Hirschsprung’s disease

Opinion statement Hirschsprung’s disease (HSCR) is the most common congenital malformation of the enteric nervous system and requires early diagnosis and surgical repair for the best comprehensive outcome. The early diagnosis of this disorder permits the use of primary endorectal pull-through (PERPT), which is now the definitive surgical therapy for HSCR. PERPT has become the preferred method of treatment for HSCR, and large numbers of successfully treated patients have been described in the recent medical literature. The rate of postoperative complications is generally similar to that following a two-stage surgical repair, but PERPT patients may be at a slightly higher risk for Hirschsprung’s-associated enterocolitis. Despite recent surgical advances in the treatment of HSCR, a two-stage surgical repair involving a temporary diverting colostomy may still be necessary in up to one third of patients. Candidates for a staged repair include those HSCR patients with long-segment or total colonic disease or when there has been a delay in diagnosis that results in a markedly dilated proximal colon or patient clinical instability. Internal anal sphincter hypertonicity, occurring either as isolated primary anal achalasia or as a postoperative complication, can be successfully managed by either botulinum toxin injections or anal myectomy. The measurement of colonic motility in surgically repaired patients with a long-standing postoperative abnormality of bowel function can identify several distinct motility disorders that are amenable to separate and individualized therapies. The single most important element in the management of HSCR remains the clinical judgement of the surgeon of record, who utilizes all discernible clinical data to elect the manner of surgical repair in a given patient.     

Hirschsprung’s disease

Summary and Conclusions True Hirschsprung’s disease, occurring in the adult, is not reported frequently in medical literature. The patient presented herewith illustrates the essential features of Hirschsprung’s disease, namely, unrelenting constipation since birth, massive dilatation of the sigmoid flexure with a distal narrowed segment, and a rectal muscle biopsy showing no ganglion cells. Rectal muscle biopsy is conclusive in making the diagnosis of Hirschsprung’s disease. By microscopic examination of the muscle of the bowel wall, the extent of the disease in the colon can be determined. Active Staff. Resident Staff.     

The development of colon innervation in trisomy 16 mice and Hirschsprung’s disease

AIM To study the colon innervation of trisomy16 mouse, an animal model for Downssyndrome, and the expression of protein geneproduct 9.5 (PGP 9.5) in the stenosed segmentof colon in Hirschsprungs disease (HD).METHODS Trisomy 16 mouse breeding;cytogenetic analysis of trisomy 16 mice; andPGP 9.5 immunohistochemistry of colons oftrisomy 16 mice and HD were carried out.RESULTS Compared with their normallittermates, the nervous system of colon intrisomy 16 mice was abnormally developed.There existed developmental delay of muscularplexuses of colon, no submucosal plexus wasfound in the colon, and there was 5mmaganglionic bowel aparting from the anus intrisomy 16 mice. The mesentery nerve fiberswere as well developed as shown in their normallittermates. Abundant proliferation of PGP 9.5positive nerve fibers was revealed in thestenosed segment of HD colon.CONCLUSION Trisomy 16 mice could serve asan animal model for Hirschsprung s disease foraganglionic bowel in the distal part of colon.Abundant proliferation of PGP 9.5 positive fibersresulted from extrinsic nerve compensation,since no ganglionic cells were observed in thestenosed segment of the colon in HD. HD has agenetic tendency.     

Adolescents and young adults with Hirschsprung’s disease

A majority of children and adolescents who have successful surgery to resect colon affected by Hirschsprung’s disease suffer from digestive disorders, defecation problems, or both into adult life. In those with persistent symptoms following Hirschsprung’s surgery, colon manometry facilitates a physiologic explanation for symptoms and guides treatment. Only a few patients born with Hirschsprung’s disease make it to adult age before diagnosis and surgery, but their management does not differ from that of children with Hirschsprung’s disease. The quality of life for patients with Hirschsprung’s disease depends on psychosocial factors and not on childhood suffering or chronic symptoms.     

Mutation of RET gene in Chinese patients with Hirschsprung’s disease

AIM:To investigate the pathogenic mechanism of Hischsprung’s disease(HD)at the molecular level and to elucidate the relationship between RET oncogene and Chinese patients with HD.     

Prognostic significance of granulomas in children with Crohn’s disease

Objectives: Granulomas have long been considered the histological hallmark of Crohn's disease (CD). Currently, there is considerable dispute with regards to their prognostic implications. We aimed to determine the effect of granulomas on phenotypic features and disease's long-term outcomes in a large cohort of pediatric CD patients.

Materials and methods: Medical records of pediatric CD patients diagnosed at the Schneider Children’s Medical Center were reviewed retrospectively. Patients were categorized into two groups based on the presence or absence of granulomas at diagnosis. Baseline characteristics included anthropometric, clinical, laboratory, radiological and endoscopic data. Outcome measures included flares, hospitalizations, biological therapy and surgery.

Results: Of 289?CD patients diagnosed between 2001 and 2015, 99 patients (34%) had granulomas. Median age of the entire cohort at diagnosis was 14.2 years (females, 42.6%), with a median follow-up of 8.5 years. Patients with granulomas had a significantly higher percentage (47.5% vs. 23.7%, p?=?.001) of upper gastrointestinal involvement and ileo-colonic disease (64.9% vs. 49.5%, p?=?.01). Extraintestinal manifestations were twice as common in patients without granulomas (16.3% vs. 8.1%, p?=?.05). Patients with granulomas were more likely to be hospitalized (HR =1.43, 95% CI: 1.0–2.0) and to receive biologic therapy (HR?=?1.52, 95% CI: 1.1–2.11). Additionally, both of these disease outcomes occurred significantly earlier (p?=?.013 and p?=?.027, respectively). In contrast, patients with granulomas did not exhibit increased risk of flares or bowel resection.

Conclusion: Patients with granulomas exhibited a distinct phenotype at diagnosis and demonstrated a more severe disease course.     

Clinical significance of Angiopoietin-1 in Behcet’s disease patients with vascular involvement

Behcet’s disease (BD) is a chronic multisystem inflammatory disorder of unclear etiology. Vascular inflammation, endothelial dysfunction and angiogenesis may be in part responsible for the pathogenesis of BD. Angiopoietin-1 (Ang-1) is a recent angiogenic mediator. The aim of the present study was to assess Ang-1 in the plasma of BD patients as well as to analyze its association with clinical, and laboratory parameters of the disease. The present study included 47 BD patients and 30 age- and gender-matched healthy controls. Demographic, clinical, disease activity and severity were prospectively assessed. Plasma Ang-1 levels were measured using enzyme-linked immunosorbent assay. The plasma level of Ang-1 in BD patients was significantly lower than healthy controls (p = 0.005). Plasma Ang-1 level in patients with vascular affection was significantly lower than those without vascular affection (p = 0.045). Levels of Ang-1 showed a significant positive correlation with steroid dose. Patients who received cyclophosphamide or steroids showed a significant increase in plasma Ang-1 level. This was further confirmed by the results of the multivariate analysis. There was no significant association between plasma Ang-1 levels and other clinical manifestations or disease activity and severity. Plasma Ang-1 levels were diminished in our BD patients especially in patients with vascular involvement. Larger studies with further investigations of the precise role of Ang-1 in the pathogenesis of BD are needed and might lead to novel therapies for the clinical management of BD     

Chronological changes in the systemic manifestations of intestinal Behcet’s disease and their significance in diagnosis

Purpose

Intestinal Behçet's disease (BD) is challenging to diagnose, especially if the patient presents with typical colonoscopic findings of intestinal BD without systemic manifestations of BD. We performed this study to evaluate the systemic manifestations of BD in patients with typical colonoscopic findings of intestinal BD at the time of initial presentation and to identity the chronologic changes of these features during an extended follow-up period.

Methods

One hundred twenty-six consecutive patients who showed typical colonoscopic findings of intestinal BD at a single institution in Korea were enrolled. Clinical and endoscopic data were collected from a medical database and using a written questionnaire. Parameters including demographic characteristics and the subset type of BD at the initial and endpoints of the follow-up were analyzed.

Results

The mean follow-up period was 63.9?±?50.9 months. The number of cases that satisfied the International Study Group for Behçet’s Disease criteria at initial diagnosis, 19.0%, increased to 53.2% by the end of follow-up. When the Japanese criteria were used for classification, the proportion of complete and incomplete type BD increased (2.4% and 26.2% to 18.3% and 49.2%, respectively), while that of suspected and not-satisfied subtype BD decreased (22.2% and 49.2% to 19.0% and 13.5%, respectively) during the follow-up period.

Conclusions

Our data suggest that patients who lack the systemic manifestations of BD could be included in the category of intestinal BD when typical intestinal lesion is identified, indicating that close examination and early treatment should be considered in such patients.     

Mutation of RET proto-oncogene in Hirschsprung＇s disease and intestinal neuronal dysplasia

AIM:To investigate the genetic relationship betweenHirschsprung's disease(HD)and intestinal neuronaldysplasia(IND)in Chinese population.METHODS:Peripheral blood samples were obtainedfrom 30 HD patients,20 IND patients,18 HD/INDcombined patients and 20 normal individuals as control.Genomic DNA was extracted according to standardprocedure.Exons 11,13,15,17 of RET proto-oncogenewere amplified by polymerase chain reaction(PCR).The mutations of RET proto-oncogene were analyzedby single strand conformational polymorphism(SSCP)and sequencing of the positive amplified products wasperformed.RESULTS:Eight germline sequence variants were de-tected.In HD patients,2 missense mutations in exon 11at nucleotide 15165 G→A(G667S),2 frameshift muta-tions in exon 13 at nucleotide 18974(18974insG),1missense mutation in exon 13 at nucleotide 18919 A→G(K756E)and 1 silent mutation in exon 15 at nucleo-tide 20692 G→A(Q916Q)were detected.In HD/INDcombined patients,1 missense mutation in exon 11 atnucleotide 15165 G→A and 1 silent mutation in exon 13at nucleotide 18888 T→G(L745L)were detected.Nomutation was found in IND patients and controls.CONCLUSION:Mutation of RET proto-oncogene isinvolved in the etiopathogenesis of HD.The frequency ofRET proto-oncogene mutation is quite different betweenIND and HD in Chinese population.IND is a distinctclinical entity genetically different from HD.     

Palmitoylation in Crohn’s disease: Current status and future directions

S-palmitoylation is one of the most common post-translational modifications in nature; however, its importance has been overlooked for decades. Crohn’s disease (CD), a subtype of inflammatory bowel disease (IBD), is an autoimmune disease characterized by chronic inflammation involving the entire gastrointestinal tract. Bowel damage and subsequent disabilities caused by CD are a growing global health issue. Well-acknowledged risk factors for CD include genetic susceptibility, environmental factors, such as a westernized lifestyle, and altered gut microbiota. However, the pathophysiological mechanisms of this disorder are not yet comprehensively understood. With the rapidly increasing global prevalence of CD and the evident role of S-palmitoylation in CD, as recently reported, there is a need to investigate the relationship between CD and S-palmitoylation. In this review, we summarize the concept, detection, and function of S-palmitoylation as well as its potential effects on CD, and provide novel insights into the pathogenesis and treatment of CD.     

Amelioration of pathologic α-synuclein-induced Parkinson’s disease by irisin

Physical activity provides clinical benefit in Parkinson’s disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood–brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the α-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test. Recombinant sustained irisin treatment of primary cortical neurons attenuated α-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of α-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic α-syn by enhancing endolysosomal degradation of pathologic α-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by progressive worsening of motor symptoms, including bradykinesia, resting tremor, and rigidity (1, 2). Nonmotor symptoms often precede and accompany the motor symptoms and include autonomic dysfunction and neuropsychiatric sequelae (3). The most notable loss of neurons occurs in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), although neuronal loss also occurs in the locus coeruleus, dorsal raphe nucleus, the dorsal motor nucleus of the vagus, and nucleus basalis of Meynert (4). In addition to neuronal loss, there is accumulation of misfolded pathologic α-synuclein that drives the pathogenesis of PD, including the neuronal dysfunction and the ultimate of neuronal degeneration (5, 6). Current treatments for PD include the replacement of dopamine (DA) via L-DOPA, DA agonists, and other agents to treat the nonmotor symptoms. As the disease progresses, deep brain stimulation and other neurosurgical approaches can be used to treat the side effects of DA replacement therapy. Importantly, these treatments only address the symptomology, and over time there is a progressive decline in normal function. Moreover, there are no treatments that slow the progression or inhibit the underlying drivers of PD pathogenesis. As such, treatments that result in durable arrest of PD symptoms are urgently needed.Irisin is a small polypeptide that is secreted by skeletal muscle and other tissues into the blood of mice and humans (7, 8). The amino acid sequence is conserved 100% between mice and humans, suggesting a critical, conserved function. Importantly, the expression of irisin and its precursor protein FNDC5 is increased in muscle in response to many forms of exercise, both in rodents and in humans. Irisin levels increase in the blood of humans with exercise training, as determined by tandem mass spectrometry (8). In adipose cells, osteocytes, osteoclasts, and astrocytes integrin αV/β5 is the major functioning receptor for irisin (9, 10).Physical activity can prevent and ameliorate the symptoms of multiple forms of neurodegeneration, including Alzheimer’s disease (AD) and PD (11–14). Since irisin carries some of the benefits of exercise to adipose tissues, we and others have begun to study the effects of irisin in various models of neurodegeneration. In the earliest study, we showed that elevated expression of FNDC5 in the liver via the use of adenoviral vectors, and presumptive elevations of irisin in the blood, stimulated an “exercise-like” program of gene expression in the hippocampus (15). Moreover, the expression of FNDC5 with these same viral vectors rescued memory deficits in a mouse model of AD (16). Most recently, irisin itself was shown to be the active moiety regulating cognitive function in four separate mouse models. Importantly, elevation of the blood levels of the mature, cleaved irisin using adeno-associated virus (AAV) was sufficient to improve cognitive function and reduce neuroinflammation in two distinct models of AD (9). Furthermore, irisin itself crossed the blood–brain barrier (BBB), at least when the protein was produced from the liver with these AAV vectors.In the current study, we examine the effects of irisin on the pathophysiology of PD, using the α-synuclein preformed fibril (α-syn PFF) seeding model in vitro and in vivo. Pathologic α-syn is thought to spread “prion-like” in the brains of PD patients and certain other neurological disorders, where they cause neuronal death and dysfunction. We show here that irisin has powerful effects in preventing both the accumulation of pathologic α-syn and neuronal cell death in primary cell culture. Furthermore, elevation of blood irisin levels in mice normalizes the histological manifestations in the SNpc and the PD-like symptomology involving movement and grip strength induced by intrastriatal injection of α-syn PFF. Together, these data suggest the potential therapeutic value of irisin in PD and other neurodegenerative states that involve α-syn.     

Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson’s disease

Intraneuronal inclusions of misfolded α-synuclein (α-syn) and prion-like spread of the pathologic α-syn contribute to progressive neuronal death in Parkinson’s disease (PD). Despite the pathologic significance, no efficient therapeutic intervention targeting α-synucleinopathy has been developed. In this study, we provide evidence that astrocytes, especially those cultured from the ventral midbrain (VM), show therapeutic potential to alleviate α-syn pathology in multiple in vitro and in vivo α-synucleinopathic models. Regulation of neuronal α-syn proteostasis underlies the therapeutic function of astrocytes. Specifically, VM-derived astrocytes inhibited neuronal α-syn aggregation and transmission in a paracrine manner by correcting not only intraneuronal oxidative and mitochondrial stresses but also extracellular inflammatory environments, in which α-syn proteins are prone to pathologic misfolding. The astrocyte-derived paracrine factors also promoted disassembly of extracellular α-syn aggregates. In addition to the aggregated form of α-syn, VM astrocytes reduced total α-syn protein loads both by actively scavenging extracellular α-syn fibrils and by a paracrine stimulation of neuronal autophagic clearance of α-syn. Transplantation of VM astrocytes into the midbrain of PD model mice alleviated α-syn pathology and protected the midbrain dopamine neurons from neurodegeneration. We further showed that cografting of VM astrocytes could be exploited in stem cell–based therapy for PD, in which host-to-graft transmission of α-syn pathology remains a critical concern for long-term cell therapeutic effects.

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder with movement symptoms characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta of the midbrain with the concomitant loss of nigrostriatal DA neurotransmission. A pathologic hallmark of PD is intraneuronal inclusion of α-synuclein (α-syn) aggregates, called Lewy bodies and Lewy neurites. The α-syn aggregates cause various cellular dysfunctions including mitochondrial impairment, defective endoplasmic reticulum (ER) function, autolysosomal pathways, and synaptic and nuclear dysfunctions (1, 2). Aggregated α-syn is released from neuronal cells and acts as a ligand for patterned recognition receptors, which activate inflammatory responses in glial cells (3, 4). Furthermore, the pathologic protein aggregates undergo neuron-to-neuron transmission in a prion-like fashion (reviewed in ref. 5). The α-syn propagation and neuroinflammation are closely related to disease progression and clinical severity (6).Given its pathologic significance, the α-syn proteinopathy is a major research focus to develop disease-modifying therapies for PD and other synucleinopathic disorders such as Lewy body dementia, multiple system atrophy, and certain forms of Alzheimer’s disease. However, no therapeutic intervention to effectively eliminate the pathologic α-syn has been developed to date. In addition to the diseased conditions, the aggregated species of α-syn are also accumulated in the midbrain SN during normal aging, but not in young brain tissues (7), suggesting the existence of homeostatic regulation to prevent and resolve α-syn aggregation in young and healthy brains. This suggests homeostatic functions may be useful in developing therapeutic tools. In this regard, astrocytes are a prime cell type to be studied for therapeutic applications, as this glia cell type has multiple functions related to maintaining brain homeostasis, including those for correct functioning of neurons and protecting neuronal cells from pathologic insults (reviewed in ref. 8). Recent studies have shown the capacity of astrocytes to efficiently take up and degrade α-syn (9–12). Due to the astrocyte scavenging effect, α-syn inclusions are usually not detected in astrocytes of PD patients except in advanced stages of the disease (13–18). In addition, in contrast to efficient transmission of neuronal α-syn proteins into astrocytes, α-syn transfer from astrocytes to neuronal cells is inefficient (11), collectively suggesting a role for astrocytes in scavenging α-syn rather than in spreading it. The role of homeostatic astrocytes in α-syn pathology, however, remains to be unraveled.In this study, we showed that astrocytes, especially those cultured from the ventral midbrain (VM), the brain region primarily affected in PD, substantially alleviate neuronal α-syn pathology by regulating a series of the proteostasis procedures associated with formation, transmission, disaggregation, and clearance of toxic α-syn aggregates. Upon transplantation, VM-type astrocytes efficiently eliminated pathologic α-syn accumulation and α-syn–induced DA neuron degeneration in the midbrain of PD model mice. We further show that host-to-graft propagation of toxic α-syn, reported as a critical concern in the cell-based therapeutic approach for PD (19, 20), was greatly prevented by cografting the cultured astrocytes. Based on these findings, the therapeutic actions of astrocytes are proposed for use in relieving α-syn–mediated neuronal toxicity and in setting up a desirable cell-based therapy free from host-to-graft α-syn propagation in PD.     

Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington’s disease

Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington’s disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Here, by using a sensitive mtDNA-targeted sequencing method, we studied mtDNA heteroplasmies in lymphoblasts and longitudinal blood samples of HD patients. We found a significant increase in the fraction of mtDNA heteroplasmies with predicted pathogenicity in lymphoblasts from 1,549 HD patients relative to lymphoblasts from 182 healthy individuals. The increased fraction of pathogenic mtDNA heteroplasmies in HD lymphoblasts also correlated with advancing HD stages and worsened disease severity measured by HD motor function, cognitive function, and functional capacity. Of note, elongated CAG repeats in HTT promoted age-dependent expansion of pathogenic mtDNA heteroplasmies in HD lymphoblasts. We then confirmed in longitudinal blood samples of 169 HD patients that expansion of pathogenic mtDNA heteroplasmies was correlated with decline in functional capacity and exacerbation of HD motor and cognitive functions during a median follow-up of 6 y. The results of our study indicate accelerated decline of mtDNA quality in HD, and highlight monitoring mtDNA heteroplasmies longitudinally as a way to investigate the progressive decline of mitochondrial function in aging and age-related diseases.

Huntington’s disease (HD) is a monogenic disorder caused by the expansion of cytosine–adenine–guanine trinucleotide (CAG) repeats in the HTT gene at chromosome 4p16.3 (1). Although HTT is expressed in various tissues, the brain, particularly the striatum, is vulnerable to mutant huntingtin (mHTT)-associated toxicity (2). The average age at onset of the characteristic motor symptoms of HD is between 40 and 50 y old, followed by a progressive decline of motor, cognitive, and psychiatric functions for an average of 20 y prior to death (3).The biological processes that determine the onset and progression of HD are still elusive. Recent studies suggest that mitochondrial dysfunction may be involved in HD pathogenesis (4, 5). Mitochondria are subcellular organelles of eukaryotes, which play vital roles in maintaining energetic and metabolic homeostasis (6, 7). Evidence for mitochondrial dysfunction in HD was first reported in the postmortem brain of HD patients, which show low mitochondrial oxidative phosphorylation (OXPHOS) protein activity and energy deficits (8–10). Mitochondrial dysfunction was further found in peripheral tissues and cell lines of HD patients, such as blood, lymphoblasts, skeletal muscle, and skin fibroblasts (11–17).Several molecular mechanisms have been proposed to connect mHTT to mitochondrial dysfunction. Studies in HD knockin mice indicate that toxic fragments derived from mHTT can suppress mitochondrial biogenesis and energy metabolism (18). mHTT has also been found to physically interact with mitochondria, reducing mitochondrial membrane potential (13, 19). Furthermore, mHTT may stimulate mitochondrial network fragmentation (20–22), and it has recently been found to impair mitophagy (23–28), an evolutionarily conserved quality control system in eukaryotes to selectively remove dysfunctional mitochondria (29). Perturbation of mitochondrial tubular networks, morphology, and mitophagy are pathological features common to various neurodegenerative diseases (30, 31).Mitochondrial function is determined not only by the nuclear genome but also by the mitochondrial genome (mtDNA). Human mtDNA is a 16.6-kb circular DNA located within mitochondria. It encodes 13 evolutionarily conserved proteins in four of the five OXPHOS protein complexes (32). The accumulation of mtDNA mutations in somatic tissues has been suggested as a possible driver of age-related mitochondrial dysfunction (33). Transgenic mice with an increased level of mtDNA mutations manifest progeroid phenotypes and early neurodegeneration that resemble human aging (34, 35). Clonal expansion of preexisting mtDNA mutations in somatic tissues has also been shown to contribute to accelerated mitochondrial aging and OXPHOS defects in human diseases (36, 37).Because there are multiple copies of mtDNA in a single cell, mutations can arise and coexist with wild-type mtDNA in a state called heteroplasmy, which has been linked to a variety of mitochondrial disorders in humans (32, 38). Our previous study on lymphoblasts from the 1,000 Genomes project indicates that about 90% of individuals in the general population carry at least one heteroplasmy in mtDNA, and purifying selection keeps most pathogenic heteroplasmies at a low fraction (39). Thus, when such a selective constraint on mitochondria is weakened under certain conditions (40), such as the presence of mHTT (20–28), these low-fraction pathogenic heteroplasmies may increase in their fractions in cells, culminating in dysfunctional mitochondria and related energy deficits (32).In the current study, we hypothesized that HD progression is partially driven by the deterioration of mtDNA quality. Since HTT is universally expressed, and mitochondrial dysfunction has been repeatedly observed in peripheral tissues (11–16), we surmised that HD-associated mtDNA changes can be detected in peripheral tissues and cell lines of HD patients, such as blood-derived lymphoblasts, which are readily available in large patient cohorts and thus can provide increased power for identifying mtDNA changes in HD. To test this hypothesis, we employed a sensitive mtDNA targeted sequencing approach, STAMP (sequencing by targeted amplification of multiplex probes) (41), to assess mtDNA heteroplasmies in lymphoblast and longitudinal blood samples from HD patients and healthy control individuals in the European Huntington’s Disease Network’s REGISTRY study (hereafter referred to as REGISTRY) (42). We achieved ultradeep sequencing coverage on mtDNA in these samples and revealed an accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in HD, illustrating a molecular feature underlying HD biology.     

Coincidence of active Crohn’s disease and florid endometriosis in the terminal ileum: A case report

Crohn’s disease (CD), a variant of chronic inflammatory bowel disease, frequently affects the terminal ileum and coecal region. The clinical symptoms are often subtle and depend on the inflammatory activity of disease. In women of child-bearing age, florid intestinal endometriosis can simulate CD. Moreover, current pathophysiological concepts include intestinal endometriosis as a putative founder lesion for consecutive CD establishment. The report summarizes clinical and histomorphological data of a 35-year-old woman with the rare coincidence of florid intestinal endometriosis and CD both affecting the terminal ileum. The patient was suffering over 10 years from strong abdominal disorders including constipation, diarrhea, weight loss, and diffuse abdominal pain. In magnetic resonance imaging-Sellink, strong inflammation and intestinal obstruction of the terminal ileum were found. The laparoscopy revealed further evidence for existence of an inflammatory disease like CD, but brownish spots on the peritoneum were found indicative for endometriosis. Surgical resection of the terminal ileum and the coecal segment was performed followed by histopathological investigations. In transmural sections of the terminal ileum, histomorphological features of florid endometriosis intermingled with florid CD was found. The diagnostic findings were substantiated with a panel of immunohistological stainings. In conclusion, the findings demonstrate that florid endometriosis persists in florid CD lesions and the putative link between intestinal endometriosis and CD is more complex than previously assumed.     

Exploring the relationship between novel Coronavirus pneumonia and Parkinson’s disease

The hypothesis is that there is 0a relationship between Parkinson’s disease and coronavirus disease 2019 (COVID-19). By summarizing the pathogenesis of Parkinson’s disease and COVID-19 and the impact of COVID-19 on the central nervous system, the relationship between Parkinson’s disease and COVID-19 was analyzed, including whether Parkinson’s disease is a predisposition factor for COVID-19 and whether COVID-19 causes the occurrence of Parkinson’s disease. Discuss the impact of COVID-19 on patients with Parkinson’s disease, including symptoms and life impact. To summarize the principles, goals and methods of home rehabilitation for Parkinson’s disease patients during COVID-19. Through the analysis of this paper, it is believed that COVID-19 may cause Parkinson’s disease. Parkinson’s disease has the condition of susceptibility to COVID-19, but this conclusion is still controversial.     

Rifaximin and Crohn’s disease

In a recent article,Longman and Swaminath analyzed our paper on the use of rifaximin in patients with moderately active Crohn’s disease(CD).Here we report some considerations concerning their article.The exploratory post-hoc subgroup analysis showed that early-stage disease and,differently from that written by Longman and Swaminath,also colonic involvement seemed to be associated with a significant higher efficacy of rifaximin-EIR 800 mg twice daily.Early-stage disease is generally considered as the more easily treatable phase of CD,and the better response to rifaximin in Crohn’s colitis is in accordance with the high concentration of bacteria in the colon.In addition,patients with C reactive protein level>5 mg/L achieved remission more significantly than patients with normal values,thus suggesting that the symptoms were probably caused by inflammation instead of by non-inflammatory causes.We also analyze the role of rifaximin against gut bacteria and the clinical situations that could obtain the best results from antibiotics.