Intratracheal instillation of polyacrylic acid induced pulmonary fibrosis with elevated transforming growth factor-ß1 and connective tissue growth factor.

We investigated the intratracheal instillation of Polyacrylic acid (PAA) in rats to determine if it would cause pulmonary disorders, and to see what factors would be associated with the pathological changes. Male F344 rats were intratracheally instilled with low (0.2 mg/rat) and high (1.0 mg/rat) doses of PAA. They were sacrificed at 3 days, 1 week, 1 month, 3 months, and 6 months after PAA exposure to examine inflammatory and fibrotic changes in the lungs. There was a persistent increase in the neutrophil count, lactate dehydrogenase (LDH) levels, cytokine-induced neutrophil chemoattractant (CINC) values in bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in lung tissue. Transforming growth factor-beta 1 (TGF-ß1), a fibrotic factor, showed a sustained increase in the BALF until 6 months after intratracheal instillation, and connective tissue growth factor (CTGF) in lung tissue was elevated at 3 days after exposure. Histopathological findings in the lung tissue showed persistent (more than one month) inflammation, fibrotic changes, and epithelial-mesenchymal transition (EMT) changes. There was also a strong correlation between TGF-ß1 in the BALF and, especially, in the fibrosis score of histopathological specimens. Intratracheal instillation of PAA induced persistent neutrophilic inflammation, fibrosis, and EMT in the rats' lungs, and TGF-ß1 and CTGF appeared to be associated with the persistent fibrosis.

The Effects of Endoplasmic Reticulum Stress via Intratracheal Instillation of Water-Soluble Acrylic Acid Polymer on the Lungs of Rats.

Polyacrylic acid (PAA), an organic chemical, has been used as an intermediate in the manufacture of pharmaceuticals and cosmetics. It has been suggested recently that PAA has a high pulmonary inflammatory and fibrotic potential. Although endoplasmic reticulum stress is induced by various external and intracellular stimuli, there have been no reports examining the relationship between PAA-induced lung injury and endoplasmic reticulum stress. F344 rats were intratracheally instilled with dispersed PAA (molecular weight: 269,000) at low (0.5 mg/mL) and high (2.5 mg/mL) doses, and they were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months after exposure. PAA caused extensive inflammation and fibrotic changes in the lungs' histopathology over a month following instillation. Compared to the control group, the mRNA levels of endoplasmic reticulum stress markers Bip and Chop in BALF were significantly increased in the exposure group. In fluorescent immunostaining, both Bip and Chop exhibited co-localization with macrophages. Intratracheal instillation of PAA induced neutrophil inflammation and fibrosis in the rat lung, suggesting that PAA with molecular weight 269,000 may lead to pulmonary disorder. Furthermore, the presence of endoplasmic reticulum stress in macrophages was suggested to be involved in PAA-induced lung injury.

Hemodynamic parameters at rest predicting exercise capacity in patients supported with left ventricular assist device.

Left ventricular assist devices improve prognosis and quality of life, but exercise capacity remains limited in most patients after device implantation. Left ventricular assist device optimization through right heart catheterization reduces device-related complications. However, hemodynamic parameters associated with exercise capacity under optimized conditions. The aim of this study was to elucidate the predictors of exercise capacity from hemodynamic parameters at rest after left ventricular assist device optimization. We retrospectively reviewed 24 patients who underwent a ramp test with right heart catheterization, echocardiography and cardiopulmonary exercise testing more than 6 months after left ventricular assist device implantation. Pump speed was optimized to a lower setting that achieved right atrial pressure < 12 mmHg, pulmonary capillary wedge pressure < 18 mmHg, and cardiac index > 2.2 L/min/m2, then exercise capacity was assessed by cardiopulmonary exercise testing. After left ventricular assist device optimization, the mean right atrial pressure, pulmonary capillary wedge pressure, cardiac index, and peak oxygen consumption were 7 ± 5 mmHg, 10 ± 7 mmHg, 2.7 ± 0.5 L/min/m2, and 13.2 ± 3.0 mL/min/kg, respectively. Pulse pressure, stroke volume, right atrial pressure, mean pulmonary artery pressure, and pulmonary capillary wedge pressure were significantly associated with peak oxygen consumption. Multivariate linear regression analysis of factors predicting peak oxygen consumption revealed that pulse pressure, right atrial pressure, and aortic insufficiency remained independent predictors (ß = 0.401, p = 0.007; ß = - 0.558, p < 0.001; ß = - 0.369, p = 0.010, respectively). Our findings suggests that cardiac reserve, volume status, right ventricular function, and aortic insufficiency predict exercise capacity in patients with a left ventricular assist device.

Stent-Graft Placement for Radiation-Induced Abdominal Aortic Stenosis after Renal Autotransplantation.

Renovascular hypertension (RVH) is a common cause of secondary hypertension. However, there have been no reports on RVH due to radiation-induced abdominal aorta stenosis after renal autotransplantation. A 27-year-old woman with a history of neuroblastoma treated by radiation therapy and RVH treated with renal autotransplantation presented with hypertension and dyspnea. At age 19, she had experienced hypertensive heart failure due to RVH from radiation-induced left renal artery stenosis and had undergone renal autotransplantation involving the extraction of her left kidney. Her systolic blood pressure (BP) was well-controlled but had increased progressively. She was diagnosed with hypertensive heart failure and admitted to hospital. Although her dyspnea soon subsided after treatment, her BP remained high. Renal artery ultrasound revealed no obvious stenosis. The ankle brachial pressure index (ABI) showed a significant bilateral decrease to 0.71/0.71 (right/left) from 0.94/0.95 eight years before. Magnetic resonance angiography and aortic angiography revealed severe stenosis in the abdominal aorta, and the systolic pressure gradient of intra-aortic blood flow, distal and proximal to a stenotic lesion, was 58 mmHg. These arterial stenoses in the irradiated area were highly suggestive of radiation-induced vasculopathy. She finally underwent an endovascular VIABAHN VBX balloon-expandable stent-graft placement for this radiation-induced abdominal aorta stenosis, which resolved the pressure gradient. After the procedure, her ABI improved to 0.91/0.88 and her BP was well-controlled. This is the first case of successful stent-graft placement for RVH after renal autotransplantation due to radiation-induced abdominal aorta stenosis as a consequence of neuroblastoma.

Nivolumab-induced Myositis and Myocarditis with Positive Anti-titin Antibody and Anti-voltage-gated Potassium Channel Kv1.4 Antibody.

Immune checkpoint inhibitors (ICIs) are complicated by immune-related adverse events (irAEs), such as myositis, myocarditis, and myasthenia gravis (MG). Anti-titin antibody and anti-voltage-gated potassium channel Kv1.4 antibody are anti-striated antibodies that are frequently detected in MG patients with myositis and/or myocarditis. However, the clinical relationship between positive anti-striated antibodies and irAEs of ICIs remains unknown. We herein report a case of nivolumab-induced myositis and myocarditis with positive anti-titin antibody and anti-voltage-gated potassium channel Kv1.4 antibody in a patient with non-small-cell lung cancer. We also review reported cases of positive anti-striated antibodies related to irAEs of ICIs.

Performance of the Jarvik 2000 left ventricular assist device on mid-term hemodynamics and exercise capacity.

The hemodynamic and exercise capacity performance of the Jarvik 2000 left ventricular assist device (LVAD), which is generally used in patients with small body size and relatively preserved cardiac function, is not well understood. We retrospectively examined 18 patients implanted with the Jarvik 2000 LVAD. Pump rotation speed was optimized by the hemodynamic ramp test one year after implantation based on the criteria of mean pulmonary capillary wedge pressure (PCWP) < 18 mmHg, mean right atrial pressure (RAP) < 12 mmHg, and cardiac index (CI) > 2.2 L/min/m2 as well as echocardiographic parameters. Exercise capacity was assessed by cardiopulmonary exercise test in an optimized setting. To investigate the impacts of larger body surface area (BSA) and extremely impaired pre-implantation cardiac function on hemodynamics and exercise capacity, two correlation analyses based on BSA and original CI were performed. At a pump speed of 9500 ± 707 rpm, the mean pulmonary artery pressure, PCWP, RAP, and CI were 17 ± 5 mmHg, 9 ± 5 mmHg, 6 ± 4 mmHg, and 2.82 ± 0.54 L/min/m2, respectively. Only one patient failed to achieve the hemodynamic criteria. The peak VO2 and VE/VCO2 slope were 12.9 ± 3.1 mL/min/kg and 37.7 ± 15.0, respectively. There was an inverse correlation between original CI and heart rate (r = -0.60, p = 0.01), and a weak correlation between BSA and PCWP (r = 0.43, p = 0.08). Based on this study, the overall performance of the Jarvik 2000 device was acceptable, and the patients' body size and original cardiac function had minimum effect on the performance of this device.

Renal Hyperperfusion Injury After Percutaneous Angioplasty for Renovascular Hypertension as a Sequela of Neuroblastoma.

Hyperperfusion injury is a rare but critical complication associated with revascularization for long-standing severe artery stenosis. Here we report a rare case of a patient with renal hyperperfusion injury after undergoing percutaneous transluminal renal angioplasty for renovascular hypertension as a sequela of neuroblastoma after radiation therapy. (Level of Difficulty: Advanced.).

Anti-transcription intermediary factor 1 gamma (TIF1γ) antibody-positive dermatomyositis associated with ascending colon cancer: a case report and review of the literature.

BACKGROUND: Anti-transcriptional intermediary factor 1 gamma (TIF1γ) antibody is a marker for predicting cancer association in patients with dermatomyositis (DM). The overall survival rate in DM patients with cancer was reported to be considerably worse than that in DM patients without cancer. However, the treatment for cancer-associated DM remains controversial, because the treatment priority between surgical resection for the tumor and internal treatments, including glucocorticoids, immunosuppressive agents, and intravenous immune globulin, has not been established. CASE PRESENTATION: We report the case of a 57-year-old Japanese man diagnosed with anti-TIF1γ antibody-positive DM associated with ascending colon cancer. His clinical symptoms included facial and brachial edema, muscle weakness, dysphagia, myalgia, and rash. Physical examination revealed periorbital edema and Gottron's papules over his knuckles with brachial edema, and tenderness and weakness of the proximal limb muscles. The findings of hyperintense muscles in T2-weighted sequences of brachial contrast-enhanced magnetic resonance imaging and the infiltration of lymphocytic cells and CD4-positive lymphocytes from muscle biopsy were compatible with the diagnostic criteria for dermatomyositis. Anti-TIF1γ antibody was positive by immunoprecipitation assay. He first started internal treatment including intravenous immunoglobulin, steroid pulse, prednisolone, and azathioprine, followed by surgical resection for the tumor because of the elevation of creatine kinase and progression of dysphagia. However, clinical symptoms did not improve, and the patient died 6 months later. CONCLUSIONS: We faced difficulties in determining the treatment priority between surgical resection and internal treatment for our case; therefore, this case would be educational for readers. We searched PubMed to identify English-language case reports of anti-TIF1γ antibody-positive dermatomyositis with malignancy and found 21 reported cases. We herein review and summarize previously reported cases of anti-TIF1γ antibody-positive DM with malignancy. Cancer screening is essential in patients with anti-TIF1γ antibody-positive dermatomyositis because it is associated with a high prevalence of malignancies. Our review revealed that initial surgical treatment should be recommended for better prognosis if the general condition allows.

A case of cardiac amyloidosis in an elderly Japanese patient with amyloidogenic transthyretin Val122Ile variant.

A 76-year-old Japanese man with a history of stomach cancer and chronic atrial fibrillation was referred to our department with left atrial thrombus. He had a history of gastric amyloidosis diagnosed by a pathological specimen of the stomach; however, further examination for amyloidosis was not performed. The patient displayed clinical signs and symptoms of heart failure and echocardiography showed a thick left ventricular wall. Since cardiac amyloidosis was suspected, the patient underwent cardiac magnetic resonance imaging and 99mTc-pyrophosphate scintigraphy. These results are consistent with transthyretin amyloidosis (ATTR amyloidosis). DNA analysis of transthyretin (TTR) was performed and a heterozygous Val122Ile mutation was identified. Notably, his only son requested the analysis; however, no mutations were noted. ATTR Val122Ile is one of the mutations in TTR that are associated with hereditary amyloidosis, causing severe cardiomyopathy. The prevalence of the ATTR Val122Ile mutation is 3.9% in the African-American population. However, the occurrence of this mutation in Asian populations is very rare. This is the second reported case of the ATTR Val122Ile variant in Japan and the first case tested including familial genes. .

Hepatic methotrexate-associated lymphoproliferative disorders identified by multiple liver tumors: a case report and review of the literature.

BACKGROUND: Methotrexate, an immunosuppressant, is widely used as the standard therapeutic drug for rheumatoid arthritis. With the increasing frequency of use of methotrexate, adverse effects of methotrexate have been reported, one of which is known as methotrexate-associated lymphoproliferative disorders. The etiology of hepatic methotrexate-associated lymphoproliferative disorders remains largely unknown. To date, there have only been ten cases of hepatic methotrexate-associated lymphoproliferative disorders reported in the English literature and a case report is very rare. CASE PRESENTATION: An 82-year-old Japanese man with rheumatoid arthritis treated with methotrexate presented with fever. Contrast-enhanced computed tomography showed multiple hypovascular nodules in his liver, spleen, and lung, and para-aortic lesions. Endoscopic ultrasound-guided fine-needle aspiration biopsy for liver tumors was performed, and pathological results identified cluster of differentiation 20-positive lymphocytes. Discontinuance of methotrexate led to regression of the nodules and a final definitive diagnosis of methotrexate-associated lymphoproliferative disorders was made. CONCLUSIONS: We review 11 reported cases of hepatic methotrexate-associated lymphoproliferative disorders including the present case. Physicians should discontinue methotrexate in patients with rheumatoid arthritis treated with methotrexate when elevated soluble interleukin-2 receptor and hypovascular lesions in contrast-enhanced computed tomography are confirmed considering the possibility of methotrexate-associated lymphoproliferative disorders.

Hypothalamic hypopituitarism secondary to suprasellar metastases from small cell lung cancer: a case report and review of the literature.

BACKGROUND: Metastasis to the pituitary gland is an infrequent clinical problem, and the symptoms caused by metastases have been reported in only 2.5-18.2% of the cases. However, metastasis to the suprasellar lesion has rarely been reported in the literature. To the best of our knowledge, only nine cases of hypothalamic hypopituitarism due to metastases of solid tumors have been reported in English-language journals. CASE PRESENTATION: A 67-year-old Japanese man presented to our hospital with generalized weakness, lethargy, and weight loss. Laboratory data showed hypoglycemia together with low thyroid-stimulating hormone and free thyroxine. We suspected hypopituitarism and performed imaging of the head, which revealed multiple tumors, one of which was in the suprasellar region. Computed tomography of the chest showed a tumor shadow, and a bronchoscopic biopsy pathologically showed small cell lung cancer. Hormone profiling demonstrated hypothalamic pan-hypopituitarism. We diagnosed hypothalamic hypopituitarism secondary to metastases from the primary lung cancer and initiated radiation, chemotherapy, and hormone replacement, but the patient died 10 months later. CONCLUSIONS: We report a case of a 67-year-old man with hypothalamic hypopituitarism secondary to a suprasellar metastasis from a primary small cell lung cancer, and we review ten cases of hypothalamic hypopituitarism due to metastases, including our patient. Recognizing hypopituitarism can be challenging, especially in the elderly, whose symptoms such as lethargy and visual decline may be mistaken for the natural aging process. In patients with established metastatic conditions, the symptoms may be wrongly attributed to malignancy or to the side effects of therapy. When a patient is suspected of having hypopituitarism, a hormone load test can help to diagnose the type of hypopituitarism. It is important to evaluate the brain and the whole body to confirm whether metastasis and primary cancer exist. Because the mortality rate is very high, aggressive intervention for both diagnosis and therapy is required in cases of hypothalamic hypopituitarism secondary to tumor metastasis.

Successful treatment of hepatic gas gangrene by open drainage: A case report and review of the Japanese literature.

INTRODUCTION: Liver gas gangrene is rare and has a low prognosis. This case, reports a successful treatment of hepatic gas gangrene using an open drainage technique, followed by antibiotics and hyperbaric oxygen therapy (HBO). PRESENTATION OF THE CASE: An 82-year-old male with a history of left hepatectomy and bile duct resection for hilar cholangiocarcinoma presented with chilling, lethargy and dyspnea. He had a history of diabetes mellitus, hypertension, atrial fibrillation, and angina pectoris. Physical examination revealed scleric icterus, right hypochondrium tenderness and percussion tenderness of the liver, with warm extremities. Laboratory findings revealed leukocytosis and increased levels of hepatobiliary enzymes. A computed tomography (CT) scan showed gas accumulation in an S8 lesion with portal vein gas. Percutaneous drainage was performed immediately, and broad-spectrum antibiotics were started, but the drainage was insufficient. Consequently, laparotomy drainage was carried out, followed by HBO. No abscess was detected at one-year of follow-up. DISCUSSION: Hepatic gas gangrene progresses rapidly and has a high mortality rate. Malignant disease and diabetes mellitus may be predisposing factors. While half of non-clostridial cases survive, most cases of hepatic gas gangrene are associated with clostridial infection and have a fatal outcome. CONCLUSION: All survival cases of hepatic gas gangrene were treated by laparotomy drainage, thus immediate laparotomy seems essential to prevent a fatal outcome.