Differential methylation of TCF7L2 promoter in peripheral blood DNA in newly diagnosed, drug-naïve patients with type 2 diabetes

TCF7L2 is the susceptibility gene for Type 2 diabetes (T2D) with the largest effect on disease risk that has been discovered to date. However, the mechanisms by which TCF7L2 contributes to the disease remain largely elusive. In addition, epigenetic mechanisms, such as changes in DNA methylation patterns, might have a role in the pathophysiology of T2D. This study aimed to investigate the differences in terms of DNA methylation profile of TCF7L2 promoter gene between type 2 diabetic patients and age- and Body Mass Index (BMI)- matched controls. We included 93 type 2 diabetic patients that were recently diagnosed for T2D and exclusively on diet (without any pharmacological treatment). DNA was extracted from whole blood and DNA methylation was assessed using the Sequenom EpiTYPER system. Type 2 diabetic patients were more insulin resistant than their matched controls (mean HOMA IR 2.6 vs 1.8 in controls, P<0.001) and had a poorer beta-cell function (mean HOMA B 75.7 vs. 113.6 in controls, P<0.001). Results showed that 59% of the CpGs analyzed in TCF7L2 promoter had significant differences between type 2 diabetic patients and matched controls. In addition, fasting glucose, HOMA-B, HOMA-IR, total cholesterol and LDL-cholesterol correlated with methylation in specific CpG sites of TCF7L2 promoter. After adjustment by age, BMI, gender, physical inactivity, waist circumference, smoking status and diabetes status uniquely fasting glucose, total cholesterol and LDL-cholesterol remained significant. Taken together, newly diagnosed, drug-naïve type 2 diabetic patients display specific epigenetic changes at the TCF7L2 promoter as compared to age- and BMI-matched controls. Methylation in TCF7L2 promoter is further correlated with fasting glucose in peripheral blood DNA, which sheds new light on the role of epigenetic regulation of TCF7L2 in T2D.

Differential effects of two virtual reality interventions: distraction versus pain control

There is evidence that virtual reality (VR) pain distraction is effective at improving pain-related outcomes. However, more research is needed to investigate VR environments with other pain-related goals. The main aim of this study was to compare the differential effects of two VR environments on a set of pain-related and cognitive variables during a cold pressor experiment. One of these environments aimed to distract attention away from pain (VRD), whereas the other was designed to enhance pain control (VRC). Participants were 77 psychology students, who were randomly assigned to one of the following three conditions during the cold pressor experiment: (a) VRD, (b) VRC, or (c) Non-VR (control condition). Data were collected regarding both pain-related variables (intensity, tolerance, threshold, time perception, and pain sensitivity range) and cognitive variables (self-efficacy and catastrophizing). Results showed that in comparison with the control condition, the VRC intervention significantly increased pain tolerance, the pain sensitivity range, and the degree of time underestimation. It also increased self-efficacy in tolerating pain and led to a reduction in reported helplessness. The VRD intervention significantly increased the pain threshold and pain tolerance in comparison with the control condition, but it did not affect any of the cognitive variables. Overall, the intervention designed to enhance control seems to have a greater effect on the cognitive variables assessed. Although these results need to be replicated in further studies, the findings suggest that the VRC intervention has considerable potential in terms of increasing self-efficacy and modifying the negative thoughts that commonly accompany pain problems.

The association between obesity and back pain in nine countries: a cross-sectional study

BACKGROUND: The association between obesity and back pain has mainly been studied in high-income settings with inconclusive results, and data from older populations and developing countries are scarce. The aim of this study was to assess this association in nine countries in Asia, Africa, Europe, and Latin America among older adults using nationally-representative data. METHODS: Data on 42116 individuals ≥50 years who participated in the Collaborative Research on Ageing in Europe (COURAGE) study conducted in Finland, Poland, and Spain in 2011-2012, and the World Health Organization's Study on Global Ageing and Adult Health (SAGE) conducted in China, Ghana, India, Mexico, Russia, and South Africa in 2007-2010 were analysed. Information on measured height and weight available in the two datasets was used to calculate Body Mass Index (BMI). Self-reported back pain occurring in the past 30 days was the outcome. Multivariable logistic regression analysis was used to assess the association between BMI and back pain. RESULTS: The prevalence of back pain ranged from 21.5% (China) to 57.5% (Poland). In the multivariable analysis, compared to BMI 18.5-24.9 kg/m(2), significantly higher odds for back pain were observed for BMI ≥35 kg/m(2) in Finland (OR 3.33), Russia (OR 2.20), Poland (OR 2.03), Spain (OR 1.56), and South Africa (OR 1.48); BMI 30.0-34.0 kg/m(2) in Russia (OR 2.76), South Africa (OR 1.51), and Poland (OR 1.47); and BMI 25.0-29.9 kg/m(2) in Russia (OR 1.51) and Poland (OR 1.40). No significant associations were found in the other countries. CONCLUSIONS: The strength of the association between obesity and back pain may vary by country. Future studies are needed to determine the factors contributing to differences in the associations observed.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Brain Dopamine and Serotonin Receptors in the Perception of Pain. Positron Emission Tomography Studies in Healthy Subjects

The role of dopamine and serotonin in spinal pain regulation is well established. However, little is known concerning the role of brain dopamine and serotonin in the perception of pain in humans. The aim of this study was to assess the potential role of brain dopamine and serotonin in determining experimental pain sensitivity in humans using positron emission tomography (PET) and psychophysical methods. A total of 39 healthy subjects participated in the study, and PET imaging was performed to assess brain dopamine D2/D3 and serotonin 5-HT_1A receptor availability. In a separate session, sensitivity to pain and touch was assessed with traditional psychophysical methods, allowing the evaluation of potential associations between D2/D3 and 5-HT_1A binding and psychophysical responses. The subjects’ responses were also analyzed according to Signal Detection Theory, which enables separate assessment of the subject’s discriminative capacity (sensory factor) and response criterion (non-sensory factor). The study found that the D2/D3 receptor binding in the right putamen was inversely correlated with pain threshold and response criterion. 5-HT_1A binding in cingulate cortex, inferior temporal gyrus and medial prefrontal cortex was inversely correlated with discriminative capacity for touch. Additionally, the response criterion for pain and intensity rating of suprathreshold pain were inversely correlated with 5-HT_1A binding in multiple brain areas. The results suggest that brain D2/D3 receptors and 5-HT_1A receptors modulate sensitivity to pain and that the pain modulatory effects may, at least partly, be attributed to influences on the response criterion. 5-HT_1A receptors are also involved in the regulation of touch by having an effect on discriminative capacity.

Survival and Quality of Life among Patients with Severe Lower Extremity Peripheral Arterial Disease

Lower extremity peripheral arterial disease (PAD) is associated with decreased functional status, diminished quality of life (QoL), amputation, myocardial infarction, stroke, and death. Nevertheless, public awareness of PAD as a morbid and mortal disease is low. The aim of this study was to assess the incidence of major lower extremity amputation due to PAD, the extent of reamputations, and survival after major lower extremity amputation (LEA) in a population based PAD patient cohort. Furthermore, the aim was to assess the functional capacity in patients with LEA, and the QoL after lower extremity revascularization and major amputation. All 210 amputees due to PAD in 1998–2002 and all 519 revascularized patients in 1998–2003 were explored. 59 amputees alive in 2004 were interviewed using a structured questionnaire of QoL. Two of each amputee age-, gender- and domicile-matched controls filled in and returned postal self-administered QoL questionnaire as well as 231 revascularized PAD patients (the amount of these patients who engaged themselves to the study), and one control person for each patient completed postal self-administered QoL questionnaire. The incidence rate of major LEA was 24.1/100 000 person-years and it was considerably high during the years studied. The one-month mortality rate was 21%, 52% at one-year, and the overall mortality rate was 80%. When comparing the one-year mortality risk of amputees, LEAs were associated with a 7.4-fold annual mortality risk compared with the reference population in Turku. Twenty-two patients (10%) had ipsilateral transversions from BK to AK amputation. Fifty patients (24%) ended up with a contralateral major LEA within two to four amputation operations. Three bilateral amputations were performed at the first major LEA operation. Of the 51 survivors returning home after their first major LEA, 36 (71%) received a prosthesis; (16/36, 44%) and were able to walk both in- and outdoors. Of the 68 patients who were discharged to institutional care, three (4%) had a prosthesis one year after LEA. Both amputees and revascularized patients had poor physical functioning and significantly more depressive symptoms than their controls. Depressive symptoms were more common in the institutionalized amputees than the home-dwelling amputees. The surviving amputees and their controls had similar life satisfaction. The amputees felt themselves satisfied and contented, whether or not they lived in long-term care or at home. PAD patients who had undergone revascularizations had poorer QoL than their controls. The revascularized patients’ responses on their perceived physical functioning gave an impression that these patients are in a declining life cycle and that revascularizations, even when successful, may not be sufficient to improve the overall function. It is possible that addressing rehabilitation issues earlier in the care may produce a more positive functional outcome. Depressive symptoms should be recognized and thoroughly considered at the same time the patients are recovering from their revascularization operation. Also primary care should develop proper follow-up, and community organizations should have exercise groups for those who are able to return home, since they very often live alone. In rehabilitation programs we should consider not only physical disability assessment but also QoL.

Parents as Pain Killers in the Pain Management of Preterm Infants

Vanhemmat keskoslasten kivun lievittäjinä Tutkimuksen tarkoituksena oli kehittää uusi kivunlievitysmenetelmä, Vanhempien käsikapalo, keskoslasten kivunhoitoon vastasyntyneiden teho-osastolla. Vanhempien käsikapalon tehokkuutta verrattiin kahdessa satunnaistetussa kontrolloidussa crossover-tutkimusasetelmassa ei-lääkkeelliseen näyttöön perustuvaan hoitoon (P.O. glukoosiliuos), lääkkeelliseen menetelmään (I.V. oksikodoni) ja lumeeseen (P.O. vesi) tai kontrolli hoitoon kantapääpiston ja hengitysteiden imemisen aikana. Lisäksi mitattiin kivunhoidon lyhytaikaisia sivuvaikutuksia (hapetuksen- ja pulssinlasku) ja pidempiaikaisia vaikutuksia uneen. Tutkittujen lasten ikä oli 28 raskausviikkoa (n = 20) ja 28 1/7 (n = 20). Toimenpidekipua arvioitiin Premature Infant Pain Profile (PIPP) -kipumittarilla. Interventioiden jälkeen unen rakenne analysoitiin 13 tunnin polysomnografia-rekisteröinneistä. Viimeisessä vaiheessa haastateltiin äitejä (n = 23), jotka olivat käyttäneet vanhempien käsikapaloa 2–4 viikkoa vastasyntyneiden teho-osastolla, strukturoidulla the Clinical Interview for Parents of High-Risk Infants -haastattelulla, johon oli lisätty kysymyksiä lapsen kivunhoidosta. Kantapääpiston aikana PIPP–pisteet olivat merkitsevästi matalampia P.O. glukoosiliuoksella (ka 4,85 ± 1,73, p ≤ 0,001) ja vanhempien käsikapalolla (ka 5,20 ± 1,70, p = 0,004) verrattuna lumeeseen (ka 7,05 ± 2,16). Hengitysteiden imemisen yhteydessä PIPP–pisteet olivat matalampia P.O. glukoosiliuoksella (ka 11,05 ± 2,31, p = 0,014) ja vanhempien käsikapalolla (ka 11,25 ± 2,47, p = 0,034) verrattuna lumeeseen (ka 12,40 ± 2,06). Oksikodonin teho oli verrattavissa lumeeseen kummankin toimenpiteen aikana. P.O. glukoosiliuoksen (21,3 %) ja lumeen (12,5 %) annosteluun liittyi merkittävästi enemmän lyhytaikaisia sivuvaikutuksia verrattuna oksikodoniin (5 %) tai vanhempien käsikapaloon (5 %). Oksikodoni muutti keskoslasten unen rakennetta vähentämällä merkittävästi aktiivisen unen määrää verrattuna muihin hoitoihin. Vanhemmat suhtautuivat positiivisesti käsikapalon käyttöön. Äitien osallistuminen kivunhoitoon voitiin jaotella kolmeen eri tyylin, jotka selittyivät äidin kiintymyksen tunteilla ja lapsen tehohoitoon liittyvällä stressillä. Vanhempien käsikapalo on suositeltavampi lyhyen toimenpidekivun lievittäjä kuin P.O. glukoosiliuos tai I.V. oksikodoni, kun tehokkuus, turvallisuus ja perhe otetaan huomioon.

Therapeutic Properties of Superoxide Dismutase 3 and Mesenchymal Stromal Cells in Peripheral Ischemia

The aim of this study was to characterize the cellular mechanisms leading to the beneficial effect of anti-oxidative gene therapy and pro-angiogenic stem cell therapy in acute peripheral ischemia. Post-ischemic events aim to re-establish tissue blood perfusion, to clear cellular debris, and to regenerate lost tissue by differentiation of satellite cells into myoblasts. Although leukocytes have an essential role in clearing cellular debris and promoting angiogenesis, they also contribute to tissue injury through excessive ROS production. First, we investigated the therapeutic properties of extracellular superoxide dismutase (SOD3) gene transfer. SOD3 was shown to reduce oxidative stress, to normalize glucose metabolism, and to enhance cell proliferation in the ischemic muscle. Analysis of the mitogenic Ras-Erk1/2 pathway showed SOD3 mediated induction offering a plausible explanation for enhanced cell proliferation. In addition, SOD3 reduced NF-κB activity by enhancing IκBα expression thus leading to reduced expression of inflammatory cytokines and adhesion molecules with consequent reduction in macrophage infiltration. Secondly, we sought to determine the fate and the effect of locally transplanted mesenchymal stem/stromal cells (MSCs) in acute ischemia. We showed that a vast majority of the transplanted cells are cleared from the injury site within 24 hours after local transplantation. Despite rapid clearance, transplantation was able to temporarily promote angiogenesis and cell proliferation in the muscle. Lack of graft-derived growth factor expression suggests other than secretory function to mediate this observed effect. In conclusion, both SOD3 and MSCs could be utilized to alleviate peripheral ischemia induced tissue injury. We have described a previously unidentified growth regulatory role for SOD3, and suggest a novel mechanism whereby transplanted MSCs enhance the reparative potential of the recipient tissue through physical contacts.

A Comparative Study of the Effectiveness of a Prefabricated Appliance and a Stabilization Appliance in the Treatment of Myofascial pain and Headache

The aim of this thesis was to evaluate the short- and long-term effectiveness of a prefabricated occlusal appliance (R) on patients with myofascial pain and headache by comparing it with the treatment of the stabilization appliance (S). Another aim was to evaluate the effect of appliance treatment on stress-related salivary parameters like cortisol and IgA, as well as on flow rate values in these patients. Sixty-five patients diagnosed with myofascial temporomandibular disorder (TMD) pain, of whom 94% suffered concomitantly from headache, at two centres for Stomatognathic Physiology, one in Sweden and one in Finland, were included in this randomized controlled trial using Research Diagnostic Criteria for TMD (RDC/TMD), with history questionnaires and clinical examinations performed at baseline and at 6- and 10-weeks, and 6- and 12-month follow-ups. Patients were randomly assigned either to the R or the S group. Treatment outcome was measured according to IMMPACT (Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials), i.e. four chronic pain outcome domains: pain intensity, overall improvement, physical and emotional functioning. Changes in frequency and intensity of headache were recorded. Thirty-nine patients participated in the saliva study. Salivary analyses were performed at 6 and 10 weeks. The results revealed no differences between groups at baseline. At all follow-ups, all four outcome measures, as well as frequency and intensity of headache, showed statistically significant within-group improvement compared to baseline, without significant differences between groups. No treatment-induced changes in saliva parameters could be registered. In conclusion, the effectiveness of the prefabricated appliance seemed to be similar to that of the stabilization appliance in alleviating myofascial pain, and frequency and intensity of headache, in the short as well as the long term. However, no changes in salivary parameters were observed during treatment.

Association between peripheral arterial disease and creactive protein in the japanese-brazilian population

OBJECTIVE: To evaluate the relationship between peripheral arterial disease and elevated levels of C-reactive protein in the Japanese-Brazilian population of high cardiovascular risk.METHODS: We conducted a cross-sectional study derived from a population-based study on the prevalence of diabetes and associated diseases in the Japanese-Brazilian population. One thousand, three hundred and thirty individuals aged e" 30 underwent clinical and laboratory examination, including measurement of ultrasensitive C-reactive protein. The diagnosis of peripheral arterial disease was performed by calculating the ankle-brachial index. We considered with peripheral arterial disease patients who had ankle-brachial index d" 0.9. After applying the exclusion criteria, 1,038 subjects completed the study.RESULTS: The mean age of the population was 56.8 years; 46% were male. The prevalence of peripheral arterial disease was 21%, with no difference between genders. Data analysis showed no association between peripheral arterial disease and ultrasensitive C-reactive protein. Patients with ankle-brachial index d" 0.70 showed higher values of ultrasensitive C-reactive protein and worse cardiometabolic profile. We found a positive independent association of peripheral arterial disease with hypertension and smoking.CONCLUSION: The association between low levels of ankle-brachial index and elevated levels of ultrasensitive C-reactive protein may suggest a relationship of gravity, aiding in the mapping of high-risk patients.

Safety and tolerability of controlled-release oxycodone on postoperative pain in patients submitted to the oncologic head and neck surgery

Objective: To evaluate the safety and tolerability of controlled-release oxycodone in the treatment of postoperative pain of head and neck oncologic resections.Methods: We conducted a prospective, observational and open study, with 83 patients with moderate to severe pain after head and neck oncological operations. All patients received general anesthesia with propofol, fentanyl and sevoflurane. Postoperatively, should they have moderate or severe pain, we began controlled-release oxycodone 20 mg 12/12 b.i.d on the first day and 10 mg b.i.d. on the second. We assessed the frequency and intensity of adverse effects, the intensity of postoperative pain by a verbal numeric scale and the use of rescue analgesia from 12 hours after administration of the drug and between 7 and 13 days after the last oxycodone dose.Results: The most common adverse events were nausea, vomiting, dizziness, pruritus, insomnia, constipation and urinary retention, most mild. No serious adverse events occurred. In less than 12 hours after the use of oxycodone, there was a significant decrease in the intensity of postoperative pain, which remained until the end of the study. The rescue medication was requested at a higher frequency when the opioid dose was reduced, or after its suspension.Conclusion: Controlled release oxycodone showed to be safe and well tolerated and caused a significant decrease in post-operative pain.

Irritable bowel syndrome in women with chronic pelvic pain in a Northeast Brazilian city

PURPOSES: To determine the prevalence of irritable bowel syndrome (IBS) in women with chronic pelvic pain (CPP) and its associated features; to determine whether IBS and CPP constitute the same syndrome. METHODS: Cross-sectional population survey with systematic sequential sampling according to census districts in which 1470 women were interviewed with respect to the sample calculation. The participants resided in their own homes, were at least 14 years of age, experienced menarche and presented CPP according to the American College of Obstetrics and Gynaecology. The dependent variable was IBS based on Rome III criteria in women with CPP, and the following independent variables were possibly associated with IBS: age, schooling, duration of pain, sedentary lifestyle, migraine, depression, insomnia, back pain, dysmenorrhea, dyspareunia, depression, history of violence, and intestinal symptoms. The sample was subdivided into groups with and without IBS. After the descriptive analysis of the variables was performed, the respective frequencies were evaluated using GraphPad Prism 5 software. To evaluate the association between the dependent variable and the independent variables, the χ² test was used with a significance level of 5%. RESULTS: The prevalence of IBS in women with CPP was 19,5%. Pain duration (p=0.03), back pain (p=0.002), history of physical or sexual abuse (p=0.002), and intestinal complaints were more prevalent in the group with IBS and CPP. There was no difference between the groups regarding other criteria. CONCLUSION: The data confirmed the literature, identified several aspects that were shared between the pathologies and supported the hypothesis that both pathologies can constitute the same syndrome.