curcuma longa Extract in the treatment of autoimmune diseases. Then the literature was screened and the data were extracted. Meta-analysis was performed using RevMan 5.3 software. Results: A total of 34 records were included, involving 31 RCTs and 10 types of autoimmune disease. Among them, ankylosing spondylitis (AS) involves one RCT, Behcet 's disease (BD) involves one RCT, Crohn 's disease involves two RCTs, multiple sclerosis (MS) involves two RCTs, oral lichen planus involves six RCTs, psoriasis involves two RCTs, rheumatoid arthritis (RA) involves five RCTs, systemic lupus erythematosus (SLE) involves two RCTs, arteritis involves one RCT, ulcerative colitis (UC) involves nine RCTs. Among them, most of the RCTs of ulcerative colitis (UC), oral lichen planus, RA showed that curcumin and curcumin extracts improved clinical or laboratory results. Crohn ' s disease, MS, SLE, psoriasis included two RCTs; they all showed improvements (at least one RCT reported improvements in clinical outcomes). AS, BD and arteritis included only one RCT, and the clinical results showed improvement. However, due to the small number of RCTs and the small number of patients involved in each disease, there is still a need for more high-quality RCTs. Conclusion: Curcumin and Curcuma longa Extract had good clinical efficacy in the treatment of Psoriasis, UC and RA, so Curcumin and Curcuma longa Extract could be used in the treatment of the above diseases in the future. The results of Meta-analysis showed that Curcumin and Curcuma longa Extract did not show efficacy in the treatment of oral lichen planus, while Takayasu arteritis, SLE, MS, AS, BD and CD did not report sufficient clinical data for meta-analysis. Therefore, large-sample, multi-center clinical trials are still needed for revision or validation.

The protective mechanism of folic acid on hyperhomocysteinemia-related arterial injury in spontaneously hypertensive rats: Folic acid against arterial inflammation.

BACKGROUND: Hypertension associated with hyperhomocysteinemia (HHcy) is correlated with a high risk of vascular diseases. Studies found that folic acid (FA) supplementation can reduce the risk of cardiovascular and cerebrovascular events. The aim of the present study was to explore the potential mechanisms of FA attenuating HHcy-related arterial injury in spontaneously hypertensive rats (SHRs). METHODS: 24 SHRs were randomized into the control group, the HHcy group, and the HHcy + FA group (8 per group). The SHRs in the HHcy group and the HHcy + FA group were given DL-Hcy intraperitoneally to mimic hypertension associated with HHcy. The SHRs in the HHcy + FA group were given FA by gavage to mimic an FA-fortified diet. The histopathology and immunohistochemistry of rat aorta and carotid artery were analyzed, and the relative expression levels of immune/inflammation and oxidative stress molecules in arterial tissue were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. RESULTS: FA significantly reduced the expression levels of nuclear factor-κ-gene binding (NF-κB) p65/Rela and interleukin-6 (IL-6) in rat arterial tissues, as well as the levels of plasma HHcy and serum malondialdehyde (MDA) in hypertension associated with HHcy rats (p < 0.05). At the same time, FA significantly increased the serum superoxide dismutase (SOD) level in hypertension associated with HHcy rats, and even the SOD level of the HHcy + FA group was higher than that of the control group (p < 0.05). However, HHcy induced the opposite results of the above indicators in SHRs compared with the control group (p < 0.05). CONCLUSIONS: The arterial protection mechanisms of FA are related to reducing the concentration of HHcy to eliminate the tissue toxicity of HHcy, inhibiting NF-κBp65/Rela/IL-6 pathway molecules to regulate inflammatory response, and promoting the potential anti-oxidative stress pathway molecules to reduce oxidative stress level.

Roles of selenoprotein S in reactive oxygen species-dependent neutrophil extracellular trap formation induced by selenium-deficient arteritis.

Selenium (Se) deficiency and poor plasma Se levels can cause cardiovascular diseases by decreasing selenoprotein levels. Neutrophil extracellular traps (NETs) may be the vicious cycle center of inflammation in vasculitis. Here, we show that Se deficiency induced arteritis mainly by reducing selenoprotein S (SelS), and promoted the progression of arteritis by regulating the recruitment of neutrophils and NET formation. Silencing SelS induced chicken arterial endothelial cells (PAECs) to secrete cytokines, and activated neutrophils to promote NET formation. Conversely, scavenging DNA-NETs promoted cytokine secretion in PAECs. The NET formation regulated by siSelS was dependent on a reactive oxygen species (ROS) burst. We also found that the PPAR pathway was a major mediator of NET formation induced by Se-deficient arteritis. Overall, our results reveal how Se deficiency regulates NET formation in the progression of arteritis and support silencing-SelS worsens arteritis.

Risk of Nonarteritic Anterior Ischemic Optic Neuropathy After Cataract Surgery.

PURPOSE: To determine whether the development of nonarteritic anterior ischemic optic neuropathy (NAION) is increased after receiving cataract surgery in a large general population. DESIGN: Nationwide, population-based, retrospective cohort study. METHODS: Setting: A 12-year nationwide, population-based, retrospective cohort study including 1,025,340 beneficiaries in the 2002-2013 Korean National Health Insurance Service database. PATIENTS: We identified 40,356 patients who had undergone cataract surgery and matched non-cataract surgery controls (1:2) using estimated propensity scores in reference to age, sex, demographics, comorbidities, and co-medications. OBSERVATIONS: Kaplan-Meier curves and Cox proportional hazard models were generated to determine the risk of developing NAION in the cataract surgery group compared to the non-cataract surgery group. MAIN OUTCOME MEASURES: Effect (hazard ratio [HR]) of cataract surgery on NAION development. RESULTS: The 10-year incidence probability of NAION was 0.70% (95% confidence interval [CI], 0.55%-0.86%) in the cataract surgery group and 0.27% (95% CI, 0.25%-0.29%) in the non-cataract surgery group (P < .0001, log-rank test). The cataract surgery group had an increased risk of developing NAION compared to the non-cataract surgery group (HR = 1.80; 95% CIs, 1.46-2.21) even after adjusting for demographics, comorbidities, Charlson comorbidity index, and co-medications. CONCLUSION: Our results suggest that patients undergoing cataract surgery have an increased risk of NAION.

Risk of Stroke After Nonarteritic Anterior Ischemic Optic Neuropathy.

PURPOSE: To determine whether nonarteritic ischemic optic neuropathy (NAION) raises the risk of subsequent stroke in the general population. DESIGN: Population-based, retrospective cohort study. METHODS: Setting: Nationwide, population-based, retrospective cohort study. PATIENTS: Of 1 025 340 beneficiaries in the National Health Insurance Service-National Sample Cohort database (2002-2013), we included 400 952 eligible individuals in the analysis. OBSERVATIONS: To determine the effect of incident NAION on the occurrence of subsequent stroke, we used time-varying covariate Cox regression models. Model 1 included only incident NAION as a time-varying covariate. Model 2 included Model 1 and defined demographics. Model 3 included Model 2, comorbidity, co-medication, and Charlson index score. MAIN OUTCOME MEASURES: Effect (hazard ratio [HR]) of NAION on stroke development. RESULTS: Of 400 952 eligible individuals, 1125 patients developed NAION and 16 998 patients suffered from stroke. NAION was not associated with an increased risk of subsequent stroke in Model 1, with HR of 1.31 (95% confidence interval [CI], 0.89-1.92). This was consistent, after adjusting for demographics and/or confounding factors, in Model 2 (HR = 1.19, 95% CI, 0.81-1.75) and Model 3 (HR = 1.10, 95% CI, 0.75-1.62). CONCLUSIONS: Our results suggest that NAION per se is not associated with a subsequent risk of stroke in the general population.

The suppressive effect of the three-herb extract mixture on vascular and liver inflammation in atherogenic diet with high fructose-fed mice.

CONTEXT: Cynanchum wilfordii (Maximowicz) Hemsley (Apocynaceae), Arctium lappa L. var. rubescens Frivald (Asteraceae) and Dioscorea opposite Thunb (Dioscoreaceae) root extracts have been widely used as an alternative for intervening obesity. OBJECTIVES: The synergistic effect of three-herb mixture of C. wilfordii, A. lappa and D. opposita was determined on aortic and liver inflammatory responses. MATERIALS AND METHODS: CWE, ALE and DOE were prepared from the root of C. wilfordii, A. lappa and D. opposite by 70% ethanol extraction, respectively. CADE was prepared using a powder mixture of 2 CWE:1 ALE:1 DOE. C57BL/6 mice were fed an atherogenic diet combined with 10% fructose (ATHFR) in the presence of 200 mg/kg/day CWE, ALE, DOE or CADE for 8 weeks (each group, n = 6). Biochemical profiles, protein expression of vascular cell adhesion molecule-1 (VCAM-1) on the aorta and liver were determined. RESULTS: CADE could significantly suppress the protein expression of VCAM-1 in both the aorta and liver (80% reduction) compared to ATHFR-fed mice. Impairment of liver function was significantly ameliorated by CADE supplement, as determined by GOT (60% reduction) and GPT (51% reduction) levels. CONCLUSIONS: CADE should be considered when developing medications to suppress the vascular and liver inflammatory responses for individuals who are either non-responsive or resistant to lipid-lowering drugs.

Prevalence and incidence of non-arteritic anterior ischaemic optic neuropathy in South Korea: a nationwide population-based study.

AIMS: To determine the age and sex-specific prevalence and incidence of non-arteritic anterior ischaemic optic neuropathy (NAION) in South Korea. METHODS: This is a nationwide population-based study using data from the Korean national health claims database to identify patients with NAION using the registration programme database, which comprises ophthalmologist-confirmed NAION from 2011 through 2015. We evaluated prevalence and incidence rates using these data. RESULTS: Among 25 816 797 of entire population 40 years of age or older, 26 167 patients had NAION (47.8% men) during the 5-year study period. The prevalence in the general population 40 years of age or older was 102.87 (95% CI 95.22 to 110.53) per 100 000 people. In men, it was 111.10 (95% CI 101.19 to 121.02), and in women, it was 94.64 (95% CI 89.25 to 100.03) per 100 000 people. The prevalence increased with advancing age and peaked at 70-74 years in men and 65-69 years in women. The incidence in the general population 40 years of age or older was 11.35 (95% CI 10.37 to 12.33) per 100 000 person-years. In men, it was 14.89 (95% CI 12.26 to 16.91), and in women, it was 9.92 (95% CI 8.85 to 10.99) per 100 000 person-years. The incidence increased with advancing age and peaked at 80-84 years in men and 70-74 years in women. CONCLUSIONS: The prevalence and incidence estimates of NAION are comparable with those of Caucasians. These detailed estimates could promote understanding of the disease's pathophysiology and allow for appropriate planning within the healthcare system.

Conservative treatment of patients with thromboangiitis obliterans or cannabis-associated arteritis presenting with critical lower limb ischaemia.

BACKGROUND: Proper management of patients with thromboangiitis obliterans (TAO) or cannabis-associated arteritis (CAA), presenting with critical lower limb ischaemia (CLI) remains controversial, and data are limited. PATIENTS AND METHODS: Patients with TAO or CAA presenting with CLI between 2011 and 2016 were retrospectively evaluated. Patients requiring primary intervention were excluded. Conservative treatment included: (a) weight-adjusted bemiparin plus six hours/day intravenous iloprost for 28 days, (b) aspirin (100 mg/day) plus cilostazol (100 mg twice/day) after discharge, and (c) strict recommendations/monitoring for smoking cessation. Main outcomes included symptom recession, ankle-brachial index (ABI) improvement, and healing of lesions at the time of discharge as well as amputation, revascularization, and abstinence rate during follow-up. RESULTS: Overall, 23 patients (TAO: 15; CAA: 8) were included within six years, none of the patients reported any other factor than smoking. All patients presented with rest pain and 12 patients with ulcer or necrotic lesions. Mean ABI measurement at presentation was 0.46 ± 0.2, after 28 days of treatment, all patients showed improvement regarding clinical picture and ABI measurement (0.54 ± 0.1; p < 0.05). During follow-up, only three patients underwent bypass surgery and two patients underwent major amputation, although the smoking abstinence rate was very low (13 %). CONCLUSIONS: Intravenous iloprost plus bemiparin for 28 days together with per os aspirin plus cilostazol seem to produce promising results in patients with TAO/CAA, treated for CLI, even with a low smoking abstinence rate. However, larger series are needed to further evaluate inter-group differences and potential prognostic factors.

Cannabis arteritis.

Cannabis is the most consumed psychoactive substance by young people. Chronic use of cannabis can lead to cannabis arteritis, which is a very rare peripheral vascular disease similar to Buerger's disease. It is affecting young adults, especially men, consuming cannabis. A 27-year old woman, with no particular past medical history except for long-term use of cannabis and tobacco developed a digital necrosis in the left hand. She denied using other illicit drugs. Doppler ultrasound examination of the upper limbs was unremarkable. Toxicological analysis revealed the presence of cannabis in both biological fluid and hair strand. Despite medical treatment, cessation of the cannabis and tobacco consumption and hyperbaric oxygen therapy, an amputation of necrotic parts was then required. This case shows the prolonged use of cannabis could be a risk factor for young adult arteritis. Faced with a rapidly progressive arteritis occurring in young adult, the physician should consider the history of use of cannabis. Hair analysis can be useful for confirmation of the chronic consumption of drugs.

[Medicinal laws and application examples of traditional Chinese medicine prescriptions for multiple aorto-arteritis].

To collect the literature on traditional Chinese medicine treatment for multiple aorto-arteritis from China National Knowledge Infrastructure(CNKI), establish prescriptions database after screening and normalizing the prescriptions reported in these literature, and analyze their medicinal rules by using traditional Chinese medicine inheritance support system. A total of 126 prescriptions for multiple aorto-arteritis were screened, containing 212 kinds of Chinese herbs. 26 core herb combinations were obtained by analysis of the commonly used herbs and their use frequencies. The treatment for multiple aorto-arteritis was manly of tonifying qi to nourish blood, promoting blood circulation to remove blood stasis, warming yang to dredge collaterals, and four new prescriptions were obtained. On this basis, two clinical cases were taken as the examples by analyzing the medicinal rules and the features of multiple aorto-arteritis. The first case showed that the herb combination of this study conformed to the basic core drug application mode and the core pathogenesis of multiple aorto-arteritis. The second case reflected the characteristics of the new prescriptions' herb combinations based on entropy hierarchical clustering. The practical analysis of the two clinical cases further indicated the reliability of the results. This study has certain guiding significance and reference value on new medicine research and development as well as clinical traditional Chinese medicine treatment for multiple aorto-arteritis.

Tratamiento médico de las arteritis inflamatorias / No disponible

No disponible

Coronary and systemic arterial physiology and immunohistochemical markers related to early coronary arterial lesions in beagle dogs given the potassium channel opener, ZD6169, or the endothelin receptor antagonist, ZD1611.

We evaluated immunohistochemistry (von Willebrand Factor [vWF] or fibrinogen) and systemic and coronary arterial physiological parameters in beagle dogs to investigate early arterial lesions induced by the potassium channel opener, ZD6169, or the endothelin receptor antagonist, ZD1611. Dogs given an oral dose of ZD6169 (experiment 1) were terminated 1 day later and showed arterial and myocardial lesions. Minimal arterial lesions exhibited few condensed medial smooth muscle cells only, with others showing segmental medial necrosis occasionally with medial/adventitial acute inflammation. Intercellular immunostaining was seen in ostensibly normal tissue, where no pathology was present in conventionally stained sections. vWF and fibrinogen are valuable tools for detecting disruption of arterial integrity. In experiment 2, 2 dogs were given a single high dose of ZD6169 or ZD1611 and BP/HR monitored by conventional measures or telemetry. Substantially reduced systolic/diastolic BP and increased HR occurred within 10 min of ZD6169 infusion: ZD1611 caused minor BP decrease and HR increase. In experiment 3, both drugs given to anaesthetized dogs induced markedly exaggerated systolic phasic forward and reverse flow in left descending and right coronary arteries. Diastolic coronary artery flows were unaffected with ZD1611 and increased slightly with ZD6169. In both coronary arteries, the ZD1611-induced increase in flows paralleled decreased resistance.

Cysteine, histidine and glycine exhibit anti-inflammatory effects in human coronary arterial endothelial cells.

The activation of nuclear factor-kappa B (NF-κB) in vascular endothelial cells may be involved in vascular pathogeneses such as vasculitis or atherosclerosis. Recently, it has been reported that some amino acids exhibit anti-inflammatory effects. We investigated the inhibitory effects of a panel of amino acids on cytokine production or expression of adhesion molecules that are involved in inflammatory diseases in various cell types. The activation of NF-κB was determined in human coronary arterial endothelial cells (HCAECs) because NF-κB modulates the production of many cytokines and the expression of adhesion molecules. We examined the inhibitory effects of the amino acids cysteine, histidine and glycine on the induction of NF-κB activation, expression of CD62E (E-selectin) and the production of interleukin (IL)-6 in HCAECs stimulated with tumour necrosis factor (TNF)-α. Cysteine, histidine and glycine significantly reduced NF-κB activation and inhibitor κBα (IκBα) degradation in HCAECs stimulated with TNF-α. Additionally, all the amino acids inhibited the expression of E-selectin and the production of IL-6 in HCAECs, and the effects of cysteine were the most significant. Our results show that glycine, histidine and cysteine can inhibit NF-κB activation, IκBα degradation, CD62E expression and IL-6 production in HCAECs, suggesting that these amino acids may exhibit anti-inflammatory effects during endothelial inflammation.

[Treatment of large vessel vasculitis]. / Tratamiento de las vasculitis de grandes vasos.

Large vessels vasculitis: Giant cells arteritis (GCA), and Takayasu's arteritis (TA) are a pair of systemic chronic inflammatory diseases characterized by specific involvement of large caliber, elastic-layered arteries. Presently, and derived from the paucity of clinical controlled trials approaching the issue, the management of GCA and TA is largely based on the clinical judgment of the treating physician. Glucocorticoids and immunosuppressive drugs are used when clear evidence of inflammatory activity is observed. The traditional management approach is to start with systemic glucocorticoid therapy at immunosuppressive dose, followed by cytotoxic immunosuppressive drugs (methotrexate, azatioprine, cyclophosphamide or mycofenolate mofetil) aimed at maintaining remission and decreasing corticosteroid therapy time. Recently, based on the potential pathogenic role of tumor necrosis factor α in these diseases, a series of reports addressing the benefic effect of αTNF-blockers in patients who have been resistant to the traditional management approach have been published. Non- reversible vascular lesions (such as occlusion or stenosis) may require surgical treatment (stent or bypass), however this must be done only when a complete control of the inflammatory activity has been reached.

Tratamiento de las vasculitis de grandes vasos / Treatment of large vessel vasculitis

Las vasculitis primarias de grandes vasos: la arteritis de células gigantes (ACG) y la arteritis de Takayasu (AT) son enfermedades inflamatorias crónicas que afectan principalmente las arterias elásticas de gran calibre. En la actualidad hay escasas evidencias que permitan conocer cuál es el mejor tratamiento en cuanto a eficacia y seguridad, así como la mejor estrategia para mantener la remisión y mejorar el pronóstico debido a que casi no hay estudios controlados sobre el tópico, por lo que en la mayoría de los casos el tratamiento se basa en el juicio del clínico. Los glucocorticoides e inmunosupresores están indicados si hay una clara evidencia de actividad. El enfoque tradicional consiste en el uso de glucocorticoides a dosis inmunosupresoras para el manejo de los episodios de actividad inflamatoria, seguido de inmunosupresores citotóxicos (metotrexato, azatioprina, ciclofosfamida o micofenolato de mofetilo) para mantener la remisión y disminuir el tiempo en corticoterapia. En fechas recientes, y dado el papel patogénico potencial del factor de necrosis tumoral en estos padecimientos, hay reportes alentadores del uso de inhibidores de esta citocina en el tratamiento de pacientes refractarios al enfoque tradicional. Las lesiones que dejan como secuela oclusión o estenosis vascular habitualmente no son reversibles con el tratamiento médico, por lo que en ocasiones requieren de tratamiento quirúrgico (angioplastia o bypass), el cual debe realizarse solo cuando la actividad de la enfermedad esté controlada de forma adecuada (AU)

Large vessels vasculitis: Giant cells arteritis (GCA), and Takayasu’s arteritis (TA) are a pair of systemic chronic inflammatory diseases characterized by specific involvement of large caliber, elastic-layered arteries. Presently, and derived from the paucity of clinical controlled trials approaching the issue, the management of GCA and TA is largely based on the clinical judgment of the treating physician. Glucocorticoids and immunosuppressive drugs are used when clear evidence of inflammatory activity is observed. The traditional management approach is to start with systemic glucocorticoid therapy at immunosuppressive dose, followed by cytotoxic immunosuppressive drugs (methotrexate, azatioprine, cyclophosphamide or mycofenolate mofetil) aimed at maintaining remission and decreasing corticosteroid therapy time. Recently, based on the potential pathogenic role of tumor necrosis factor in these diseases, a series of reports addressing the benefic effect of TNF-blockers in patients who have been resistant to the traditional management approach have been published. Non- reversible vascular lesions (such as occlusion or stenosis) may require surgical treatment (stent or bypass), however this must be done only when a complete control of the inflammatory activity has been reached (AU)

Cannabis and skin diseases.

From time out of mind, man has grown hemp for both "industrial" and "recreational" use (it is then referred to as cannabis). Of course, cannabis has strong psychoactive properties and is one of the most commonly used "soft drugs" in the world. Clinicians should know the adverse effects on mucous membranes and on skin, which may sometimes entail an absolutely necessary stopping of consumption. Raynaud's phenomenon, as well as arteritis due to cannabis consumption may be extremely severe and result in worrying situations for both clinicians and patients.