Machine learning-based reproducible prediction of type 2 diabetes subtypes.

AIMS/HYPOTHESIS: Clustering-based subclassification of type 2 diabetes, which reflects pathophysiology and genetic predisposition, is a promising approach for providing personalised and effective therapeutic strategies. Ahlqvist's classification is currently the most vigorously validated method because of its superior ability to predict diabetes complications but it does not have strong consistency over time and requires HOMA2 indices, which are not routinely available in clinical practice and standard cohort studies. We developed a machine learning (ML) model to classify individuals with type 2 diabetes into Ahlqvist's subtypes consistently over time. METHODS: Cohort 1 dataset comprised 619 Japanese individuals with type 2 diabetes who were divided into training and test sets for ML models in a 7:3 ratio. Cohort 2 dataset, comprising 597 individuals with type 2 diabetes, was used for external validation. Participants were pre-labelled (T2Dkmeans) by unsupervised k-means clustering based on Ahlqvist's variables (age at diagnosis, BMI, HbA1c, HOMA2-B and HOMA2-IR) to four subtypes: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD). We adopted 15 variables for a multiclass classification random forest (RF) algorithm to predict type 2 diabetes subtypes (T2DRF15). The proximity matrix computed by RF was visualised using a uniform manifold approximation and projection. Finally, we used a putative subset with missing insulin-related variables to test the predictive performance of the validation cohort, consistency of subtypes over time and prediction ability of diabetes complications. RESULTS: T2DRF15 demonstrated a 94% accuracy for predicting T2Dkmeans type 2 diabetes subtypes (AUCs ≥0.99 and F1 score [an indicator calculated by harmonic mean from precision and recall] ≥0.9) and retained the predictive performance in the external validation cohort (86.3%). T2DRF15 showed an accuracy of 82.9% for detecting T2Dkmeans, also in a putative subset with missing insulin-related variables, when used with an imputation algorithm. In Kaplan-Meier analysis, the diabetes clusters of T2DRF15 demonstrated distinct accumulation risks of diabetic retinopathy in SIDD and that of chronic kidney disease in SIRD during a median observation period of 11.6 (4.5-18.3) years, similarly to the subtypes using T2Dkmeans. The predictive accuracy was improved after excluding individuals with low predictive probability, who were categorised as an 'undecidable' cluster. T2DRF15, after excluding undecidable individuals, showed higher consistency (100% for SIDD, 68.6% for SIRD, 94.4% for MOD and 97.9% for MARD) than T2Dkmeans. CONCLUSIONS/INTERPRETATION: The new ML model for predicting Ahlqvist's subtypes of type 2 diabetes has great potential for application in clinical practice and cohort studies because it can classify individuals with missing HOMA2 indices and predict glycaemic control, diabetic complications and treatment outcomes with long-term consistency by using readily available variables. Future studies are needed to assess whether our approach is applicable to research and/or clinical practice in multiethnic populations.

Young-onset type 2 diabetes mellitus enhances proteinuria, but not glomerular filtration rate decline: A Japanese cohort study.

AIMS/INTRODUCTION: The time course of chronic kidney disease in young-onset type 2 diabetes mellitus remains unclear. We compared the trajectories of proteinuria and estimated glomerular filtration rate (eGFR) decline between young-onset (aged ≤40 years) and late-onset (aged >40 years) type 2 diabetes mellitus in a Japanese multicenter cohort. MATERIALS AND METHODS: Participants without diabetic kidney disease were divided into two groups according to age at diagnosis: young- and late-onset. The primary endpoint was eGFR <60 mL/min/1.73 m2, proteinuria or both. Multivariable Cox proportional hazards were calculated to estimate incidence. RESULTS: Among 626 participants with type 2 diabetes mellitus, 78 (12.4%) had young-onset and 548 (87.6%) had late-onset diabetes. The incidence of eGFR <60 mL/min/1.73 m2 was lower (16.7% vs 33.5%, P = 0.003), but that of proteinuria was higher (46.2% vs 28.9%, P = 0.002) in the young-onset type 2 diabetes mellitus group. The Kaplan-Meyer curve showed that young-onset type 2 diabetes mellitus was associated with a decreased hazard ratio (HR) for eGFR <60 mL/min/1.73 m2 and an increased HR for proteinuria compared with late-onset type 2 diabetes mellitus. In the multivariate Cox analysis, young-onset type 2 diabetes mellitus increased the HR (95% confidence interval) of proteinuria (1.53, 95% confidence interval 1.03-2.26), but did not change the eGFR <60 mL/min/1.73 m2 HR. CONCLUSIONS: Young-onset type 2 diabetes mellitus has a lower HR of eGFR <60 mL/min/1.73 m2 and an increased HR of proteinuria compared with late-onset type 2 diabetes mellitus, indicating that young-onset type 2 diabetes mellitus has a different time course for the development of proteinuria and subsequent eGFR decline.

The effect of native language and bilingualism on multimodal perception in speech: A study of audio-aerotactile integrationa).

Previous studies of speech perception revealed that tactile sensation can be integrated into the perception of stop consonants. It remains uncertain whether such multisensory integration can be shaped by linguistic experience, such as the listener's native language(s). This study investigates audio-aerotactile integration in phoneme perception for English and French monolinguals as well as English-French bilingual listeners. Six step voice onset time continua of alveolar (/da/-/ta/) and labial (/ba/-/pa/) stops constructed from both English and French end points were presented to listeners who performed a forced-choice identification task. Air puffs were synchronized to syllable onset and randomly applied to the back of the hand. Results show that stimuli with an air puff elicited more "voiceless" responses for the /da/-/ta/ continuum by both English and French listeners. This suggests that audio-aerotactile integration can occur even though the French listeners did not have an aspiration/non-aspiration contrast in their native language. Furthermore, bilingual speakers showed larger air puff effects compared to monolinguals in both languages, perhaps due to bilinguals' heightened receptiveness to multimodal information in speech.

Role of perirenal adiposity in renal dysfunction among CKD individuals with or without diabetes: a Japanese cross-sectional study.

INTRODUCTION: It remains unclear whether increased perirenal fat (PRF) accumulation is equally related to renal involvement in patients with and without diabetes mellitus (DM). We evaluated the association between PRF volume (PRFV) and low glomerular filtration rate (GFR) and proteinuria in people with or without type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: We performed a cross-sectional analysis of 473 individuals without T2DM (non-DM, n=202) and with T2DM (DM, n=271). PRFV (cm3), obtained from non-contrast CT, was indexed as PRF index (PRFV/body surface area, cm3/m2). Multivariate-adjusted models were used to determine the ORs of PRFV and PRFV index for detecting estimated GFR (eGFR) decrease of <60 mL/min/1.73 m2 proteinuria onset, or both. RESULTS: Although body mass index (BMI), visceral fat area, and waist circumference were comparable between the non-DM and DM groups, kidney volume, PRFV, and PRFV index were higher in individuals with T2DM than in those without T2DM. In the multivariate analysis, after adjusting for age, sex, BMI, hypertension, smoking history, and visceral fat area ≥100 cm2, the cut-off values of PRFV index were associated with an eGFR<60 in individuals with DM (OR 6.01, 95% CI 2.20 to 16.4, p<0.001) but not in those without DM. CONCLUSIONS: PRFV is associated with low eGFR in patients with T2DM but not in those without T2DM. This suggests that PRF accumulation is more closely related to the onset and progression of diabetic kidney disease (DKD) than non-DKD. Clarifying the mechanisms through which PRF influences DKD development could pave the way for novel prevention and treatment strategies.

Synthesis and biological evaluation of novel 18F-labeled 2,4-diaminopyrimidine derivatives for detection of ghrelin receptor in the brain.

The ghrelin receptor (GHSR) is known to regulate various physiological processes including appetite, food intake, and growth hormone release. Its expression is mainly observed in the brain, pancreas, stomach, and intestine. However, the functions of the receptor have not been fully elucidated. GHSR imaging with positron emission tomography (PET) is expected to further understanding of the functions and pathologies of the receptor. In this study, we newly designed and synthesized diaminopyrimidine derivatives ([18F]BPP-1 and [18F]BPP-2) and evaluated their utility as novel PET probes targeting GHSR. In in vitro competitive binding assays, the binding affinity of BPP-2 for GHSR (Ki = 274 nM) was comparable to that of the diaminopyimidine lead compound Abb8a (Ki = 109 nM). In a biodistribution study using normal mice, [18F]BPP-2 displayed low uptake in the brain and moderate uptake in the pancreas, but high radioactivity accumulation in bone was observed due to its defluorination in vivo. Taken together, although further improvement of the pharmacokinetics is needed, the diaminopyrimidine scaffold has potential for the development of useful GHSR-targeting PET probes.

Immunoexpression of SIRT1, 6, and 7 in oral leukoplakia and oral squamous cell carcinoma.

Sirtuins (SIRTs) are a family of proteins involved in the metabolic process responsible for extending the lifespan. The role of SIRT1, 6, and 7 in oral squamous cell carcinoma (OSCC) and oral leukoplakia (OLP), one of its precursors, is still elusive. In this study, 82 OLP and 77 OSCC were immunohistochemically examined for SIRT1, 6, and 7. Stained sections were thoroughly scanned and evaluated using a digital image analysis program. The SIRT1, 6, and 7 expressions were detected in the nuclei of epithelial and carcinoma cells in various degrees. Afterward, any correlations among SIRTs, including associations with clinicopathological features and the Kaplan-Meier curves were analyzed. OSCC demonstrated significantly higher SIRT1 expression than OLP, while non-dysplastic lesions showed significantly higher SIRT6 expression than other lesions. A strong correlation was observed between SIRT6 and 7 in OLP, SIRT1 and 6 in in OSCC and in SIRT6 and 7 when all lesion types were considered. There were no significant differences between SIRTs reactivity and the clinical features in OLP. For OSCC, SIRT1 and 6 was found to be directly associated with site of the lesion, while SIRT7 showed a direct relationship between gender, stromal lymphocytic infiltration, and depth of the invasion. OSCC with high SIRT7 expression revealed a slightly lower survival probability, although not statistically significant (p = 0.1019). Our findings suggest that SIRT1, 6, and 7 may play correlated and diverse roles in the development and advancement of OSCC.

Identification, characterization, and application of a d-cysteine desulfhydrase from rice seed (Oryza sativa L.).

Cysteine desulfhydrases decompose cysteine to produce pyruvate, ammonium, and hydrogen sulfide. Using d-cysteine (D-cys) as a substrate, an enzyme with this activity was purified from rice seeds and identified at the native protein level. MALDI-TOF-MS analysis of its tryptic peptides revealed a 426 amino acid protein encoded by the OsDCD1 gene (Os02g0773300). Recombinant OsDCD1 (rOsDCD1) was expressed in Escherichia coli cells and purified as a single protein by column chromatography. Gel filtration column chromatography indicated that the native enzyme was a homodimer. The enzyme exhibited maximum catalytic activity at approximately pH 7.5 and 40 °C and was stable at pH 5.5-7.5 and < 37 °C. Kinetics analysis indicated Km and Vmax values for D-cys of 136 µM and 45.5 µmol/min/mg protein, respectively. In contrast, l-cysteine (L-cys) acted as an inhibitor with mixed non-competitive inhibition. Based on the substrate specificity of rOsDCD1, the amount of D-cys in rice flour was quantified. Even in the presence of up to 1 mM L-cys, the quantification of low concentrations of D-cys was unaffected. We demonstrate for the first time that the amount of D-cys in rice flour varies in the range of 0.76-0.93 µmol/g depending on the variety.

Antagonistic interactions between odorants alter human odor perception.

The olfactory system uses hundreds of odorant receptors (ORs), the largest group of the G-protein-coupled receptor (GPCR) superfamily, to detect a vast array of odorants. Each OR is activated by specific odorous ligands, and like other GPCRs, antagonism can block activation of ORs. Recent studies suggest that odorant antagonisms in mixtures influence olfactory neuron activities, but it is unclear how this affects perception of odor mixtures. In this study, we identified a set of human ORs activated by methanethiol and hydrogen sulfide, two potent volatile sulfur malodors, through large-scale heterologous expression. Screening odorants that block OR activation in heterologous cells identified a set of antagonists, including ß-ionone. Sensory evaluation in humans revealed that ß-ionone reduced the odor intensity and unpleasantness of methanethiol. Additionally, suppression was not observed when methanethiol and ß-ionone were introduced simultaneously to different nostrils. Our study supports the hypothesis that odor sensation is altered through antagonistic interactions at the OR level.

Effect of dapagliflozin on 24-hour glycemic variables in Japanese patients with type 2 diabetes mellitus receiving basal insulin supported oral therapy (DBOT): a multicenter, randomized, open-label, parallel-group study.

INTRODUCTION: This study aimed to evaluate the impacts of dapagliflozin on 24-hour glucose variability and diabetes-related biochemical variables in Japanese patients with type 2 diabetes who had received basal insulin supported oral therapy (BOT). RESEARCH DESIGN AND METHODS: Changes in mean daily blood glucose level before and after 48-72 hours of add-on or no add-on of dapagliflozin (primary end point) and diabetes-related biochemical variables and major safety variables during the 12 weeks (secondary end point) were evaluated in the multicenter, randomized, two-arm, open-label, parallel-group comparison study. RESULTS: Among 36 participants, 18 were included in the no add-on group and 18 were included in the dapagliflozin add-on group. Age, gender, and body mass index were comparable between the groups. There were no changes in continuous glucose monitoring metrics in the no add-on group. In the dapagliflozin add-on group, mean glucose (183-156 mg/dL, p=0.001), maximum glucose (300-253, p<0.01), and SD glucose (57-45, p<0.05) decreased. Time in range increased (p<0.05), while time above the range decreased in the dapagliflozin add-on group but not in the no add-on group. After 12-week treatment with dapagliflozin add-on, 8-hydroxy-2'-deoxyguanosine (8OHdG), as well as hemoglobin A1c (HbA1c), decreased. CONCLUSIONS: This study showed that the mean daily blood glucose and other daily glucose profiles were amended after 48-72 hours of dapagliflozin add-on in Japanese patients with type 2 diabetes who received BOT. The diabetes-related biochemical variables such as HbA1c and urinary 8OHdG were also obtained during the 12 weeks of dapagliflozin add-on without major adverse events. A preferable 24-hour glucose profile in 'time in ranges' and an improvement in reactive oxygen species by dapagliflozin warrant us to evaluate these benefits in larger clinical studies. TRIAL REGISTRATION NUMBER: UMIN000019457.

Brain p3-Alcß peptide restores neuronal viability impaired by Alzheimer's amyloid ß-peptide.

We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3-Alcß37 is generated from the neuronal protein alcadein ß through cleavage of γ-secretase, similar to the generation of amyloid ß (Aß) derived from Aß-protein precursor/APP. Neurotoxicity by Aß oligomers (Aßo) is the prime cause prior to the loss of brain function in AD. We found that p3-Alcß37 and its shorter peptide p3-Alcß9-19 enhanced the mitochondrial activity of neurons and protected neurons against Aßo-induced toxicity. This is due to the suppression of the Aßo-mediated excessive Ca2+ influx into neurons by p3-Alcß. Successful transfer of p3-Alcß9-19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human Aß42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Aß and reduced p3-Alcß37 levels, the administration of p3-Alcß9-19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.

Effective treatment with mepolizumab in a patient with severe eosinophilic granulomatosis with polyangiitis complicated with small intestine perforation.

Eosinophilic granulomatosis with polyangiitis (EGPA) is systemic vasculitis caused by eosinophilia affecting small to medium-sized blood vessels, which damages the organs. Antineutrophil cytoplasmic antibody-associated vasculitis EGPA treatment guidelines added anti-interleukin-5 antibody mepolizumab to the standard treatment protocol for active-non-severe EGPA based on the MIRRA study. Nevertheless, the role of mepolizumab in treating patients with active severe EGPA has not been established. We treated a patient with EGPA complicated with small intestine perforation using steroid pulse intravenous, high-dose glucocorticoids, intravenous high-dose immunoglobulin therapy, and mepolizumab without immunosuppression agents; the patient went into remission, suggesting that mepolizumab is an effective therapeutic agent that could lead to remission in severe EGPA.

A nutritional assessment tool, GNRI, predicts sarcopenia and its components in type 2 diabetes mellitus: A Japanese cross-sectional study.

Background: There are few reports evaluating the relationship between undernutrition and the risk of sarcopenia in type 2 diabetes mellitus (T2DM) patients. Objective: We investigated whether undernutritional status assessed by the geriatric nutritional risk index (GNRI) and controlling nutritional status (CONUT) were associated with the diagnosis of sarcopenia. Methods: This was a cross-sectional study of Japanese individuals with T2DM. Univariate or multivariate logistic regression analysis was performed to assess the association of albumin, GNRI, and CONUT with the diagnosis of sarcopenia. The optimal cut-off values were determined by the receiver operating characteristic (ROC) curve to diagnose sarcopenia. Results: In 479 individuals with T2DM, the median age was 71 years [IQR 62, 77], including 264 (55.1%) men. The median duration of diabetes was 17 [11, 23] years. The prevalence of sarcopenia was 41 (8.6%) in all, 21/264 (8.0%) in men, and 20/215 (9.3%) in women. AUCs were ordered from largest to smallest as follows: GNRI > albumin > CONUT. The cut-off values of GNRI were associated with a diagnosis of sarcopenia in multiple logistic regression analysis (odds ratio 9.91, 95% confidential interval 5.72-17.2), P < 0.001. The superiority of GNRI as compared to albumin and CONUT for detecting sarcopenia was also observed in the subclasses of men, women, body mass index (BMI) < 22, and BMI ≥ 22. Conclusions: Results showed that GNRI shows a superior diagnostic power in the diagnosis of sarcopenia. Additionally, its optimal cut-off points were useful overall or in the subclasses. Future large and prospective studies will be required to confirm the utility of the GNRI cut-off for undernutrition individuals at risk for sarcopenia.

[Clinical Features of Endocrine Disorders with Immune Checkpoint Inhibitor in Patients with Non-Small Cell Lung Cancer].

Immune checkpoint inhibitors(ICIs)could cause immune-related adverse events(irAEs), of which endocrine disorders are relatively common. Symptoms include fatigue, anorexia, and shock, making diagnosis and treatment difficult. This study aimed to analyze the characteristics of patients with non-small cell lung cancer concomitant with endocrine disorders as irAEs. In total, 83 patients who were administered ICIs for advanced or postoperative recurrent non-small cell lung cancer between February 2016 and February 2021 were identified. We retrospectively studied the clinical course and findings of 7 patients who developed endocrine disorders after treatment. Four patients had hypopituitarism, and 3 patients had thyroid dysfunctions. There were 6 male patients and 1 female patient. Regarding anticancer agents, 5 patients received ICI alone, and 2 patients received ICI plus cytotoxic chemotherapies. The patients received treatment from the irAE treatment team in our hospital, and 5 of 7 patients could were able to be readministered ICIs. Endocrine disorders as irAEs require collaboration with specialized departments for early diagnosis and treatment.

Accumulation of amyloid-ß in the brain of mouse models of Alzheimer's disease is modified by altered gene expression in the presence of human apoE isoforms during aging.

Apolipoprotein E4 (apoE4) is a risk factor for Alzheimer's disease (AD). Here, we investigated brain amyloid-ß (Aß) accumulation throughout the aging process in an amyloid precursor protein (APP) knock-in (KI) mouse model of AD that expresses human APPNL-G-F with or without human apoE4 or apoE3. Brain Aß42 levels were significantly lower in 9-month-old mice that express human isoforms of apoE than in age-matched APP-KI control mice. Linear accumulation of Aß42 began in 5-month-old apoE4 mice, and a strong increase in Aß42 levels was observed in 21-month-old apoE3 mice. Aß42 levels in cerebroventricular fluid were higher in apoE3 than in apoE4 mice at 6-7 months of age, suggesting that apoE3 is more efficient at clearing Aß42 than apoE4 at these ages. However, apoE3 protein levels were lower than apoE4 protein levels in the brains of 21-month-old apoE3 and apoE4 mice, respectively, which may explain the rapid increase in brain Aß42 burden in apoE3 mice. We identified genes that were downregulated in a human apoE-dependent (apoE4 > apoE3) and age-dependent (apoE3 = apoE4) manner, which may regulate brain Aß burden and/or AD progression. Analysis of gene expression in AD mouse models helps identify molecular mechanisms of pleiotropy by the human APOE gene during aging.

Clinical differences among patients with myeloperoxidase-antineutrophil cytoplasmic antibody-positive interstitial lung disease.

INTRODUCTION: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and idiopathic interstitial lung diseases (IIPs) are positive for myeloperoxidase (MPO)-ANCA. MPO-ANCA-positive vasculitis mainly comprises microscopic polyangiitis (MPA) and unclassifiable vasculitis. These diseases are frequently complicated by interstitial lung disease (ILD). Few studies have reported the clinical differences between the subtypes of MPO-ANCA-positive ILD. Therefore, this study aimed to examine the clinical findings and courses of MPO-ANCA-positive ILD. METHOD: This retrospective study enrolled 100 patients with MPO-ANCA-positive ILD who were categorized into three groups: MPA (n = 44), unclassifiable vasculitis (n = 29), and IIP (n = 27). Our study compared the clinical findings and prognosis of these patients and analyzed the poor prognostic factors. Furthermore, we assessed the association between the patients with and without acute exacerbation of ILD (AE-ILD). RESULTS: Our study found clinical differences in serum markers, clinical symptoms, and treatment regimens among the three groups. ILD complications, as the main cause of death, differed among the three groups (P = 0.04). Patients with unclassifiable vasculitis showed higher survival rates than those with IIP (P = 0.046). Patients with AE-ILD showed fewer general symptoms (P = 0.02) and lower survival rates (P < 0.01) than those without AE-ILD. In multivariate analysis, AE-ILD development was a strong poor prognostic factor for MPO-ANCA-positive ILD. CONCLUSIONS: The subtypes of MPO-ANCA-positive ILD have different clinical features and prognoses. Patients who develop AE-ILD require careful evaluation of clinical courses. Key Points • In myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive interstitial lung disease (ILD), patients with unclassifiable vasculitis showed a better prognosis than those with idiopathic ILD.. • Development of acute exacerbation in ILD was a strong poor prognostic factor in patients with MPO-ANCA-positive ILD..

Deletion of miR-150 Prevents Spontaneous T Cell Proliferation and the Development of Colitis.

Background and Aims: To examine the roles of microRNAs in the development of colitis, we conducted the RNA-sequencing studies using RNA derived from normal and colitogenic CD4+ T cells. Colitogenic CD4+ T cells demonstrated the increased expression of miR-150. We focused on the involvement of miR-150 in the colitis. Methods: We crossed miR-150 knockout mice and T-cell-specific Rap1KO mice, which is colitis model mice and spontaneously develop the colitis with tubular adenomas in microbiota-dependent manner. Results: MiR-150 silencing completely inhibited the expansion of pathogenic Th17 cells and the development of colitis. Conclusion: MiR-150 is a potential therapeutic target of inflammatory bowel diseases.

A pregnant woman with severe dyspnoea.

Preterm delivery is a feasible option in the third trimester of pregnancy in the treatment of pregnant women with acute respiratory distress syndrome due to miliary tuberculosis with respiratory failure https://bit.ly/3stKOzj.

Characterization of bioactive substances involved in the induction of bone augmentation using demineralized bone sheets.

PURPOSE: To investigate the bone augmentation ability of demineralized bone sheets mixed with allogeneic bone with protein fractions containing bioactive substances and the interaction between coexisting bioactive substances and proteins. METHODS: Four types of demineralized bone sheets mixed with allogeneic bone in the presence or absence of bone proteins were created. Transplantation experiments using each demineralized bone sheet were performed in rats, and their ability to induce bone augmentation was analysed by microcomputed tomography images. Bioactive substances in bone proteins were isolated by heparin affinity chromatography and detected by the measurement of alkaline phosphatase activity in human periodontal ligament cells and dual luciferase assays. Noncollagenous proteins (NCPs) coexisting with the bioactive substances were identified by mass spectrometry, and their interaction with bioactive substances was investigated by in vitro binding experiments. RESULTS: Demineralized bone sheets containing bone proteins possessed the ability to induce bone augmentation. Bone proteins were isolated into five fractions by heparin affinity chromatography, and transforming growth factor-beta (TGF-ß) was detected in the third fraction (Hep-c). Dentin matrix protein 1 (DMP1), matrix extracellular phosphoglycoprotein (MEPE), and biglycan (BGN) also coexisted in Hep-c, and the binding of these proteins to TGF-ß increased TGF-ß activity by approximately 14.7% to 32.7%. CONCLUSIONS: Demineralized bone sheets are capable of inducing bone augmentation, and this ability is mainly due to TGF-ß in the bone protein mixed with the sheets. The activity of TGF-ß is maintained when binding to bone NCPs such as DMP1, MEPE, and BGN in the sheets.

Ectopic adrenocorticotropic hormone-secreting carcinoid with solitary cryptococcosis in the lungs.

BACKGROUND: Carcinoid tumors can on rare occasions ectopically produce adrenocorticotropic hormone (ACTH), causing Cushing's syndrome, and patients could become immunocompromised. Care must therefore be taken regarding infectious complications. In particular, ACTH-producing pulmonary carcinoid is not easy to diagnose by itself, and when combined with pulmonary nodules as infectious foci, each is very difficult to diagnose. CASE: The patient was a 71-year-old woman with refractory diabetes. She showed clinical symptoms of Cushing's syndrome during treatment for diabetes and ectopic ACTH production was suspected based on biochemical and imaging tests. Nodules were identified in the left lung apex and lingual segment. Examination of resected nodules revealed that the nodule in the apex was pulmonary cryptococcosis, while the nodule in the lingual segment represented typical carcinoid. After surgery, clinical symptoms, laboratory findings, and diabetes all improved. CONCLUSION: We present this very instructive case in terms of the difficulty of diagnosing ACTH-producing tumors, the possibility of infection complicating the immunodeficiency caused by ACTH-producing tumors, and the surgical strategy.