Combination treatment of inflammatory bowel disease:Present status and future perspectives

The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to say that in these patients,not only the scientific background of the gastroenterologist is tested,but also the abundance of“gifts”that he should possess(insight,intuition,determ-ination,ability to take initiative,etc.)for the successful outcome of the treatment.In daily clinical practice,depending on the severity of the attack,IBD is treated with one or a combination of two or more pharmaceutical agents.These combin-ations include not only the first-line drugs(e.g.,mesalazine,corticosteroids,antibiotics,etc)but also second-and third-line drugs(immunosuppressants and biologic agents).It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied.Therefore,a part of these patients are going to surgery.In recent years,several small-size clinical studies,reviews,and case reports have been published combining not only biological agents with other drugs(e.g.,immunosuppressants or corticosteroids)but also the combination of two biologi-cal agents simultaneously,especially in severe cases.In our opinion,it is at least a strange(and largely unexplained)fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few.As mentioned above,there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations.The appropriate dosage,the duration of the administration,the suitable timing for checking the clinical and laboratory outcome,as well as the treatment side-effects,should be the subject of intense clinical research shortly.In this editorial,we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients.We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.

A review of the neurotransmitter system associated with cognitive function of the cerebellum in Parkinson's disease

The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent but partially overlap.The dopaminergic system acts on the anterior brain and is responsible for executive function,working memory,and planning.In contrast,the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function.Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson’s disease.Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections.However,whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated.Furthermore,the precise role of the cerebellum in patients with Parkinson’s disease and cognitive impairment remains unclear.Therefore,in this review,we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition,as reported by previous studies,and investigated the role of the cerebellum in patients with Parkinson’s disease and cognitive impairment,as determined by functional neuroimaging.Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson’s disease.

Navigating Long-Term Management Challenges in Short Bowel Syndrome: A Case Report of Chronic Intestinal Failure Complicated by Kidney Dysfunction

The most common cause of intestinal failure is short bowel syndrome (SBS), occurring as a result of a small functional intestine length, usually less than 200 cm, leading to intestinal malabsorption. A 59-year-old female with a past medical history of Crohns disease status post total colectomy with ileostomy over 20 years ago came to the hospital due to progressive weakness. Despite medical management, the patient had high ileostomy output, leading to electrolyte disbalance, metabolic acidosis, dehydration, and progressive kidney decline. Due to the high dependence on continuous fluid supplementation, it was decided to place a port for parenteral hydration to maintain fluid replacements and homeostasis after discharge. Prompt initiation of parenteral fluid replacement and close follow-up on patients with ileostomy and intestinal failure is strongly recommended to avoid complications and prevent intestinal, liver, or kidney transplants.

Persistent Xerophthalmia in a Patient with Rheumatological Disease and Priiviary Sjogren’s Syndrome: Case Report from Northern Brazil

This case study aims to contribute to the literature in order to highlight the importance of this collaboration between medical specialties. A female patient R.N.N. F, age 66, from the city of Manaus, with a previous diagnosis of Sjogren’s syndrome in regular follow-up by the Rheumatology team at the Araujo Lima outpatient clinic and referred to the Ophthalmology sector for complementary evaluation related to visual discomfort. The fundoscopy performed in the patient was within normal limits, but the symptoms experienced by her proved to be an important clinical finding, which has ratified the need for regular and multidisciplinary follow-up. This report unequivocally demonstrates that even in the face of tests considered within the expected limits for a given population, the clinical presentation can be specific and particular for each analyzed individual. Early screening exams should contemplate the patient in a holistic and individualized way whenever possible.

Realizing the potential of exploiting human IPSCs and their derivatives in research of Down syndrome

Down syndrome(DS)is a genetic condition characterized by intellectual disability,delayed brain development,and early onset Alzheimer’s disease.The use of primary neural cells and tissues is important for understanding this disease,but there are ethical and practical issues,including availability from patients and experimental manipulability.Moreover,there are significant genetic and physiological differences between animal models and humans,which limits the translation of the findings in animal studies to humans.Advancements in induced pluripotent stem cells(iPSC)technology have revolutionized DS research by providing a valuable tool for studying the cellular and molecular pathologies associated with DS.Induced pluripotent stem cells derived from cells obtained from DS patients contain the patient’s entire genome including trisomy 21.Trisomic iPSCs as well as their derived cells or organoids can be useful for disease modeling,investigating the molecular mechanisms,and developing potential strategies for treating or alleviating DS.In this review,we focus on the use of iPSCs and their derivatives obtained from DS individuals and healthy humans for DS research.We summarize the findings from the past decade of DS studies using iPSCs and their derivatives.We also discuss studies using iPSC technology to investigate DS-associated genes(e.g.,APP,OLIG1,OLIG2,RUNX1,and DYRK1A)and abnormal phenotypes(e.g.,dysregulated mitochondria and leukemia risk).Lastly,we review the different strategies for mitigating the limitations of iPSCs and their derivatives,for alleviating the phenotypes,and for developing therapies.

Immune checkpoint inhibitor therapy-induced autoimmune polyendocrine syndrome typeⅡand Crohn's disease:A case report

BACKGROUND The development of immune checkpoint inhibitors(ICIs)has heralded a new era in cancer treatment,enabling the possibility of long-term survival in patients with metastatic disease.Unfortunately,ICIs are increasingly implicated in the development of autoimmune diseases.CASE SUMMARY We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab,docetaxel,and cisplatin therapy who developed autoimmune polyendocrine syndrome typeⅡ(APS-2)including thyroiditis and type 1 diabetes mellitus and Crohn’s disease(CD).He developed thirst,abdominal pain,and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab.Biochemistry confirmed APS-2 and thyrotoxicosis.He was commenced on an insulin infusion.However,his abdominal pain persisted.Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine.He was continued on insulin and mesalazine therapy.CONCLUSION Immunotherapy can affect all kinds of organs.When clinical symptoms cannot be explained by a single disease,clinicians should consider the possibility of multisystem damage.

Research Survey of Animal Model of Hepatic Fibro-sis Integrated with Western Medicine Diseases and Traditional Chinese Medicine^TCM~)Syndrome

Although the animal models of hepatic fibrosis developed by former researchers have pathological changes of hepatic fibrosis, they do not include charac- teristics of important TCM syndromes such as stagnation of qi, deficiency of qi, liver depression, phlegm-dampness and blood stasis because of single-factor model- ing. Animal models of hepatic fibrosis and animal models integrated disease and syndrome were reviewed, and several new types of integrated disease and syndrome animal models constructed by multiple-factor modeling method were evaluated, under the guidance of etiological theory of TCM. This kind of hepatic fibrosis model animals has dual characteristics of disease and syndrome. It is consistent with pathological characteristics of hepatic fibrosis in western medicine when replicating the basic characteristics accorded with TCM syndrome. Thus, the pathogenesis and pathogenic process of clinical disease and syndrome formation is simulated more ac- curately, providing a new platform and pathway for studying hepatic fibrosis disease with integrated traditional Chinese and western medicine.

Screening for celiac disease in Down's syndrome patients revealed cases of subtotal villous atrophy without typical for celiac disease HLA-DQ and tissue transglutaminase antibodies

A1M： To investigate the prevalence of celiac disease （CD） as well as CD marker antibodies and susceptibility HLA-DQ haplotypes in 134 karyotyped Down＇s syndrome （DS） patients. METHODS： Immunoglobulin A （IgA） and G （IgG） type anti-gliadin antibodies （AGA）, IgA type anti-tissue transglutaminase （tTG） antibodies （anti-tTG） with antigen of guinea pig and human source were determined by enzyme-linked immunosorbent assay and endomysium antibodies （EHA） by indirect immunofiuoresence test. HLA-DQA1＊0501/DQB1＊0201 （DQ2） was revealed by polymerase chain reaction. Celiac disease was diagnosed by revised ESPGHAN criteria. RESULTS： 41% of DS patients had AGA, 6.0% IgA anti-tTG with guinea pig antigen, and 3.0 % [gA EMA （all positive for anti-tTG with human tTG）. Subtotal villous atrophy was found in 5 out of 9 DS patients who had agreed to small bowel biopsy. One of them had DQA1＊0S01/DQB1＊0201 and anti-tTG and EMA i.e. typical for CD markers （this case also fulfilled the ESPGHAN diagnostic criteria）, but other four lacked these markers. Three non-biopsied DS patients had also most probably CD because DQA1＊0S01/DQB1＊0201 and IgA anti-tTG （EMA） were detected. Thus, the prevalence of CD among our DS patients population is 3.0 % （95 % of confidence interval [CI]： 0.1-5.9 %）. CONCLUSION： We confirm the increased frequency of CD among DS patients. In addition, we have revealed a subgroup of patients with subtotal villous atrophy but without characteristic for CD immunological and genetic markers. Whether these cases represent CD （with atypical immunopathogenesis） or some other immune enteropathy, requires further investigations.

Resolution of Crohn's disease and complex regional pain syndrome following treatment of paratuberculosis

A cohort of family members with various chronic diseases including Crohn's disease, asthma, complex regional pain syndrome, hypothyroidism, type 1 diabetes mellitus, and lymphangiomatosis and/or evidence of infection by Mycobacterium avium subsp. paratuberculosis(MAP) are described in this series of case reports. MAP was cultured from the blood of three members affected by the first five diseases and there was accompanying elevated anti-MAP Ig G in two members. The patient affected by the sixth disease has a markedly elevated anti-MAP titer. The two patients affected by the first four diseases have been treated with a combination of anti-MAP antibiotics and ultraviolet blood irradiation therapy with resolution of the disease symptomatology and inability to culture MAP in post treatment blood samples. These case reports of patients with MAP infections provide supportive evidence of a pathogenic role of MAP in humans.

A case of Noonan syndrome and Whipple's disease in the same patient

We report the first known case of both Noonan syndrome and Whipple's disease occurring in the same patient.A 36-year-old female with history of Noonan syndrome developed fatigue,anorexia,arthritis of the knees and hands with a diffuse hyperpigmented rash,night sweats,and an unintentional fifteen pound weight loss over 4 mo.Small bowel enteroscopy demonstrated mild edematous yellowish mucosa without friability.Random small bowel biopsies revealed extensive periodic acid-Schiff positive material within the foamy macrophages.She was treated with a 12 mo course of trimethoprim-sulfamethoxazole DS with clinical improvement to baseline status.

Emerging role of dual biologic therapy for the treatment of inflammatory bowel disease

Biologic agents have now been used in the management of inflammatory bowel disease(IBD)for many years where experience,expertise and confidence in their use has developed over time.In the United Kingdom,there are well established guidelines and recommendations for both single agent biologic treatments,and with combination therapy of a biologic agent with a small molecule agent in maintenance therapy.In recent times,there has been increasing interest and experience using dual biologic therapy(DBT)in IBD,primarily in difficult to treat and refractory cases with high disease burden.However,published data on use,experience and safety profiles is limited and large-scale studies remain low in number in this developing area.We therefore aim to present a summary and review of the available published data in this area to help us better understand the emerging role of DBT in IBD.

Effect of cerebralcare granule®combined with donepezil on Alzheimer’s disease

Background:The current prevalence of Alzheimer’s disease(AD)in the elderly has risen from 1%at 65 to 40%to 50%at 95,and the overall proportion is rising.Emerging evidence suggests that ros-driven oxidative stress is a crucial mediator of the aging process.Thus,in recent years,oxidative damage and inflammation have become targets for exploring pharmacological strategies for treating age-related diseases.Methods:In C57BL/6J mice,to determine whether the mechanism of action of cerebralcare granule®(CG)combined with donepezil(Don)treatment is better than dementia alone,we constructed a mouse model and treated it with CG in combination with Don.Results:A combination of Don and CG significantly reduces the damage caused by lipid peroxidation in the hippocampus of AD mice,reduces oxidative damage,and reduces inflammation,increases the activity of antioxidant enzymes,which is finally manifested as the improvement effect on the learning and memory impairment of AD mice.Conclusion:CG combined with Don has a better effect on improving cognitive and behavioral deficits caused by D-galactose in AD mice than Don alone.The mechanism may be related to reducing inflammation via the NF-κB pathway,resisting oxidative damage and increasing acetylcholine levels.

Pathogenesis of hepatic steatosis:The link between hypercortisolism and non-alcoholic fatty liver disease

Based on the available literature,non alcoholic fatty liver disease or generally speaking,hepatic steatosis,is more frequent among people with diabetes and obesity,and is almost universally present amongst morbidly obese diabetic patients.Non alcoholic fatty liver disease is being increasingly recognized as a common liver condition in the developed world,with non alcoholic steatohepatitis projected to be the leading cause of liver transplantation.Previous data report that only 20%of patients with Cushing’s syndrome have hepatic steatosis.Aiming at clarifying the reasons whereby patients suffering from Cushing’s syndrome-a condition characterized by profound metabolic changes-present low prevalence of hepatic steatosis,the Authors reviewed the current concepts on the link between hypercortisolism and obesity/metabolic syndrome.They hypothesize that this low prevalence of fat accumulation in the liver of patients with Cushing’s syndrome could result from the inhibition of the so-called low-grade chronicinflammation,mainly mediated by Interleukin 6,due to an excess of cortisol,a hormone characterized by an anti-inflammatory effect.The Cushing’s syndrome,speculatively considered as an in vivo model of the hepatic steatosis,could also help clarify the mechanisms of non alcoholic fatty liver disease.

Co-existence of non-alcoholic fatty liver disease and inflammatory bowel disease: a review article

Emerging data have highlighted the co-existence of nonalcoholic fatty liver disease(NAFLD) and inflammatory bowel disease; both of which are increasingly prevalent disorders with significant complications and impact on future health burden. Cross-section observational studies have shown widely variable prevalence rates of co-existing disease,largely due to differences in disease definition and diagnostic tools utilised in the studies. Age,obesity,insulin resistance and other metabolic conditions are common risks factors in observational studies. However,other studies have also suggested a more dominant role of inflammatory bowel disease related factors such as disease activity,duration,steroid use and prior surgical intervention,in the development of NAFLD. This suggests a potentially more complex pathogenesis and relationship between the two diseases which may be contributed by factors including altered intestinal permeability,gut dysbiosis and chronic inflammatory response. Commonly used immunomodulation agents pose potential hepatic toxicity,however no definitive evidence exist linking them to the development of hepatic steatosis,nor are there any data on the impact of therapy and prognosis in patient with co-existent diseases. Further studies are required to assess the impact and establish appropriate screening and management strategies in order to allow early identification,intervention and improve patient outcomes.

Diagnosis and management of functional symptoms in inflammatory bowel disease in remission

Inflammatory bowel disease(IBD) patients in remission may suffer from gastrointestinal symptoms that resemble irritable bowel syndrome(IBS). Knowledge on this issue has increased considerably in the last decade, and it is our intention to review and summarize it in the present work. We describe a problematic that comprises physiopathological uncertainties, diagnostic difficulties, as IBS-like symptoms are very similar to those produced by an inflammatory flare, and the necessity of appropriate management of these patients, who, although in remission, have impaired quality of life. Ultimately, from almost a philosophical point of view, the presence of IBS-like symptoms in IBD patients in remission supposes a challenge to the traditional functional-organic dichotomy, suggesting the need for a change of paradigm.

Large-vessel thrombosis in intestinal Behet's disease complicated with myelodysplastic syndrome and trisomy 8

Behet's disease is characterized by recurrent oral ulcers, genital ulcers, uveitis and skin lesions. Myelodysplastic syndrome (MDS) is characterized by problems due to ineffective hematopoiesis. Several studies have identified a relationship between MDS and Behet's disease, especially intestinal Behet's disease. Trisomy 8 seems to play an important role in these disorders as well. The present case was a 24-year-old woman who had a huge tonsil ulcer with initial symptoms of odynophagia and intermittent fever. We also noted folliculitis on her upper back. Five days later, she began to experience diarrhea and abdominal pain. Abdominal computed tomography and subsequent surgery revealed ileum perforation and enterocolitis with multiple ulcers. Later, she was admitted again for a vulvar suppurative ulcer and suspicious Bartholin's cyst infection. The patient's clinical presentations met the criteria for Behet's disease. Six months after the bowel perforation event, we noted the development of pancytopenia in a routine laboratory examination. All the examinations led to the diagnosis of MDS with trisomy 8. The most unusual finding was that multiple large vessel thrombi developed during follow-up. Previous studies have suggested that trisomy 8 in MDS leads to concurrent intestinal Behet's disease. Moreover, the inflammatory and immune genes related to thrombus formation are overexpressed in cases of MDS with trisomy 8. Trisomy 8 must play a role in thrombosis. Further studies are needed to help clarify the pathophysiology and pathogenesis of these disorders.

Association between orofacial granulomatosis and Crohn's disease in children:Systematic review

AIM: To review pediatric cases of orofacial granulomatosis (OFG), report disease characteristics, and explore the association between OFG and Crohn’s disease.

Bone cement implantation syndrome during hip replacement in a patient with pemphigus and Parkinson’s disease: A case report

BACKGROUND Bone cement implantation syndrome(BCIS)is characterized by hypotension,arrhythmia,diffuse pulmonary microvascular embolism,shock,cardiac arrest,any combination of these factors,or even death following bone cement implantation.CASE SUMMARY An 80-year-old patient with pemphigus and Parkinson’s disease underwent total hip replacement under spinal subarachnoid block and developed acute pulmonary embolism after bone cement implantation.The patient received mask mechanical ventilation with a continuous intravenous infusion of adrenaline(2μg/mL)at a rate of 30 mL/h.Subsequently,the symptoms of BCIS were markedly alleviated,and the infusion rate of adrenaline was gradually reduced until the infusion was completely stopped 45 min later.The patient was then transferred to the Department of Orthopedics,and anticoagulation therapy began at 12 h postoperatively.No other complications were observed.CONCLUSION This is a rare case of BCIS in a high-risk patient with pemphigus and Parkinson’s disease.

Pseudothrombus deposition accompanied with minimal change nephrotic syndrome and chronic kidney disease in a patient with Waldenstrom’s macroglobulinemia: A case report

BACKGROUND Waldenstr?m’s macroglobulinemia(WM) is a rare lymphoid neoplasia, which can have renal complications. These rarely occur, and most common renal manifestations are mild proteinuria and microscopic hematuria. Herein we describe a case of WM that presented with pseudothrombi depositing in capillaries associated with minimal change nephrotic syndrome and chronic kidney disease(CKD).CASE SUMMARY A 52-year-old man presented with features suggesting nephrotic syndrome.Extensive workups were done, and there were elevated serum levels of interleukin-6 and vascular endothelial growth factor(VEGF), capillary pseudothrombus accumulation associated with minimal change nephrotic syndrome, CKD, and WM. Treatment was directed at the patient’s WM with bortezomib, thalidomide, and dexamethasone whereby serum immunoglobulin M(IgM) decreased. The damage of IgM on the kidney was corrected; thus, the patient’s proteinuria and serum creatinine had improved. The patient is still under clinical follow-up.CONCLUSION It is essential for clinicians to promptly pay more attention to patients presenting with features of nephrotic syndrome and do extensive workups to come up with a proper therapy strategy.

Diagnostic and surgical challenges of progressive neck and upper back painless masses in Madelung’s disease: A case report and review of literature

BACKGROUND Madelung’s disease(MD)is a chronic alcoholism-associated metabolic syndrome characterized by symmetrical subcutaneous deposition of adipose tissue in the head,neck,shoulders,back,trunk,and nerve roots of the upper and lower limbs.It is relatively rare in Asian individuals and is prone to misdiagnosis.Herein,we report a case of a patient with MD who had undergone surgical management at our hospital,and we discuss the pathogenesis,diagnosis,and treatment of MD.CASE SUMMARY We report a case of MD in a 65-year-old man of Han descent.The patient had multiple,painless progressive masses for more than five years in the neck and more than 30 years in the upper back.Because of neck mobility limitations and progressive cosmetic deformities caused by the masses,he was admitted to our hospital.He drank approximately 500 mL of liquor per day and smoked heavily for more than 30 years.Contrast-enhanced computed tomography of the neck and chest documented abundant unencapsulated,subcutaneous fatty deposits.We prepared a staged operation plan.The patient was diagnosed with MD;he was advised to abstain from alcohol and was followed up regularly.After a 3-month follow-up,no recurrence of fat accumulation was found in the surgical areas.CONCLUSION This report presents a case of surgical treatment for MD to improve clinicians'understanding of the disease.