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We report a case of a pulmonary necrotizing sarcoid granulomatosis (NSG)-like lesion possibly associated with coinfection of Mycobacterium avium and Propionibacterium acnes. A solitary nodule in the right middle lobe of the lung was notable for coagulative necrosis with aggregates of sarcoid-like epithelioid granulomas. Small arteries were damaged by granulomas. Both M. avium and P. acnes were detected in the lesion. Furthermore, more P. acnes genomes were detected in the granulomas than in the non-lesion lung. These findings blur the pathophysiologic boundaries among NSG, sarcoidosis, and mycobacteriosis, and suggest that NSG needs to be recognized as continuous spectra of sarcoidosis/mycobcteriosis.

Ivabradine, which reduces heart rate (HR) without affecting sympathetic nerve activity, improves mortality and morbidity in patients with systolic dysfunction. However, its impact on up-titrating a concomitant beta-blocker dose in such a cohort, via increasing cardiac output and blood pressure and improving tolerability to beta-blockers, remains unknown. In this single-center, prospective, randomized control trial, patients with systolic dysfunction, defined as left ventricular ejection fraction50%, sinus rhythm, heart rate75 bpm, systolic blood pressure between 90 and 110 mmHg, and New York Heart Association functional class III or IV, who are refractory to up-titration of a beta-blocker due to symptomatic hypotension, dizziness, or worsening heart failure, were assigned to the 20 ivabradine arm or the 20 conventional therapy arm and followed-up for 6 months. The primary outcome is the daily dose of beta-blocker at 6-months follow-up. The secondary outcomes are echocardiographic parameters including overlap between E-wave and A-wave in transmitral diastolic filling flow, plasma B-type natriuretic peptide level, 6-minute walk distance, and heart failure readmission rate. By conducting this study, we hope to demonstrate the clinical benefit of ivabradine therapy in up-titrating beta-blockers and improving clinical outcomes in patients with systolic dysfunction.

A 46-year-old woman with uveitis was referred to our respiratory diseases department in July 2018. Her medical history included transient bilateral hilar mediastinal lymphadenopathy (BHL) and multiple pulmonary nodules in May 2013 during pegylated interferon-alpha and ribavirin treatment for chronic hepatitis C infection. Five years post-treatment, chest X-ray revealed BHL and nodular recurrence. A biopsy of the subcutaneous buttock nodules revealed scattered non-caseating epithelioid granulomas with positive PAB immunohistochemical staining. This seem to be the first report of Propionibacterium acnes-associated sarcoidosis possibly initially triggered by interferon-alpha therapy. Understanding the mechanisms underlying interferon-triggered P. acnes-associated sarcoidosis may clarify the sarcoidosis immunopathogenesis.

Aims Lymph node metastasis (LNM) has not been found in more than 85% of patients with early invasive colorectal adenocarcinoma (T1-CRAC) who undergo surgery after therapeutic endoscopy due to the risk for LNM. Better histological risk assessment for LNM of endoscopically resected T1-CRAC is important to avoid unnecessary additional surgery. Methods and results We evaluated cancer gland rupture (CGR), i.e. cancer glands with a discontinuous epithelial lining, at the invasive front, as a potential risk factor for LNM by histological examination of differentiated T1-CRAC from 217 patients who underwent surgery with or without therapeutic endoscopy. CGR was represented by C-shaped neoplastic glands with a variable inflammatory or stromal reaction, and was occasionally accompanied by mucus lake or abscess formation. CGR was observed in 168 (77%) cases, including all 20 cases with LNM, and the odds ratio of LNM was higher for CGR than for deep invasion (depth of submucosal invasion ≥1000 μm). All cases with LNM were found among 148 cases with deep invasion and positive CGR, whereas no LNM was detected in 29 cases with deep invasion and negative CGR, regardless of vascular invasion or tumour budding. In the 148 cases, LNM was detected in 18 (19%) of 93 cases with positive vascular invasion or high-grade tumour budding, and in two (4%) of 55 cases without either. Conclusions Our findings suggest that CGR is an easily applied and objective histological finding for predicting LNM that could be useful for assessing the risk for LNM of endoscopically resected T1-CRAC with deep invasion.

Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has been shown to be useful in treating either advanced or recurrent KRAS/NRAS/BRAF wild-type colorectal cancer. We herein report the case of a 60-year-old man with short bowel syndrome who developed hematochezia due to panitumumab-induced colitis with vitamin K deficiency during third-line chemotherapy. The cause of vitamin K deficiency was the lack of intravenous vitamin K supplementation following a change from central venous nutrition to peripheral venous nutrition. We advise clinicians to carefully check for colitis and manage the infusions of chemotherapy patients with short bowel syndrome.

Background and objectives: Current guidelines criteria do not satisfactorily discriminate responders to cardiac resynchronization therapy (CRT). QRS amplitude is an established index to recognize the severity of myocardial disturbance and might be a key to optimal patient selection for CRT. Materials and Methods: (1) Initial R-wave amplitude, (2) S-wave amplitude, and (3) a summation of maximal R- or R′-wave amplitude and S-wave amplitude were measured at baseline. These parameters were averaged according to right (V1 to V3) or left (V4 to V6) precordial leads. The impact of these parameters on response to CRT, which was defined as a decrease in left ventricular end-systolic volume ≥15% at six-month follow-up, was investigated. Results: Among 47 patients (71 years old, 28 men) who received guideline-indicated CRT implantation, 25 (53%) achieved the definition of CRT responder. Among baseline electrocardiogram parameters, only the higher S-wave amplitude in right precordial leads was an independent predictor of CRT responders (odds ratio: 2.181, 95% confidence interval: 1.078–4.414, p = 0.030) at a cutoff of 1.44 mV. The cutoff was independently associated with cumulative incidence of heart failure readmission and appropriate electrical defibrillation following CRT implantation (p &lt, 0.05, respectively). Conclusions: Prominent S-wave in right precordial leads might be a promising index to predict left ventricular reverse remodeling and greater clinical outcomes following CRT implantation.

Background: Hypertrophic pachymeningitis (HP) is a rare disorder that involves localized or diffuse thickening of the dura mater. HP is associated with various inflammatory, infectious, and malignant diseases, such as rheumatic arthritis, sarcoidosis, anti-neutrophil cytoplasmic antibody-associated vasculitis, IgG4-related disorders, syphilis, tuberculosis, bacterial and fungal infections, cancer, and idiopathic diseases, when evaluation fails to reveal a cause. Among them, chronic infection with Propionibacterium acnes is a rare etiology of HP, and its pathology remains unclear. Case Presentation: An 80-year-old man having refractory otitis media with effusion of the right ear presented with progressive right-sided headache and nausea. Post-contrast brain magnetic resonance imaging revealed right mastoiditis and remarkable thickening of the dura mater and enhancement of pia mater extending from the right middle cranial fossa to the temporal lobe. HP secondary to middle ear infection was suspected, and a biopsy of the right mastoid was performed. An anaerobic culture of the biopsied right mastoid showed the growth of P. acnes, and histopathological examination using P. acnes-specific monoclonal antibody (PAB antibody) revealed the infiltration of inflammatory cells with P. acnes. Moreover, using PAB antibody, P. acnes was detected in the biopsy specimen of the thickening dura mater. No granulomas were identified in either specimen. HP was resolved with long-term administration of antibiotics and steroids. Conclusion: This is the first documentation of pathologically demonstrated chronic HP associated with P. acnes infection followed by refractory otitis media. This report showed that chronic latent P. acnes infection induces chronic inflammation, which cannot be controlled without administering steroids. Keywords: Propionibacterium acnes, otitis media, pachymeningitis, mastoiditis, dura mater

Several studies demonstrated that Propionibacterium acnes may be involved in sarcoidosis pathogenesis. Presence of P. acnes was found in granulomas of the majority of Japanese sarcoidosis patients. However, presence of P. acnes in tissue has never been related to sarcoidosis phenotypes and clinical outcome. Therefore, the aims of our study were to demonstrate whether P. acnes can be detected in granulomas of Dutch sarcoidosis patients and to investigate whether its presence is related to a clinical phenotype and/or course of disease. Sections of formalin-fixed paraffin-embedded tissue blocks of 76 sarcoidosis patients were examined by immunostaining with a P. acnes-specific monoclonal antibody (PAB antibody) using a Ventana BenchMark ULTRA. Clinical outcome status (COS) was determined and classified into two phenotype groups: A: resolved, minimal or persistent disease without treatment (COS 1–6) and B: persistent disease with need for treatment (COS 7–9). P. acnes was detected in samples of 31 patients (41%) and located within granulomas in samples of 13 patients (17%). The frequency of P. acnes detected in granulomas at diagnosis was significantly higher in patients with phenotype B compared to patients with phenotype A (29% versus 0%, p=0.021). Presence of P. acnes in granulomas can be confirmed in Dutch sarcoidosis patients. It is intriguing that presence of P. acnes in granulomas is more frequently found in patients with chronic disease requiring treatment. This adds to the rationale that a subgroup of sarcoidosis patients might benefit from antibiotic therapy., Significantly more sarcoidosis patients with a chronic disease course requiring treatment have presence of P. acnes in granulomas. This contributes to the premise that it is relevant to further explore antibacterial therapy in sarcoidosis. https://bit.ly/36wCbbw

BackgroundEarly-onset sarcoidosis (EOS) and Blau syndrome (BS) are systemic inflammatory granulomatous diseases without visible pulmonary involvement, and are distinguishable from their sporadic and familial forms. The diseases are characterized by a triad of skin rashes, symmetrical polyarthritis, and recurrent uveitis. The most common morbidity is ocular involvement, which is usually refractory to conventional treatment. A gain-of-function mutation in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene has been demonstrated in this disease; however, little is known about the relationship between the activation ofNOD2and the pathophysiology of EOS/BS. Here we describe EOS/BS with a novel mutation in theNOD2gene, as well as detection ofPropionibacterium acnes(P. acnes) in the granulomatous inflammation.Case presentationAn 8-year-old Japanese girl presented with refractory bilateral granulomatous panuveitis. Although no joint involvement was evident, she exhibited skin lesions on her legs; a skin biopsy revealed granulomatous dermatitis, andP. acneswas detected within the sarcoid granulomas by immunohistochemistry withP. acnes-specific monoclonal (PAB) antibody. Genetic analyses revealed that the patient had aNOD2heterozygous D512V mutation that was novel and not present in either of her parents. The mutantNOD2showed a similar activation pattern to EOS/BS, thus confirming her diagnosis. After starting oral prednisolone treatment, she experienced an anterior vitreous opacity relapse despite gradual prednisolone tapering; oral methotrexate was subsequently administered, and the patient responded positively.ConclusionsWe presented a case of EOS/BS with a novel D512V mutation in theNOD2gene. In refractory granulomatous panuveitis cases without any joint involvement, EOS/BS should be considered as a differential diagnosis; genetic analyses would lead to a definite diagnosis. Moreover, this is the first report ofP. acnesdemonstrated in granulomas of EOS/BS. Since intracellularP. acnesactivates nuclear factor-kappa B in aNOD2-dependent manner, we hypothesized that the mechanism of granuloma formation in EOS/BS may be the result ofNOD2activity in the presence of the ligand muramyl dipeptide, which is a component ofP. acnes.These results indicate that recognition ofP. acnesthrough mutantNOD2is the etiology in this patient with EOS/BS.

Diagnostic utility of a homeobox transcription factor, engrailed homeobox 1 (En1) in the histopathology of salivary gland neoplasms was studied. The expression of En1 was immunohistochemically examined in 51 cases of adenoid cystic carcinoma (AdCC) and 143 cases of other salivary gland neoplasms. In all 51 AdCCs, En1 was expressed in 30-100% of tumor cells. In eight of nine polymorphous adenocarcinomas (PACs), En1 was expressed in 40-100% of tumor cells. Less than 5% of tumor cells expressed En1 in three of 12 epithelial-myoepithelial carcinomas, one of 17 basal cell adenomas (BCAs), and one of 34 pleomorphic adenomas (PAs). Among 55 other carcinoma cases, 1-30% of tumor cells expressed En1 in three salivary duct carcinomas (SDCs) ex PA. None of the myoepitheliomas and Warthin tumors expressed En1. When the cut-off value of the percentage of En1-expressing cells was set to 25%, all 51 AdCCs, eight of nine PACs and one SDC ex PA were En1-positive and the others were En1-negative. En1 is expressed consistently in AdCCs, frequently in PACs, but rarely in other salivary gland neoplasms. En1 is a possible diagnostic marker for AdCC and PAC in the histopathology of salivary gland neoplasms.

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Propionibacterium acnes is implicated in the pathogenesis of sarcoidosis. We investigated the usefulness of immunohistochemistry (IHC) with a commercially available P. acnes-specific monoclonal antibody (PAB antibody) for differentiating sarcoidosis from other granulomatous diseases. Formalin-fixed paraffin-embedded tissue samples from 94 sarcoidosis patients and 30 control patients with other granulomatous diseases were examined by the original manual IHC method. We also compared the detection frequency of P. acnes in sarcoid granulomas between manual and automated IHC methods. P. acnes was detected in sarcoid granulomas of samples obtained by transbronchial lung biopsy (64%), video-associated thoracic surgery (67%), endobronchial-ultrasound-guided transbronchial-needle aspiration (32%), lymph node biopsy (80%), and skin biopsy (80%) from sarcoidosis patients, but not in any non-sarcoid granulomas of the samples obtained from control patients. P. acnes outside granulomas, however, was frequently detected in both groups. The detection status of P. acnes in granulomas did not correlate with the clinical characteristics of sarcoidosis patients. The automated Leica system exhibited the best detection sensitivity (72%) and almost an identical localization for P. acnes in sarcoid granulomas compared with the manual method. IHC with a PAB antibody is useful for differentiating sarcoidosis from other granulomatous diseases by detecting P. acnes in granulomas. An automated method by the Leica system can be used in pathology laboratories for differential diagnosis of granulomas by IHC with the PAB antibody.

Background Iodine-123 metaiodobenzylguanidine (123 I-MIBG) is useful for detecting sympathetic innervation in the heart, and has been closely associated with fatal arrhythmias. However, such imaging is typically calibrated to the area of highest uptake and thus is unable to identify areas of hyperinnervation. We hypothesized that normal 123 I-MIBG uptake regions in the denervated heart would demonstrate nerve sprouting and correlate with the potential for arrhythmogenesis. Methods Twenty New Zealand white rabbits treated with phenol or sham were prepared under anesthesia. Sympathetic innervation was quantified using autoradiography and immunostaining 4 weeks after phenol application, and electrophysiological study was performed. Results 123 I-MIBG revealed maximal local differences in isotope uptake in the border zone between areas with attenuated and abundant MIBG compared with that seen between adjacent regions within the lowest uptake areas. On immunostaining, heterogeneous and decreased expressions of growth-associated protein 43 signal were observed in the MIBG-attenuated areas; however, abundant signals were recognized in the MIBG-abundant areas. Upregulation of the tyrosine hydroxylase signal was observed at the part of the MIBG-abundant area. In electrophysiological study, the dispersion of activation recovery interval (ARI) was increased in the phenol-applied areas by norepinephrine infusion. Stellate stimulation exacerbated the ARI dispersion in both the phenol-applied and nonapplied areas, and was associated with increased inducibility of ventricular tachycardia and ventricular fibrillation. Conclusions The presence of hyperinnervation in the nondenervated regions of denervated rabbit hearts suggests that heterogeneous neural remodeling occurs in regions with seemingly normal 123 I-MIBG uptake and contributes to electrical instability.

Background/aims To detect Propionibacterium acnes from intraocular granuloma in patients with ocular sarcoidosis. Methods Ten patients (10 eyes) with uveitis associated with sarcoidosis, who underwent vitrectomy to remove the epiretinal membrane were analysed. The patients were 70.4±7.6 (mean±SD) years of age, and the observation period from diagnosis of sarcoidosis until vitrectomy was 27.6±15.1 months. Histopathological examination of paraffin-embedded sections of the excised epiretinal membranes was conducted by H&E staining and immunohistochemical staining using PAB antibody, which is a monoclonal antibody against P. acnes . Four patients with idiopathic epiretinal membrane and four patients with epiretinal membrane caused by chronic uveitis other than sarcoidosis were included as control. Results Granuloma in the epiretinal membrane was observed in 4 of 10 patients with sarcoidosis, and all the granulomas were positive for PAB. In one patient without granuloma in the epiretinal membrane, PAB immunoreactivity was found in inflammatory cells, presumably macrophages. No granuloma and no PAB immunoreactivity were detected in all control patients, except one with chronic uveitis in whom faint PAB immunoreactivity was detected in inflammatory cells. Conclusions P. acnes was detected from granulomas formed in the epiretinal membrane of patients with sarcoidosis. The significance of P. acnes in the pathogenesis of uveitis associated with sarcoidosis remains to be determined.

Sarcoidosis is a systemic granulomatous disease that can affect any organ including the nose. Nasal crusting and congestion are common nasal symptoms of sarcoidosis, whereas cases of saddle-nose deformity are rarely reported. We describe here a case of sarcoidosis that presented with saddle nose resembling relapsing polychondritis. Since sarcoidosis shares clinical features with relapsing polychondritis, the differential diagnosis of saddle nose can be challenging without a clear pathology.

A 77-year-old female underwent screening mammography with abnormal results. Core needle biopsy revealed a granulomatous lesion without necrosis, and sarcoidosis was considered although tuberculosis and granulomatous mastitis could not be ruled out. Three months later, the patient detected breast and axillary masses. Malignancy was suspected and both lesions were excised. The specimens contained epithelioid cell granulomas with no necrosis. Her angiotensin-converting enzyme level was normal, and radiographic examination revealed no evidence of involvement of other organs, including the lungs and mediastinal lymph nodes. Although sarcoidosis was highly suspected, it was not definitive. Immunohistochemistry with the PAB antibody, which specifically reacts with Propionibacterium acnes, the most commonly implicated causative agent of sarcoidosis, showed positive signals in granulomatous inflammation of the breast and within granulomas of the sentinel lymph node. This is the first case report of primary sarcoidosis of the breast involving the draining lymph node with confirmed P. acnes infection. Keywords: Immunohistochemistry, Mammary sarcoidosis, Isolated sarcoidosis, PAB antibody, Granulomatous mastitis, Tuberculosis mastitis

Adenocarcinoma within anorectal fistulae is rare and is sometimes associated with Crohn’s disease. Crohn’s disease-associated adenocarcinoma within anorectal fistulae has a poor prognosis; however, little is known about the clinicopathological differences between Crohn’s disease-associated adenocarcinoma within anorectal fistulae and usual adenocarcinoma within anorectal fistulae. We retrospectively searched patients’ charts and pathology archives at Tokyo Yamate Medical Center and Tokyo Medical and Dental University Hospital for adenocarcinoma within anorectal fistulae. Clinical and pathological data were collected and immunohistochemical examinations were conducted. Overall survival rate was estimated using the Kaplan–Meier method. Prognostic factors of overall survival were assessed using univariate and multivariate Cox regression analyses. We examined 82 cases of adenocarcinoma within anorectal fistulae. Fifty-nine of 82 cases (72%) had usual adenocarcinoma within anorectal fistulae, while the remaining 23 cases (28%) had Crohn’s disease-associated adenocarcinoma within anorectal fistulae. Patients with Crohn’s disease-associated adenocarcinoma within anorectal fistulae were diagnosed at a younger age and at a more advanced stage than those with usual adenocarcinoma within anorectal fistulae. Macroscopic and histological types were also different between usual adenocarcinoma within anorectal fistulae and Crohn’s disease-associated adenocarcinoma within anorectal fistulae. Crohn’s disease-associated adenocarcinoma within anorectal fistulae included more ulcerative types and high-grade adenocarcinomas. The rate of lymphovascular invasion was higher in Crohn’s disease-associated adenocarcinoma within anorectal fistulae. Immunohistochemically, the expression of E-cadherin, p53, and MUC5AC differed between usual adenocarcinoma within anorectal fistulae and Crohn’s disease-associated adenocarcinoma within anorectal fistulae. Patients with Crohn’s disease-associated adenocarcinoma within anorectal fistulae exhibited worse overall survival than those with usual adenocarcinoma within anorectal fistulae, and vascular invasion was the strongest significant independent predictor of overall survival in patients with adenocarcinoma within anorectal fistulae. In conclusion, usual adenocarcinoma within anorectal fistulae and Crohn’s disease-associated adenocarcinoma within anorectal fistulae have different clinicopathological characteristics and should be considered separate clinical entities.

The etiology of sarcoidosis is still obscure; however, Mycobacteria and Propionibacterium acnes are considered the most implicated etiological agent for sarcoidosis. To investigate whether P. acnes is an etiological agent for sarcoid uveitis, we analyzed the frequency of P. acnes detected within the biopsied retinas from patients with ocular sarcoidosis by immunohistochemistry with a P. acnes-specific monoclonal antibody (PAB antibody). Eleven patients (12 eyes) with sarcoid uveitis were enrolled in this study. Eight patients with rhegmatogenous retinal detachment, two patients with non-sarcoid uveitis, and two patients with vitreoretinal lymphoma were enrolled as controls. In the sarcoidosis group, granulomas were mainly observed in the inner retinal layer filled with CD4+ cells and CD68+ cells, indicating the Th1 immune response. P. acnes, identified as round bodies that reacted with the PAB antibody, were present in 10/12 samples (83%) from 9/11 patients (82%) with sarcoidosis. These round bodies were scattered within the retinal granulomas mainly in the inner retinal layer. In the control group, no round bodies were detected. Our results suggested that P. acnes could be associated with sarcoid uveitis. We hypothesize that sarcoid granulomas may be formed by a Th1 immune response to P. acnes hematogenously transmitted to the retina.

The medical doctor's much experiences are very important for the success of surgeries. Therefore, surgeries using experimental animals have been carried out for training experts' skill improvement from long ago. However, human beings are different in size and structure from other animals in some organs, so it is difficult to perform surgical training using living bodies of other animals. In recent years, a medical surgical simulator has been widely attracting attention for promoting the improvement of techniques by training and understanding of surgical contents. It is preferable that models of various organs have the same characteristics as real, but precise models are currently under development. Here, we targeted a human brain whose structure is different from other animals and whose medical operations are important and hard. In particular, we focused on the dura mater that protects the brain. In this study, we attempted to create some non-wet dura mater model for medical simulation of brain surgery operation. Some dura mater models combined resins and fiber sheets were fabricated. Characteristics of the produced models were investigated and responses of the model to the actual surgical tool were measured, and they were compared with pig dura mater. It was shown to be able to prepare dura mater models with properties similar to those of pig dura mater in viscoelasticity and scalpel insertion test.

Sarcoidosis is a systemic granulomatous disease with unknown cause, which very rarely occurs exclusively in the central nervous system. The authors performed biopsy sampling of a mass that developed in the left tentorium cerebelli that appeared to be a malignant tumor. The mass was diagnosed as a sarcoid granuloma, which was confirmed with the onset of antibody reaction product against Propionibacterium acnes. Findings suggesting sarcoidosis to be an immune response to P. acnes infection have recently been reported, and they give insight for diagnosis and treatment of this disease. The authors report the possible first case that was confirmed with P. acnes infection in a meningeal lesion in solitary neurosarcoidosis.

Helicobacter pylori has been considered to be non-invasive and to rarely infiltrate the gastric mucosa, even though there is an active Th1 immune response in the lamina propria of the H. pylori-infected stomach. To elucidate whether H. pylori invades the lamina propria and translocates to the gastric lymph nodes, we examined H. pylori in formalin-fixed and paraffin-embedded tissue sections of stomach and gastric lymph nodes obtained from 51 cancer patients using real-time PCR and immunohistochemistry (IHC) with a novel anti-H. pylori monoclonal antibody that recognizes lipopolysaccharides. Fresh gastric lymph nodes were used to culture for H. pylori. In 46 patients with H. pylori in the stomach, the bacterium was found in the lymph nodes from 21 patients by culture, 37 patients by PCR, and 29 patients by IHC. H. pylori captured by macrophages was found in the lamina propria of 39 patients. In the lymph nodes, the bacterium was found in many macrophages and a few interdigitating dendritic cells at the paracortical areas. H. pylori was also found in the intracellular canaliculi of parietal cells in 21 patients, but intracytoplasmic invasion into gastric epithelial cells was not identified. When compared to the commercially available anti-H. pylori antibodies, the novel antibody showed the highest sensitivity to detect H. pylori-positive macrophages, whereas no difference was found for H. pylori in the mucous layer. The H. pylori-positive macrophages in the lamina propria correlated with chronic gastritis as well as translocation of such cells to the lymph nodes. These results suggest that H. pylori-induced gastric epithelial damage allows the bacteria to invade the lamina propria and translocate to the gastric lymph nodes, which may chronically stimulate the immune system. The bacteria captured by macrophages, whether remaining alive or not, may contribute to the induction and development of H. pylori-induced chronic gastritis.

Background Although rare, cardiac sarcoidosis (CS) is potentially fatal. Early diagnosis and intervention are essential, but histopathologic diagnosis is limited. We aimed to detect Propionibacterium acnes, a commonly implicated etiologic agent of sarcoidosis, in myocardial tissues obtained from CS patients. Methods and results We examined formalin-fixed paraffin-embedded myocardial tissues obtained by surgery or autopsy and endomyocardial biopsy from patients with CS (n = 26; CS-group), myocarditis (n = 15; M-group), or other cardiomyopathies (n = 39; CM-group) using immunohistochemistry (IHC) with a P. acnes-specific monoclonal antibody. We found granulomas in 16 (62%) CS-group samples. Massive (≥14 inflammatory cells) and minimal (

Radioiodide is commonly used to diagnose and treat hyperthyroidism and thyroid carcinoma. However, we could not find any experimental data that strictly compared the biodistribution and thyroid uptake of radioactive iodide between the oral and intravenous (iv) routes with time. This prompted us to compare 123I biodistribution and thyroid uptake to clarify the differences between oral and iv bolus administration in rats. The rats were divided into two groups, A and B (n = 5, each). In the first imaging experiment, Na123I solution (35 MBq/200 μL) was administered as a bolus to the rats orally in group A and intravenously in group B. Two weeks later, the second imaging experiment was performed as a crossover experiment. 123I biodistribution was evaluated visually and quantitatively with a gamma camera at 10 min, 3, 6, 12, 24, and 48 h after 123I administration. Thyroid uptake was compared between oral and iv groups. Correlation of 123I thyroid uptake and whole-body excretion was evaluated. The area under the curve (AUC) of thyroid uptake was also calculated. 123I biodistribution differed visually during 6 h between the two groups. 123I thyroid uptake was significantly higher in the iv group at 10 min (P

of AD was performed. All animal experiments were carried out under the approval of the relevant Institutional Animal Review Committee of Ege University, (Number: 2010-155) Izmir, Turkey. Results: Higher uptakes on hippocampus were observed at Ab 1-42 injected side in animal model of AD when compared with the control and na€ive groups. Saturated studies with Bioquin-7-carboxylic acid compound showed that 99mTc labeled Bioquin-HMPAO compound has specificity on amyloid plaques (Figure 1). Conclusions: Consequences of the whole experimental studies, it is proposed that the radiolabeled compound (99m Tc-Bioquin-HMPAO) might be improved and used as a novel brain amyloid plaque specific agent promising early diagnosis potential of AD.

Wave intensity (WI) is a new hemodynamic index, which is defined as (dP/dt)(dU/dt) at any site of the circulation, where dP/dt and dU/dt are the time derivatives of blood pressure and velocity, respectively. Arterial WI in normal subjects has two positive sharp peaks. The first peak occurs during early systole when a forward-traveling compression wave is generated by the left ventricle. The magnitude of this peak increases markedly with an increase in cardiac contractility. The second peak, which occurs towards the end of systole, is caused by generation of a forward-traveling expansion wave by the ability of the left ventricle to actively stop aortic blood flow. The interval between the R wave of the ECG and the first peak of WI (R-1st peak interval) and the interval between the first and second peaks (1st-2nd interval) are approximately equal to the preejection period and left ventricular ejection time, respectively. Using a combined Doppler and echo-tracking system, we obtained carotid arterial WI noninvasively. We examined the characteristics of WI in 11 patients with mitral regurgitation (MR) before and after surgery, and 24 normal volunteers. In the MR group before surgery, the second peak was decreased and the (1st-2nd interval)/(R-R interval) ratio was reduced, compared with the normal group (140 +/- 130 vs 750 +/- 290mmHg m/s3. P0.0083; 20.7% +/- 3.4% vs 26.7% +/- 2.8%, P0.083). There were no significant differences in the first peak between the normal group and the MR group before and after surgery. The second peak in the MR group was increased significantly (P0.016 vs before surgery) to 1,150 +/- 830mmHg m/s3 in the early period after surgery (stage I), and to 1,090 +/- 580mmHgm/s3 in the late period after surgery (stage II). These values did not differ significantly from that of the normal group. At stage I, the (R-1st peak interval)/ (R-R interval) ratio was increased from 13.4% +/- 2.7% to 20.6% +/- 5.6% (P0.016 vs before surgery). At stage II, this ratio decreased to 16.2% +/- 2.8% (P0.016 vs stage I). but was still significantly higher than that before surgery. The (1st-2nd interval)/(R-R interval) ratio increased significantly after surgery (P0.016 vs before surgery) to values (27.0% +/- 4.5% at stage I and 28.9% +/- 2.6% at stage II) which did not differ significantly from that of the normal group. The recovery of the second peak after surgery suggests that the left ventricle had recovered the ability to actively stop aortic blood flow. Wave intensity is useful for analyzing changes in the working condition of the heart.

BACKGROUND: Recent reports on Propionibacterium acnes (P. acnes) suggest that this bacterium is prevalent in the prostate, is associated with acute and chronic prostatic inflammation, and might have a role in prostate carcinogenesis. METHODS: To evaluate the pathogenic role of this indigenous bacterium, we screened for the bacterium in radical prostatectomy specimens using enzyme immunohistochemistry with a novel P. acnes-specific monoclonal antibody (PAL antibody), together with an anti-nuclear factor-kappa B (NF-κB) antibody. We examined formalin-fixed and paraffin-embedded tissue sections of radical prostatectomy specimens from 28 patients with prostate cancer and 18 age-matched control patients with bladder cancer, but without prostate cancer. RESULTS: Immunohistochemistry with the PAL antibody revealed small round bodies within some non-cancerous glandular epithelium and stromal macrophages in most prostate samples. Prostate cancer samples had higher frequencies of either cytoplasmic P. acnes or nuclear NF-κB expression of glandular epithelium and higher numbers of stromal macrophages with P. acnes than control samples. These parameters were also higher in the peripheral zone than in the transitional zone of the prostate, especially in prostate cancer samples. Nuclear NF-κB expression was more frequent in glands with P. acnes than in glands without P. acnes. The number of stromal macrophages with the bacterium correlated with the grade of chronic inflammation in both the PZ and TZ areas and with the grade of acute inflammation in the TZ area. CONCLUSIONS: Immunohistochemical analysis with a novel monoclonal antibody for detecting P. acnes in the prostate suggested that intraepithelial P. acnes infection in non-cancerous prostate glands and inflammation caused by the bacterium may contribute to the development of prostate cancer.

Recently, overexpression of γ-glutamylcyclotransferase (GGCT) has been reported in various cancer tissues suggesting that it has significant potential as a diagnostic marker. The aim of this study was to examine the suitability of GGCT for the detection of high-risk lesions at an early stage of esophageal squamous cell carcinoma (ESCC). A total of 200 lesions, including 120 invasive ESCC, 80 esophageal squamous intraepithelial neoplasia consisting of 40 low-grade intraepithelial neoplasia (LGIEN) and 40 high-grade intraepithelial neoplasia (HGIEN), as well as 20 confounding lesions, were examined by immunohistochemical (IHC) staining for GGCT. IHC staining for Ki-67 and p53 was also performed in esophageal squamous intraepithelial neoplasia to compare the diagnostic power of GGCT. Increased expression of GGCT was common in invasive ESCC and HGIEN (87.5% and 85.0%, respectively), but was much less frequently observed in LGIEN (17.5%). GGCT expression significantly correlated with the presence of lymph node metastasis and the degree of differentiation. In the differential diagnosis of LGIEN and HGIEN, GGCT possessed both high sensitivity and high specificity, while Ki-67 and p53 only possessed either high sensitivity or high specificity. Additionally, GGCT expression was higher in 7 out of 8 ESCC cell lines (KYSE series) than in a normal esophageal squamous cell line (Het-1A). The expression levels strongly correlated with enzymatic activity (r=.92; P.001). These results indicate that overexpressed GGCT retains its enzymatic activity and can become a valuable biomarker for the diagnosis of HGIEN that is likely to progress to subepithelial invasion.

Background Propionibacterium acnes has recently been implicated as a cause of chronic prostatitis and this commensal bacterium may be linked to prostate carcinogenesis. The occurrence of intracellular P. acnes infection in prostate glands and the higher frequency of P. acnes-positive glands in radical prostatectomy specimens from patients with prostate cancer (PCa) than in those from patients without PCa led us to examine whether the P. acnes-positive gland frequency can be used to assess the risk for PCa in patients whose first prostate biopsy, performed due to an increased prostate-specific antigen (PSA) titer, was negative. Methods We retrospectively collected the first and last prostate biopsy samples from 44 patients that were diagnosed PCa within 4 years after the first negative biopsy and from 36 control patients with no PCa found in repeated biopsy for at least 3 years after the first biopsy. We evaluated P. acnes-positive gland frequency and P. acnes-positive macrophage number using enzyme-immunohistochemistry with a P. acnes-specific monoclonal antibody (PAL antibody). Results The frequency of P. acnes-positive glands was higher in PCa samples than in control samples in both first biopsy samples and in combined first and last biopsy samples (P < 0.001). A frequency greater than the threshold (18.5 and 17.7, respectively) obtained by each receiver operating characteristic curve was an independent risk factor for PCa (P = 0.003 and 0.001, respectively) with odds ratios (14.8 and 13.9, respectively) higher than those of serum PSA titers of patients just before each biopsy (4.6 and 2.3, respectively). The number of P. acnes-positive macrophages did not differ significantly between PCa and control samples. Conclusions These results suggested that the frequency of P. acnes-positive glands in the first negative prostate biopsy performed due to increased PSA titers can be supportive information for urologists in planning repeated biopsy or follow-up strategies.

Mycobacterium tuberculosis can survive for a long time in the body of a healthy host, causing no symptoms after primary infection. Years or decades later, M. tuberculosis can be reactivated in some carriers, leading to symptoms of post-primary tuberculosis. During the asymptomatic period, M. tuberculosis is believed to survive in old foci of infection, yet these foci are uniformly negative by culture and acid-fast staining, which are conventional methods to detect mycobacteria. The precise location and amount of M. tuberculosis in these foci, therefore, are not well understood. Here we report that granulomatous lesions with calcification, a well-known characteristic of old tubercles, contained considerable amounts of M. tuberculosis genomes and cell wall components. These calcified lesions exhibited little inflammation but all were positive for M. tuberculosis by real-time polymerase chain reaction and by immunohistochemistry with a novel monoclonal antibody against lipoarabinomannan, a cell wall component of mycobacteria. We found many lipoarabinomannan-containing granules in the necrotic areas of the lesions that were negative by Ziehl-Neelsen staining but included some bacillus-like structures. The risk of reactivation of latent tuberculosis from these calcified granulomatous lung lesions should be considered.

To understand the pathophysiology of diseased hearts, we devised a new regional myocardial function curve and investigated its properties. Regional work per unit volume of the myocardium (RWM) was calculated by integrating mean wall stress (σ) with respect to the natural logarithm of the reciprocal of wall thickness [ln(1/H)] over a cardiac cycle. Regarding the end-diastolic ln(1/H) as the preload for the region of concern on the assumption that the myocardium is incompressible, we defined the relation between RWM and end-diastolic ln(1/H) as the regional myocardial function curve. In ten mongrel dogs, we measured left ventricular pressure, left ventricular internal diameter, and wall thickness with a catheter-tip micromanometer and ultrasonic dimension gauges during volume loading to obtain the regional myocardial function curve. We examined the sensitivity of the regional myocardial function curve to changes in contractile state (isoproterenol, propranolol) and changes in afterload (pressure loading by a balloon-occlusion catheter). The linear fit to the data points of the regional myocardial function curve under each condition always achieved a very good correlation coefficient (greater than 0.62). Isoproterenol increased the slope of the regional myocardial function curve from 9.7 ± 0.9 (SEM) mJ/cm3 to 14.4 ± 1.0 mJ/cm3 (P < 0.01), with no significant changes in the x-intercept, while propranolol decreased it to 5.6 ± 1.2mJ/cm3 (P < 0.01) with no significant changes in the x-intercept. The multiple linear regression model with constant x-intercept of the regional myocardial function curve also showed a very high correlation coefficient (greater than 0.98) and sensitivity to changes in contractile state in each dog. The changes in afterload within the physiological range (within a range of peak σ of 4.0–12.0kPa) did not change the slope or the x-intercept of the regional myocardial function curve. We conclude that the relation between RWM and end-diastolic ln(1/H) is a regional myocardial function curve of the ventricle and its slope is useful for comparing myocardial contractility among different regions and different pathological states in the same heart, and among ventricles of different sizes. The present method can be easily extended to the clinical setting.

Sarcoidosis likely results from the exposure of a genetically susceptible subject to an environmental agent, possibly an infectious one. Mycobacterial and propionibacterial organisms are the most commonly implicated potential etiologic agents. Propionibacterium acnes is the only microorganism, however, found in sarcoid lesions by bacterial culture. To evaluate the pathogenic role of this indigenous bacterium, we screened for the bacterium in sarcoid and non-sarcoid tissues using immunohistochemical methods with novel P. acnes-specific monoclonal antibodies that react with cell-membrane-bound lipoteichoic acid (PAB antibody) and ribosome-bound trigger-factor protein (TIG antibody). We examined formalin-fixed and paraffin-embedded samples of lungs and lymph nodes from 196 patients with sarcoidosis, and corresponding control samples from 275 patients with non-sarcoidosis diseases. The samples were mostly from Japanese patients, with 64 lymph node samples from German patients. Immunohistochemistry with PAB antibody revealed small round bodies within sarcoid granulomas in 20/27 (74%) video-assisted thoracic surgery lung samples, 24/50 (48%) transbronchial lung biopsy samples, 71/81 (88%) Japanese lymph node samples, and 34/38 (89%) German lymph node samples. PAB antibody did not react with non-sarcoid granulomas in any of the 45 tuberculosis samples or the 34 samples with sarcoid reaction. In nongranulomatous areas, small round bodies detected by PAB antibody were found in alveolar macrophages of lungs and paracortical macrophages of lymph nodes from many sarcoid and some non-sarcoid patients. Large-spheroidal acid-fast bodies, Hamazaki-Wesenberg bodies, which were found in 50% of sarcoid and 15% of non-sarcoid lymph node samples, reacted with both PAB and TIG antibodies. Electron microscopy revealed that these Hamazaki-Wesenberg bodies had a single bacterial structure and lacked a cell wall with occasional protrusions from the body. The high frequency and specificity of P. acnes, detected by PAB antibody within sarcoid granulomas, indicates that this indigenous bacterium might be the cause of granuloma formation in many sarcoid patients. © 2012 USCAP, Inc. All rights reserved.

γ-Glutamyl cyclotransferase (GGCT) contributes to the γ-glutamyl cycle that regulates glutathione metabolism. Although GGCT has been implicated in several studies as a possible cancer marker, little is known about its distribution in cells and tissues. The authors investigated GGCT expression in normal tissues and tumors using Western blots and immunohistochemistry with a novel anti-GGCT monoclonal antibody. GGCT was detected in most organs and was mainly found in epithelial cells. Although the intracellular distribution was mainly cytoplasmic, in some situations, nuclear staining was strong. A significant increase in the expression of GGCT was found in tumors of the lung, esophagus, stomach, bile duct, and uterine cervix. In contrast, there was a significant decrease in expression in renal and urothelial tumors. These results suggest that GGCT may be a biomarker of tumors in a limited range of organs.

Wave intensity (WI) is a new hemodynamic index that provides information about the dynamic behavior of the heart and the vascular system and their interaction. Carotid arterial wave intensity in normal subjects has two positive peaks. The first peak, W(1), occurs during early systole, the magnitude of which increases with increases in cardiac contractility. The second peak, W(2), which occurs towards the end of ejection, is related to the ability of the left ventricle to actively stop aortic blood flow. Between the two positive peaks, a negative area, NA, is often observed, which signifies reflections from the cerebral circulation. The time interval between the R-wave of ECG and the first peak (R - W(1)) corresponds to the pre-ejection period, and that between the first and second peaks (W(1) - W(2)) corresponds to ejection time. We developed a new ultrasonic on-line system for obtaining WI and arterial stiffness (beta). The purpose of this study was (1) to report normal values of various indices derived from WI and beta measured with this system, and (2) to evaluate the intraobserver and interobserver reproducibility of the measurements. The measurement system is composed of a computer, a WI unit, and an ultrasonic machine. The WI unit gives the instantaneous change in diameter of the artery and the instantaneous mean blood velocity through the sampling gate. Using these parameters and blood pressure measured with a cuff-type manometer, the computer gives WI and beta. We applied this method to the carotid artery in 135 normal subjects. The mean values of W(1), W(2), NA, R - W(1), and W(1) - W(2) were 8 940 +/- 3 790 mmHg m/s(3), 1 840 +/- 880 mmHg m/s(3), 27 +/- 13 mmHg m/s(2), 104 +/- 14 ms, and 270 +/- 19 ms, respectively. These values did not show a significant correlation with age. The mean value of beta was 10.4 +/- 4.8 and the values significantly correlated with age (men: r = 0.66, P0.0001; women: r= 0.81, P0.0001). The reproducibility was evaluated by intraobserver intrasession (IA), intraobserver intersession (IE), and interobserver intrasession variability (IO). The reproducibility of R - W(1) and W(1) - W(2) was high: the mean coefficient of variation (mCV) of IA was less than 3%; 95% confidence limits from the mean values (CL) were less than 8% for IE and less than 4% for IO. The reproducibility of W(1) and beta was good: mCV for IA was less than 10%; CL for IE and IO were less than 17%. W(2) and NA showed a higher variability than other indices: mCV for IA was less than 13%, and CL for IE and IO were less than 36%. However, two sessions by the same observer and two sessions by different observers were not biased. Wave intensity measurements with this system are clinically acceptable.

The forces underlying left ventricular ejection were investigated by applying a wavefront analysis to blood pressure (P) and velocity (U) waveforms measured in the ascending aorta of anesthetized dogs (n = 13). Wavefronts travel forward (to the periphery) and/or backward (to the heart) after peripheral reflection. They are characterized by the rate of pressure change they cause, i.e., the time derivative of pressure (dP/dt): compression wavefronts have dP/dt0: expansion wavefronts have dP/dt0. Wave intensity is defined as (dP/dt)(dU/dt), where dU/dt is the time derivative of U. Forward wavefronts contribute positively to wave intensity and backward wavefronts contribute negatively. Therefore, wave intensity indicates whether the effects of forward wavefronts are predominant or whether those of backward wavefronts predominate in the formation of pressure and velocity waveforms. Under control conditions, wave intensity was positive in early and late systole, indicating that forward compression and expansion wavefronts dominate aortic acceleration and deceleration, respectively. Compression wave intensity was increased during inotropic stimulation by dobutamine (10-15 microg/kg per min i.v. infusion; +161% +/- 31% mean change in peak value +/- SEM (%), P0.05), and was reduced during beta-blockade by propranolol (1 mg/kg i.v. injection; -58% +/- 7%, P0.05). Expansion wave intensity was unchanged by dobutamine and propranolol (n = 6). In a separate group of animals (n = 7), expansion wave intensity was reduced during vasodilatation by nitroglycerin (0.5mg i.v. injection and 0.02 microg/kg per min infusion; -32% +/- 12%, P0.05), but was unchanged during vasoconstriction by methoxamine (2 mg i.v. injection). However, methoxamine reduced compression wave intensity (-46% +/- 14%, P0.05). These results indicate that (1) compression and expansion wavefronts generated by the left ventricle dominate acceleration and deceleration in the ascending aorta, (2) compression wave intensity is related to the inotropic state of the left ventricle, but is reduced during vasoconstriction, and (3) expansion wave intensity is reduced during vasodilatation. This time domain analysis of traveling wavefronts readily provides information concerning the dynamics of the ventriculoarterial interaction.

Objectives: The aim of the present study was to test two hypotheses: (1) the momentum of the blood flowing out of the left ventricle toward the aorta (inertia force) plays an important role in the initiation of decay and the maximum rate of decay (peak (−d P /d t )) of left ventricular pressure ( P ); (2) a normal heart itself generates the inertia force which enhances its function. Methods: The contribution of the inertia force to (−d P /d t ) was theoretically given as ρ c α , where ρ is the blood density, c the pulse wave velocity, and α the deceleration rate of aortic blood flow. The correlations of peak (−d P /d t ) with ρ c α and with the time constant ( τ ) of the pressure decay during isovolumic relaxation, which was considered to represent myocardial relaxation characteristics, were compared in seven dogs. We developed a method of grading the strength of the inertia force, using the phase loop of left ventricular pressure (d P /d t vs. P relation). The method was applied to the records of 25 patients with ischemic heart disease, from which high fidelity left ventricular pressure recordings were available. Results: The correlation of peak (−d P /d t ) with ρcα was much higher than with τ (0.75 vs. −0.46). 16 of the 25 patients showed evidence of the inertia force. However, other patients showed no inertia force. The strength of the inertia force showed a significant ( P

It is possible that the momentum of blood flowing out of the ventricle near end-systole plays an important role in the initiation of the decline and formation of the maximum rate of decline in left ventricular pressure. We hypothesize that a healthy heart utilizes this momentum of blood effectively.