炎性反应性肠病诊断及治疗临床分析

目的:通过对炎性反应性肠炎的临床特点、诊断方法及治疗方法进行充分科学的总结以及结果仔细的分析。方法:选择100例患有炎性反应肠炎的患者,将其临床资料进行科学回顾性的仔细分析,并且要告知患者在其临床表现需要进行科学的观察,对此要积极对炎性反应性肠炎的诊断和治疗方法进行合理的总结,同时对患者通过治疗后其疗效能够进行合理的总结和分析,积极的提出多种有效的治疗措施。结果:经过UC和CD对患者进行诊断之后,并且在发病的情况上,每年都出现上升的趋势,患者中的女性患者会多于男性患者,但是对于UC与CD等发病的情况,根据患者在年龄上的不同,没有出现明显的差异。对于通过UC来诊断,其主要就是通过内镜对患者的钡灌肠进行检查,通常的治疗方法,大多数都是来自传统治疗措施来有效实施,其治疗效果相对明显;并且在接受CD诊断,主要是通过内镜和手术之后,在手术治疗后能够得到确诊,而且在治疗的方法上,就会采取多方位的手术方式。结论:对于出现炎性反应性肠炎的患者其发病的次数,逐年体现出上升的趋势,对于患者在诊断中,主要以患者的临床表现作为此次治疗的依据,并且要结合相应的肠镜和病理作为主要方式,对于患者在接受治疗的主要方面,是通过对传统的规范性科学方式进行治疗,对此,也取得了相对较好的治疗效果,这样,对于患者需要做好健康教育及定期的相应回访工作。

嗜黏蛋白阿克曼氏菌在肠道疾病和代谢紊乱中的关键作用

肠道微生物群在宿主代谢和炎性反应调节中发挥重要作用,许多疾病的发生与肠道菌群失衡密切相关。Akkermansia muciniphila(A.muciniphila)是疣微菌门中第一个被成功分离鉴定和培养的肠道共生菌,最初从人类粪便样本中被分离出来,因具备黏蛋白的降解特性,使其成为肠道黏膜中的关键菌种之一。不断有研究表明A.muciniphila的丰度与动物和人体的健康密切相关,使其成为近年来肠道微生态和益生菌的研究热点。此外,A.muciniphila的丰度在炎症性肠病(主要是溃疡性结肠炎)和代谢紊乱患者中降低,这表明它可能具有潜在的抗炎特性。本文将系统阐述A.muciniphila与肠道免疫和系统代谢疾病之间的关联,重点探讨其在改善肠道屏障、免疫应答及宿主代谢方面的功能和可能作用机制,为以A.muciniphila为基础开发疾病治疗新方法提供证据和思路。

增殖性化脓性口炎

增殖性化脓性口炎(PD-PSV)是一种少见的累及皮肤黏膜的脓疱性和增生性疾病,与炎性肠炎相伴发,因而PD-PSV临床报道少,极其容易误诊。本文检索数十年间所报道的34例PD-PSV患者,从历史沿革、流行病学、临床表现、组织病理学特征、治疗和鉴别诊断等方面进行综述。

GPR30在炎症中作用的研究进展

GPR30是一种新发现的G蛋白偶联雌激素受体,其与配体结合后,G蛋白结构解离为Gα和Gβγ,可激发酪氨酸激酶等下游激酶,在机体生理状态参与细胞的生长、迁移、凋亡,也参与了炎症性肠炎、肿瘤、牙周炎、多发性硬化症、帕金森病、动脉粥样硬化、脑缺血性发作等多种疾病的炎症反应。GPR30具有减少炎症介质产生和促进免疫细胞反应的双面作用,可能与研究的疾病模型、组织细胞类型不同有关,其在疾病中与炎症相关的具体作用仍存在许多争议。

Positions of selective leukocytapheresis in the medical therapy of ulcerative colitis

Ulcerative colitis （UC） and Crohn＇s disease （CD） are the major forms of idiopathic inflammatory bowel disease （IBD）. Both UC and CD are debilitating chronic disorders that afflict millions of individuals throughout the world with symptoms which impair function and quality of life. The etiology of IBD is inadequately understood and therefore, drug therapy has been empirical instead of being based on sound understanding of IBD pathogenesis. This is a major factor for poor drug efficacy and drug related side effects that often add to the disease complexity. The development of biologicals notably infliximab to intercept tumor necrosis factor （TNF）-α reflects some progress, albeit major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD seems to be perpetuated by inflammatory cytokines like TNF-α, interleukin （IL）-Iβ, IL-6 and IL-8 for which activated peripheral granulocytes and monocytes/macrophages （GH） are major sources. Further, in IBD, peripheral GHs are elevated with activation behavior, increased survival time and are found in vast numbers within the inflamed intestinal mucosa; they are suspected to be major factors in the immunopathogenesis of IBD. Hence, peripheral blood GMs should be appropriate targets of therapy. The Adacolumn is a medical device developed for selective depletion of GH by receptor-mediated adsorption （GHA）. Clinical data show GMA, in patients with steroid dependent or steroid refractory UC, is associated with up to 85% efficacy and tapering or discontinuation of steroids, while in steroid nai＇ve patients （the best responders）, GHA spares patients from exposure to steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse suppresses relapse thus sparing the patients from the morbidity associated with IBD relapse. Further, GHA appears to reduce the number of patients being submitted to colectomy or exposure to unsafe immunosupressants. First UC episode, steroid naivety and short disease duration appear good predictors of response to GMA and based on the available data, GMA seems to have an excellent safety profile.

Qualitative and quantitative analyses of the bifidobacterial microbiota in the colonic mucosa of patients with colorectal cancer, diverticulitis and inflammatory bowel disease

AIM： To characterize the bifidobacterial microbiota of the colonic mucosa in patients with colon cancer, inflammatory bowel disease or diverticulitis. METHODS： A sample of the distal colonic mucosa was taken during surgery from a total of 34 patients, twenty-one with diagnosed colorectal cancer, nine with diverticulitis and four with inflammatory bowel disease, requiring surgery for their condition. Bacterial DNA was extracted from the resected mucosal samples and bifidobacterial mucosa-associated microbiota was qualitatively and quantitatively determined by means of qualitative and quantitative PCR. RESULTS： Bifidobacteria were found in 100% of the samples from patients with diverticulitis or IBD and a 76% of those suffering colon cancer. The species B. Iongum and B. bifidum were the most widely found, followed by B. animalis, B. catenulatum and B. adolescentis. B. breve, B. dentium and B. angulatum were not detected in any sample. A significantly higher occurrence of B. Iongum was observed in patients with diverticulitis than in those with colon cancer or IBD （100%, 62% and 75%, respectively, P 〈 0.05）. Similar results were obtained for B, animalis （56%, 0% and 25%, P 〈 0.05）, while B. adolescentis was only found in the mucosa from patients with colon cancer （5 out of 21, 24%）. At the quantitative level, patients with colon cancer or IBD showed lower counts of total Bifidobacterium （4.94 and 5.91 vs 6.96 log Cells/sample, respectively, P 〈 0.05） and of the species B. longum （4.05 and 4.79 vs 6.76, P 〈 0.05） than those with diverticulitis.CONCLUSION： Aberrancies in mucosa associated microbiota are present in different intestinal diseases. This may indicate a role of the microbiota in the pathogenesis of these diseases.

New serological biomarkers of inflammatory bowel disease

Serological biomarkers in inflammatory bowel disease (IBD) are a rapidly expanding list of non-invasive tests for objective assessments of disease activity, early diagnosis, prognosis evaluation and surveillance. This review summarizes both old and new biomarkers in IBD, but focuses on the development and character-ization of new serological biomarkers (identifi ed since 2007). These include fi ve new anti-glycan antibodies, anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-manobioside IgG (AMCA), and antibod-ies against chemically synthesized (∑) two major oligomannose epitopes, Man α-1,3 Man α-1,2 Man (∑Man3) and Man α-1,3 Man α-1,2 Man α-1,2 Man (∑Man4). These new biomarkers serve as valuable complementary tools to existing biomarkers not only in differentiating Crohn's disease (CD), ulcerative colitis (UC), normal and other non-IBD gut diseases, but also in predicting disease involvement (ileum vs colon), IBD risk (as subclinical biomarkers), and disease course (risk of complication and surgery). Interestingly, the prevalence of the antiglycan antibodies, including anti-Saccharomyces cerevisiae antibodies (ASCA), ALCA and AMCA, was found to be associated with single nucleotide polymorphisms (SNPs) of IBD susceptible genes such as NOD2/CARD15, NOD1/CARD4, toll-likereceptors (TLR) 2 and 4, and β-defensin-1. Further-more, a gene dosage effect was observed: anti-glycan positivity became more frequent as the number of NOD2/CARD15 SNPS increased. Other new serum/ plasma IBD biomarkers reviewed include ubiquitination factor E4A (UBE4A), CXCL16 (a chemokine), resistin, and apolipoprotein A-IV. This review also discusses the most recent studies in IBD biomarker discovery by the application of new technologies such as proteomics, fourier transform near-infrared spectroscopy, and mul-tiplex enzyme-linked immunosorbent assay (ELISA)'s (with an emphasis on cytokine/chemokine profiling). Finally, the prospects of developing more clinically use-ful novel diagnostic algorithms by incorporating new technologies in serological biomarker profiling and integrating multiple biomarkers with bioinformatics analysis/modeling are also discussed.

Disease activity and cancer risk in inflammatory bowel disease associated with primary sclerosing cholangitis

AIM: To investigate the phenotype of inflammatory bowel disease associated with primary sclerosing cholangitis (PSC-IBD). METHODS: Data from 75 PSC-IBD patients evaluated in our tertiary center between 1963 and 2006 were collected and compared to 150 IBD patients without PSC, matched for sex, birth date, IBD diagnosis date and initial disease location regarding ileal, different colonic segments, and rectum, respectively. RESULTS: While PSC-IBD patients received more 5-aminosalicylates (8.7 years/patient vs 2.9 years/ patient, P < 0.001), they required less immuno-suppressors (24% vs 46% at 10 years; P < 0.001) and less intestinal resection (10% vs 44% at 10 years, P < 0.001). The 25-year cumulative rate of colectomy was 25.1% in PSC-IBD and 37.3% in controls (P = 0.004). The 25-year cumulative rate of colorectal cancer was 23.4% in PSC-IBD vs 0% in controls (P = 0.002). PSC was the only independent risk factor for the development of colorectal cancer (OR = 10.8; 95% CI, 3.7-31.3). Overall survival rate without liver transplantation was reduced in PSC-IBD patients (67% vs 91% in controls at 25 years, P = 0.001).CONCLUSION: This study confirms that patients with PSC-IBD have a particular disease phenotype independent of the initial disease location. Although their disease is less active and they use more 5-aminosalicylates, they present a higher risk of colorectal cancer.

Haemostatic system in inflammatory bowel diseases:New players in gut inflammation

Inflammation and coagulation constantly influence each other and are constantly in balance.Emerging evidence supports this statement in acute inflammatory diseases,such as sepsis,but it also seems to be very important in chronic inflammatory settings,such as inflammatory bowel disease(IBD).Patients with Crohn's disease and ulcerative colitis have an increased risk of thromboembolic events,and several abnormalities concerning coagulation components occur in the endothelial cells of intestinal vessels,where most severe inflammatory abnormalities occur.The aims of this review are to update and classify the type of coagulation system abnormalities in IBD,and analyze the strict and delicate balance between coagulation and inflammation at the mucosal level.Recent studies on possible therapeutic applications arising from investigations on coagulation abnormalities associated with IBD pathogenesis will also be briefly presented and critically reviewed.

Cerebral sinus thrombosis in patients with inflammatory bowel disease: A case report

Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease of the gastrointestinal tract. The pathophysiology of IBD is probably the result of the complex interaction of genetic susceptibility and environmental influences. There is a well-known risk of thrombosis in patients with IBD. We present the case of a 53-year-old man with ulcerative colitis, who spontaneously developed intracranial sinus thrombosis that was treated with low molecular weight heparin. Literature was searched to assess the frequency and characteristics of cerebral sinus thrombosis in IBD and the role of certain etiopathological factors in such thrombotic patients.

Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease

AIM： To evaluate fecal calprotectin （FC） as a surrogate marker of treatment outcome of relapse of inflammatory bowel disease （IBD） and, to compare FC with fecal myeloperoxidase （MPO） and fecal eosinophil protein X （EPX）. METHODS： Thirty eight patients with IBD, comprising of 27 with ulcerative colitis （UC） and 11 with Crohn＇s disease （CD） were investigated before treatment （inclusion）, and after 4 and 8 wk of treatment. Treatment outcomes were evaluated by clinical features of disease activity and endoscopy in UC patients, and disease activity in CD patients. In addition, fecal samples were analyzed for FC by enzyme-linked immunosorbent assay （ELISA）, and for MPO and EPX with radioimmunoassay （RIA）. RESULTS： At inclusion 37 of 38 （97%） patients had elevated FC levels （〉 94.7 μg/g）. At the end of the study, 31 of 38 （82%） patients fulfilled predefined criteria of a complete response IUC 21/27 （78%）; CD 10/11 （91%）]. Overall, a normalised FC level at the end of the study predicted a complete response in 100% patients, whereas elevated FC level predicted incomplete response in 30%. Normalised MPO or EPX levels predicted a complete response in 100% and 90% of the patients, respectively. However, elevated MPO or EPX levels predicted incomplete response in 23% and 22%, respectively. CONCLUSION： A normalised FC level has the potential to be used as a surrogate marker for successful treatment outcome in IBD patients. However, patients with persistent elevation of FC levels need further evaluation. FC and MPO provide superior discrimination than EPX in IBD treatment outcome.

Hepatitis B virus prevalence and transmission risk factors in inflammatory bowel disease patients at Clementino Fraga Filho university hospital

AIM: To evaluate the prevalence of hepatitis B virus (HBV) infection in inflammatory bowel disease (IBD) patients that followed up in our hospital and try to identify the possible risk factors involved in this infection transmission. METHODS: This was a cross-sectional study for which 176 patients were selected according to their arrival for the medical interview. All these patients had already IBD diagnosis. The patient was interviewed and a questionnaire was filled out. RESULTS: In the group of 176 patients whom we examined, we found that 17% (30) were anti-HBc positive. Out of 30 patients with positive anti-HBc, 2.3% (4) had positive HBsAg and negative HBV-DNA. In an attempt to identify the possible HBV infection transmission risk factors in IBD patients, it was observed that 117 patients had been submitted to some kind of surgical procedure, but only 24 patients had positive anti-HBc (P = 0.085). It was also observed that surgery to treat IBD complications was not a risk factor for HBV infection transmission, since we did not get a statically significant P value. However, IBDpatients that have been submitted to surgery to treat IBD complications received more blood transfusions then patients submitted to other surgical interventions (P = 0.015). CONCLUSION: There was a high incidence of positive anti-HBc (17%) and positive HBsAg (2.3%) in IBD patient when compared with the overall population (7.9%).

Etiopathogenesis of inflammatory bowel diseases

Theories explaining the etiopathogenesis of inflammatory bowel disease （IBD） have been proposed ever since Crohn＇s disease （CD） and ulcerative colitis （UC） were recognized as the two major forms of the disease. Although the exact cause（s） and mechanisms of tissue damage in CD and UC have yet to be completely understood, enough progress has occurred to accept the following hypothesis as valid： IBD is an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. Among an almost endless list of environmental factors, smoking has been identified as a risk factor for CD and a protective factor for UC. Among microbial factors, no convincing evidence indicates that classical infectious agents cause IBD, while mounting evidence points to an abnormal immune response against the normal enteric flora as being of central importance. Gut inflammation is mediated by cells of the innate as well as adaptive immune systems, with the additional contribution of non-immune cells, such as epithelial, mesenchymal and endothelial cells, and platelets.

Role of ATG16L,NOD2 and IL23R in Crohn's disease pathogenesis

Inflammatory bowel disease is a group of diseases that includes Crohn＇s disease （CD） and ulcerative colitis. CD is characterized as a chronic inflammatory disease of the gastrointestinal tract, ranging from the mouth to the anus. Although there are gross pathological and histological similarities between CD and Johne＇s dis- ease of cattle, the cause of CD remains controversial. It is vital to understand fully the cause of this disease because it affects approximately 500 000 people in North America and Europe. It ranges from 27 to 48 cases per 100 000 people. There are many theories on the cause of CD ranging from possible association with environmental factors including microorganisms to imbalance in the intestinal normal flora of the pa- tients. Regardless of the environmental trigger, there is strong evidence that a genetic disposition is a major key in acquiring CD. Many studies have proven the link between mutations in the ATG16L, NOD2/CARD15, IBDS, CTLA4, TNFSF15 and IL23R genes, and CD. The purpose of this review is to examine all genetic aspects and theories of CD, including up to date multiple popu- lation studies performed worldwide.

Nutritional status and nutritional therapy in inflammatory bowel diseases

Underweight and specific nutrient deficiencies are frequent in adult patients with inflammatory bowel disease(IBD).In addition,a significant number of children with IBD,especially Crohn's disease(CD) have impaired linear growth.Nutrition has an important role in the management of IBD.In adults with CD,enteral nutrition(EN) is effective in inducing clinical remission of IBD,although it is less efficient than corticosteroids.Exclusive EN is an established primary therapy for pediatric CD.Limited data suggests that EN is as efficient as corticosteroids for induction of remission.Additional advantages of nutritional therapy are control of inflammation,mucosal healing,positive benefits to growth and overall nutritional status with minimal adverse effects.The available evidence suggests that supplementary EN may be effective also for maintenance of remission in CD.More studies are needed to confirm these findings.However,EN supplementation could be considered as an alternative or as an adjunct to maintenance drug therapy in CD.EN does not have a primary therapeutic role in ulcerative colitis.Specific compositions of enteral dietselemental diets or diets containing specific components-were not shown to have any advantage over standard polymeric diets and their place in the treatment of CD or UC need further evaluation.Recent theories suggest that diet may be implicated in the etiology of IBD,however there are no proven dietary approaches to reduce the risk of developing IBD.

Lansoprazole-associated collagenous colitis:Diffuse mucosal cloudiness mimicking ulcerative colitis

There have only been a few reports on lansoprazole-associated collagenous colitis. Colonic mucosa of collagenous colitis is known to be endoscopically normal. We present a case of collagenous colitis where the mucosa showed diffuse cloudiness mimicking ulcerative colitis. A 70-year-old woman developed watery diarrhea four to nine times a day. She had interstitial pneumonia at 67 and reflux esophagitis at 70 years. Lansoprazole 30 mg/d had been prescribed for reflux esophagitis for nearly 6 mo. Lansoprazole was withdrawn due to its possible side effect of diarrhea. Colonoscopy disclosed diffuse cloudiness of the mucosa which suggested ulcerative colitis. Consequently sulfasalazine 2 g/d was started. The patient's diarrhea dramatically disappeared on the following day. However, biopsy specimens showed subepithelial collagenous thickening and infi ltration of inflammatory cells in the lamina propria, confirming the diagnosis of collagenous colitis. One month after sulfasalazine therapy was initiated, colonoscopic and histological abnormalities resolved completely. Five months later the diarrhea recurred. The findings on colonoscopy and histology were the same as before, confirming a diagnosis of collagenous colitis relapse. We found that the patient had begun to take lansoprazole again 3 mo ahead of the recent diarrhea. Withdrawal of lansoprazole promptly resolved the diarrhea. Endoscopic and histological abnormalities were also completely resolved, similar to the first episode. Retrospectively, the date of commencement of sulfasalazine and discontinuation of lansoprazole in the first episode was found to be the same. We conclude that this patient had lansoprazole-associated collagenous colitis.

Persistence of gene expression changes in noninflamed and inflamed colonic mucosa in ulcerative colitis and their presence in colonic carcinoma

AIM： A few studies have applied genomic-wide gene expression analysis in inflamed colon tissue sample in ulcerative colitis （UC）. We reported the first study of non-inflamed mucosal gene expression in UC and explored its clinical implication. METHODS： Non-inflamed mucosa was obtained from 6 UC patients who received total colectomy. The gene expression of UC in noninflamed mucosa was monitored with a microarray. For a selected gene, RT-PCR was performed to verify array results and to further examine expression pattern in inflamed mucosa of UC, colorectal cancer tissue and normal mucosa using additional matched pairs. RESULTS： Two genes showing 2.5-fold decreased expression with significance set at in UC samples were borneo box a4 （HOXa4） and mads box transcription enhancer factor 2, polypeptide B （MEF2b）. RT-PCR showed that MEF2b expression in non-inflamed mucosa was significantly downregulated, whereas the expression of MEF2b increased in accordance with the severity of mucosal inflammation. HOXa4 expression both in inflamed and non-inflamed mucosa in UC was consistently downregulated, and the downregulation of HOXa4 was also found in colorectal carcinoma. CONCLUSION： It is suggested that the MEF2b expression in UC which increase in accordance with inflammation may be induced by the inflammatory mediator. In contrast the downregulation of HOXa4 may be partly involved in the pathogenesis of disease including UC and UC-related carcinogenesis.

Colorectal cancer and dysplasia in inflammatory bowel disease

Both ulcerative colitis and Crohn’s disease carry an increased risk of developing colorectal cancer. Established risk factors for cancer among patients with inflammatory bowel disease (IBD) include the younger age at diagnosis, greater extent and duration of disease, increased severity of inflammation, family history of colorectal cancer and coexisting primary sclerosing cholangitis. Recent evidence suggests that current medical therapies and surgical techniques for inflammatory bowel disease may be reducing the incidence of this complication. Nonetheless heightened vigilance and a careful, comprehensive approach to prevent or minimize the complications of invasive cancer are warranted in this unique cohort of patients. Current guidelines for the prevention and early detection of cancer in this high risk population are grounded in the concept of an inflammation-dysplasia- carcinoma sequence. A thorough understanding of the definition and natural history of dysplasia in IBD, as well as the challenges associated with detection and interpretation of dysplasia are fundamental to developing an effective strategy for surveillance and prevention, and understanding the limitations of the current approach to prevention. This article reviews the current consensus guidelines for screening and surveillance of cancer in IBD, as well as presenting the evidence and rationale for chemoprevention of cancer and a discussion of emerging technologies for the detection of dysplasia.

Severe chest pain in a pediatric ulcerative colitis patient after 5-aminosalicylic acid therapy

Severe reactions to mesalamine products are rarely seen in pediatric patients. We report a case of a 12-year-old boy who had a severe cardiac reaction to a mesalamine product Asacol. Past medical history is significant for ulcerative colitis (UC) diagnosed at 9 years of age. Colo- noscopy one week prior to admission revealed pancoli- tis. He was treated with Asacol 800 mg three times per day and prednisone 20 mg/d. He was subsequently ad- mitted to the hospital for an exacerbation of his UC and started on intravenous solumedrol. He had improvement of his abdominal pain and diarrhea. The patient com- plained of new onset of chest pain upon initiating Asacol therapy. Electrocardiogram (ECG) revealed non-specific ST-T wave changes with T-wave inversion in the lateral leads. Echocardiogram (ECHO) revealed low-normal to mildly depressed left ventricular systolic function. The left main coronary artery and left anterior descending artery were mildly prominent measuring 5 mm and 4.7 mm, respectively. His chest pain completely resolved within 24-36 h of discontinuing Asacol. A repeat echo- cardiogram performed two days later revealed normal left ventricular function with normal coronary arteries (< 3.5 mm). Onset of chest pain after Asacol and im- mediate improvement of chest pain, as well as improve- ment of echocardiogram and ECG findings after discon- tinuing Asacol suggests that our patient suffered from a rare drug-hypersensitivity reaction to Asacol.

Rifaximin in the treatment of inflammatory bowel disease

The gut microbiota plays a role in promoting and maintaining inflammation in inflammatory bowel diseases （IBD）, hence the rationale for the use of antibiotics in the treatment of those disorders. Antibiotics, however, may induce untoward effects, especially during longterm therapy. Rifaximin α polymer is an antibacterial agent that is virtually unabsorbed after oral administration and is devoid of systemic side effects. Rifaximin has provided promising results in inducing remission of Crohn＇s disease （up to 69% in open studies and significantly higher rates than placebo in double blind trials） and ulcerative colitis （76% in open studies and significantly higher rates than placebo in controlled studies） and might also have a role in maintaining remission of ulcerative colitis and pouchitis. The potential therapeutic activity of rifaximin in IBD deserves to be further investigated and confirmed in larger, controlled studies. The optimal dosage still needs to be better defined.