ORIHIME study: real-world treatment patterns and clinical outcomes of 338 patients with acquired hemophilia A from a Japanese administrative database.

BACKGROUND: Acquired hemophilia A (AHA) is a rare disorder, and clinical practices for treating AHA have not been fully clarified in Japan. OBJECTIVES: This study aims to investigate the epidemiology of AHA and real-world treatment practices in Japan. PATIENTS/METHODS: This observational study was based on a health administrative database of hospitalized patients diagnosed with AHA who were treated with immunosuppressants. RESULTS: The study included 214 males and 124 females (mean age 75.7 years). The most frequently used bypassing agent was recombinant activated factor VII. The predominant choice of immunosuppressant for first-line treatment was steroid monotherapy. Median days from the index date to the start of rehabilitation was 65.0 for cardiovascular, 35.5 for respiratory and 23.0 for locomotor. The proportion of patients with an activities of daily living (ADL) score < 70 points was high at both first admission and final discharge (47.4% and 38.8%). The percentage of deaths during hospitalization was 18.6%. CONCLUSIONS: This study clarified the treatment patterns and clinical outcomes of AHA in a large population in Japan. This was the first study showing ADL score distribution and time to rehabilitation. Further investigation is needed to develop better clinical practices for treatment of AHA.

Burden of congenital hemophilia A requiring treatment in Japan: The HIKOBOSHI study.

Background: Treatment of congenital hemophilia A (HA) in Japan has greatly improved with the widespread adoption of prophylactic factor (F)VIII concentrates. However, it is unknown if this has translated into a real-world reduction in disease and treatment burden. Objectives: To describe HA disease burden in Japan based on information from two medical information databases, JMDC and Real World Data Co., Ltd. (RWD). Methods: Eligible individuals were diagnosed with congenital HA and prescribed FVIII concentrates, bypassing agents, or emicizumab. Treatment patterns and disease burden data were derived from health insurance claims and electronic medical records. Results: Data on 459 people with HA were retrospectively collected from 2005 to 2020 in the JMDC database (median [min, max] of 37 [2, 186] months of available records), and 229 people with HA from 1985 to 2020 in the RWD database (median [min, max] of 154 [0, 409] months of available records). Mean (standard deviation) ages at the time of the first record were 25.0 (16.8) years (JMDC) and 19.2 (20.3) years (RWD). In the JMDC database, mean monthly FVIII dose increased from 2201 IU in 2005 to 8239 IU in 2013 to 11,377 IU in 2019; HA-related drug costs increased accordingly. Mean (95% confidence interval) annual outpatient and out-of-hours visits decreased slightly between 2013 and 2019 (outpatient visits: from 22.9 [16.8-29.0] to 14.3 [12.6-16.1] per person; out-of-hours visits: from 1.3 [0.2-2.5] to 0.6 [0-1.4]). There was no change in mean number of hospitalizations. Conclusions: Challenges remain in HA, including treatment burden, outpatient visits, and hospitalizations.

Effects of Dapagliflozin on Adipose and Liver Fatty Acid Composition and mRNA Expression Involved in Lipid Metabolism in High-Fat-Fed Rats.

BACKGROUND: SGLT2 inhibitor enhances not only glucose excretion but also fatty acid utilization. Those facts suggest that SGLT2 inhibitor affects fat accumulation and lipid storage. OBJECTIVE: In the present study, we evaluated the effects of dapagliflozin on fatty acid composition and gene expression involved in fatty acid metabolism in rat adipose and liver tissues. METHODS: We administered 1 mg/kg/day dapagliflozin for 7 weeks to male high-fat-fed rats (DAPA group), and then weights and 22 fatty acid contents in the epididymal (EPI), mesenteric (MES), retroperitoneal (RET), and subcutaneous (SUB) adipose tissues, and the liver were compared with the vehicle-administered control group. RESULTS: In the EPI, RET, and SUB in the DAPA group, contents of several fatty acids were lower (P<0.05) than those in the control group, while no significant difference was detected in tissue weight. In the MES, tissue weight and a wide variety of fatty acid contents, including saturated, monounsaturated, and polyunsaturated fatty acids, were lower (P<0.05). As for the liver tissue, no significant difference was observed in fatty acid contents between the groups. mRNA expression of Srebp1c in EPI was significantly higher (P<0.05) in the DAPA group than in the control group, while Scd1 expression in the liver was lower (P<0.01). CONCLUSION: These results suggest that dapagliflozin might suppress lipid accumulation especially in the MES, and could reduce contents of fatty acids not in the liver but in adipose tissues in high-fat-fed rats. In addition, dapagliflozin could influence mRNA expression involved in lipogenesis in the EPI and liver.

Physically-based structural modeling of a typical regenerative tissue analog bridges material macroscale continuum and cellular microscale discreteness and elucidates the hierarchical characteristics of cell-matrix interaction.

This paper presents a comprehensive physically-based structural modelling for the passive and active biomechanical processes in a typical engineered tissue - namely, cell-compacted collagen gel. First, it introduces a sinusoidal curve analog for quantifying the mechanical response of the collagen fibrils and a probability distribution function of the characteristic crimp ratio for taking into account the fibrillar geometric entropic effect. The constitutive framework based on these structural characteristics precisely reproduces the nonlinearity, the viscoelasticity, and fairly captures the Poisson effect exhibiting in the macroscale tensile tests; which, therefore, substantially validates the structural modelling for the analysis of the cell-gel interaction during collagen gel compaction. Second, a deterministic molecular clutch model specific to the interaction between the cell pseudopodium and the collagen network is developed, which emphasizes the dependence of traction force on clutch number altering with the retrograde flow velocity, actin polymeric velocity, and the deformation of the stretched fibril. The modelling reveals the hierarchical features of cellular substrate sensing, i.e. a biphasic traction force response to substrate elasticity begins at the level of individual fibrils and develops into the second biphasic sensing by means of the fibrillar number integration at the whole-cell level. Singular in crossing the realms of continuum and discrete mechanics, the methodologies developed in this study for modelling the filamentous materials and cell-fibril interaction deliver deep insight into the temporospatially dynamic 3D cell-matrix interaction, and are able to bridge the cellular microscale and material macroscale in the exploration of related topics in mechanobiology.

Effects of dapagliflozin on peripheral sympathetic nerve activity in standard chow- and high-fat-fed rats after a glucose load.

To clarify the effects of long-term administration of SGLT2 inhibitor, a hypoglycemic agent, on basal sympathetic nerve activity (SNA) and on SNA under development of insulin resistance, we measured peripheral SNA in response to a glucose load in standard chow- (SCF) and high-fat-fed (HFF) rats treated with or without dapagliflozin for 7 weeks. We conducted an intravenous glucose administration (IVGA), and evaluated SNA microneurographically recorded in the unilateral sciatic nerve. Dapagliflozin did not affect the steady state action potential (AP) rate just before the IVGA (baseline) in both the SCF and HFF rats. After the IVGA, in the SCF rats, the AP rate in dapagliflozin-treated group transiently decreased within 20 min after the IVGA, and was significantly lower (P < 0.05) than non-treated group for 60 min. In the HFF rats, no significant difference was seen in the AP rate between dapagliflozin-treated and non-treated groups. The rate in the dapagliflozin-treated group after the IVGA was significantly lower (P < 0.05) than the baseline whereas such difference was not found in the non-treated group. In conclusion, dapagliflozin attenuate SNA in response to glucose load, and that the SNA response is different between standard chow-fed- and high-fat-fed rats.

Evaluation of Skeletal Muscle Dysfunction Associated With Acute Inflammation by Electrical Impedance Myography: A Case Report on Skeletal Muscle Dysfunction After Cardiac Surgery and Literature Review.

Electrical impedance myography (EIM) is an evaluation technique for skeletal muscles that uses electrical impedance technology. Recent reviews have shown that EIM is useful as a method to assess changes in skeletal muscle quality and quantity with aging. These may be utilized for functional changes in inflammatory skeletal muscles, such as disease and operation. In this report, the impedance parameters using EIM present perioperative skeletal muscle changes in patients after cardiac surgery. In addition, we will describe the efficacy of EIM in skeletal muscle dysfunction due to inflammation or disease. This study aimed to elucidate the efficacy of EIM in acute inflammation-associated skeletal muscle dysfunction.

Effectiveness of impedance parameters for muscle quality evaluation in healthy men.

We investigated the relationship between impedance parameters and skeletal muscle function in the lower extremities, as well as the effectiveness of impedance parameters in evaluating muscle quality. Lower extremity impedance of 19 healthy men (aged 23-31 years) measured using the direct segmental multi-frequency bioelectrical impedance analysis were arc-optimized using the Cole-Cole model, following which phase angle (PA), [Formula: see text], and ß were estimated. Skeletal muscle function was assessed by muscle thickness, muscle intensity, and isometric knee extension force (IKEF). IKEF was positively correlated with PA (r = 0.58, p < 0.01) and ß (r = 0.34, p < 0.05) was negatively correlated with [Formula: see text] (r = - 0.43, p < 0.01). Stepwise multiple regression analysis results revealed that PA, ß, and [Formula: see text] were correlated with IKEF independently of muscle thickness. This study suggests that arc-optimized impedance parameters are effective for evaluating muscle quality and prediction of muscle strength.

Development of an ELISA for Measurement of Urinary 3-Hydroxypropyl Mercapturic Acid (3-HPMA), the Marker of Stroke.

We previously observed an inverse correlation between stroke and urinary 3-hydroxypropyl mercapturic acid (3-HPMA), an acrolein-glutathione metabolite, through its measurement by liquid chromatography with tandem mass spectrometry (LC-MS/MS). However, the cost of equipment for LC-MS/MS and its maintenance fee is very expensive and a cost-efficient method is required. In this study, we have developed a sensitive enzyme-linked immunosorbent assay (ELISA) system to measure 3-HPMA using a chicken antibody recognizing 3-HPMA-conjugated chicken albumin as antigen. Linearity to measure 3-HPMA was obtained from 0 to 10 µM, indicating that this ELISA system is useful for measurement of urine 3-HPMA. It was confirmed that 3-HPMA in urine of stroke patients decreased significantly compared with that of control subjects using the ELISA system. Using the ELISA kit, it became possible to evaluate the risk of brain stroke by not only plasma but also by urine. These results confirm that shortage of glutathione to detoxify acrolein is one of the major causes of stroke incidence. Our method contributes to maintenance of quality of life (QOL) of the elderly.

Unknown biological effects of L-glucose, ALA, and PUFA.

Key substrates including glucose, amino acids, and fatty acids play core roles in nutrient metabolism. In this review, we describe phenomena observed when key substrates are applied to cells. We focused on three promising substrates: L-glucose derivatives, 5-aminolevulinic acid, and polyunsaturated fatty acid. Since they are assumed to give a specific reaction when they are transported into cells or metabolized in cells, they are expected to be applied in a clinical setting. We provide the latest knowledge regarding their behaviors and effects on cells.

Clinical Features of Systemic Metastatic Retinal Lymphoma in Japanese Patients.

PURPOSE: Systemic metastatic retinal lymphoma (SMRL) originates in systemic organs. It has been reported to exhibit clinical features similar to those of primary vitreoretinal lymphoma (PVRL). We report six cases of SMRL in a single-center survey in Japan. METHODS: The clinical and pathologic features in SMRL at the Kyushu University Hospital were retrospectively studied. RESULTS: The mean patient age at the onset of ocular involvement was 75.3 years. Four patients had brain involvement. The primary sites were: breast (2); chest (1); testis (1); intestinal tract (1); and nasal sinus (1). In all patients, the cytology of vitreous samples indicated diffuse large B-cell lymphoma (DLBCL). CONCLUSIONS: DLBCL is the most common subtype in our study. The prevalence of CNS involvement in patients with SMRL is similar to that with PVRL. The testis and breast may be common sites of origin for SMRL.

[A Case of Primary Dural Lymphoma of Jugular Tubercle Mimicking Lower Clival Meningioma].

Primary dural lymphoma (PDL) is a rare type of primary central nervous system lymphoma (PCNSL); however, its clinical etiology and appearance on magnetic resonance images (MRI) are similar to those of meningioma. We report a case of PDL mimicking a meningioma in the jugular tubercle, with hemiparesis and double vision, and review the published PDL case reports. A 41-year-old woman experienced numbness on her right side, and reported right hemiparesis and double vision 2 days thereafter. Her cranial computed tomography (CT) scan showed a mass lesion in the posterior fossa, and contrasted MRI revealed homogenous tumor with a dural tail sign in the left jugular tubercle. The patient was diagnosed as having jugular tubercle meningioma. However, her symptoms disappeared promptly with the injection of dexamethasone, and follow-up MRI showed that the tumor had diminished. After 9 months, her double vision recurred and MRI results indicated tumor regrowth. She underwent sub-total resection of the tumor via the left trans-condylar fossa approach. A histological diagnosis was PDL. She was treated with 3 courses of high-dose methotrexate, and subsequent MRI results showed a partial reduction of the residual tumor. PDL is histologically associated with marginal zone lymphoma (MZL), and is sensitive to radiation and chemotherapy. This patient responded well to high-dose methotrexate alone. PDL is one of the important differential diagnoses of meningioma.

PPARγ activation alters fatty acid composition in adipose triglyceride, in addition to proliferation of small adipocytes, in insulin resistant high-fat fed rats.

It was reported that adipocyte size is potentially correlated in part to amount of long chain polyunsaturated fatty acids (PUFAs) and insulin resistance because several long chain PUFAs can be ligands of peroxisome proliferator-activated receptors (PPARs). In our previous study, marked reduction of PUFAs was observed in insulin-resistant high-fat fed rats, which may indicate that PUFAs are consumed to improve insulin resistance. Although PPARγ agonist, well known as an insulin sensitizer, proliferates small adipocytes, the effects of PPARγ agonist on FA composition in adipose tissue have not been clarified yet. In the present study, we administered pioglitazone, a PPARγ agonist, to high-fat fed rats, and measured their FA composition of triglyceride fraction in adipose tissue and adipocyte diameters in pioglitazone-treated (PIO) and non-treated (control) rats. Insulin sensitivity was obtained with hyperinsulinemic euglycemic clamp. Average adipocyte diameter in the PIO group were smaller than that in the control one without change in tissue weight. In monounsaturated FAs (MUFAs), 14:1n-5, 16:1n-7, and 18:1n-9 contents in the PIO group were lower than those, respectively, in the control group. In contrast, 22:6n-3, 20:3n-6, 20:4n-6, and 22:4n-6 contents in the PIO group were higher than those, respectively, in the control group. Insulin sensitivity was higher in the PIO group than in the control one. These findings suggest that PPARγ activation lowered MUFAs whereas suppressed most of C20 or C22 PUFAs reduction, and that the change of fatty acid composition may be relevant with increase in small adipocytes.

Stress relaxation and stress-strain characteristics of porcine amniotic membrane.

BACKGROUND: Recently, amniotic membrane (AM) as scaffold is accumulating much more attention in tissue engineering. It is well-known that the mechanical properties of the scaffold inevitably affect the biological process of the incorporated cells. OBJECTIVE: This study investigates the stress relaxation and stress-strain characteristics of AM, which have not been sufficiently elucidated before. METHODS: Porcine AM samples were prepared at four different AM regions and at three different directions. Ramp-and-hold and stretch-to-rupture tests were conducted on a uniaxial tensile apparatus. A nonlinear viscoelastic model with two relaxation coefficients is proposed to fit the ramp-and-hold data. Rupture strain, rupture stress, and elastic modulus of the linear portion of the stress-strain curve are used to characterize the strength properties of the AM. RESULTS: Sample direction has no significant effect on the mechanical properties of the AM. Samples at the ventral region has the maximum rupture strength and elastic modulus, respectively, 2.29±0.99MPa and 6.26±2.69MPa. The average of the relaxation coefficient for the fast and slow relaxation phases are 12.8±4.4s and 37.0±7.7s, respectively. CONCLUSIONS: AM is a mechanically isotropic and heterogeneous material. The nonlinear viscoelastic model is suitable to model the AM viscoelasticity and potential for other biological tissues.

Temperature control of the motility of actin filaments interacting with myosin molecules using an electrically conductive glass in the presence of direct current.

The motility of actin filaments interacting with heavy meromyosin molecules was directly observed on indium tin oxide-coated glass (ITO-glass), over which a surface current flowed. Because the increase in surface current applied to ITO-glass increases the temperature, we focused on the temperature-dependence of the sliding velocity and the effect of the current flow on the orientation of filament motion. Using high precision fluorescence measurements, the displacement vectors of filaments were collected at intervals of 1/30 s. The direction of filament motion was independent to that of current flow up to 0.17 A (7.7 A/m of surface current density); however, the velocity increased by approximately 2-fold when the surface temperature increased from 25 °C to 37 °C. The moving actin filaments exhibited a broader velocity distribution at high temperature than at low temperature. Collectively, these data suggest that using ITO-glass with a surface current to generate a well-controlled temperature change may serve to evaluate temperature-dependent transient responses in protein activity under a microscope, without interference from electrical effects.

Effects of aldose reductase inhibitor on microneurographically assessed peripheral sympathetic nerve activity in rats.

Autonomic neuropathy, one of the serious complications of diabetes, decreases quality of life. Aldose reductase inhibitor (ARI) blocks sorbitol production, and results in prevention of damage of nerve fibers. Beneficial effects of ARI have usually been confirmed through nerve conduction velocity tests in motor and sensory nerves. On the other hand, few reports have dealt with the effects of ARI on the small fiber activity such as sympathetic nerve one. In the present study, we administered eparlestat, ARI orally for 3weeks, to streptozotocin-induced diabetic (STZ+ARI) rats, and then recorded peripheral sympathetic nervous signal detected with microneurographic technique. Action potentials (APs) and bursts of APs were detected from the recorded signal, and their rates and incidences (=rates/heart rate) were compared with those in non-diabetic control (normal) and ARI-untreated streptozotocin-induced diabetic (STZ) rats. While streptozotocin and/or epalrestat did not influence burst parameters in all the three groups, AP parameters in the STZ+ARI and normal groups were higher than those in the STZ group. However, response of AP parameters to the intravenous glucose administration (IVGA) was not large in the STZ+ARI group, similar to that of the STZ group and different from that of the normal group in which AP parameters increased after IVGA. The results suggest that epalrestat may prevent sympathetic nerve activity (SNA) from reduction under hyperglycemic and insulin-depleted conditions, that enhancement of SNA was not induced after IVGA under that condition, and that AP parameters might be useful to assess the degree of neuropathy.

A fibril-based structural constitutive theory reveals the dominant role of network characteristics on the mechanical behavior of fibroblast-compacted collagen gels.

In this paper, we present a general, fibril-based structural constitutive theory which accounts for three material aspects of crosslinked filamentous materials: the single fibrillar force response, the fibrillar network model, and the effects of alterations to the fibrillar network. In the case of the single fibrillar response, we develop a formula that covers the entropic and enthalpic deformation regions, and introduce the relaxation phase to explain the observed force decay after crosslink breakage. For the filamentous network model, we characterize the constituent element of the fibrillar network in terms its end-to-end distance vector and its contour length, then decompose the vector orientation into an isotropic random term and a specific alignment, paving the way for an expanded formalism from principal deformation to general 3D deformation; and, more important, we define a critical core quantity over which macroscale mechanical characteristics can be integrated: the ratio of the initial end-to-end distance to the contour length (and its probability function). For network alterations, we quantitatively treat changes in constituent elements and relate these changes to the alteration of network characteristics. Singular in its physical rigor and clarity, this constitutive theory can reproduce and predict a wide range of nonlinear mechanical behavior in materials composed of a crosslinked filamentous network, including: stress relaxation (with dual relaxation coefficients as typically observed in soft tissues); hysteresis with decreasing maximum stress under serial cyclic loading; strain-stiffening under uniaxial tension; the rupture point of the structure as a whole; various effects of biaxial tensile loading; strain-stiffening under simple shearing; the so-called "negative normal stress" phenomenon; and enthalpic elastic behaviors of the constituent element. Applied to compacted collagen gels, the theory demonstrates that collagen fibrils behave as enthalpic elasticas with linear elasticity within the gels, and that the macroscale nonlinearity of the gels originates from the curved fibrillar network. Meanwhile, the underlying factors that determine the mechanical properties of the gels are clarified. Finally, the implications of this study on the enhancement of the mechanical properties of compacted collagen gels and on the cellular mechanics with this model tissue are discussed.

Life-Threatening Intracranial Hypotension after Skull Base Surgery with Lumbar Drainage.

Although lumbar drainage (LD) is widely used in skull base surgery (SBS), no cases with intracranial hypotension (IH) following LD-assisted SBS have been reported, and skull base surgeons lack awareness of this potentially life-threatening condition. We report two cases of IH after LD-assisted SBS, a spheno-orbital meningioma and an osteosarcoma in the orbit. Despite a minimal amount of cerebrospinal fluid (CSF) drainage and early LD removal, severe postural headache and even a deteriorating consciousness level were observed in the early postoperative course. Neuroimages demonstrated epidural fluid collections, severe midline shift, and tonsillar sag compatible with IH. Epidural blood patch (EBP) immediately and completely reversed the clinical and radiologic findings in both patients. IH should be included in the differential diagnosis of postural headache after LD-assisted SBS that can be managed successfully with EBP. Persistent leakage of CSF at the LD-inserted site leads to IH. Broad dural dissection and wide removal of bony structure may be involved in the midline shift. EBP should be performed soon after conservative management fails. Further reports will determine the risk factors for IH development following LD-assisted SBS.

Black soybean extract reduces fatty acid contents in subcutaneous, but not in visceral adipose triglyceride in high-fat fed rats.

It is known that black soybean (BS) extract, rich in polyphenols, has beneficial effects against obesity, inflammation and insulin resistance. However, detailed effects of BS on lipid metabolism have not been documented well. In the present study, we compared fatty acid composition in visceral and subcutaneous adipose tissues of high-fat fed (HFF) rats and BS administered HFF rats. Black soybean administration for 6 weeks influenced neither body nor adipose tissue weights, blood glucose, plasma insulin levels, or insulin sensitivity. However, BS reduced several saturated (C14:0 and C16:0), monounsaturated (C14:1n-5 and C18:1n-9) and n-6 polyunsaturated (C18:2n-6, C20:3n-6, C20:4n-6 and C22:4n-6) fatty acid contents in subcutaneous fat without any change in n-3 polyunsaturated fatty acid contents. No such effect was observed in fatty acid composition in visceral fat. Long-chain fatty acids are involved in regulation of inflammation. Therefore, those reduced fatty acids may be linked to the effects on suppressing inflammation.

Black soybean extract improves lipid profiles in fenofibrate-treated type 2 diabetics with postprandial hyperlipidemia.

Black soybeans (Glycine max (L.) Merr.) are known to be rich in polyphenols, including anthocyanins, and they have been consumed since ancient times for their beneficial effects on health. In addition, it has been reported that black soybean (BS) seed coat may ameliorate obesity and insulin resistance. In the present study, we administered BS extract to type 2 diabetics for 2 months to investigate the effects of BS on glycemic control and lipid metabolism parameters. In addition, we administered BS and antihyperlipidemic agent, fenofibrate, to patients with type 2 diabetes complicated by postprandial hyperlipidemia for 2 months and assessed the combined effects of fenofibrate and BS on serum lipid profile. The results showed that administration of the BS alone had no effect on the blood glucose or lipid levels, but that administration of fenofibrate alone and fenofibrate in combination with the BS significantly lowered their serum triglyceride (TG) level at fasting state, and the percent decrease in the serum TG level after combined administration was significantly higher than in the subjects who received fenofibrate alone. Furthermore, the serum LDL cholesterol concentration, which did not decrease when fenofibrate was administered alone, decreased significantly when the BS and fenofibrate were administered in combination. These results suggest that combined administration of the BS with fenofibrate enhanced the antihyperlipidemic action of fenofibrate, and the results of this study demonstrated the usefulness of the BS in clinical practice.