Bacteriophage Prevents Alcoholic Liver Disease

<正>Alcoholic hepatitis is a severe alcohol-associated liver disease with minimal treatment options. A recent study by Duan et al. uncovers that the exotoxin-secreting gut bacterium Enterococcus faecalis is a critical contributor to alcoholic hepatitis. This bacterium can now be eliminated with a bacteriophage, suggesting a new way to treat this life-threatening disease.     

Coronary Heart Disease in Moyamoya Disease: Are They Concomitant or Coincidence?

The purpose of this study was to determine the prevalence and characteristics of symptomatic coronary heart disease (CHD) in patients with moyamoya disease (MMD). This retrospective study evaluated 456 patients who received examination for MMD between 1995 and 2012. We reviewed the patients'' medical history and coronary imaging, including conventional coronary angiography and coronary computed tomography angiogram (CTA). Among 456 patients with MMD, 21 (4.6%) patients were found to have symptomatic CHD. Ten patients were treated with coronary artery bypass graft or percutaneous coronary intervention for unstable angina or myocardial infarction. Eleven were treated with medication for stable angina (n = 6) and variant angina with mild degree of stenosis (n = 5).The median age of these patients was 44 yr (range, 27-59). The median Framingham score at diagnosing MMD was < 1% (range, < 1%-16%). The old age was associated with CHD in uni- and multivariate analyses (P = 0.021, OR, 1.053; 95% CI, 1.008-1.110). Considering low age of onset and low stroke risk factor, CHD might be a systemic manifestation that is clinically relevant to MMD.

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Kienbock's Disease的诊疗体会

Kienbock's病,即通常说的月骨缺血性坏死,是一种罕见的,在急诊室内很难被诊断出来的腕关节疼痛性疾病.漏诊、误诊或延误诊断,常常导致病情的进展,最终导致外科手术选择的减少.本文我们通过详细介绍1例罕见病例的病史,鉴别诊断,影像学检查和患者管理,向分诊护士和急诊室外科医生展示对该疾病诊断的重要性.     

Anorectal Crohn’s Disease

In some patients with Crohn's disease the anorectal complications are the major cause of symptoms and morbidity. Anorectal Crohn's disease may be present in patients with intestinal Crohn's disease, may be the initial manifestation of the disease, or rarely occurs without involvement of Crohn's disease elsewhere in the intestinal tract. The pathogenesis of these anorectal complications remains to be clarified. The anorectal examination is very important in the assessment of patients with suspected or documented inflammatory bowel disease. Meticulous physical examination, examination under anaesthesia and radiological imaging modalities may be utilised to specifically identify the location of abscesses and fistulae. Treatment strategy should be directed toward symptomatic relief; the most important symptom is pain. In most patients this pain will be attributable to an incompletely drained rectal abscess. Simple incision and drainage procedures are often all that is required as initial treatment of anorectal abscesses. Treatment of the anorectal fistulae that occur secondary to Crohn's disease requires combined medical and surgical therapy. Drug therapy is more often initiated for Crohn's disease that involves other areas of the gastrointestinal tract. The anorectal manifestations often respond to these same medications. Lay-open procedures (fistulotomies) are often all that is required surgically for simple (low) anorectal fistulae. High (complex) fistulae that involve large portions of the anorectal muscular ring are more difficult to treat. Patients with these fistulae must be treated on an individual basis, usually local surgical therapy combined with a medical regimen. Many surgical procedures are performed and many classes of medications are utilised on patients with these complex anorectal fistulae. Choosing the appropriate surgical and medical interventions is often quite difficult. Although sulfasalazine, mesalazine and corticosteroids have no lasting or maintenance value for fistulae, the immunosuppressive agents mercaptopurine, azathioprine and cyclosporin, the antibacterial metronidazole and the anti-tumour necrosis factor-alpha monoclonal antibody infliximab have varying degrees of effect. The goal of the combined regimen is to cure the fistula, or at least make it minimally symptomatic, without altering the patient's continence.     

Diabetes, Renal and Cardiovascular Disease in p47 phox−/− Chronic Granulomatous Disease

Chronic granulomatous disease is a rare immunodeficiency due to defects in the phagocyte NADPH oxidase. The X-linked form (gp91 ^phox deficiency) accounts for about 70 % of cases; autosomal recessive p47 ^phox deficiency accounts for about 25 % of cases. We identified a 10 % incidence of diabetes in p47 ^phox deficient CGD, but none in X-linked CGD. Renal and cardiovascular diseases were also higher in p47 ^phox deficiency. p47 ^phox deficient CGD has non-infectious morbidities distinct from those in X-linked CGD.     

Is Cancer a Metabolic Disease?

Although cancer has historically been viewed as a disorder of proliferation, recent evidence has suggested that it should also be considered a metabolic disease. Growing tumors rewire their metabolic programs to meet and even exceed the bioenergetic and biosynthetic demands of continuous cell growth. The metabolic profile observed in cancer cells often includes increased consumption of glucose and glutamine, increased glycolysis, changes in the use of metabolic enzyme isoforms, and increased secretion of lactate. Oncogenes and tumor suppressors have been discovered to have roles in cancer-associated changes in metabolism as well. The metabolic profile of tumor cells has been suggested to reflect the rapid proliferative rate. Cancer-associated metabolic changes may also reveal the importance of protection against reactive oxygen species or a role for secreted lactate in the tumor microenvironment. This article reviews recent research in the field of cancer metabolism, raising the following questions: Why do cancer cells shift their metabolism in this way? Are the changes in metabolism in cancer cells a consequence of the changes in proliferation or a driver of cancer progression? Can cancer metabolism be targeted to benefit patients?CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.     

Adalimumab in Crohn’s Disease

Adalimumab is a subcutaneously administered, recombinant, human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). The clinical efficacy and safety of adalimumab in patients with moderate to severe Crohn's disease has been demonstrated in four pivotal, randomized, double-blind trials (CLASSIC-I, GAIN, CHARM, and CLASSIC-II) that included a total of >1400 patients. In the CLASSIC-I trial, adalimumab was significantly more effective than placebo for induction of remission in patients who had not previously received anti-TNF therapy. Adalimumab was also more effective than placebo for induction of remission in the GAIN study in patients who had either lost responsiveness or developed intolerance to infliximab. The CHARM trial showed that, among patients who responded to open-label adalimumab induction, maintenance therapy with adalimumab 40 mg weekly or every other week for up to 1 year was associated with significantly greater remission rates than placebo at weeks 26 and 56. In addition, significantly more adalimumab than placebo recipients achieved corticosteroid-free remission and had complete fistula closure. In CLASSIC-II, an extension of the CLASSIC-I trial, patients who were in remission after a short course of adalimumab and were randomized to receive up to 1 year's treatment with adalimumab 40 mg weekly or every other week were significantly more likely to remain in remission than those randomized to receive placebo. In general, the tolerability profile of adalimumab in patients with Crohn's disease was similar to that in patients with rheumatoid arthritis or other approved indications.     

Critical Role of Truncated α-Synuclein and Aggregates in Parkinson's Disease and Incidental Lewy Body Disease

The role of Lewy bodies, Lewy neurites and α-synuclein (αSYN) in the pathophysiology and diagnosis of Parkinson's disease (PD) is unclear. We used postmortem human tissue, a panel of antibodies (Abs) and confocal microscopy to examine the three-dimensional neurochemical anatomy of the nigrostriatal system. Abs were specific to truncated (tαSYN), phosphorylated and full-length αSYN. The findings demonstrate the critical role of tαSYN in initiating aggregation, a role for other forms of αSYN in aggregate expansion, a reason for the wide variety of proteins present in different aggregates, an explanation for the laminar appearance of aggregates described historically using different methods, the existence of proximal greater than distal aggregation in the vulnerable nigrostriatal pathway, the independent transport of different forms of αSYN as cargo along axons and a possible sequence for the formation of Lewy bodies. Findings differed between incidental Lewy body disease and PD only quantitatively. These findings have implications for understanding the pathogenesis and treatment of PD.     

Memantine : “Hypothesis Testing” not “Disease Modifying” in Alzheimer’s Disease

This commentary discusses the role of memantine in treating Alzheimer Disease.Memantine is one of the drugs approved in both Europe and the United States for the symptomatic cognitive treatment of Alzheimer’s disease (AD). Indeed, clinical trials have shown a significant mean difference between memantine and placebo with the Severe Impairment Battery, a cognitive scale used when the Mini-Mental State Examination score is below 10—a low level of mental functioning that does not allow the application of the more precise Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) scale. Unfortunately, the effect of memantine on mild-moderate AD is much smaller than that of cholinesterase inhibitors (1 point in ADAS-Cog versus 4 points at 24 weeks).¹ On this basis, memantine has been indicated and approved for moderate–severe AD. However, the effect of memantine on cognition, even within this subgroup of AD cases, is not particularly consistent, with some trials reporting no effect.² Fluctuations of cognitive status in patients with severe dementia, together with the lack of a scale able to precisely detect changes in global mental functions, might explain such inconsistencies, yet it is clear that effects of memantine are not particularly robust even in the most positive studies.One of the major goals in developing or assessing therapeutic modalities for AD is to target pathways that render “disease modifying effects.” Clinically, such disease modification would result in an increasing difference, over time, between treatment and placebo arms. Because amyloid and tau are the dominant scientific hypotheses of the causes of AD, it is not surprising that they have become prime therapeutic or disease-modifying targets. In this issue of The American Journal of Pathology, Martinez-Coria and colleagues³ report that transgenic mice show striking reductions in oligomeric amyloid and tau phosphorylation, improved cognitive performance, and restoration of LTP after treatment with memantine. Although many may view these data as the first indication of a “disease modifying” mechanism of action for memantine, this is inconsistent with the clinical experience and reports using memantine, where only limited effects are noted.These data, however, are extremely important in two key regards. First, perhaps more so than any other, they highlight the disparity between animal “models” of AD and human AD. It is an unfortunate fact that although the literature is replete with “cures” for various models of AD, none so far have passed muster in human clinical trials.^4,5,6,7 As such, perhaps we should not be surprised that memantine, a drug with some clinical effects, albeit marginal, is so effective in an animal model. Second, relatedly, we should ask why such model/human differences exist.In this vein, it is often overlooked that the amyloid hypothesis⁸ and the tau hypothesis remain as hypothetical constructs, not facts.^9,10 Hypotheses are tested experimentally, and when supported the hypothesis remains intact; however, when experiments reveal failures in the hypothesis, the hypothesis should be changed. The triple transgenic mouse, which presents with amyloid and tau pathologies and cognitive impairments¹¹ support the hypotheses as do “therapeutic” approaches, such as presented here, whereby reductions in amyloid or tau pathologies result in cognitive improvements. On the other hand, things are not quite so clear in human AD. Simply put, if memantine has equivalently dramatic effects on amyloid or tau phosphorylation in human AD yet only results in minimal cognitive benefits, the hypotheses are not supported. Moreover, that other anti-amyloid approaches that “cure” mice also have minimal or no effect in humans would not support the amyloid hypothesis.In conclusion, although the term “disease-modifying” appears to have become synonymous with “amyloid- or tau-modifying,” changes in one hypothetical molecular target or another is not “disease modification.” Rather, one also needs to show an equivalently modified disease course. As such, memantine is not a “disease-modifying” drug. However, memantine may be a “hypothesis-modifying” drug.     

The Cost of Crohn’s Disease

New biological medical therapies and innovative surgical approaches have revolutionised the care of patients with Crohn's disease. Until these innovations began to be utilised over the past decade, studies of the economics of Crohn's disease care were relatively scarce. Questions from both clinical and economic standpoints now arise over potential choices between medical and surgical approaches to patients with Crohn's disease. Initial economic studies suggested that the vast majority of costs in Crohn's disease were due to inpatient services and surgery. The large variance in cost data between patients resulted in a very small percentage of patients accounting for a disproportionately large percentage of the overall costs, with the bulk of costs, charges and reimbursements accrued by surgical cases. Studies suggest that surgery would need to result in a decreased utilisation of outpatient services in order to be 'cost-effective'. Evaluation of the clinical course of Crohn's disease suggests that the surgically-induced remission state is the longest remission state generally experienced by the patients, although sophisticated cost analysis fails to show enough of a remission benefit to offset the high costs associated with surgical procedures and post-operative convalescence. Bowel-sparing intestinal strictureplasty and minimally invasive laparoscopic surgeries have the potential to substantially decrease the costs associated with disease. These techniques need to be applied to a larger percentage of surgical Crohn's patients before the overall economic benefits can be fully assessed. Indirect costs and disability may account for most of the overall costs associated with Crohn's disease. Quality-of-life analyses have revealed that patients ill with Crohn's disease perform poorly, and the detrimental effects of medications or surgery may further increase disability in these patients. Future cost-utility studies may reveal the extent to which overall costs are affected by these issues. This review of the currently available literature on the economics of Crohn's disease suggests that medical therapy which can substantially reduce the utilisation of hospitalisations and surgery might be cost effective, even if the acquisition cost of the drug is high. However, broader application of specialised surgical techniques, together with the long post-operative remission state enjoyed by most Crohn's patients, may also offer a cost-effective long term approach to the disease. It is likely that both surgical and medical approaches will continue to be used in the treatment of Crohn's disease, with options for each patient being carefully considered on an individual basis.     

APS—More Systemic Disease than SLE

The antiphospholipid syndrome is a systemic autoimmune disease that can have serious consequences for patients. Importantly, there is a wide range of clinical presentations. In this issue we have attempted to provide an overview of these features and place it in the context of autoimmunity.     

Immunoinflammatory Aspects of Parkinson’s Disease

Neuroscience and Behavioral Physiology - This review analyzes immunological impairments in Parkinson’s disease (PD). We present data on neuroinflammation, with which cell degeneration in the...     

Brucellosis – Regionally Emerging Zoonotic Disease?

Aim

To gain deeper insight into the seroprevalence of brucellosis, which remains a zoonotic disease of worldwide public health concern, by reviewing studies from countries including North Africa, the Middle East, and India.

Methods

Studies on brucellosis performed in countries that are neighbors or important trading partners of the European Union and on trade animals and their products were analyzed. We reviewed 37 seroprevalence studies on brucellosis published from 1948 to 2009 retrieved from PubMed, Google, and ScienceDirect.

Results

The set of studies was heterogeneous in the number of samples and laboratory tests used. We included studies from Algeria (n = 1), Egypt (n = 7), India (n = 3), Iran (n = 3), Iraq (n = 1), Jordan (n = 5), Libya (n = 3), Saudi Arabia (n = 3), Syria (n = 1), Turkey (n = 5), and Yemen (n = 2). The total number of animals in these studies was 116 317 (cattle 75 375; buffalo 9644; sheep 10 550; goats 14 447; camels 6301). The prevalence of brucellosis in different animal species varied widely. Representative surveillance data have not recently been published in any of the countries.

Conclusions

Wars in the Middle East, insufficient preventive measures, the lack of adequate control programs in some countries, as well as uncontrolled animal transportation through “open” borders increased the risk that brucellosis will spread in some regions. New seroprevalence data are needed urgently to evaluate the current situation and for continuous monitoring of necessary control programs.Brucellosis is one of the most important worldwide zoonoses affecting livestock and humans (1). Brucellae are facultative intracellular, Gram-negative coccobacilli that lack capsules, flagelle, and endospores. The genus Brucella comprises a group of closely related bacteria. The species B. melitensis (which infects sheep and goats), B. suis (swine), and B. abortus (cattle) cause significant economic losses for animal owners and severe human disease. Brucella spp are also a focus of interest as they are categorized as biological agents due to their high contagiousness and their impact on human and animal health. The zoonotic pathogens B. abortus, B. melitensis, and B. suis were designated as select agents of Category B by the Centres for Disease Control in Atlanta, USA. This review analyzes studies from North Africa, the Middle East, and India to gain a clear picture of our current understanding of brucellosis and assess threats to transmission into the European Union (EU). The review also identifies areas where research is sorely needed to ensure that brucellosis epidemics are avoided in the future.     

Antibiotic Use in Crohn’s Disease

On the assumption that bacteria in the gut may be a cause of symptoms and/or complications of Crohn's disease, various antibiotics are efficaciously employed in some affected patients. However, we do not know exactly why and how they are helpful. A possible explanation is that one or several bacterial species may have a primary role in the aetiology of Crohn's disease, but this is not supported by the data in our possession. Another hypothesis is that intestinal bacteria may cause flare-up of the disorder, either by inducing intestinal lesions or by an interaction with the immune system, but we know today that specific pathogens can cause flares only in a minority of cases. On the contrary, there is considerable evidence that the intestinal microflora and its products may amplify and perpetuate inflammation in Crohn's disease. Despite the fact that few controlled trials have been conducted, and have shown inconclusive results, antibiotics are widely employed for improving symptoms and for inducing remission of active phases. At present, a combination of metronidazole and ciprofloxacin, active against many enteric bacteria, has proved to be effective in the treatment of Crohn's disease complications. This therapy also seems to be effective in acute flares as an alternative to, or in combination with, corticosteroids.     

Certolizumab Pegol in Crohn’s Disease

Certolizumab pegol is a pegylated humanized Fab' fragment of an anti-tumor necrosis factor-alpha (TNFalpha) monoclonal antibody, which binds with high affinity to both membrane-bound and soluble TNFalpha and demonstrates high neutralizing potency for these factors. The elimination half-life of certolizumab in humans has been extended to approximate/= 2 weeks through pegylation, allowing subcutaneous administration of this agent once every 4 weeks. Subcutaneous certolizumab pegol 400mg once every 4 weeks (with an additional 400mg dose at week 2) was effective as induction and maintenance therapy in patients with moderate to severe Crohn's disease in whom baseline serum C-reactive protein levels were >/=10 mg/L, according to data from two well designed, randomized phase III trials. Certolizumab pegol was, in general, well tolerated, and adverse events associated with the drug were of a mild to moderate nature; no instances of lupus were reported in any of the trials.     

Immunological Aspects of Alzheimer’s Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease causing progressive impairment of memory and cognitive function. The amyloid cascade hypothesis suggests that mismetabolism of the β-amyloid (Aβ) precursor protein (APP) followed by subsequent formation of non-fibrillar and fibrillar Aβ deposits leads to glial activation and eventually to neurotoxicity, causing cognitive impairment. Several lines of evidence indicate that an inflammatory process contributes to the pathology of AD. First, inflammatory proteins have been identified as being associated with neuritic plaques and in glial cells surrounding these plaques. Second, certain polymorphisms of acute-phase proteins and cytokines associated with AD plaques increase the risk or predispose for earlier onset of developing AD. Third, epidemiological studies indicate that anti-inflammatory drugs can retard the development of AD. Several steps in the pathological cascade of AD have been identified as possible targets for actions of nonsteroidal anti-inflammatory drugs. For instance, microglia are considered a target because this cell type is closely involved in AD pathology through secretion of neurotoxic substances and by modulating a positive feedback loop of the inflammatory mechanism that may be involved in the pathological cascade in AD. On the basis of studies in APP transgenic mice, immunisation with Aβ was recently suggested as a novel immunological approach for the treatment of AD. Immunisation elicits Aβ-specific antibodies that could affect several early steps of the amyloid-driven cascade. Antibodies could prevent Aβ from aggregating into fibrils and accelerate clearance of Aβ by stimulating its removal by microglial cells. This review outlines the pathological and genetic evidence that an inflammatory mechanism is involved in AD and the therapeutic approaches based on inhibition or mediation of inflammation.