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Background: Combination therapy with different classes of antihypertensive drugs often is needed to achieve controlled blood pressure (BP). The combination of an angiotensin II receptor antagonist (AIIA) and a calcium antagonist is a preferred option for reducing uncontrolled BP.Objective: The aim of this study was to assess the clinical efficacy and tolerability of nilvadipine, a dihydropyridine calcium antagonist, in combination with an AIIA.Methods: Patients with essential hypertension whose BP was not controlled by an AIIA alone were eligible for this multicenter, open-label, uncontrolled study. One of 3 AIIAs (candesartan cilexetil, losartan potassium, or valsartan) was given for at least 10 weeks before the addition of nilvadipine (daily dose, 4 or 8 mg orally). This combination therapy was given for 8 weeks. BP and heart rate were measured between 2 and 4 weeks before and 0, 4, and 8 weeks after the start of combination therapy. Adverse events were monitored at each visit.Results: Thirty-one patients (18 women [58.1%], 13 men [41.9%]; mean [SD] age, 58.5 [10.5] years) were enrolled. At weeks 4 and 8 of combination therapy, mean systolic BP (SBP) and diastolic BP (DBP) were significantly decreased (P<0.01) (at week 8, by 22.0 mm Hg and 12.5 mm Hg, respectively). The mean BP-lowering effect did not differ significantly between the 3 AIIAs tested. Pulse pressure also decreased significantly at week 8, by 9.6 mm Hg (P<0.01). The responder rate (ie, the percentage of patients with DBP <90 mm Hg or a decrease in DBP >/= 10 mm Hg) was 72.0% at week 8. Three patients experienced a total of 4 adverse events: mild or severe flushing, mild headache, and mild palpitation. All of these symptoms resolved after nilvadipine treatment was discontinued.Conclusions: Nilvadipine in combination with an AIIA showed good antihypertensive efficacy and was well tolerated in the hypertensive patients in this study. This combination also significantly decreased pulse pressure, suggesting that this combination therapy also may have a beneficial effect in elderly patients with isolated systolic hypertension. [ABSTRACT FROM AUTHOR]

As a metabolic organ, the liver plays a variety of roles, including detoxification. It has been difficult to obtain stable supplies of hepatocytes for transplantation and for accurate hepatotoxicity determination in drug discovery research. Human pluripotent stem cells, capable of unlimited self-renewal, may be a promising source of hepatocytes. In order to develop a stable supply of embryonic stem cell (ESC)-derived hepatocytes, we have purified human ESC-derived hepatic progenitor cells with exposure to cytocidal puromycin by using their ability to metabolize drugs. Hepatic progenitor cells stably proliferated at least 2 20 -fold over 120 days, maintaining hepatic progenitor cell-like properties. High drug-metabolizing hepatic progenitor cells can be matured into liver cells by suppressing hepatic proliferative signals. The method we developed enables the isolation and proliferation of functional hepatic progenitors from human ESCs, thereby providing a stable supply of high-quality cell resources at high efficiency. Cells produced by this method may facilitate cell therapy for hepatic diseases and reliable drug discovery research., (Copyright © 2023. Published by Elsevier Inc.)

Background: The liver plays an important role in various metabolic processes, including protein synthesis, lipid and drug metabolisms and detoxifications. Primary culture of hepatocytes is used for the understanding of liver physiology as well as for the drug development. Hepatocytes are, however, hardly expandable in vitro making it difficult to secure large numbers of cells from one donor. Alternatively, systems using animal models and hepatocellular carcinoma cells have been established, but interspecies differences, variation between human cell sources and limited hepatic functions are among the challenges faced when using these models. Therefore, there is still a need for a highly stable method to purify human hepatocytes with functional sufficiency. In this study, we aimed to establish an in vitro long-term culture system that enables stable proliferation and maintenance of human hepatocytes to ensure a constant supply., Methods: We first established a growth culture system for hepatocytes derived from patients with drug-induced liver injury using fetal mouse fibroblasts and EMUKK-05 medium. We then evaluated the morphology, proliferative capacity, chromosome stability, gene and protein expression profiles, and drug metabolic capacity of hepatocytes in early, middle and late passages with and without puromycin. In addition, hepatic maturation in 3D culture was evaluated from morphological and functional aspects., Results: In our culture system, the stable proliferation of human hepatocytes was achieved by co-culturing with mouse fetal fibroblasts, resulting in dedifferentiation into hepatic progenitor-like cells. We purified human hepatocytes by selection with cytocidal puromycin and cultured them for more than 60 population doublings over a span of more than 350 days. Hepatocytes with high expression of cytochrome P450 genes survived after exposure to cytocidal antibiotics because of enhanced drug-metabolizing activity., Conclusions: These results show that this simple culture system with usage of the cytocidal antibiotics enables efficient hepatocyte proliferation and is an effective method for generating a stable supply of hepatocytes for drug discovery research at a significant cost reduction., (© 2022. The Author(s).)

Background: Many drugs have the potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4), in hepatocytes. Hepatocytes can be accurately evaluated for drug-mediated CYP3A4 induction; this is the gold standard for in vitro hepatic toxicology testing. However, the variation from lot to lot is an issue that needs to be addressed. Only a limited number of immortalized hepatocyte cell lines have been reported. In this study, immortalized cells expressing CYP3A4 were generated from a patient with drug-induced liver injury (DILI)., Methods: To generate DILI-derived cells with high expression of CYP3A4, a three-step approach was employed: (1) Differentiation of DILI-induced pluripotent stem cells (DILI-iPSCs); (2) Immortalization of the differentiated cells; (3) Selection of the cells by puromycin. It was hypothesized that cells with high cytochrome P450 gene expression would be able to survive exposure to cytotoxic antibiotics because of their increased drug-metabolizing activity. Puromycin, a cytotoxic antibiotic, was used in this study because of its rapid cytocidal effect at low concentrations., Results: The hepatocyte-like cells differentiated from DILI-iPSCs were purified by exposure to puromycin. The puromycin-selected cells (HepaSM or SI cells) constitutively expressed the CYP3A4 gene at extremely high levels and exhibited hepatocytic features over time. However, unlike primary hepatocytes, the established cells did not produce bile or accumulate glycogen., Conclusions: iPSC-derived hepatocyte-like cells with intrinsic drug-metabolizing enzymes can be purified from non-hepatocytes and undifferentiated iPSCs using the cytocidal antibiotic puromycin. The puromycin-selected hepatocyte-like cells exhibited characteristics of hepatocytes after immortalization and may serve as another useful source for in vitro hepatotoxicity testing of low molecular weight drugs., (© 2021. The Author(s).)

Ammonia has a cytotoxic effect and can therefore be used as a selection agent for enrichment of zone I hepatocytes. However, it has not yet been determined whether ammonia-treated hepatocyte-like cells are able to proliferate in vitro. In this study, we employed an ammonia selection strategy to purify hepatocyte-like cells that were differentiated from human embryonic stem cells (ESCs) and from induced pluripotent stem cells (iPSCs). The resistance to cytotoxicity or cell death by ammonia is likely attributable to the metabolism of ammonia in the cells. In addition to ammonia metabolism-related genes, ammonia-selected hepatocytes showed increased expression of the cytochrome P450 genes. Additionally, the ammonia-selected cells achieved immortality or at least an equivalent life span to human pluripotent stem cells without affecting expression of the liver-associated genes. Ammonia treatment in combination with in vitro propagation is useful for obtaining large quantities of hepatocytes.

We report a case of a metastatic lung tumor from an occult thyroid oncocytic carcinoma, growing into the bronchial lumen. A 70-year-old woman was referred to our hospital because of abnormal shadows which had been increasing in size for 4 years, in the chest radiograph. Bronchoscopy revealed an endobronchial tumor at the orifice of the left B4b. Histological and immunohistological examination of the lesion showed tumor cells with immunoreactivity for thyroglobulin, and a metastatic oncocytic carcinoma from the thyroid was diagnosed. Closer examination of the neck revealed thyroid carcinoma, and total thyroidectomy was performed. Endobronchial metastasis of thyroid oncocytic carcinoma is very rare. In this case, immunohistological examination was useful for detecting the primary site.

A 63-year-old man was admitted to our hospital with fever and chest pain. Chest radiography revealed left pleural effusion with left pneumothorax and small nodular shadows in the right lung field. On CT of the chest and abdomen, multiple nodules were seen in both lung fields, and masses appeared in the liver and spleen. Fiberoptic colonoscopy showed obstruction at the end of the transverse colon. Biopsy of this obstruction proved it to be cancer. In this patient, a colo-pleural fistula was also diagnosed using thoracoscopy under local anesthesia and from the inflow of contrast medium from the colon into the thoracic cavity seen in abdominal radiographs. This was a rare case of a colo-pleural fistula without diaphragmatic deficiencies. Medical thoracoscopy is useful for the diagnosis of complicated pleural effusions as was seen in this case.

A 68-year-old woman presented with Sjögren's syndrome. Chest X-ray films disclosed consolidated shadows in the right S2 and an infiltration shadow in the right S8 with small nodules. Pathological examination of transbronchial lung biopsy (TBLB) specimens revealed lymphocytic infiltrations that stained positive with UCHL-1 and L 26 in immunohistochemical studies. Lung tissue specimens obtained by video-assisted thoracic surgery showed lympho-epithelial lesions with dense lymphocytic infiltration. Southern blot hybridization and polymerase chain reaction (PCR) assays demonstrated monoclonality and immunoglobulin heavy chain gene rearrangement. These findings yielded a diagnosis of mucosa-associated lymphoid tissue (MALT) lymphoma. The detection of rear-ranged genes encoding for immunoglobulin heavy chains is useful for the diagnosis of primary pulmonary lymphoproliferative disorders, especially malignant lymphomas.

We investigated the outcome of 12 patients with interstitial pneumonia (IP) associated with polymyositis and dermatomyositis (PM/DM). The mean age of the patients was 53. There were 3 cases of PM/DM preceding the respiratory symptoms (RS), 7 cases of simultaneous PM/DM and RS, and 2 cases of PM/DM delayed with RS. In these 3 groups, there was a tendency for cases with PM/DM preceding RS to be younger. Jo-1 antibody was positive in only one case of the simultaneous group. Patients in whom IP preceded PM/DM or was simultaneous with PM/DM showed a better response to corticosteroid. The chest CT findings and TBLB findings showed a BOOP pattern in these patients. TBLB findings are not useful for diagnosing the pathological type, however they are useful for evaluating the effectiveness of steroid therapy on IP in PM/DM.

In May 1995, a 52-year-old man complaining of fever and dyspnea was admitted to a hospital. Based on clinical and radiographic findings, hypersensitivity pneumonitis was suspected. Steroid pulse therapy was unsuccessful, and he was then transferred to our hospital. A chest X-ray film showed bilateral ground-glass shadows and a high-resolution CT scan showed cystic air spaces. The number of CD4-positive lymphocytes in peripheral blood was very low. A test for anti-human immunodeficiency virus antibody was positive and Pneumocystic carinii was found in bronchoalveolar lavage fluid. The acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia were diagnosed. In this patient, the level of serum KL-6, a new marker of interstitial pneumonitis, was very high, and KL-6 was expressed on type II pneumocytes. The level of serum KL-6 may be useful as a marker of the activity of Pneumocystis carinii pneumonia.

A 53-year-old man was admitted to our hospital with a skin eruption, a high fever, and diplopia in April of 1992. He had been given a diagnosis of diffuse panbronchiolitis in 1981. After administration of erythromycin began in 1987, symptoms and chest roentgenographic findings gradually improved. Arteritis of peribronchial muscular arteries with medial destruction was seen in lung biopsy specimens, and periglomerular granulomatous inflammation and necrotizing glomerulitis were seen in renal biopsy specimens. P-ANCA was found, but a test for cytoplasmic ANCA (which is the most specific antigen of Wegener's granulomatosis) was negative. Chronic pulmonary infection due to diffuse panbronchiolitis might have formed ANCA, which may have caused the vasculitis in this patient.

A patient with adult Still's disease and Sjögren's syndrome failed to respond to conventional doses of corticosteroids. Therefore intravenous pulse methylprednisolone combined with oral cyclophosphamide was given which subsequently resolved the flare of rashes, fevers, and arthritis. This combination therapy may be a useful therapy to consider in patients with adult Still's disease who are resistant to conventional treatment and may allow a reduction in daily corticosteroid requirement.

A case of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) associated with pulmonary cryptococcosis which was successfully treated with fluconazole (FCZ) and flucytosine (5-FC) is described. A 63-year-old woman who had been treated with steroid for SLE and low dose methotrexate (MTX) for RA was admitted to Jichi Medical School Hospital because of abnormal shadow in the chest X-ray film. Physical examination revealed no abnormality. A chest CT film showed multiple nodular shadows localized in the right lower lobe. An ultrasonically guided trans-cutaneous lung biopsy performed on 10th hospital day established a diagnosis of pulmonary cryptococcosis. Following the treatment with FCZ and 5-FC for a month, her abnormal lung shadows improved and serum cryptococcal antigen level was decreased. A survey of the literature from 1955 to 1990 revealed 44 cases of SLE associated with cryptococcosis in Japan, in addition to our case, most of whom were on corticosteroid therapy. The majority of patients were young women, representing the usual population of patients with SLE. 34 of these patients had cryptococcal meningitis; 22, pulmonary cryptococcosis; 6, sepsis; 6 cutaneous cryptococcosis. Twenty patients died. Deep fungal infections should be considered whenever patients with SLE have fever of unknown origin, diffuse pulmonary infiltrates, or unexplained CNS symptoms.