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Objective: Intracellular amyloid β-protein (Aβ) contributes to neurodegeneration in Alzheimer disease (AD). Apomorphine (APO) is a dopamine receptor agonist for Parkinson disease and also protects against oxidative stress. Efficacy of APO for an AD mouse model and effects of APO on cell cultures are studied.Methods: The triple transgenic AD mouse model (3xTg-AD) has 2 familial AD-related gene mutations (APP(KM670/671NL) /PS1(M146V)) and a tau gene mutation (Tau(P301L)). Six-month-old 3xTg-AD mice were treated with subcutaneous injections of APO once a week for 1 month. Memory function was evaluated by Morris water maze before and after the treatment. Brain tissues were examined by immunohistochemical staining and Western blotting. Effects of APO on intracellular Aβ degradation, activity of Aβ-degrading enzymes, and protection against oxidative stress were studied in cultured SH-SY5Y cells.Results: After APO treatment, short-term memory function was dramatically improved. Significant decreases in the levels of intraneuronal Aβ, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular Aβ, increased activity of proteasome and insulin-degrading enzyme, protected against H(2) O(2) toxicity, and decreased p53 protein levels in the cultured cells.Interpretation: 3xTg-AD mice show intraneuronal Aβ accumulation and memory disturbances before extracellular Aβ deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal Aβ and p-tau levels by APO treatment strongly suggest that intraneuronal Aβ is an important therapeutic target and APO will be a novel drug for AD. [ABSTRACT FROM AUTHOR]

Apomorphine hydrochloride (APO) is known to be a dopamine receptor agonist, and has recently been found to be a novel drug for Alzheimer's disease (AD). We found that APO treatment ameliorated oxidative stress in an AD mouse model and specifically attenuated the hydrogen peroxide-induced p53-related apoptosis in the SH-SY5Y neuroblastoma cell line. To further understand the mechanism behind this action, we investigated the actions of APO on intracellular redox systems, such as the glutathione cycle and catalase. We studied the effects of specific inhibitors for glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (BCNU, MCS, and ATZ, respectively) on the effects of APO. Treatments with MCS or BCNU, but not ATZ, significantly attenuated the protective effects of APO. Interestingly, APO treatment elevated GPx activity, but did not increase the expression of the GPx1 protein. Although BCNU treatment attenuated APO effects, GR activity was not elevated by APO treatment. The same effects were observed in primary neuronal cultures. In addition, treatment with dopamine D1, D2, D3 and D4 receptor antagonists did not counteract the protective action of APO. Thus, APO may enhance GPx activity through dopamine receptor-independent pathways. [ABSTRACT FROM AUTHOR]

Background: The initial outcomes of transcatheter aortic valve replacement in patients with left ventricular outflow tract calcification are poor. Furthermore, balloon-expandable transcatheter aortic valve replacement is associated with an increased risk of annular rupture, and self-expandable transcatheter aortic valve replacement is associated with worse post-operative residual paravalvular leakage grades. Therefore, developing an optimal method for transcatheter aortic valve replacement for patients with left ventricular outflow tract calcification is desirable., Case Summary: We present two cases of successful balloon-expandable transcatheter aortic valve replacement, wherein the transcatheter heart valve was implanted above the left ventricular outflow tract calcification to avoid annular rupture and paravalvular leakage, and one case each of balloon-expandable and self-expandable transcatheter aortic valve replacements, wherein the transcatheter heart valve was implanted at a normal height. Although annular rupture did not occur in any of the cases, more-than-mild paravalvular leakage persisted post-operatively in cases where the transcatheter heart valve was placed at a normal height., Discussion: Annular rupture is more likely to occur in areas with high calcification at the joint than in noncalcified areas. Furthermore, the greater the calcification in the landing zone of the transcatheter heart valve, the more the paravalvular leakage persists. Therefore, high implantation of transcatheter heart valves above the left ventricular outflow tract calcification can be an effective method to avoid annular rupture and paravalvular leakage., Competing Interests: Conflict of interest: K.M. is a clinical TAVR proctor of Edwards Lifesciences and Medtronic., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Elbow flexion is essential for the functional use of the hand. The reconstructive procedure may also change depending on the location of the sarcoma. The nonresected muscle may alter the function of the elbow. If the proximal part of the triceps muscle remains intact, it is considered functional. Functional muscle transfer is not required in such cases. A 50-year-old patient presented with a soft-tissue defect after a wide resection of a leiomyosarcoma affecting the left elbow. The wide resection resulted in the resection of the distal third of the triceps brachii, exposing the olecranon. We performed reconstruction using a pedicled latissimus dorsi musculocutaneous flap. The flap was transferred to the elbow through a subcutaneous tunnel. Ten months after surgery, the elbow function improved. In our patient, the thoracodorsal nerve was cut to prevent mixed nerve signals. We found that patients with distal muscle defects do not require functional muscle grafting. Pedicled latissimus dorsi musculocutaneous flap transfer is a straightforward and useful procedure for reconstructing the upper arm region., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Although each 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE) has been used to diagnose cardiac sarcoidosis (CS), active CS is still misdiagnosed., Methods: Active CS, diagnosed by PET alone, was defined as focal or focal on diffuse FDG uptake pattern. In fusion PET/CMR imaging, using a regional analysis with AHA 17-segment model, the patients were categorized into four groups: (1) PET-/LGE-, (2) PET+/LGE-, (3) PET+/LGE+, and (4) PET-/LGE+. PET+/LGE+ was defined as active CS., Results: 74 Patients with suspected CS were enrolled. Between PET alone and fusion PET/CMR imaging, 20 cases had mismatch evaluations of active CS, and most had diffuse or focal on diffuse FDG uptake pattern on PET alone imaging. 40 Patients fulfilled the 2016 the Japanese Circulation Society diagnostic criteria for CS. The interobserver diagnostic agreement was excellent (κ statistics 0.89) and the overall accuracy for diagnosing CS was 87.8% in fusion PET/CMR imaging, which were superior to those in PET alone imaging (0.57 and 82.4%, respectively). In a sub-analysis of diffuse and focal on diffuse patterns, the agreement (κ statistics 0.86) and overall accuracy (81.8%) in fusion PET/CMR imaging were still better., Conclusions: Fusion PET/CMR imaging with regional analysis offered reliable and accurate diagnosis of CS, covering low diagnostic area by FDG-PET alone., (© 2020. American Society of Nuclear Cardiology.)

Aims: The clinical impact of the type of atrial fibrillation (AF) has not been completely elucidated in non-ischemic cardiomyopathy (NICM). Although the structure and function of the left atrium (LA) provide prognostic information in patients with heart failure, the relationship of the AF type with LA structure and function in NICM is unclear. Methods: Consecutive patients with NICM who underwent cardiac magnetic resonance were evaluated and followed. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for major adverse cardiovascular events (MACE) related to the AF type, such as paroxysmal AF, chronic AF, and new-onset AF (NOAF). Results: Among 625 patients with NICM (mean age, 64.4 ± 14.2 years; women, 39.7%), 133 had a history of AF at baseline; of these, 60 had paroxysmal AF. Each baseline AF type was associated with higher LA volume and lower LA emptying fraction but not with an increased incidence of MACE ( p = 0.245). New-onset AF developed in 5.9% of patients with sinus rhythm over a median follow-up period of 609 days, and maximum LA volume was a strong and independent predictor [ p < 0.001, area under the ROC curve (AUC): 0.795]. Maximum LA volume was superior to LA emptying fraction and B-type natriuretic peptide (AUC: 0.683 and 0.680, respectively). The use of β-blocker and the age of the patient were associated with the incidence of NOAF (HR: 0.37, 95% CI: 0.16-0.84 and HR: 1.05, 95% CI: 1.01-1.09, respectively). Kaplan-Meier analysis showed that patients with NOAF had a higher incidence of MACE than those with sinus rhythm or baseline AF ( p = 0.002). NOAF and LA emptying fraction were independent predictors of MACE (HR: 2.28, 95% CI: 1.20-3.97 and HR: 0.98, 95% CI: 0.96-0.99, respectively) after adjusting for age, sex, body mass index, and diagnosis. Conclusions: Paroxysmal and chronic AF in patients with NICM were not associated with an increased incidence of MACE despite their association with LA volume and function. NOAF was independently associated with poor prognosis. Higher maximum LA volume predicted the onset and lower LA emptying fraction was independently associated with poor prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Okune, Yasuda, Soejima, Kakehi, Kawamura, Kurita, Nakazawa and Iwanaga.)

A 50-year-old woman presented with coma and hemorrhagic shock. A rapid influenza antigen test revealed influenza A infection; other laboratory examinations ruled out any other suspected infections. She was diagnosed with hemorrhagic shock and encephalopathy syndrome (HSES) induced by influenza A. She was administered methylprednisolone pulse therapy and peramivir. Subsequently, she was discharged without any sequelae. Only a few cases of influenza-induced HSES have been reported, and the clinical outcomes were very poor. We herein report a successfully treated adult case of influenza-induced HSES and review this rare syndrome.

Apomorphine (APO) promotes intraneuronal amyloid-β (Aβ) degradation and improves memory function in an Alzheimer's disease (AD) model, 3xTg-AD mice. Since insulin resistance is increased in AD neurons, we investigated the effects of APO on brain insulin resistance in 3xTg-AD mice at early and late stages. After 1-month subcutaneous injection of Apokyn® to 3xTg-AD mice at 6 or 12 months of age, memory function was significantly improved in both age groups. Protein levels of insulin-degrading enzyme (IDE), which is linked to insulin signaling and degrades Aβ, significantly increased in the 3xTg-AD mice brain compared with non-transgenic mice, and were further increased by APO. Protein levels of two types of serine-phosphorylated insulin receptor substrate-1 (IRS-1), pS616 and pS636/639, significantly decreased following APO treatment in the 13-month-old 3xTg-AD mice brain, suggesting improved brain insulin resistance. Immunostaining of the IDE, pS616 and pS636/639 IRS-1 demonstrated similar changes due to APO treatment. Thus, brain insulin resistance is considered an important therapeutic target in AD, and APO may provide improved neuronal insulin resistance.

Amyloid-β protein (Aβ) accumulates in the neurons of Alzheimer's disease (AD) patients at an early stage of the disease. Recently, we found that Aβ with a toxic turn at positions 22 and 23 accumulates in neurons in AD brain. Here, we studied the accumulation of Aβ, toxic turn Aβ and high-molecular-weight Aβ oligomers in presenilin 1 (PS1) gene-transfected SH-SY5Y cells as well as in the brains of 3xTg-AD mice and AD patients. Immunostaining revealed that accumulation of toxic turn Aβ was promoted in G384A- and I143T-mutant PS1-transfected cells and further enhanced by co-transfection of cells with the Aβ-precursor protein (AβPP) gene. In contrast, accumulation of high-molecular-weight Aβ oligomers was promoted in mutant PS1 cells but attenuated by co-transfection of cells with the AβPP gene. Toxic turn Aβ was detected in the neurons of 3xTg-AD mice aged 2 months, when the mice were cognitively unimpaired. In contrast, high-molecular-weight Aβ oligomers were detected in the neurons of 7-month-old mice, when memory dysfunction is apparent. Furthermore, immunostaining and western blotting for Rab4, Rab6 and GRP78 revealed increased levels of these proteins in mutant PS1 cells and their accumulation in the neurons of 3xTg-AD mice. Remarkably, GRP78 immunoreactivity was increased at 2 months of age. Double-label immunostaining of AD brain revealed an apparent association between toxic turn Aβ and GRP78, an endoplasmic reticulum (ER) stress marker. Intraneuronal accumulation of toxic turn Aβ may be associated with ER stress in the brains of AD model mice and AD patients at an early stage.

: Models written in description languages such as CellML are becoming a popular solution to the handling of complex cellular physiological models in biological function simulations. However, in order to fully simulate a model, boundary conditions and ordinary differential equation (ODE) solving schemes have to be combined with it. Though boundary conditions can be described in CellML, it is difficult to explicitly specify ODE solving schemes using existing tools. In this study, we define an ODE solving scheme description language-based on XML and propose a code generation system for biological function simulations. In the proposed system, biological simulation programs using various ODE solving schemes can be easily generated. We designed a two-stage approach where the system generates the equation set associating the physiological model variable values at a certain time t with values at t + Δt in the first stage. The second stage generates the simulation code for the model. This approach enables the flexible construction of code generation modules that can support complex sets of formulas. We evaluate the relationship between models and their calculation accuracies by simulating complex biological models using various ODE solving schemes. Using the FHN model simulation, results showed good qualitative and quantitative correspondence with the theoretical predictions. Results for the Luo-Rudy 1991 model showed that only first order precision was achieved. In addition, running the generated code in parallel on a GPU made it possible to speed up the calculation time by a factor of 50. The CellML Compiler source code is available for download at http://sourceforge.net/projects/cellmlcompiler.

To cope with the complexity of the biological function simulation models, model representation with description language is becoming popular. However, simulation software itself becomes complex in these environment, thus, it is difficult to modify target computation resources or numerical calculation methods or simulation conditions. Typical biological function simulation software consists of 1) model equation, 2) boundary conditions and 3) ODE solving scheme. Introducing the description model file such as CellML is useful for generalizing the first point and partly second point, however, third point is difficult to handle. We introduce a simulation software generation system which use markup language based description of ODE solving scheme together with cell model description file. By using this software, we can easily generate biological simulation program code with different ODE solving schemes. To show the efficiency of our system, experimental results of several simulation models with different ODE scheme and different computation resources are shown.

To elucidate whether people with hair follicles containing many Propionibacterium acnes cells are prone to acne, we developed a novel method to count the number of P. acnes in hair follicles. We sampled sebaceous material in hair follicles by aspiration at a constant negative pressure from the nose, forehead, and upper arm of 86 patients with acne vulgaris and 209 control subjects with healthy skin, including 84 subjects age-matched to the patients. Genome-equivalents of P. acnes in samples were estimated by real-time quantitative PCR (TaqMan). Numbers of P. acnes genome-equivalents were extremely low in control subjects less than 10 years of age and generally higher at greater ages, with much variation in subjects in the same decade of life. In men, the median count was highest in controls aged 15-19 years; in women, it peaked twice, in controls aged 15-19 years and again in those aged 40 years or older. P. acnes counts on the forehead and nose were higher in the acne patients aged 10-14 years than in the age-matched controls in both sexes. The counts at three sites were similar in acne patients and controls aged 15 to 29 years in both sexes. The results suggest that people with hair follicles containing many P. acnes cells are not particularly prone to acne, except for younger teenagers. Our aspiration method with estimation by real-time PCR can be used to examine the cutaneous microflora of P. acnes.

We report a 53-year-old woman with probable Bassen-Kornzweig syndrome. Her parents were a consanguineous marriage. At two years of age, she developed night blindness. During her childhood she had severe diarrhea that disappeared in adulthood. At 26 years of age, she was diagnosed as having retinitis pigmentosa and her visual acuity became worse thereafter. She noted tremor in the right hand at 37 years of age, gait ataxia at 42, and developed tremor in the bilateral lower extremities at 48. On admission, bilateral visual disturbance, resting and postural tremor, moderately poor coordination, mild distal dominant sensory impairment, an absence of tendon reflex in all four extremities, moderate to severe gait ataxia, and positive Romberg sign were found. Muscle rigidity and akinesia were not observed. Intelligence and muscle power were normal and pathological reflexes were absent. Acanthocytes were found in blood. Serum chemistry showed remarkable decreases in total cholesterol (54 mg/dl, normal 180-220), triglyceride (0 mg/dl, normal 30-150), beta-lipoprotein (3 mg/dl, normal 190-500), apoA-1 protein (66 mg/dl, normal 105-184), apoA-2 protein (11 mg/dl, normal 26-46), apoB protein (0 mg/dl, normal 38-104), apoC-2 protein (1.1 mg/dl, normal 1.2-6.4), vitamin A (297 ng/ml, normal 431-1,041), and vitamin E (0.19 ng/dl, normal 0.75-1.41). While, a marked increase in PIVKA II (703 mAU/ml, normal<40) due to a decrease in vitamin K was found. She was thus diagnosed as having Bassen-Kornzweig syndrome or hypo-betalipoproteinemia. Although brain MRI was normal, single-photon emission CT (SPECT) showed mildly decreased perfusion in the left parietal cortex and right striatum. Motor nerve conduction velocities were normal, but sensory nerve action potentials were not evoked in all four extremities. Surface EMG recorded on the right radial extensor and flexor carpi muscles at rest showed a 4.5 Hz tremor. Vitamin replacement therapy with vitamin A (10,000 IU/day), E (200 mg/day), and K (10 mg/day) was initiated. Several days after treatment, amplitude of resting tremor ameliorated mildly. Clonazepam was administered (0.5 mg/day) for further treatment. After one-month of treatment, vitamin A (656 ng/ml) and E (0.39 mg/dl) levels were elevated and PIVKA II level (29 mAU/ml) decreased. Only a mild right hand tremor remained, but sensory impairment and gait ataxia were not changed. The cause of Bassen-Kornzweig syndrome is a deletion of the microsomal triglyceride transfer protein (MTP) gene. While, familial hypo-betalipoproteinemia, due to a mutation of apolipoprotein B gene, is known to show the same phenotype. Because of the patient's refusal of genetic examination, which disease she has cannot be conclusively determined. Intention tremor was reported in Bassen-Kornzweig syndrome. However, her 4.5 Hz tremor was also present at rest, which resembled resting tremor in Parkinson's disease. Pathophysiology of Bassen-Kornzweig syndrome is known to be due to hypo-vitaminosis. Decreased [18F]-dopa uptake in striatum of patients with long-term hypo-vitamin E has been reported in PET study. Mild hypoperfusion was found in the striatum of the present cases: indicating that her tremor was associated with striatonigral damage. Thus, careful observation of extrapyramidal signs is necessary in abeta- or hypo-betalipoproteinemia.

Laboratory and clinical studies of cefoperazone (CPZ), a new semisynthetic cephalosporin, were investigated and following results were obtained. (1) Blood level: CPZ was given intravenous dose of 25 mg/kg and 50 mg/kg to each 3 children. In the former, the blood level of 15 minutes after injection was 194.2 mcg/ml on average and the half life was 106.2 minutes. In the latter, the blood level was 320.0 mcg/ml on average and half life was 102.2 minutes. (2) Urinary concentration: In the cases of the dose of 25 mg/kg, 35.9% of CPZ was recovered on average from the urine within 6 hours after injection, and the urinary concentration reached to 2,148.6 mcg/ml (0 approximately 2 hours). And in the cases of the dose of 50 mcg/kg, the recovery rate in urine was 43.6%, and the urinary concentration was 3,008.3 mcg/ml. (3) Cerebrospinal fluid level: CSF level was determined in a patient with bacterial meningitis by S. pneumoniae. Ninety mg/kg of CPZ were given intravenous injection. After 60 minutes CSF level was 3.35 mcg/ml, and after 80 minutes the blood level was 192.0 mcg/ml. (4) Bacteriological evaluation: Against 164 strains isolated clinical specimens, the bacteriological evaluation on CPZ was performed in comparison with cefotaxime (CTX), cefazolin (CEZ) and piperacillin (PIPC) by inoculum size of 10(8) cells/ml. CPZ showed antibacterial activity against Gram-negative bacteria almost similar to CTX and PIPC. (5) CLINICAL RESULTS: CPZ was given 48.3 approximately 360 mg/kg/day (average 146.1 mg/kg/day) by intravenous route to 46 patients with various infection. The overall efficacy rate was 80.4%. The rate of bacteriological effectiveness was 78.9% in 19 cases. (6) Side effects: As side effects, diarrhea, fever, rash, urticaria, leukopenia, eosinophilia, elevation of GOT, GPT, and LDH were observed, but not seriously.