Nitrogen reduction by the Fe sites of synthetic [Mo3S4Fe] cubes.

Nitrogen (N2) fixation by nature, which is a crucial process for the supply of bio-available forms of nitrogen, is performed by nitrogenase. This enzyme uses a unique transition-metal-sulfur-carbon cluster as its active-site co-factor ([(R-homocitrate)MoFe7S9C], FeMoco)1,2, and the sulfur-surrounded iron (Fe) atoms have been postulated to capture and reduce N2 (refs. 3-6). Although there are a few examples of synthetic counterparts of the FeMoco, metal-sulfur cluster, which have shown binding of N2 (refs. 7-9), the reduction of N2 by any synthetic metal-sulfur cluster or by the extracted form of FeMoco10 has remained elusive, despite nearly 50 years of research. Here we show that the Fe atoms in our synthetic [Mo3S4Fe] cubes11,12 can capture a N2 molecule and catalyse N2 silylation to form N(SiMe3)3 under treatment with excess sodium and trimethylsilyl chloride. These results exemplify the catalytic silylation of N2 by a synthetic metal-sulfur cluster and demonstrate the N2-reduction capability of Fe atoms in a sulfur-rich environment, which is reminiscent of the ability of FeMoco to bind and activate N2.

Sarcoidosis and sarcoidal foreign body reaction after permanent eye makeup application: Analysis by immunohistochemistry with commercially available antibodies specific to Cutibacterium acnes and Mycobacteria.

We report two cases of eyebrow granulomas in patients who underwent a permanent eye makeup procedure. A rash was observed 16 months after the procedure in Case 1, and 10 years after the procedure in Case 2. Histopathologically, both patients exhibited noncaseating epithelioid cell granulomas. In Case 1, most of the black-brown granules of the permanent makeup were not present in the granulomas but were localized in the upper dermis. In contrast, in Case 2, some of the black-brown granules were phagocytized in the granulomas, preferentially within the giant cells. Based on systemic examinations, the patients from Cases 1 and 2 were diagnosed with sarcoidosis and sarcoidal foreign body reaction, respectively. To clarify the pathogenesis of our cases, we performed immunohistochemistry using commercially available monoclonal antibodies specific to Cutibacterium acnes, previously Propionibacterium acnes (PAB), and Mycobacteria (LAM antibody). PAB antibody results were positive in granulomas only in Case 1, and the LAM antibody results were negative in both cases. Immunohistochemical detection of C. acnes in granulomas could provide useful information for differentiating between cutaneous sarcoidosis and sarcoidal foreign body reactions.

Homeobox transcription factor engrailed homeobox 1 is a possible diagnostic marker for adenoid cystic carcinoma and polymorphous adenocarcinoma.

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.

Implication of Ivabradine Therapy in Up-Titrating Beta-Blocker Dose in Patients with Systolic Dysfunction.

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 fraction < 50%, sinus rhythm, heart rate > 75 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 Simple Predictive Marker in Cardiac Resynchronization Therapy Recipients: Prominent S-Wave in Right Precordial Leads.

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 < 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.

Cancer gland rupture as a potential risk factor for lymph node metastasis in early colorectal adenocarcinoma with deep submucosal invasion.

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.

Propionibacterium acnes-associated chronic hypertrophic pachymeningitis followed by refractory otitis media: a case report.

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.

Propionibacterium acnes-associated sarcoidosis complicated by acute bird-related hypersensitivity pneumonitis.

BACKGROUND: The number of reports on sarcoidosis complicated by hypersensitivity pneumonitis (HP) is limited, and most describe cases complicated by chronic bird-related HP. Here, we present for the first time a case with Propionibacterium acnes-associated sarcoidosis complicated by acute bird-related HP. CASE PRESENTATION: A 62-year-old man with a past medical history of sarcoidosis was admitted to our department, and chest computed tomography showed diffuse ground-glass opacities, which appeared as he rapidly increased the number of pigeons he kept for a competition. Random transbronchial lung biopsy revealed well-formed non-caseating epithelioid granulomas, which contained positively stained substances on immunohistochemistry using the PAB antibody, a specific monoclonal antibody against P. acnes lipoteichoic acid. Poorly formed non-caseating granulomas without positively stained substances were also detected. CONCLUSION: We describe the successful identification of this exceptionally rare case of sarcoidosis complicated by acute bird-related HP in which two morphologically and immunohistologically different types of granulomas were present in the same lung.

Adenocarcinoma within anorectal fistulae: different clinicopathological characteristics between Crohn's disease-associated type and the usual type.

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.

CHAC1 overexpression in human gastric parietal cells with Helicobacter pylori infection in the secretory canaliculi.

BACKGROUND: Cation transport regulator 1 (CHAC1), a newly discovered enzyme that degrades glutathione, is induced in Helicobacter pylori (H. pylori)-infected gastric epithelial cells in culture. The CHAC1-induced decrease in glutathione leads to an accumulation of reactive oxygen species and somatic mutations in TP53. We evaluated the possible correlation between H. pylori infection and CHAC1 expression in human gastric mucosa. MATERIALS AND METHODS: Both fresh-frozen and formalin-fixed paraffin-embedded tissue samples of gastric mucosa with or without H. pylori infection were obtained from 41 esophageal cancer patients that underwent esophago-gastrectomy. Fresh samples were used for real-time polymerase chain reaction for H. pylori DNA and CHAC1 mRNA, and formalin-fixed samples were used for immunohistochemistry with anti-CHAC1 and anti-H. pylori monoclonal antibodies. Double-enzyme or fluorescence immunohistochemistry and immuno-electron microscopy were used for further analysis. RESULTS: Significant CHAC1 overexpression was detected in H. pylori-infected parietal cells that expressed the human proton pump/H,K-ATPase α subunit, whereas a constitutively low level of CHAC1 mRNA expression was observed in the other samples regardless of the H. pylori infection status, reflecting the weak CHAC1 expression detected by immunohistochemistry in the fundic-gland areas. Immuno-electron microscopy revealed intact H. pylori cells in the secretory canaliculi of infected parietal cells. Some parietal cells exhibited positive nuclear signals for Ki67 in the neck zone of the gastric fundic-gland mucosa with H. pylori infection. CONCLUSION: Cation transport regulator 1 overexpression in H. pylori-infected parietal cells may cause the H. pylori-induced somatic mutations that contribute to the development of gastric cancer.

Cubane-Type [Mo3 S4 M] Clusters with First-Row Groups†4-10 Transition-Metal Halides Supported by C5 Me5 Ligands on Molybdenum.

A synthetic protocol was developed for a series of cubane-type [Mo3 S4 M] clusters that incorporate halides of first-row transition metals (M) from Groups 4-10. This protocol is based on the anionic cluster platform [Cp*3 Mo3 S4 ]- ([1]- ; Cp*=η5 -C5 Me5 ), which crystallizes when K(18-crown-6) is used as the counter cation. Treatment of in situ-generated [1]- with such transition-metal halides led to the formation of [Mo3 S4 M] clusters, in which the M/halide ratio gradually changes from 1:2 to 1:1.5 and to 1:1, when moving from early to late transition metals. This trend suggests a tendency for early transition metals to tolerate higher oxidation states and adopt larger ionic radii relative to late transition metals. The properties of the [Mo3 S4 Fe] cluster 6 a were investigated in detail by using 57 Fe Mössbauer spectroscopy and computational methods.

Saddle nose with sarcoidosis: "A great imitator" of relapsing polychondritis.

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.

Protein antigen of bird-related hypersensitivity pneumonitis in pigeon serum and dropping.

BACKGROUND: Avian antigen is a common cause of hypersensitivity pneumonitis (HP). Inhalation challenge with pigeon serum and pigeon dropping extract (PDE) elicits a hypersensitivity reaction in patients with bird-related hypersensitivity pneumonitis (BRHP), but the antigenic components in these materials have yet to be fully elucidated. METHOD: Pigeon serum, pigeon intestine homogenates, and PDE were immunoblotted with serum samples from 8 patients with BRHP, 2 patients with summer-type HP, 2 patients with humidifier lung, and 3 healthy volunteers. Among the protein spots found in both pigeon serum and PDE, those that reacted with sera from BRHP patients were identified by mass spectrometry. Immunoassays using recombinant protein were performed to confirm the antigenicity of the identified protein. Cytokine production by peripheral blood mononuclear cells (PBMCs) stimulated with recombinant protein was also assessed. RESULTS: Immunoglobulin lambda-like polypeptide-1 (IGLL-1) was identified from all spots on 2-DE immunoblots of both pigeon serum and PDE. The BRHP patients exhibited higher levels of serum IgG antibody against the recombinant IGLL-1 (rIGLL-1) compared to the control subjects, as well as a stronger PBMCs proliferative response to rIGLL-1. Cytokine production by PBMCs from BRHP patients after rIGLL-1 exposure indicated that the protein could induce Th1 prone immune responses: an increase in TNF-α and an absence of elevated IL-10 production. CONCLUSIONS: Pigeon IGLL-1 was identified as the BRHP antigen present in both pigeon serum and PDE.

Construction of Condensed Polycyclic Aromatic Frameworks through Intramolecular Cycloaddition Reactions Involving Arynes Bearing an Internal Alkyne Moiety.

Facile synthetic methods for condensed polycyclic aromatic compounds via aryne intermediates are reported. The generation of arynes bearing a (3-arylpropargyl)oxy group from the corresponding o-iodoaryl triflate-type precursors efficiently afforded arene-fused oxaacenaphthene derivatives, which were formed through intramolecular [2+4] cycloaddition. Extending the method to the generation of arynes bearing a 1,3-diyne moiety led to a continuous generation of naphthalyne intermediate through the hexadehydro Diels-Alder reaction involving the aryne triple bond. This novel type of aryne-relay chemistry enabled the synthesis of a unique aminoarylated oxaacenaphthene derivative and highly ring-fused anthracene derivatives.

Normal 123 I-MIBG uptake areas may be associated with hyperinnervation and arrhythmia risk in phenol model rabbit hearts.

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.

Adverse Events Requiring Hospitalization Following Catheter Ablation for Atrial Fibrillation in Heart Failure with versus without Systolic Dysfunction.

BACKGROUND: The safety and efficacy of atrial fibrillation (AF) ablation in individuals with heart failure (HF) with preserved ejection fraction (EF), particularly concerning the occurrence of post-procedural adverse events necessitating hospitalization, including anticoagulant-associated major bleeding, still lack conclusive determination. METHODS: Data from patients with HF and AF who underwent catheter ablation for AF between 2019 and 2022 at our institution were retrospectively reviewed. All participants were divided into an EF < 50% group or an EF ≥ 50% group according to their baseline left ventricular EF. The composite incidence of the clinical events following catheter ablation was compared between the two groups: (1) all-cause death, (2) HF hospitalization, (3) stroke or systemic embolism, and (4) major bleeding. RESULTS: A total of 122 patients (75 years old, 68 male) were included. Of them, 62 (50.8%) patients had an EF ≥ 50%. EF ≥ 50% was an independent predictor of the composite endpoint (adjusted odds ratio 6.07, 95% confidence interval 1.37-26.99, p = 0.018). The incidences of each adverse event were not significantly different between the two groups, except for a higher incidence of major bleeding in the EF ≥ 50% group (12.7% vs. 0%, p = 0.026). CONCLUSIONS: Among patients with HF coupled with AF, the incidence of adverse events following AF ablation proved notably elevated in patients with EF ≥ 50% in contrast to their counterparts with EF < 50%. This disparity primarily stems from a heightened occurrence of major bleeding within the EF ≥ 50% cohort. The strategy to reduce adverse events, especially in patients with EF ≥ 50%, remains the next concern.

An autopsy case of an adult woman with Rapid-Onset Obesity with Hypoventilation, Hypothalamic, Autonomic Dysregulation, and Neuroendocrine Tumors (ROHHAD(NET)) syndrome developing nonalcoholic steatohepatitis and hepatocellular carcinoma: A case report.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is an important etiology of hepatocellular carcinoma (HCC), and there is no established therapy for this syndrome. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor (ROHHAD(NET)) is an extremely rare syndrome considered to be life-threatening, with death occurring around 10 years of age. We present the oldest known autopsy case of this syndrome that developed HCC. This case provided important information on not only improving the course of this syndrome, but also understanding the natural history and therapeutic modalities of NASH and HCC. METHODS: The patient was diagnosed with ROHHAD(NET) syndrome in childhood, and liver cirrhosis due to NASH was diagnosed at age 17. HCC was detected at age 20, and embolization and irradiation were performed. At age 21, she died from accidental acute pancreatitis and subsequent liver failure and pulmonary hemorrhage. RESULTS: Rapid onset of obesity, hypoventilation, and hypothalamic disturbance appeared in childhood and was diagnosed as this syndrome. At age 17, liver cirrhosis due to NASH was diagnosed by liver biopsy, and at age 20, HCC was diagnosed by imaging. Transarterial chemoembolization and irradiation were performed, and the HCC was well controlled for a year. CONCLUSION: At age 21, she died from accidental acute pancreatitis, subsequent liver failure and pulmonary hemorrhage. Autopsy revealed that the HCC was mostly necrotized. This case was valuable not only for other ROHHAD(NET) syndrome cases, but also in improving our understanding of the natural history of NASH and HCC.