Gastrointestinal Pain Research Articles

Sleep disturbances in systemic sclerosis: evidence for the role of gastrointestinal symptoms, pain and pruritus

SSc is a rare autoimmune CTD characterized by thickening and fibrosis of skin and internal organs. There is significant mortality and no cure. Sleep disturbance has been identified as an important contributor to poor quality of life. The objective was to investigate socio-demographic and medical factors potentially associated with sleep disturbance in SSc. The sample consisted of patients from the Canadian Scleroderma Research Group's (CSRG) 15-centre, pan-Canadian Registry assessed with the 8-item Patient-Reported Outcome Measurement Information System (PROMIS) sleep disturbance scale short form, version 1.0. Pearson's correlations were used to assess bivariate association of socio-demographic and medical variables with PROMIS sleep scores. The independent association of PROMIS sleep disturbance scores and factors previously identified as associated with sleep disturbance in the general population, in SSc and other rheumatic diseases, was assessed using multiple linear regression. Among 397 patients in the study (88% female, mean age 57.5 years), 25% (n = 98) had diffuse cutaneous SSc. Mean duration since onset of non-RP symptoms was 10.6 years. Number of gastrointestinal symptoms (standardized regression coefficient β = 0.19, P = 0.001), pain severity (β = 0.21, P < 0.001) and pruritus severity (β = 0.13, P = 0.024) were independently associated with more severe sleep disturbance. Gastrointestinal symptoms, pain and pruritus were associated with sleep disturbance in SSc. Additional research is needed on sleep in SSc so that well-informed sleep interventions can be developed and tested.

Gastrointestinal pain: Unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation

The natural hormone uroguanylin regulates intestinal fluid homeostasis and bowel function through activation of guanylate cyclase-C (GC-C), resulting in increased intracellular cyclic guanosine-3′,5′-monophosphate (cGMP). We report the effects of uroguanylin-mediated activation of the GC-C/cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress-induced visceral hypersensitivity. In vitro exposure of intestinal Caco-2 cells to uroguanylin stimulated bidirectional, active extracellular transport of cGMP into luminal and basolateral spaces. cGMP transport was significantly and concentration dependently decreased by probenecid, an inhibitor of cGMP efflux pumps. In ex vivo Ussing chamber assays, uroguanylin stimulated cGMP secretion from the basolateral side of rat colonic epithelium into the submucosal space. In a rat model of trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity, orally administered uroguanylin increased colonic thresholds required to elicit abdominal contractions in response to colorectal distension (CRD). Oral administration of cGMP mimicked the antihyperalgesic effects of uroguanylin, significantly decreasing TNBS- and restraint stress–induced visceromotor response to graded CRD in rats. The antihyperalgesic effects of cGMP were not associated with increased colonic spasmolytic activity, but were linked to significantly decreased firing rates of TNBS-sensitized colonic afferents in rats in response to mechanical stimuli. In conclusion, these data suggest that the continuous activation of the GC-C/cGMP pathway along the intestinal tract by the endogenous hormones guanylin and uroguanylin results in significant reduction of gastrointestinal pain. Extracellular cGMP produced on activation of GC-C is the primary mediator in this process via modulation of sensory afferent activity.

Complication Rates After Hip or Knee Arthroplasty in Morbidly Obese Patients

Morbid obesity has been shown to be a risk factor for increased complications after THA and TKA; however, large studies that would determine the effect size are lacking. The purposes of this study were to determine whether morbid obesity increased the risk of: (1) venous thromboembolism (VTE), (2) bleeding, (3) other adverse events, and (4) infections during the early postoperative period (up to 6 to 8 weeks) after THA or TKA? Data from the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism (RECORD) clinical trial program of rivaroxaban for prevention of VTE after THA or TKA were analyzed retrospectively. Data for 12,355 patients were reviewed to identify complication rates in morbidly obese patients (BMI≥40 kg/m2) compared with patients with a BMI less than 40 kg/m2. Explorative analyses compared the rates of asymptomatic deep vein thrombosis (DVT), symptomatic DVT, symptomatic pulmonary embolism, bleeding, and other adverse events by BMI group. There were no significant differences in asymptomatic DVT, symptomatic DVT, symptomatic pulmonary embolism, or bleeding, but there were increases in other adverse events (including receipt of blood transfusion, erythema, peripheral edema, diarrhea, gastrointestinal or abdominal pain) and infections (including respiratory tract or lung infections, wound inflammation or infection, and extrasurgical-site infections), in patients with a BMI of 40 kg/m2 or greater compared with patients with a BMI less than 40 kg/m2. After THA or TKA, morbid obesity is not associated with an increased risk of VTE or bleeding but is associated with increased early postoperative complications, including erythema, peripheral edema, diarrhea and gastrointestinal or abdominal pain, wound inflammation or infection, extrasurgical-site infections, and respiratory tract or lung infections. Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Review of Dengue Hemorrhagic Fever Fatal Cases Seen Among Adults: A Retrospective Study

BackgroundDengue is a mosquito-borne viral disease endemic in many countries in the tropics and sub-tropics. The disease affects mainly children, but in recent years it is becoming more of an adult disease. Malaysia experienced a large dengue outbreak in 2006 to 2007, involving mostly adults, with a high number of deaths.Methodology/Principal FindingsWe undertook a retrospective study to examine dengue death cases in our hospital from June 2006 to October 2007 with a view to determine if there have been changes in the presentation of severe to fatal dengue. Nine of ten fatal cases involved adult females with a median age of 32 years. All had secondary dengue infection. The mean duration of illness prior to hospitalization was 4.7 days and deaths occurred at an average of 2.4 days post-admission. Gastrointestinal pain, vomiting, diarrhea, intravascular leakages and bleeding occurred in the majority of cases. DSS complicated with severe bleeding, multi-organ failure and coagulopathy were the primary causes of deaths. Seven patients presented with thrombocytopenia and hypoalbuminemia, five of which had hemoconcentration and increased ALT and AST indicative of liver damage. Co-morbidities particularly diabetes mellitus was common in our cohort. Prominent unusual presentations included acute renal failure, acute respiratory distress syndrome, myocarditis with pericarditis, and hemorrhages over the brain and heart.ConclusionsIn our cohort, dengue fatalities are seen primarily in adult females with secondary dengue infection. The majority of the patients presented with common clinical and laboratory warning signs of severe dengue. Underlying co-morbidities may contribute to the rapid clinical deterioration in severe dengue. The uncommon presentations of dengue are likely a reflection of the changing demographics where adults are now more likely to contract dengue in dengue endemic regions.

A new approach for early onset cardiogenic shock in acute colchicine overdose: place of early extracorporeal life support (ECLS)?

Dear Editor, Colchicine belongs to the family of spindle poisons, which are mainly used to treat and prevent forms of microcrystalline arthritis, such as gout. It has a narrow therapeutic index. Colchicine overdose is associated with a high mortality rate [1]. Early symptoms usually include gastrointestinal pain; multiorgan failure typically occurs next, alongside metabolic derangements and bone marrow suppression. Prognostic factors include a supposed ingested dose of [0.8 mg/kg, cardiogenic shock, and ARDS [1]. Death from acute colchicine poisoning is usually due to hemodynamic collapse and cardiac arrhythmias. A 51-year-old male pharmacist (medical history of depression, high blood pressure, and gout treated with colchicine) was admitted to the ICU for an acute and unexplained circulatory shock. Over the course of his admission he continued to deteriorate and required high doses of norepinephrine (4.2 lg/kg/min), epinephrine (0.4 lg/kg/min), and dobutamine (10 lg/kg/min). After the first 24 h, his wife found a bottle of 1 mg Colchimax (17 tablets missing). The patient then admitted to ingesting those tablets, which was later confirmed by laboratory investigations: 9.7 nmol/L at day 1; 9.25 nmol/L at day 3; 5.75 nmol/L at day 6; and less than 1.25 nmol/L at day 16. Following the confirmation of a colchicine overdose, the patient’s clinical condition worsened. He quickly developed multiorgan failure and was hemodynamically unstable. In the ICU, it was decided to resort to a bedside-to-bench process. For the following 10 days he received extracorporeal life support (ECLS) (CARDIOHELP, Maquet, Rastatt, Germany), which was achieved through femoral venous arterial cannulation surgery with an initial rate of 3 L/min, 3,700 rev/min. He made a good recovery and showed normal organ function by day 6. The ECLS was removed on day 10 and the mechanical ventilator on day 20. He did not present any hematological failure. He suffered from an acute renal failure due to tubular necrosis that required dialysis for 36 days. The patient was discharged on day 52 with a CPC score of 1. Recent studies have proved that human [1] and animal [2] immunotherapy antibodies can be successfully used to treat colchicine overdose. However, there are a few limitations on the use of immunotherapy antibodies:

Gender differences in symptoms experienced by advanced cancer patients: a literature review

INTRODUCTION: Advanced cancer patients are multi-symptomatic and require attentive palliative care. As gender differences are apparent in multiple aspect of everyday life, this literature review aims to determine the gender differences seen in the population of advanced cancer patients and the symptoms that they experience. METHODS: A literature review was conducted using the OvidSP Medline database from 1946 to November 2012. Randomized, prospective or retrospective cohort studies on advanced cancer patients who were undergoing any type of palliative treatments (palliative radiation, chemotherapy) or those in which palliative treatments have failed (antalgic treatment) were included. The patient population, tools/questionnaire used and gender differences in symptoms found statistically or qualitatively significant in the respective studies were extracted. RESULTS: Of the 163 studies resulting from the literature search, nineteen publications were identified. Gender differences in multiple symptoms were discovered. Gender differences were commonly found in symptoms of emotional changes, fatigue, gastrointestinal symptoms (nausea, vomiting, and diarrhea) anxiety, tension, sleep problems and pain. CONCLUSION: At present, gender differences seen in the symptoms experienced by advanced cancer patients continues to be inconclusive. Further study investigating gender differences in the symptoms experienced by advanced cancer patients as the primary endpoint is recommended.

Gender differences in symptoms experienced by advanced cancer patients: a literature review

INTRODUCTION: Advanced cancer patients are multi-symptomatic and require attentive palliative care. As gender differences are apparent in multiple aspect of everyday life, this literature review aims to determine the gender differences seen in the population of advanced cancer patients and the symptoms that they experience. METHODS: A literature review was conducted using the OvidSP Medline database from 1946 to November 2012. Randomized, prospective or retrospective cohort studies on advanced cancer patients who were undergoing any type of palliative treatments (palliative radiation, chemotherapy) or those in which palliative treatments have failed (antalgic treatment) were included. The patient population, tools/questionnaire used and gender differences in symptoms found statistically or qualitatively significant in the respective studies were extracted. RESULTS: Of the 163 studies resulting from the literature search, nineteen publications were identified. Gender differences in multiple symptoms were discovered. Gender differences were commonly found in symptoms of emotional changes, fatigue, gastrointestinal symptoms (nausea, vomiting, and diarrhea) anxiety, tension, sleep problems and pain. CONCLUSION: At present, gender differences seen in the symptoms experienced by advanced cancer patients continues to be inconclusive. Further study investigating gender differences in the symptoms experienced by advanced cancer patients as the primary endpoint is recommended.

Ethnopharmacological Survey of Plants Used in the Traditional Treatment of Gastrointestinal Pain, Inflammation and Diarrhea in Africa: Future Perspectives for Integration into Modern Medicine.

Simple SummaryThis review provides an inventory of numerous plant species used as traditional remedies for pain and diarrhea in Africa. Africa can emulate advances in traditional Chinese medicine through research, commercialization, teaching traditional medicine in medical schools, and incorporating botanical products in treating veterinary and human patients. Prioritized research of plant species with proven folklore in treating pain and diarrhea using high throughput screening to identify and test bioactive compounds to verify their effectiveness, mechanisms of action and safety and translational research are needed to facilitate these advances and the integration of traditional African botanical preparations for treating pain and gastrointestinal disorders into western medicine.There is a growing need to find the most appropriate and effective treatment options for a variety of painful syndromes, including conditions affecting the gastrointestinal tract, for treating both veterinary and human patients. The most successful regimen may come through integrated therapies including combining current and novel western drugs with acupuncture and botanical therapies or their derivatives. There is an extensive history and use of plants in African traditional medicine. In this review, we have highlighted botanical remedies used for treatment of pain, diarrheas and inflammation in traditional veterinary and human health care in Africa. These preparations are promising sources of new compounds comprised of flavonoids, bioflavanones, xanthones, terpenoids, sterols and glycosides as well as compound formulas and supplements for future use in multimodal treatment approaches to chronic pain, gastrointestinal disorders and inflammation. The advancement of plant therapies and their derivative compounds will require the identification and validation of compounds having specific anti-nociceptive neuromodulatory and/or anti-inflammatory effects. In particular, there is need for the identification of the presence of compounds that affect purinergic, GABA, glutamate, TRP, opioid and cannabinoid receptors, serotonergic and chloride channel systems through bioactivity-guided, high-throughput screening and biotesting. This will create new frontiers for obtaining novel compounds and herbal supplements to relieve pain and gastrointestinal disorders, and suppress inflammation.

Minimally Invasive Thoracic Microendoscopic Diskectomy: A Tool for All Surgeons?

One of the most common pathologic conditions encountered by spine surgeons is a herniated nucleus pulposus. The incidence of symptomatic thoracic disk herniations is <1%. The relative mobility and range of motion about the ventrally located instantaneous axis of rotation partially accounts for the frequency of herniations in the lumbar and cervical spine. The thoracic spine is comparatively immobile with the sternum and rib cage providing substantial structural support, with a commensurate restriction of motion. Paraspinal muscles also contribute to diminished mobility, whereas the natural kyphosis of the thoracic spine limits the incidence of dorsal disk and annulus bulging. The structures that provide such immobilization making herniated nucleus pulposus less common in the thoracic region also serve as a barrier, of sorts, to the surgeon for surgical intervention. The transthoracic, transthoracic extrapleural, costotransversectomy, and dorsal approaches all are associated with significant drawbacks from an exposure and technical perspective. None of these approaches can be universally employed, and each is associated with approach-specific obstacles. The location, laterality, and characteristics of a disk herniation play a key role in the surgical decision-making process. A central calcified disk is better addressed through a ventral or far lateral approach, whereas a soft lateral disk herniation may be better managed via a dorsolateral approach. Patient presentation may vary, depending on the location and magnitude of the herniation. For far lateral disk herniations, radicular pain may be the presenting complaint. An acute central disk herniation may cause rapid onset of myelopathy. Upper thoracic to midthoracic disk herniations may cause a deep chest pain that can be mistaken for cardiac pain. Midthoracic to lower thoracic disk herniations may masquerade as renal colic or gastrointestinal pain. The ultimate key to the decision-making process is careful physical examination in conjunction with obtaining appropriate imaging studies.

Biological and psychological predictors of visceral pain sensitivity in healthy women

Whereas psychological, immunological and HPA-axis related factors have been implicated in pain sensitivity in several pain models, insight into the mechanisms of visceral pain sensitivity is still limited. The current study aimed to investigate psychological and biological predictors of visceral pain sensitivity in healthy subjects. In N = 59 healthy females, measures of gastrointestinal (GI) symptoms in daily life, trait and state anxiety, depression, serum cortisol, and serum levels of interleukin (IL)-6 were obtained, followed by assessment of rectal distension pain sensitivity measures (i.e. rectal distension sensory threshold, pain threshold, and pain ratings for discrete rectal distension stimuli at pain threshold level). Regression analyses revealed that more GI symptoms in daily life predicted lower sensory thresholds. Further, lower pain thresholds were predicted by increased GI symptoms, higher state anxiety and cortisol concentrations, whereas increased cortisol was also associated with lower pain ratings. IL-6 was positively related to GI symptoms and negatively to the pain threshold, but was a non-significant predictor of pain thresholds in the multiple regression analysis. Similar to findings in patients with functional GI symptoms, we showed that subclinical GI symptoms predict visceral pain sensitivity. In line with somatic pain findings, state but not trait anxiety was found to predict visceral pain sensitivity. Our findings on serum cortisol as predictor point to a differential effect of cortisol on the different aspects of pain sensitivity. Our finding on the role of IL-6 in GI symptoms and pain sensitivity is promising for understanding gastrointestinal complaints in patients and needs further investigation.

Seizures and Pain Uncertainty Associated With Parenting Stress and Rett Syndrome

Data were collected parenting stress, adaptive behavior, pain, and health issues from the caregivers of 35 girls and women with Rett syndrome (mean age = 20.3). A majority (60%) of parents reported stress in the clinical range on at least 1 subscale of the Parenting Stress Index-Short Form. Seizures and uncertainty about their daughter's gastrointestinal pain experience were significantly associated with higher levels of parenting stress. No other child factors (adaptive behavior, age, residential status) were significantly related to parenting stress. Factors related to chronic health concerns (seizures, ambiguous pain presentation) may be important when considering family stress issues in relation to general outcomes for girls with Rett syndrome and related developmental disorders.

Botany, uses, phytochemistry and pharmacology of selected Apocynaceae species: A review

The family Apocynaceae consists of tropical trees, shrubs and vines. Characteristic features of the family are that almost all species produce milky sap. Leaves are simple, opposite or whorled; flowers are large, colourful and slightly fragrant with five contorted lobes; and fruits are in pairs. With the inclusion of species of Asclepiadaceae, the family has now enlarged from two to five sub-families. The expanded family now comprises more than 150 genera and 2000 species. In traditional medicine, Apocynaceae species are used to treat gastrointestinal ailments, fever, malaria, pain and diabetes, including skin and ecto-parasitic diseases. Some are important timber species while many are planted as ornamentals. Non-medicinal uses include food, poisons, fodder, wood, ornamentals, dye and perfume. Species of Apocynaceae have been reported to possess anticancer and antimalarial properties. Species having cytotoxic activity include those of Allamanda, Alstonia, Calotropis, Catharanthus, Cerbera, Nerium, Plumeria, Tabernaemontana and Vallaris. Species of Alstonia, Calotropis, Dyera, Kopsia and Vallaris are also known to have antimalarial properties. Prompted by their anticancer and antimalarial properties; the botany, uses, phytochemistry and pharmacology of ten selected Apocynaceae species (Allamanda cathartica, Alstonia angustiloba, Calotropis gigantea, Catharanthus roseus, Cerbera odollam, Dyera costulata, Kopsia fruticosa, Nerium oleander, Plumeria obtusa and Vallaris glabra) belonging to ten genera are reviewed.

A giant fecaloma in a seven-year-old healthy boy

Fecal impaction sometimes grows into a hard and laminated large mass known as a fecaloma which may present features of acute gastrointestinal tract pain or mimic a carcinoma. Patients with fecaloma tend to have underlying conditions such as being elderly, having experienced previous abdominal surgery or having abused drugs (e.g., anticholinergics or narcotics). Although there have been a few reports concerning fecaloma in children complicated with encopresis, cerebral palsy, or Hirschsprung disease, reports of children with giant fecaloma with no underlying diseases are rare.

131I-labeled metuximab combined with chemoembolization for unresectable hepatocellular carcinoma

To investigate the safety and effectiveness of combined (131)I-metuximab and transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). One hundred and eighty-five patients (159 men and 26 women) with advanced HCC were enrolled in this study from February 2009 to July 2011. There were 95 patients in the combined metuximab and TACE group, and 90 patients in the TACE only group. The patients were followed for 12 mo. Clinical symptoms, blood cell counts, Karnofsky Performance Score (KPS) evaluation and therapeutic effects according to the Response Evaluation Criteria in Solid Tumors were recorded and evaluated. The 1-mo effective rates (complete response + partial response + stable disease) of the test group and control group were 71.23% and 38.89%, respectively (P < 0.001). The 6-, 9- and 12-mo survival rates were 86.42%, 74.07% and 60.49% for the test group and 60.0%, 42.22% and 34.44% for the control group (P < 0.001). The incidence of adverse events (gastrointestinal symptoms, fever and pain) and blood cell toxicity were significantly higher for the test group than for the control group (P < 0.001). No severe (131)I-metuximab-related complications were identified. With respect to efficacy, patients in the test group had greater improvement in tumor-related pain (P = 0.014) and increase in KPS (P < 0.001) than those in the control group. Combination of (131)I-metuximab and TACE prolonged the survival time in patients with HCC compared with TACE alone. The combination treatment was safe and effective.

Are emergency admissions in palliative cancer care always necessary? Results from a descriptive study

ObjectivesPatients with advanced cancer are often admitted to hospital as emergency cases. This may not always be medically indicated. Study objectives were to register the reasons for the emergency admissions,...

Correlation Between Dose-Volume Parameters and Patient-reported Quality of Life (QOL) During Image-guided Intensity Modulated Radiation Therapy (IGRT) for Prostate Cancer

There is increasing recognition of the importance of patient-reported QOL as an outcome in cancer treatment. However, to date, limited research has examined the relationship between radiation dose-volume parameters and patient-reported acute genitourinary (GU) and gastrointestinal (GI) symptom development during IGRT for prostate cancer. We analyzed the relationship between dose-volume parameters of the rectum and bladder with prospectively collected patient-reported QOL. One hundred four men with prostate cancer who received radiation therapy to a median 75 Gy at our institution from 2010 to 2012 were included. Weekly during treatment, patients completed a validated questionnaire assessing severity of GI (diarrhea, urgency, bleeding, pain, cramping, mucus, and tenesmus) and GU (ease of flow, dysuria, nocturia, frequency, urgency, and incontinence) symptoms on a 4 or 5-point Likert scale. The association between dose-volume parameters and maximum GI and GU symptom scores was examined using Spearman's correlation. Median age was 64 years, and 72% of patients had clinical T1c or T2a disease. The percent volume of bladder receiving at least 75 Gy and 80 Gy was significantly associated with overall GU symptom score (V75: correlation coefficient .27, p = 0.005; V80: coefficient .30, p = 0.001). GI symptom score was significantly associated with V60 (coefficient .22, p = 0.03) and V65 (coefficient .26, p = 0.007) of the rectum. The proportions of bladder and rectum receiving higher doses of radiation were significantly associated with patient-reported acute GU and GI symptoms during IGRT for prostate cancer. A better understanding of the relationship between dose-volume parameters to surrounding organs and patient-reported QOL may allow physicians to improve radiation planning to optimize patient outcomes.

Using One's Head to Treat Menopausal Symptoms

Using One's Head to Treat Menopausal Symptoms

Conditions of the feline pelvic region

Feline pelvic disease may result in hindlimb lameness, dysfunction of the terminal urogenital and gastrointestinal tracts, internal haemorrhage and pain. Long-term sequelae include chronic hindlimb lameness and/or neurological dysfunction, urinary...

Pain Syndrome Induced by Calcineurin Inhibitor and Resolved by Conversion to Sirolimus in a Child After Kidney Transplantation: A Case Report

Pain induced by calcineurin inhibitors is a rare complication of unknown pathogenesis. We have reported herein a 7-year-old child who presented with abdominal pain, vomiting, and weight loss showing no significant findings after an extensive laboratory and imaging workup. After conversion from tacrolimus to sirolimus, there was complete resolution of the gastrointestinal symptoms and pain; the patient displays excellent renal function. Calcineurin inhibitor-induced pain syndrome is diagnosis of exclusion but must be considered because the withdrawal of this immunosuppressive agent is associated with improvement in symptoms and quality of life.

Fabry disease in children: agalsidase‐beta enzyme replacement therapy

Fabry disease is a rare, multiorgan disease. The most serious complications involve the kidney, brain and heart. This study aims to assess the effect of enzyme replacement therapy (ERT) using agalsidase-beta in children with Fabry disease. We carried out a nationwide, descriptive and observational retrospective cohort study of 10 children (9-16 years at baseline), who underwent regular systematic investigations for 1-8 years after initiation of ERT with agalsidase-beta (Fabryzyme®, Genzyme). Ophthalmological, echocardiographic abnormalities and hypohidrosis were found at baseline and during the follow-up period. Serious kidney, heart or brain involvement had not developed at the last follow-up examination. For the majority of the patients improvements were found concerning headache, acroparaesthesias and gastrointestinal pain during the follow-up period. The level of energy and physical activity also increased. Treatment with agalsidase-beta was associated with a reduction of neuropathic and abdominal pain and headache. Although all aspects of the Fabry pain phenotype cannot be treated with ERT, the observed effects were clinically significant in the lives of the majority of Fabry children and together with the absence of serious Fabry manifestations at last follow-up, we argue that early initiation of ERT may be considered.