Circulating α-Klotho Counteracts Transforming Growth Factor-ß-Induced Sarcopenia.

α-Klotho is a longevity-related protein. Its deficiency shortens lifespan with prominent senescent phenotypes, including muscle atrophy and weakness in mice. α-Klotho has two forms: membrane α-Klotho and circulating α-Klotho (c-α-Klotho). Loss of membrane α-Klotho impairs a phosphaturic effect, thereby accelerating phosphate-induced aging. However, the mechanisms of senescence on c-α-Klotho loss remain largely unknown. Herein, with the aging of wild-type mice, c-α-Klotho declined, whereas Smad2, an intracellular transforming growth factor (TGF)-ß effector, became activated in skeletal muscle. Moreover, c-α-Klotho suppressed muscle-wasting TGF-ß molecules, including myostatin, growth and differentiation factor 11, activin, and TGF-ß1, through binding to ligands as well as type I and type II serine/threonine kinase receptors. Indeed, c-α-Klotho reversed impaired in vitro myogenesis caused by these TGF-ßs. Oral administration of Ki26894, a small-molecule inhibitor of type I receptors for these TGF-ßs, restored muscle atrophy and weakness in α-Klotho (-/-) mice and in elderly wild-type mice by suppression of activated Smad2 and up-regulated Cdkn1a (p21) transcript, a target of phosphorylated Smad2. Ki26894 also induced the slow to fast myofiber switch. These findings show c-α-Klotho's potential as a circulating inhibitor counteracting TGF-ß-induced sarcopenia. These data highlight the potential of a novel therapy involving TGF-ß blockade to prevent sarcopenia.

[Granulocyte-colony stimulating factor-producing multiple myeloma presenting with neutrophilia].

A 71-year-old woman complained of nausea and anorexia. Laboratory tests revealed significant neutrophilia and immunoglobulin A-kappa type M proteinemia, as well as increased plasma cells on bone marrow examination. Furthermore, the serum granulocyte-colony stimulating factor (G-CSF) concentration was high at 160 pg/ml, and the colony stimulating factor 3 receptor (CSF3R)-T618I mutation was negative. Immunohistochemical (IHC) analysis of bone marrow specimens using the anti-G-CSF antibody revealed immunopositivity of some myeloma cells. The patient was diagnosed using G-CSF-producing myeloma and was treated with daratumumab, lenalidomide, and dexamethasone. Her treatment resulted in a very good partial response, with normalization of both serum G-CSF levels and neutrophil count. There have been a few cases of G-CSF -producing myeloma reported, and it has previously been reported as chronic neutrophilic leukemia with M proteinemia. According to previous reports, techniques such as serum G-CSF measurements, IHC with an anti-G-CSF antibody, and CSF3R gene mutation analysis are useful for differentiating G-CSF-producing myeloma. However, the clinical characteristics and long-term prognosis of G-CSF-producing myeloma remain unknown. Additional case gathering and investigations are required.

A low amyloidogenic E61K transthyretin mutation may cause familial amyloid polyneuropathy.

Patients with transthyretin (TTR)-type familial amyloid polyneuropathy (FAP) typically exhibit sensory dominant polyneuropathy and autonomic neuropathy. However, the molecular pathogenesis of the neuropathy remains unclear. In this study, we characterize the features of FAP TTR the substitution of lysine for glutamic acid at position 61 (E61K). This FAP was late-onset, with sensory dominant polyneuropathy, autonomic neuropathy, and cardiac amyloidosis. Interestingly, no amyloid deposits were found in the endoneurium of the four nerve specimens examined. Therefore, we examined the amyloidogenic properties of E61K TTR in vitro. Recombinant wild-type TTR, the substitution of methionine for valine at position 30 (V30M) TTR, and E61K TTR proteins were incubated at 37°C for 72 hr, and amyloid fibril formation was assessed using the thioflavin-T binding assay. Amyloid fibril formation by E61K TTR was less than that by V30M TTR, and similar to that by wild-type TTR. E61K TTR did not have an inhibitory effect on neurite outgrowth from adult rat dorsal root ganglion (DRG) neurons, but V30M TTR did. Furthermore, we studied the sural nerve of our patient by terminal deoxynucleotidyl transferase dUTP nick end labeling and electron microscopy. A number of apoptotic cells were observed in the endoneurium of the nerve by transferase dUTP nick end labeling. Chromatin condensation was confirmed in the nucleus of non-myelinating Schwann cells by electron microscopy. These findings suggest that E61K TTR is low amyloidogenic, in vitro and in vivo. However, TTR aggregates and amyloid fibrils in the DRG may cause sensory impairments in FAP because the DRG has no blood-nerve barrier. Moreover, Schwann cell apoptosis may contribute to the neurodegeneration.

Coexistence of three nevus lipomatosus cutaneus superficialis with typical, cutaneous adenolipoma-like, and dermal spindle cell lipoma-like histopathological features in a patient.

We report an unique case of a patient who showed coexistence of three nevus lipomatosus cutaneus superficialis (NLCS) with typical, cutaneous adenolipoma (AL)-like, and dermal spindle cell lipoma (SCL)-like histopathological features. A 53-year-old woman presented with a 20-year history of skin-colored and slightly elevated nodules. These lesions were separately located on the lateral side (lesion 1) and medial side (lesion 2) of her left buttock and on her right thigh (lesion 3). Microscopically, all were ill-defined dermal lesions with some subcutaneous involvement and were mostly composed of mature adipocytes. The adipocytes formed small aggregates around blood vessels in the upper dermis. Lesions 1, 2, and 3 were diagnosed as NLCS, and additional features were recognized in lesions 2 and 3. Lesion 2 revealed eccrine glands and ducts amongst the lipomatous component, as seen in cutaneous AL. Lesion 3 had scattered CD34-positive spindle cells, which is representative of dermal SCL. These appearances were considered to be on the morphological spectrum of NLCS. In all three lesions, CD34-positive cells proliferated between the upper dermal blood vessels and their peripheral mature adipocytes. This pathological finding could be principal in NLCS and might be associated with its pathogenesis.

Cutaneous adenomyoepithelioma with histopathological heterogeneity: A case report.

Some skin adnexal tumors display both epithelial and myoepithelial cell populations and can be broadly categorized as biphasic tumors. These include apocrine hidrocystoma, mixed tumor, adenomyoepithelioma (AME), and adenoid cystic carcinoma (ACC). Myoepithelioma is the myoepithelial cell-predominant type in this category. Cutaneous AME is exceedingly rare and usually has a benign prognosis, but it is considered to have the potential for local recurrence and metastasis. We report the case of a 57-year-old man with a 1-year history of an ulcerated nodule on his scalp. Microscopically, it was a defined cutaneous nodule with a focal lobulated architecture, composed of epithelial cells forming ducts and myoepithelial cells distributed around the ducts. In addition to these findings of typical AME, the present case focally revealed atypical features, such as increased mitotic activity (7/10 high power fields), invasive growth, and necrosis. However, cytological atypia was not significant. We conclusively diagnosed cutaneous AME with atypical features, suggesting malignant potential. Moreover, areas showing appearances similar to apocrine hidrocystoma, mixed tumor, myoepithelioma, and ACC were focally observed. We present a unique case of cutaneous AME exhibiting histopathological heterogeneity. The recognition of morphological variation could be helpful in appropriately diagnosing and treating AME of the skin.

A case of total hysterectomy due to massive maternal bleeding immediately after fetoscopic laser surgery for twin-twin transfusion syndrome.

Twin-twin transfusion syndrome (TTTS) complicates approximately 10% of monochorionic twin pregnancies and is associated with almost 90% mortality if left untreated. Fetoscopic laser photocoagulation (FLP) is the first-line therapy for TTTS, and an overall twin survival rate of 75% and at least one survival rate of 90% have been established. We report a case of TTTS complicated with bleeding from the uterine wall by inserting the procedure after FLP. The patient consequently underwent emergency caesarean section. The bleeding was uncontrollable due to atonic bleeding and emergency hysterectomy was performed. To detect the possibility of amniotic fluid embolism (AFE), biochemical blood samples demonstrated that there was no inflow of fetal ingredients in blood vessels of uterine tissue. There was no evidence of damage to any specific vessels by histopathological staining. These findings indicated that the cause of massive bleeding was unlikely to have been AFE. It was concluded that atonic bleeding was likely caused by uncontrollable hemorrhage from an injury lesion where an endoscope had been inserted.

Survival After Cardiac Arrest With Instantaneous Rigorlike Stiffness: A Case Report.

Instantaneous rigor is the immediate appearance of rigor mortis after cardiac arrest. To our knowledge, no previous reports exist on resuscitation of such patients. A young athlete suddenly collapsed with cardiac arrest during a marathon; his legs stiffened with instantaneous rigorlike stiffness. This stiffening provoked hyperkalemia, rhabdomyolysis, and multiple organ failure. We decided to amputate both legs, with venoarterial extracorporeal membrane oxygenation support. The patient recovered and was discharged without neurologic impairment. This rare case highlights the potentially significant effect of instantaneous rigor.

Plaque Characteristics of Patients with Symptomatic Mild Carotid Artery Stenosis.

BACKGROUND: Carotid revascularization may be considered for severe stenosis, but its use for symptomatic mild stenosis (<50%) with vulnerable plaque or ulcer remains uncertain. The characteristics of patients with symptomatic mild stenosis who underwent revascularization are reviewed. METHODS: The subjects of this study were 18 patients with symptomatic mild stenosis (<50%) on angiography from among 175 patients who underwent revascularization in our department. The plaques were evaluated by black-blood magnetic resonance imaging (BB-MRI) and ultrasonography (US) and classified into 2 types: type 1 (n = 15), a lesion with an ulcer or mobile plaque or thrombosis on angiography or US; and type 2 (n = 3), a lesion without any of the above. Fourteen patients underwent carotid endarterectomy (CEA), and 4 patients underwent carotid artery stenting. RESULTS: The stenosis on angiography was 27.2% ± 10.7 (5%-41%), and the area carotid artery stenosis rate on US was 69.8 ± 14.5% (44.5%-97%). The stenosis rate of these 2 methods was not at all correlated. In type 1 plaque that underwent CEA, 10 of 11 patients had vulnerable plaque by histopathology, and 1 patient had thrombus on the plaque by operative findings. In type 2 plaque that underwent CEA, all patients had vulnerable plaque by histopathology. During the follow-up period, none of the patients had restenosis or stroke. CONCLUSIONS: The findings of US and BB-MRI in patients with symptomatic mild stenosis (<50%) on angiography are important for determining treatment. If BB-MRI or US shows the findings of vulnerable plaque in mild stenosis, surgical treatment may be considered for these patients.

Sphingosine-1-phosphate receptor 1 as a prognostic biomarker and therapeutic target for patients with primary testicular diffuse large B-cell lymphoma.

Sphingosine-1-phosphate (S1P) is a potent lipid mediator that is produced during the metabolism of sphingolipid by sphingosine kinase. S1P has been implicated in the migration and trafficking of lymphocytes and several lymphoid malignancies through S1P receptors. Moreover, the overexpression of sphingosine-1-phosphate receptor 1 (S1PR1) has been correlated with the constitutive activation of signal transducer and activator of transcription (STAT)3 and poor prognosis of diffuse large B-cell lymphoma (DLBCL). Thus, in this study, we examined the expression of S1PR1 in 198 DLBCL samples collected from nodal and various extranodal sites and sub-classified formalin-fixed paraffin-embedded tissue samples into germinal centre B-cell-like (GCB) and non-GCB subgroups using immunohistochemistry. These analyses showed S1PR1 overexpression in 15·7% of all cases with DLBCL and in 54·2% of 24 cases with primary testicular (PT)-DLBCL; S1PR1 expression correlated with S1PR1mRNA expression and STAT3 phosphorylation in fresh samples. Analyses of data from a single institution suggested that S1PR1 overexpression was an independent negative prognostic marker in 68 patients with DLBCL of clinical stages I and II. The present high prevalence of S1PR1 overexpression warrants the consideration of PT-DLBCL as a distinct disease subtype and suggests the potential of the S1P/S1PR1 axis as a therapeutic target.

Tissue gadolinium deposition in hepatorenally impaired rats exposed to Gd-EOB-DTPA: evaluation with inductively coupled plasma mass spectrometry (ICP-MS).

PURPOSE: This study was undertaken to quantify tissue gadolinium (Gd) deposition in hepatorenally impaired rats exposed to gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) by means of inductively coupled plasma mass spectrometry (ICP-MS) and to compare differences in Gd distribution among major organs as possible triggers for nephrogenic systemic fibrosis. MATERIALS AND METHODS: Five hepatorenally impaired rats (5/6-nephrectomized, with carbon-tetrachloride-induced liver fibrosis) were injected with Gd-EOB-DTPA. Histological assessment was conducted and Gd content of the skin, liver, kidneys, lungs, heart, spleen, diaphragm, and femoral muscle was measured by inductively coupled plasma mass spectrometry (ICP-MS) at 7 days after last injection. In addition, five renally impaired rats were injected with Gd-EOB-DTPA and the degree of tissue Gd deposition was compared with that in the hepatorenally impaired rats. RESULTS: ICP-MS analysis revealed significantly higher Gd deposition in the kidneys, spleen, and liver (p = 0.009-0.047) in the hepatorenally impaired group (42.6 ± 20.1, 17.2 ± 6.1, 8.4 ± 3.2 µg/g, respectively) than in the renally impaired group (17.2 ± 7.7, 5.4 ± 2.1, 2.8 ± 0.7 µg/g, respectively); no significant difference was found for other organs. In the hepatorenally impaired group, Gd was predominantly deposited in the kidneys, followed by the spleen, liver, lungs, skin, heart, diaphragm, and femoral muscle. Histopathological investigation revealed hepatic fibrosis in the hepatorenally impaired group. CONCLUSIONS: Compared with renally impaired rats, tissue Gd deposition in hepatorenally impaired rats exposed to Gd-EOB-DTPA was significantly increased in the kidneys, spleen, and liver, probably due to the impairment of the dual excretion pathways of the urinary and biliary systems.

[A mixed germ cell tumor that underwent dramatic size changes].

This report describes a mixed germ cell tumor that underwent dramatic size changes. A 12-year-old boy presented to our hospital with a headache that had persisted for two months. Initial magnetic resonance imaging (MRI) revealed a pineal tumor and hydrocephalus. The patient required external ventricular drainage and underwent two endoscopic biopsies. His evaluation involved a total of nine computed tomography (CT) scans prior to the second biopsy;the tumor size had decreased before the second endoscopic biopsy. The tumor consisted of both a germinoma and a teratoma component. The patient was treated with three courses of carboplatin-etoposide (CBDCA-VP) chemotherapy and whole-ventricle radiotherapy (32.1 Gy). However, during the adjuvant therapy, the tumor size increased, necessitating total tumor resection. We speculate that the tumor's initial size reduction was caused by leakage of the cyst component and exposure to the brain CT irradiation. The tumor's subsequent increase in size was due to the recollection of the cystic components and intracranial growing teratoma syndrome (iGTS). Therefore, frequent brain CTs and angiography should be avoided before definitive pathological diagnosis is achieved. Further, the tumor size should be considered, with surgical resection being performed at the optimal time.

ANCA-associated vasculitis with scleritis, corneal melt, and perforation rescued by rituximab: Case report and literature review.

Key Clinical Message: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, specifically with myeloperoxidase (MPO)-ANCA, would have a risk for developing corneal melt and perforation abruptly in a short period. It is desirable to have a team of collaboration of rheumatologists and other specialties. Abstract: An 80-year old man who had been diagnosed 5.5 years previously as ANCA-associated vasculitis by temporal artery biopsy developed corneal melt and perforation with scleritis in both eyes. He underwent successful cataract surgery and retained ambulatory vision with the aid of intravenous rituximab. Two additional patients with similar manifestations were found in the literature.

Multifocal primary central nervous system angiosarcoma: illustrative case.

BACKGROUND: Angiosarcoma is a malignant mesenchymal tumor derived from vascular endothelial cells in which a primary intracranial origin is extremely rare. Most previous reports of primary central nervous system (CNS) angiosarcoma have been solitary cases. OBSERVATIONS: The authors report a case of primary CNS angiosarcoma that caused the development of multiple disseminated cerebral hemorrhagic lesions within a short period of time. This rapid progression of symptoms resulted in the death of the patient. During surgery, several nodules suggestive of a tumor were removed from just below the surface of the brain, mixed into the hematoma. A pathological examination revealed atypical cells mimicking blood vessels in the subarachnoid space that were positive for specific vascular endothelial markers. LESSONS: In this case, multifocal angiosarcoma occurred on the brain surface and ventricles, suggesting cerebrospinal fluid dissemination. If multiple cerebral hemorrhages are found on the brain surface, multifocal angiosarcoma should also be considered.

Preoperative examination and intraoperative cerebrospinal fluid leakage test for minimally invasive surgery of spinal extradural arachnoid cysts: illustrative case.

BACKGROUND: Spinal extradural arachnoid cysts (SEACs) are rare and can cause spinal dysfunction. Total cyst removal and duraplasty via multiple laminectomies are commonly performed. However, to avoid postoperative spinal deformity and axial pain, a minimally invasive surgery via selective laminectomy may be optimal. Therefore, preoperative detection of the dural fistula site is required. OBSERVATIONS: A 25-year-old male presented with a 2-month history of progressive gait disturbance and back pain. Conventional magnetic resonance imaging (MRI) revealed SEACs at the T9 to L2 level but did not reveal the dural fistula. Further examinations were performed using sagittal time-spatial labeling inversion pulse MRI and cone-beam computed tomography myelography with a spinal intrathecal catheter, which indicated a dural fistula on the left side at the T12 level. On the basis of these results, dural repair was performed via selective laminectomy. Furthermore, an intraoperative cerebrospinal fluid leakage test by intrathecally injecting saline via a spinal catheter confirmed complete closure of the dural fistula, with no other fistulas. LESSONS: These comprehensive pre and intraoperative examinations may be useful for minimally invasive and selective surgeries in patients with SEACs.

Immunohistological analysis of B7-H4, IDO1, and PD-L1 expression and tumor immune microenvironment based on triple-negative breast cancer subtypes.

BACKGROUND: B7 homolog 4 (B7-H4) and indoleamine 2,3-dioxygenase (IDO1) are factors involved in the inhibition of antitumor activity and are new therapeutic targets for immune checkpoint therapy. Our study aimed to simultaneously investigate the interrelationship among B7-H4, IDO1 and programmed cell death ligand 1 (PD-L1) expression in triple-negative breast cancer (TNBC), including tumor immune microenvironment (TIME) and TNBC subtypes. METHODS: Immunostaining for PD-L1, B7-H4, and IDO1 was performed on whole-slide sections of 119 cases of TNBC. The TIME was evaluated based on stromal tumor infiltrating lymphocytes (sTILs; %), pattern classification of TILs, tumor-stroma ratio (TSR), and tertiary lymphoid structure (TLS). TNBC subtypes were also determined by immunohistochemistry analysis of cytokeratin 5/6 and androgen receptor (AR) expression. RESULTS: B7-H4 expression was significantly higher in cases with a combined positive score cutoff of 5 for PD-L1 (clone 28-8; p = 0.021), inflamed TIL pattern (p = 0.007), and TLS ≥ 4 (p = 0.006). B7-H4 expression was higher in case of CK5/6 ≥ 10 (p = 0.035). The H-scores of AR and B7-H4 were inversely correlated (ρ = - 0.509, p < 0.001). B7-H4 and IDO1 expression levels were inversely correlated in cases with AR < 10 (ρ = - 0.354, p < 0.001). CONCLUSIONS: These results suggest that considering the TIL pattern and TLS and identifying the expression of PD-L1 and the basal-like type are useful for estimating B7-H4 expression. In addition, luminal androgen receptor (LAR)-type is frequently deficient in B7-H4 expression. In non-LAR types, B7-H4 and IDO1 expression are exclusive.

Becker Muscular Dystrophy Accompanied by Anti-HMGCR Antibody-positive Immune-mediated Necrotizing Myopathy.

Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease characterized by progressive muscle weakness that currently has no cure. Immune-mediated necrotizing myopathy (IMNM) is a type of autoimmune inflammatory myopathy characterized by proximal muscle weakness that is treated with immunosuppressive therapy. We herein report a patient diagnosed with BMD complicated with IMNM by a pathological analysis. Notably, the patient had an elevated serum anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody level. Oral glucocorticoid and methotrexate treatment partially improved the muscle weakness with decreased levels of serum creatine kinase. An accurate diagnosis is important for therapeutic decisions in these complicated cases.

Maximal Multistage Shuttle Run Test-induced Myalgia in a Patient with Muscle Phosphorylase B Kinase Deficiency.

Muscle phosphorylase b kinase (PHK) deficiency is a rare mild metabolic disorder caused by mutations of the PHKA1 gene encoding the αM subunit of PHK. A 16-year-old boy experienced myalgia during the maximal multistage 20-m shuttle run test targeting the maximal oxygen consumption. Although an ischemic forearm exercise test was normal, a muscle biopsy revealed subsarcolemmal glycogen accumulation. He harbored a novel insertion mutation in the PHKA1 gene that resulted in premature termination of the αM subunit close to the C-terminus. Compared with previously reported cases, his reduction in PHK activity was relatively mild.

The "Ant-farm"-like Appearance of Restricted Lower Limb Vasculitis on Fluorodeoxyglucose-positron Emission Tomography.

Restricted lower limb vasculitis is a type of localized muscle vasculitis limited to the lower limbs. The usefulness of fluorodeoxyglucose-positron emission tomography (FDG-PET) for the diagnosis of this entity has not yet been reported. We herein report three patients with a fever and persistent lower limb pain. FDG-PET revealed linear and patchy FDG uptakes in their lower limbs. Combined with magnetic resonance imaging and histological findings, they were diagnosed with lower limb vasculitis. Linear and patchy FDG uptakes are considered to reflect the presence of muscle vasculitis. The characteristic "ant-farm"-like FDG-PET images can be a diagnostic clue for the currently overlooked vasculitis.

Myxoid type and non-myxoid type of intimal sarcoma in large vessels and heart: review of histological and genetic profiles of 20 cases.

Intimal sarcoma is one of the most common and well-known primary malignant neoplasms of the aorta and heart. The authors reviewed cases of intimal sarcoma from histological, immunohistochemical and genetic perspectives. Twenty cases of intimal sarcoma were retrieved. Immunohistochemistry and FISH of MDM2 and PDGFRA genes were performed. All 20 tumours were composed of spindle-shaped, stellate, oval or polygonal tumour cells with irregular hyperchromatic nuclei arranged in a haphazard pattern, accompanied by nuclear pleomorphism and frequent mitotic figures. Other histological findings were as follows: abnormal mitosis in 10 cases (50%), necrosis in 15 cases (75%), myxoid stroma in 12 cases (60%), cartilaginous formation in 1 case (5%), haemorrhage in 12 cases (60%) and fibrinous deposition in 14 cases (70%). The tumours were positive for MDM2 in 16 cases (80%), ERG in 4 cases (20%), alpha-smooth muscle actin in 6 cases (30%), desmin in 5 cases (25%) and AE1/AE3 in 4 cases (20%). Immunohistochemical positivity was focal in each case. Loss of H3K27me3 expression was noted in 2 cases (10%). MDM2 and PDGFRA gene amplifications were detected in 11 cases (55%) and 1 case (5%), respectively. Fisher's exact test revealed a significant correlation between MDM2 gene amplification and myxoid stroma (p = 0.0194). No parameters showed any association with the anatomical location of the tumours. It was suggested that myxoid histology of intimal sarcoma may be associated with MDM2 gene amplification and that intimal sarcoma may be divided into myxoid and non-myxoid types.